Clinical Neurology News

Postdural puncture headache in women who have undergone neuraxial anesthesia in childbirth may be associated with a small but significant increase in the risk of being diagnosed with intracranial subdural hematoma, research findings suggest.

A cohort study, published online in JAMA Neurology, looked at the incidence of intracranial subdural hematoma within 2 months of delivery in 22,130,815 women, using data from the U.S. Agency for Healthcare Research and Quality’s National Readmission Database.

The overall rate of postdural puncture headaches was 309 per 100,000 deliveries, and the overall incidence of subdural hematoma was 1.5 per 100,000 deliveries. Among the women with postdural puncture headache, however, the unadjusted rate of subdural hematoma was 147 per 100,000. After adjusting for confounding factors, women who experienced postdural puncture headache had a nearly 200-fold higher risk of subdural hematoma (odds ratio, 199; P  less than .001), representing an absolute risk increase of 130 per 100,000 deliveries.

“This was a small absolute increase because of the rarity of this outcome in this population,” wrote Dr. Albert R. Moore of the Royal Victoria Hospital at McGill University, Montreal, and coauthors. “However, this is an important and devastating outcome for a common exposure in young and usually healthy mothers.”

The authors noted that these findings confirmed other reports linking postdural puncture headache and intracranial subdural hematoma. The proposed mechanism connecting the two conditions was that decreased intracranial pressure from cerebrospinal fluid leakages leads to “sagging” of the brain and tension on the veins between the dura and arachnoid, which in turn could trigger a rupture and formation of a subdural hematoma.

Other risk factors for subdural hematoma included coagulopathy, arteriovenous malformation, and delayed blood patch. The investigators also found that obesity was associated with a lower risk of headache after postdural puncture, which might be the result of increased intracranial pressure providing resistance to the development of subdural hematoma.

There was a significant interaction between postdural puncture headache, severe preeclampsia, and chronic hypertension. In the absence of postdural puncture headache, severe preeclampsia and chronic hypertension were both independently associated with significant increases in the risk of subdural hematoma, Dr. Moore and associates noted.

In women who experienced postdural puncture headache, only chronic hypertension was significantly associated with subdural hematoma, they said.

The study was limited in being observational and at risk of misclassification. In addition, there was a risk of surveillance bias in that women with postdural puncture headaches might be more likely to receive brain imaging that would pick up minor subdural hematomas, the investigators said.

The study was supported by McGill University Health Center’s department of anesthesia. The authors reported no conflicts of interest.

SOURCE: Moore A et al. JAMA Neurol. 2019 Sep 16. doi: 10.1001/jamaneurol.2019.2995.

Postdural puncture headache in women who have undergone neuraxial anesthesia in childbirth may be associated with a small but significant increase in the risk of being diagnosed with intracranial subdural hematoma, research findings suggest.

A cohort study, published online in JAMA Neurology, looked at the incidence of intracranial subdural hematoma within 2 months of delivery in 22,130,815 women, using data from the U.S. Agency for Healthcare Research and Quality’s National Readmission Database.

The overall rate of postdural puncture headaches was 309 per 100,000 deliveries, and the overall incidence of subdural hematoma was 1.5 per 100,000 deliveries. Among the women with postdural puncture headache, however, the unadjusted rate of subdural hematoma was 147 per 100,000. After adjusting for confounding factors, women who experienced postdural puncture headache had a nearly 200-fold higher risk of subdural hematoma (odds ratio, 199; P  less than .001), representing an absolute risk increase of 130 per 100,000 deliveries.

“This was a small absolute increase because of the rarity of this outcome in this population,” wrote Dr. Albert R. Moore of the Royal Victoria Hospital at McGill University, Montreal, and coauthors. “However, this is an important and devastating outcome for a common exposure in young and usually healthy mothers.”

The authors noted that these findings confirmed other reports linking postdural puncture headache and intracranial subdural hematoma. The proposed mechanism connecting the two conditions was that decreased intracranial pressure from cerebrospinal fluid leakages leads to “sagging” of the brain and tension on the veins between the dura and arachnoid, which in turn could trigger a rupture and formation of a subdural hematoma.

Other risk factors for subdural hematoma included coagulopathy, arteriovenous malformation, and delayed blood patch. The investigators also found that obesity was associated with a lower risk of headache after postdural puncture, which might be the result of increased intracranial pressure providing resistance to the development of subdural hematoma.

There was a significant interaction between postdural puncture headache, severe preeclampsia, and chronic hypertension. In the absence of postdural puncture headache, severe preeclampsia and chronic hypertension were both independently associated with significant increases in the risk of subdural hematoma, Dr. Moore and associates noted.

In women who experienced postdural puncture headache, only chronic hypertension was significantly associated with subdural hematoma, they said.

The study was limited in being observational and at risk of misclassification. In addition, there was a risk of surveillance bias in that women with postdural puncture headaches might be more likely to receive brain imaging that would pick up minor subdural hematomas, the investigators said.

The study was supported by McGill University Health Center’s department of anesthesia. The authors reported no conflicts of interest.

SOURCE: Moore A et al. JAMA Neurol. 2019 Sep 16. doi: 10.1001/jamaneurol.2019.2995.

Postdural puncture headache in women who have undergone neuraxial anesthesia in childbirth may be associated with a small but significant increase in the risk of being diagnosed with intracranial subdural hematoma, research findings suggest.

A cohort study, published online in JAMA Neurology, looked at the incidence of intracranial subdural hematoma within 2 months of delivery in 22,130,815 women, using data from the U.S. Agency for Healthcare Research and Quality’s National Readmission Database.

The overall rate of postdural puncture headaches was 309 per 100,000 deliveries, and the overall incidence of subdural hematoma was 1.5 per 100,000 deliveries. Among the women with postdural puncture headache, however, the unadjusted rate of subdural hematoma was 147 per 100,000. After adjusting for confounding factors, women who experienced postdural puncture headache had a nearly 200-fold higher risk of subdural hematoma (odds ratio, 199; P  less than .001), representing an absolute risk increase of 130 per 100,000 deliveries.

“This was a small absolute increase because of the rarity of this outcome in this population,” wrote Dr. Albert R. Moore of the Royal Victoria Hospital at McGill University, Montreal, and coauthors. “However, this is an important and devastating outcome for a common exposure in young and usually healthy mothers.”

The authors noted that these findings confirmed other reports linking postdural puncture headache and intracranial subdural hematoma. The proposed mechanism connecting the two conditions was that decreased intracranial pressure from cerebrospinal fluid leakages leads to “sagging” of the brain and tension on the veins between the dura and arachnoid, which in turn could trigger a rupture and formation of a subdural hematoma.

Other risk factors for subdural hematoma included coagulopathy, arteriovenous malformation, and delayed blood patch. The investigators also found that obesity was associated with a lower risk of headache after postdural puncture, which might be the result of increased intracranial pressure providing resistance to the development of subdural hematoma.

There was a significant interaction between postdural puncture headache, severe preeclampsia, and chronic hypertension. In the absence of postdural puncture headache, severe preeclampsia and chronic hypertension were both independently associated with significant increases in the risk of subdural hematoma, Dr. Moore and associates noted.

In women who experienced postdural puncture headache, only chronic hypertension was significantly associated with subdural hematoma, they said.

The study was limited in being observational and at risk of misclassification. In addition, there was a risk of surveillance bias in that women with postdural puncture headaches might be more likely to receive brain imaging that would pick up minor subdural hematomas, the investigators said.

The study was supported by McGill University Health Center’s department of anesthesia. The authors reported no conflicts of interest.

SOURCE: Moore A et al. JAMA Neurol. 2019 Sep 16. doi: 10.1001/jamaneurol.2019.2995.

STOCKHOLM – Compared with teriflunomide, ofatumumab is more effective at reducing relapse rates and MRI activity in patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
 

Two concurrent phase 3 trials

Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.

The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.

The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
 

Ofatumumab improved clinical and imaging outcomes

In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.

Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.

Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.

In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.

Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.

egreb@mdedge.com

SOURCE: Hauser SL et al. ECTRIMS 2019. Abstract 336.

STOCKHOLM – Compared with teriflunomide, ofatumumab is more effective at reducing relapse rates and MRI activity in patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
 

Two concurrent phase 3 trials

Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.

The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.

The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
 

Ofatumumab improved clinical and imaging outcomes

In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.

Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.

Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.

In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.

Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.

egreb@mdedge.com

SOURCE: Hauser SL et al. ECTRIMS 2019. Abstract 336.

STOCKHOLM – Compared with teriflunomide, ofatumumab is more effective at reducing relapse rates and MRI activity in patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Ofatumumab also reduces the risk of 3-month and 6-month confirmed disability worsening, compared with teriflunomide. The former therapy has a favorable safety profile, and the investigators did not observe any unexpected safety findings.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that Novartis is developing as a monthly 20-mg subcutaneous infusion. “Targeting CD20-bearing B-cells has been shown to be an effective therapeutic against MS,” said Stephen Hauser, MD, professor of neurology at the University of California, San Francisco. “CD20 targeting is very effective at nearly complete depletion of B-cells in the blood, but [performs] only partial depletion in lymph nodes. This may explain, in part, its safety profile.”
 

Two concurrent phase 3 trials

Dr. Hauser and colleagues conducted two contemporaneous phase 3 trials, ASCLEPIOS I and ASCLEPIOS II, to compare the efficacy and safety of ofatumumab with those of teriflunomide. The two multicenter trials were double blinded and had a parallel-group design. Eligible patients were between ages 18 and 55 years; had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5; and had had one or more relapse in the previous year, two or more relapses in the previous 2 years, or a positive gadolinium-enhancing MRI scan during the year before randomization. Patients with progressive MS, neuromyelitis optica, or progressive multifocal leukoencephalopathy were excluded.

The investigators randomized patients in equal groups to receive 20-mg subcutaneous injections of ofatumumab every 4 weeks (plus a daily oral placebo) or 14 mg/day of teriflunomide orally (plus placebo subcutaneous injections). Participants randomized to ofatumumab underwent an initial loading regimen of 20-mg subcutaneous doses on days 1, 7, and 14. The trials had flexible durations: The number of events determined the length of the studies, which could last for as long as 30 months. At study completion, participants were enrolled into an ongoing, open-label extension study.

The primary endpoint of both trials was the annualized relapse rate (ARR). Among the secondary endpoints were 3- and 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI-related outcomes, and serum neurofilament light chain (NfL) levels.
 

Ofatumumab improved clinical and imaging outcomes

In all, 927 patients were randomized in ASCLEPIOS I (462 to teriflunomide and 465 to ofatumumab), and 955 patients were randomized in ASCLEPIOS II (474 to teriflunomide and 481 to ofatumumab). The study completion rate was approximately 85% in ASCLEPIOS I and approximately 82% in ASCLEPIOS II. The two studies had similar populations, and the two treatment arms in each trial were well balanced. Overall, mean age was approximately 38 years, 68% of patients were female, mean disease duration was approximately 8 years, and mean EDSS score was about 3.

Compared with teriflunomide, ofatumumab reduced the ARR by 50.5% in ASCLEPIOS I and by 58.5% in ASCLEPIOS II. Ofatumumab reduced the risk of 3-month confirmed disability worsening by 34.4%, compared with teriflunomide, and reduced the risk of 6-month confirmed disability worsening by 32.5%, compared with teriflunomide. All of these differences were statistically significant. Ofatumumab tended to increase the likelihood of confirmed disability improvement, compared with teriflunomide, but the result was not statistically significant.

Ofatumumab was superior to teriflunomide on imaging and laboratory measures, as well. Compared with teriflunomide, ofatumumab significantly reduced gadolinium-enhancing T1 lesions by 97.5% in ASCLEPIOS I and by 93.8% in ASCLEPIOS II. In addition, ofatumumab significantly reduced new or enlarging T2 lesions by 82.0% in ASCLEPIOS I and by 84.5% in ASCLEPIOS II. At month 24, ofatumumab reduced serum NfL levels by 23% in ASCLEPIOS I and by 24% in ASCLEPIOS II, compared with teriflunomide.

In both studies, adverse events and serious adverse events were well balanced between treatment groups. The ofatumumab groups had a slight increase in injection-related reactions, compared with the teriflunomide groups. Most systemic injection reactions were mild to moderate.

Novartis Pharma funded the research. Dr. Hauser has received travel reimbursement from F. Hoffmann-La Roche and Novartis for meetings and presentations related to anti-CD20 therapies.

egreb@mdedge.com

SOURCE: Hauser SL et al. ECTRIMS 2019. Abstract 336.

STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.

This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.

Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).

Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.

The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.

The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.

“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.

Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.

Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.

“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.

The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.

In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.

The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.

Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.

The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.

bjancin@mdedge.com

SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.

STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.

This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.

Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).

Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.

The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.

The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.

“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.

Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.

Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.

“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.

The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.

In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.

The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.

Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.

The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.

bjancin@mdedge.com

SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.

STOCKHOLM – Children with multiple sclerosis (MS) who are initially treated with one of the newer disease-modifying therapies experienced significantly better disease activity control in terms of clinical and radiologic outcomes, compared with those started on an injectable drug in a large, observational, cohort study conducted by the U.S. Network of Pediatric MS Centers.

This was the first-ever comparative effectiveness study of initial disease-modifying therapies (DMTs) in children with MS. The take-home message was clear: “This study supports the use of newer DMTs early in the course of pediatric MS,” Kristen M. Krysko, MD, said in presenting the results at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

The study was conducted because she and her coinvestigators in the network have noted increasing use of newer DMTs, even as first-line initial treatment, in the setting of pediatric MS. This represents a break with the traditional approach, which entails starting with one of the injectables – either an interferon-beta or glatiramer acetate – because of their more favorable safety profile, then escalating therapy by switching to a newer, more potent agent in the event of a disease breakthrough, explained Dr. Krysko, a clinical fellow in neurology at the University of California, San Francisco.

Until now, there has been only limited evidence on how the newer DMTs stack up in comparison with the injectables in a pediatric MS population. The chief supporting evidence for the harder-hitting initial approach, Dr. Krysko said, has come from a randomized clinical trial in 215 children showing that fingolimod had a lower relapse rate and better MRI outcomes, compared with interferon beta-1a, during 2 years of follow-up, but at the cost of a higher rate of serious adverse events (N Engl J Med. 2018;379[11]:1017-27).

Dr. Krysko presented a prospective study conducted at 12 sites participating in the network. It included 741 children, 85% of whom had MS, with clinically isolated syndrome in the remainder. For 197 patients, the first MS treatment was an injectable. The other 544 children were started on a newer DMT, most often dimethyl fumarate, rituximab, natalizumab, or fingolimod, with a smattering of patients on teriflunomide or ocrelizumab. Patients averaged roughly a 1-year disease history at the time they went on their first DMT and were then followed for a mean of 1.5-1.8 years on that drug.

The primary outcome was the propensity score–matched, annualized relapse rate during follow-up: The annualized rate was 0.2 in the group on newer DMTs, compared with 0.47 with the injectables. The propensity score matching was used because patients were not randomized by treatment. The propensity scores attempted to neutralize potential confounders, including differences in patient demographics, baseline disease activity, and severity of a first pretreatment relapse, she explained.

The between-group difference in adjusted annualized relapse rate was statistically significant. It translated to a 55% reduction in relative risk favoring children on a newer DMT. Moreover, the number needed to treat was impressively low, at 3.7.

“This can be interpreted as [needing] to treat 3.7 individuals with newer rather than injectable DMTs to prevent one relapse,” Dr. Krysko observed.

Secondary endpoints focused on brain MRI findings. The median time to development of new or enlarging T2 hyperintense lesions was 2.79 years with the newer DMTs, compared with 0.42 years with the injectables. The adjusted risk of developing such lesions was reduced by 49% with the newer DMTs.

Similarly, the median time to development of gadolinium-enhancing lesions was 2.25 years with the injectables and had not yet been reached in patients on newer DMTs when the study closed in January 2019.

“Many children on the newer DMTs never experienced a new gadolinium-positive lesion on follow-up,” she noted.

The adjusted risk of developing a new gadolinium-enhancing lesion was 62% lower in the newer-DMT group.

In terms of the safety of the newer DMTs, there were no surprises: The adverse-event profiles mirrored those that have been examined far more extensively in adults, according to Dr. Krysko.

The newer DMTs included oral agents as well as drugs given by intravenous infusion. The IV agents generally resulted in better disease control, compared with the oral agents, as one would expect, she said. The patient numbers were not sufficient to break down the results on an individual drug basis, however, even though this was a relatively large study.

Asked if these study results warranted a sweeping change in clinical practice – a move away from the conventional escalation treatment strategy in children in favor of upfront use of the newer, more effective DMTs – Dr. Krysko said that was tempting in light of a few recent studies in adults showing that even the first treatment can affect important long-term outcomes, including conversion to secondary progressive MS. However, she said she’d like to see additional studies in children that are focused on safety before making widespread changes in treatment strategy, especially because the pediatric MS network study did not include many very young children.

The study was sponsored by the Multiple Sclerosis Society. Dr. Kysko reported having no financial conflicts in regard to the study.

bjancin@mdedge.com

SOURCE: Krysko KM et al. ECTRIMS 2019, abstract 249.

STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.

Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.

The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.

Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.

“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.

“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”

The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.

Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.

Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.

By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).

“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.

Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.

A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.

The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.

Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”

The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.

Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.

The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.

koakes@mdedge.com

SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.

STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.

Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.

The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.

Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.

“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.

“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”

The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.

Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.

Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.

By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).

“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.

Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.

A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.

The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.

Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”

The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.

Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.

The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.

koakes@mdedge.com

SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.

STOCKHOLM – Inebilizumab, a medication being developed to treat neuromyelitis optica spectrum disorder (NMO/NMOSD), fared well against placebo in a randomized trial, according to recently presented results.

Participants in the active arm of the study saw a 77% relative reduction in the risk of an attack of NMO, compared with placebo, for a number needed to treat of 3.2 to see benefit from inebilizumab, said senior investigator Bruce Cree, MD, PhD.

The multisite, international N-MOmentum study compared inebilizumab, a B-cell depleting humanized monoclonal antibody, with placebo as monotherapy for the treatment of NMOSD. The results were presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Adult patients with NMOSD were eligible if they had experienced at least one attack in the previous year, or at least two attacks in the previous 2 years, and had an Expanded Disability Status Scale (EDSS; range, 0-10; 0, normal) score of 8 or less, Dr. Cree said. Diagnostic criteria for study participation were either seropositivity for aquaporin 4-IgG or fulfillment of the 2006 Wingerchuk criteria for NMOSD if individuals were aquaporin 4-IgG negative.

Patients were about 43 years old at enrollment. More than 90% were women, and about three-quarters were white or Asian. The baseline EDSS score was about 3.5, and patients had experienced a mean of just over four attacks on study entry. The full cohort of patients was over 90% seropositive, and about 60% had been on prior immunosuppressive therapy.

“This was a monotherapy study, meaning that no background immunotherapy was permitted,” said Dr. Cree, the George A. Zimmermann Endowed Professor in Multiple Sclerosis in the department of neurology at the University of California, San Francisco. Patients were randomized 3:1 to receive either two 300-mg doses of inebilizumab by intravenous infusion on study days 1 and 13 or matched placebo infusions.

“When we think about B cells and NMO, multiple lines of evidence have suggested that NMO is a B-cell–mediated disorder resulting from pathogenic antibody production, pro-inflammatory cytokine secretion, and antigen presentation by B cells,” he explained, adding that inebilizumab targets the cell surface antigen, CD19, which is expressed “perhaps more widely than CD20.”

The randomized, double-blind, placebo-controlled phase 2/3 study was followed by an open-label extension period. “This was a time-to-event study design,” Dr. Cree explained, with the randomized period limited to 197 days. After that period, participants could enroll in the open-label extension arm and receive active treatment for at least 1 year. “In the event that a participant experienced an attack during the course of the study that was an adjudicated attack, they were pulled out and offered entry into the open-label period shortly after the attack,” he added.

Adjudicated attacks were the study’s primary endpoint, measured as the time from study day 1 to an adjudicated attack for patients in the randomized population. Dr. Cree said that study development included identifying 18 “predefined, clinically significant” attack diagnosis criteria. These included attacks of optic myelitis, neuritis, and brain-stem events.

Of the 18 criteria, 10 constituted overt clinical changes and the remaining 8 represented more moderate clinical changes that had to be accompanied by a new lesion detected on MRI. All criteria required confirmation by the adjudication committee to qualify as an attack.

By study day 197, 18 of 161 participants (11.2%) of those remaining in the randomized study arm had experienced an adjudicated NMOSD attack, compared with 22 of 52 (42.3%) of those still in the placebo arm. That drop translated into a relative risk reduction of 77.3% and a hazard ratio of 0.227 for NMOSD attack favoring inebilizumab (P less than .0001).

“That risk of attack [for participants in the inebilizumab arm] continued to be low following entry into the open-label extension, whereas patients who were initially treated with placebo experienced some attacks initially, and that looked like it began to flatten out as well” during the open-label extension arm, said Dr. Cree.

Secondary endpoints included worsening of EDSS scores, changes in low-contrast visual acuity binocular score, the cumulative number of active MRI lesions, and hospitalizations deemed to be NMOSD related. Participants receiving inebilizumab saw significant reductions in all of these endpoints except for the visual acuity measure, with no differences seen in outcomes for seropositive versus seronegative participants.

A total of 231 patients were randomized, with the eventual intention-to-treat population including 174 inebilizumab patients and 56 in the placebo arm (one patient was randomized to inebilizumab but never received a dose of study drug). All but five inebilizumab patients and two placebo patients completed the study. The independent data-monitoring committee recommended stopping enrollment in the randomized phase of the study at 231 patients for efficacy, even though there had been only 43 adjudicated attacks at that point, Dr. Cree explained.

The medication was generally well tolerated. Urinary tract infection – the most common adverse event – was experienced by 22% of patients. Infusion site reactions were more common in those receiving placebo than in those receiving inebilizumab, he noted.

Over the two total years of inebilizumab exposure to date, there have been two deaths. One was related to a severe NMO attack and the other to “an event of undetermined etiology due to a presumed inflammatory brain lesion,” Dr. Cree said, adding that “no autopsy or biopsy was performed, unfortunately.”

The investigators tracked IgG levels over the course of the study and noted that they continued to decline over the course of the study, with 14% of patients having a level less than the lower limit of normal at the 2-year mark. This suggests that IgG levels will have to be followed for patients taking the drug over the long term, he said.

Serum glial fibrillary acidic protein, a serum marker of astroglial injury, is ordinarily elevated during NMOSD attacks. For participants on inebilizumab who experienced attacks, elevations in glial fibrillary acidic protein were not as marked, which suggests that the severity of tissue injury in an attack may be attenuated by the drug, said Dr. Cree.

The study was funded by Viela Bio and Medimmune, which are developing inebilizumab. Viela Bio also funded medical writing for the presentation. Dr. Cree reported receiving consulting fees from Abbvie, Akili, Alexion, Biogen, GeNeuro, Novartis, Sanofi Genzyme, and TG Therapeutics.

koakes@mdedge.com

SOURCE: Cree B et al. ECTRIMS 2019, abstract 139.

Whether Congress will act this year to address the affordability of prescription drugs – a high priority among voters – remains uncertain. But states aren’t waiting.

Darwin Brandis/Getty Images

So far this year, 33 states have enacted a record 51 laws to address drug prices, affordability, and access. That tops the previous record of 45 laws enacted in 28 states set just last year, according to the National Academy for State Health Policy, a nonprofit advocacy group that develops model legislation and promotes such laws.

Among the new measures are those that authorize importing prescription drugs, screen for excessive price increases by drug companies, and establish oversight boards to set the prices that states will pay for drugs.

“Legislative activity in this area is escalating,” said Trish Riley, NASHP’s executive director. “This year, some states moved to launch programs that directly impact what they and consumers pay for high-cost drugs.”

And more laws could be coming before year’s end. Of the handful of states still in legislative session – including California, Massachusetts, Michigan, New Jersey, Ohio, and Pennsylvania – debate continues on dozens of prescription drug bills. In New Jersey alone, some 20 proposed laws are under consideration.

“Both Democrat and Republican leaders have shown a willingness to pursue strong measures that help consumers but also protect state taxpayer dollars,” said Hemi Tewarson, director of the National Governors Association’s health programs.

Ms. Riley, Ms. Tewarson, and others note, however, that states can go only so far in addressing rising drug prices, and that federal legislation would be necessary to have a major effect on the way the marketplace works.

Federal lawmakers are keeping a close eye on the state initiatives, Ms. Tewarson said, to gauge where legislative compromise may lie – even as Congress debates more than a dozen bills that target drug costs. Political divisiveness, a packed congressional schedule and a looming election year could stall momentum at the federal level.

The pharmaceutical industry has opposed most – though not all – state bills, said Priscilla VanderVeer, a spokeswoman for the Pharmaceutical Research and Manufacturers of America, the industry’s main trade group.

“We agree that what consumers now pay for drugs out-of-pocket is a serious problem,” said Ms. VanderVeer. “Many states have passed bills that look good on paper but that we don’t believe will save consumers money.”

Limiting gag rules for pharmacists

At least 16 states have enacted 20 laws governing the behavior of pharmacy benefit managers. The so-called PBMs serve as middlemen among drugmakers, insurance companies, and pharmacies, largely with pharmaceutical industry support.

Those laws add to the 28 passed in 2018. Most of the new laws ban “gag clauses” that some PBMs impose on pharmacists. The clauses, written into pharmacy contracts, stop pharmacists from discussing with customers whether a drug’s cash price would be lower than its out-of-pocket cost under insurance.

With widespread public outrage over gag clauses pushing states to act, federal lawmakers got the message. In October, Congress passed a federal law banning such clauses in PBM-pharmacy contracts nationwide and under the Medicare Part D prescription drug benefit. The Senate passed it 98-2.

Even so, many of this year’s PBM laws contain additional gag clause limitations that go beyond the 2018 federal law.

Importing cheaper drugs

Four states – Colorado, Florida, Maine, and Vermont – this year have enacted measures to establish programs to import cheaper prescription drugs from Canada and, in Florida’s case, potentially other countries. Six other states are considering such legislation.

Medicines from Canada and other countries are less expensive because those nations negotiate directly with drugmakers to set prices.

“This is an area where states once feared to tread,” said Jane Horvath, a consultant with NASHP who has advised Maryland and Oregon, among other states, on prescription drug policy. “Now both Republicans and Democrats view it as a way to infuse more price competition into the marketplace.”

Hurdles remain, however. A 2003 law allows states to import cheaper drugs from Canada but only if the federal Health & Human Services Department approves a state’s plan and certifies its safety. During 2004-2009, the federal government halted nascent drug import efforts in five states.

Even so, momentum for importation has built in recent years in states and Congress as drug prices have continued to rise. And the Trump administration this summer threw its support behind the idea.

Florida Gov. Ron DeSantis, a Republican and close ally of President Donald Trump, signed his state’s measure into law on June 11, claiming he did so after Trump personally promised him that the White House would back the initiative.

On July 31, HHS announced an “action plan” to “lay the foundation for safe importation of certain prescription drugs.” The plan includes a process to authorize state initiatives. It also requires formal regulatory review, including establishing Food and Drug Administration safety criteria. That process could take up to 2 years.

Two big problems remain: In the weeks since the announcement, the Canadian government has opposed any plan that would rely solely on Canada as a source of imported drugs. The pharmaceutical industry also opposes the plan.

Creating drug affordability boards

Maryland and Maine enacted laws this year that establish state agencies to review the costs of drugs and take action against those whose price increases exceed a certain threshold.

New Jersey and Massachusetts are debating similar legislation this year.

Maryland’s law establishes a five-member board to review the list prices and costs of drugs purchased by the state and Maryland’s county and local governments. The board will probe drugs that increase in price by $3,000 or more per year and new medicines that enter the market costing $30,000 or more per year or over the course of treatment.

If approved by future legislation, upper payment limits on drugs with excessive price increases or annual costs would take effect in January 2022.

“My constituents have signaled loud and clear that bringing drug prices down is one of their top priorities,” said state Sen. Katherine Klausmeier, a Democrat representing Baltimore, who sponsored the legislation.

Maine’s law also establishes a five-member board. Beginning in 2021, the board will set annual spending targets for drugs purchased by the state and local governments.

Increasing price transparency

This year, four states – Colorado, Oregon, Texas, and Washington – became the latest to enact laws requiring drug companies to provide information to states and consumers on the list prices of drugs and planned price increases.

The majority of states now have such transparency laws, and most post the data on public websites. The details vary, but all states with such laws seek to identify drugs with price increases above 10% or more a year, and drugs with price increases above set dollar values.

Oregon’s new law, for example, requires manufacturers to notify the state 60 days in advance of any planned increase of 10% or more in the price of brand-name drugs, and any 25% or greater increase in the price of generic drugs.

“That 60-days’ notice was very important to us,” said state Rep. Andrea Salinas, a Democrat and chair of the Oregon House’s health committee, who represents Lake Oswego. “It gives doctors and patients advance notice and a chance to adjust and consider what to do.”
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Whether Congress will act this year to address the affordability of prescription drugs – a high priority among voters – remains uncertain. But states aren’t waiting.

Darwin Brandis/Getty Images

So far this year, 33 states have enacted a record 51 laws to address drug prices, affordability, and access. That tops the previous record of 45 laws enacted in 28 states set just last year, according to the National Academy for State Health Policy, a nonprofit advocacy group that develops model legislation and promotes such laws.

Among the new measures are those that authorize importing prescription drugs, screen for excessive price increases by drug companies, and establish oversight boards to set the prices that states will pay for drugs.

“Legislative activity in this area is escalating,” said Trish Riley, NASHP’s executive director. “This year, some states moved to launch programs that directly impact what they and consumers pay for high-cost drugs.”

And more laws could be coming before year’s end. Of the handful of states still in legislative session – including California, Massachusetts, Michigan, New Jersey, Ohio, and Pennsylvania – debate continues on dozens of prescription drug bills. In New Jersey alone, some 20 proposed laws are under consideration.

“Both Democrat and Republican leaders have shown a willingness to pursue strong measures that help consumers but also protect state taxpayer dollars,” said Hemi Tewarson, director of the National Governors Association’s health programs.

Ms. Riley, Ms. Tewarson, and others note, however, that states can go only so far in addressing rising drug prices, and that federal legislation would be necessary to have a major effect on the way the marketplace works.

Federal lawmakers are keeping a close eye on the state initiatives, Ms. Tewarson said, to gauge where legislative compromise may lie – even as Congress debates more than a dozen bills that target drug costs. Political divisiveness, a packed congressional schedule and a looming election year could stall momentum at the federal level.

The pharmaceutical industry has opposed most – though not all – state bills, said Priscilla VanderVeer, a spokeswoman for the Pharmaceutical Research and Manufacturers of America, the industry’s main trade group.

“We agree that what consumers now pay for drugs out-of-pocket is a serious problem,” said Ms. VanderVeer. “Many states have passed bills that look good on paper but that we don’t believe will save consumers money.”

Limiting gag rules for pharmacists

At least 16 states have enacted 20 laws governing the behavior of pharmacy benefit managers. The so-called PBMs serve as middlemen among drugmakers, insurance companies, and pharmacies, largely with pharmaceutical industry support.

Those laws add to the 28 passed in 2018. Most of the new laws ban “gag clauses” that some PBMs impose on pharmacists. The clauses, written into pharmacy contracts, stop pharmacists from discussing with customers whether a drug’s cash price would be lower than its out-of-pocket cost under insurance.

With widespread public outrage over gag clauses pushing states to act, federal lawmakers got the message. In October, Congress passed a federal law banning such clauses in PBM-pharmacy contracts nationwide and under the Medicare Part D prescription drug benefit. The Senate passed it 98-2.

Even so, many of this year’s PBM laws contain additional gag clause limitations that go beyond the 2018 federal law.

Importing cheaper drugs

Four states – Colorado, Florida, Maine, and Vermont – this year have enacted measures to establish programs to import cheaper prescription drugs from Canada and, in Florida’s case, potentially other countries. Six other states are considering such legislation.

Medicines from Canada and other countries are less expensive because those nations negotiate directly with drugmakers to set prices.

“This is an area where states once feared to tread,” said Jane Horvath, a consultant with NASHP who has advised Maryland and Oregon, among other states, on prescription drug policy. “Now both Republicans and Democrats view it as a way to infuse more price competition into the marketplace.”

Hurdles remain, however. A 2003 law allows states to import cheaper drugs from Canada but only if the federal Health & Human Services Department approves a state’s plan and certifies its safety. During 2004-2009, the federal government halted nascent drug import efforts in five states.

Even so, momentum for importation has built in recent years in states and Congress as drug prices have continued to rise. And the Trump administration this summer threw its support behind the idea.

Florida Gov. Ron DeSantis, a Republican and close ally of President Donald Trump, signed his state’s measure into law on June 11, claiming he did so after Trump personally promised him that the White House would back the initiative.

On July 31, HHS announced an “action plan” to “lay the foundation for safe importation of certain prescription drugs.” The plan includes a process to authorize state initiatives. It also requires formal regulatory review, including establishing Food and Drug Administration safety criteria. That process could take up to 2 years.

Two big problems remain: In the weeks since the announcement, the Canadian government has opposed any plan that would rely solely on Canada as a source of imported drugs. The pharmaceutical industry also opposes the plan.

Creating drug affordability boards

Maryland and Maine enacted laws this year that establish state agencies to review the costs of drugs and take action against those whose price increases exceed a certain threshold.

New Jersey and Massachusetts are debating similar legislation this year.

Maryland’s law establishes a five-member board to review the list prices and costs of drugs purchased by the state and Maryland’s county and local governments. The board will probe drugs that increase in price by $3,000 or more per year and new medicines that enter the market costing $30,000 or more per year or over the course of treatment.

If approved by future legislation, upper payment limits on drugs with excessive price increases or annual costs would take effect in January 2022.

“My constituents have signaled loud and clear that bringing drug prices down is one of their top priorities,” said state Sen. Katherine Klausmeier, a Democrat representing Baltimore, who sponsored the legislation.

Maine’s law also establishes a five-member board. Beginning in 2021, the board will set annual spending targets for drugs purchased by the state and local governments.

Increasing price transparency

This year, four states – Colorado, Oregon, Texas, and Washington – became the latest to enact laws requiring drug companies to provide information to states and consumers on the list prices of drugs and planned price increases.

The majority of states now have such transparency laws, and most post the data on public websites. The details vary, but all states with such laws seek to identify drugs with price increases above 10% or more a year, and drugs with price increases above set dollar values.

Oregon’s new law, for example, requires manufacturers to notify the state 60 days in advance of any planned increase of 10% or more in the price of brand-name drugs, and any 25% or greater increase in the price of generic drugs.

“That 60-days’ notice was very important to us,” said state Rep. Andrea Salinas, a Democrat and chair of the Oregon House’s health committee, who represents Lake Oswego. “It gives doctors and patients advance notice and a chance to adjust and consider what to do.”
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Whether Congress will act this year to address the affordability of prescription drugs – a high priority among voters – remains uncertain. But states aren’t waiting.

Darwin Brandis/Getty Images

So far this year, 33 states have enacted a record 51 laws to address drug prices, affordability, and access. That tops the previous record of 45 laws enacted in 28 states set just last year, according to the National Academy for State Health Policy, a nonprofit advocacy group that develops model legislation and promotes such laws.

Among the new measures are those that authorize importing prescription drugs, screen for excessive price increases by drug companies, and establish oversight boards to set the prices that states will pay for drugs.

“Legislative activity in this area is escalating,” said Trish Riley, NASHP’s executive director. “This year, some states moved to launch programs that directly impact what they and consumers pay for high-cost drugs.”

And more laws could be coming before year’s end. Of the handful of states still in legislative session – including California, Massachusetts, Michigan, New Jersey, Ohio, and Pennsylvania – debate continues on dozens of prescription drug bills. In New Jersey alone, some 20 proposed laws are under consideration.

“Both Democrat and Republican leaders have shown a willingness to pursue strong measures that help consumers but also protect state taxpayer dollars,” said Hemi Tewarson, director of the National Governors Association’s health programs.

Ms. Riley, Ms. Tewarson, and others note, however, that states can go only so far in addressing rising drug prices, and that federal legislation would be necessary to have a major effect on the way the marketplace works.

Federal lawmakers are keeping a close eye on the state initiatives, Ms. Tewarson said, to gauge where legislative compromise may lie – even as Congress debates more than a dozen bills that target drug costs. Political divisiveness, a packed congressional schedule and a looming election year could stall momentum at the federal level.

The pharmaceutical industry has opposed most – though not all – state bills, said Priscilla VanderVeer, a spokeswoman for the Pharmaceutical Research and Manufacturers of America, the industry’s main trade group.

“We agree that what consumers now pay for drugs out-of-pocket is a serious problem,” said Ms. VanderVeer. “Many states have passed bills that look good on paper but that we don’t believe will save consumers money.”

Limiting gag rules for pharmacists

At least 16 states have enacted 20 laws governing the behavior of pharmacy benefit managers. The so-called PBMs serve as middlemen among drugmakers, insurance companies, and pharmacies, largely with pharmaceutical industry support.

Those laws add to the 28 passed in 2018. Most of the new laws ban “gag clauses” that some PBMs impose on pharmacists. The clauses, written into pharmacy contracts, stop pharmacists from discussing with customers whether a drug’s cash price would be lower than its out-of-pocket cost under insurance.

With widespread public outrage over gag clauses pushing states to act, federal lawmakers got the message. In October, Congress passed a federal law banning such clauses in PBM-pharmacy contracts nationwide and under the Medicare Part D prescription drug benefit. The Senate passed it 98-2.

Even so, many of this year’s PBM laws contain additional gag clause limitations that go beyond the 2018 federal law.

Importing cheaper drugs

Four states – Colorado, Florida, Maine, and Vermont – this year have enacted measures to establish programs to import cheaper prescription drugs from Canada and, in Florida’s case, potentially other countries. Six other states are considering such legislation.

Medicines from Canada and other countries are less expensive because those nations negotiate directly with drugmakers to set prices.

“This is an area where states once feared to tread,” said Jane Horvath, a consultant with NASHP who has advised Maryland and Oregon, among other states, on prescription drug policy. “Now both Republicans and Democrats view it as a way to infuse more price competition into the marketplace.”

Hurdles remain, however. A 2003 law allows states to import cheaper drugs from Canada but only if the federal Health & Human Services Department approves a state’s plan and certifies its safety. During 2004-2009, the federal government halted nascent drug import efforts in five states.

Even so, momentum for importation has built in recent years in states and Congress as drug prices have continued to rise. And the Trump administration this summer threw its support behind the idea.

Florida Gov. Ron DeSantis, a Republican and close ally of President Donald Trump, signed his state’s measure into law on June 11, claiming he did so after Trump personally promised him that the White House would back the initiative.

On July 31, HHS announced an “action plan” to “lay the foundation for safe importation of certain prescription drugs.” The plan includes a process to authorize state initiatives. It also requires formal regulatory review, including establishing Food and Drug Administration safety criteria. That process could take up to 2 years.

Two big problems remain: In the weeks since the announcement, the Canadian government has opposed any plan that would rely solely on Canada as a source of imported drugs. The pharmaceutical industry also opposes the plan.

Creating drug affordability boards

Maryland and Maine enacted laws this year that establish state agencies to review the costs of drugs and take action against those whose price increases exceed a certain threshold.

New Jersey and Massachusetts are debating similar legislation this year.

Maryland’s law establishes a five-member board to review the list prices and costs of drugs purchased by the state and Maryland’s county and local governments. The board will probe drugs that increase in price by $3,000 or more per year and new medicines that enter the market costing $30,000 or more per year or over the course of treatment.

If approved by future legislation, upper payment limits on drugs with excessive price increases or annual costs would take effect in January 2022.

“My constituents have signaled loud and clear that bringing drug prices down is one of their top priorities,” said state Sen. Katherine Klausmeier, a Democrat representing Baltimore, who sponsored the legislation.

Maine’s law also establishes a five-member board. Beginning in 2021, the board will set annual spending targets for drugs purchased by the state and local governments.

Increasing price transparency

This year, four states – Colorado, Oregon, Texas, and Washington – became the latest to enact laws requiring drug companies to provide information to states and consumers on the list prices of drugs and planned price increases.

The majority of states now have such transparency laws, and most post the data on public websites. The details vary, but all states with such laws seek to identify drugs with price increases above 10% or more a year, and drugs with price increases above set dollar values.

Oregon’s new law, for example, requires manufacturers to notify the state 60 days in advance of any planned increase of 10% or more in the price of brand-name drugs, and any 25% or greater increase in the price of generic drugs.

“That 60-days’ notice was very important to us,” said state Rep. Andrea Salinas, a Democrat and chair of the Oregon House’s health committee, who represents Lake Oswego. “It gives doctors and patients advance notice and a chance to adjust and consider what to do.”
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

STOCKHOLM – Among patients with multiple sclerosis (MS), average daily step count correlates with clinical measures of ambulation, cognitive function, brain atrophy on MRI, and quality of life, according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.

Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.

The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.

In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.

Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).

As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.

Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.

Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.

egreb@mdedge.com

SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.

STOCKHOLM – Among patients with multiple sclerosis (MS), average daily step count correlates with clinical measures of ambulation, cognitive function, brain atrophy on MRI, and quality of life, according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.

Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.

The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.

In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.

Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).

As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.

Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.

Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.

egreb@mdedge.com

SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.

STOCKHOLM – Among patients with multiple sclerosis (MS), average daily step count correlates with clinical measures of ambulation, cognitive function, brain atrophy on MRI, and quality of life, according to research presented at the annual congress of the European Committee for Treatment and Research in MS. Remote gait monitoring using a popular fitness tracker may offer a surrogate measure of MS disability in clinical trials, the researchers reported.

Many outcome measures in MS are evaluated in controlled contexts and do not indicate how patients are functioning outside of the clinical setting, said Valerie J. Block, PhD, from the Weill Institute for Neurosciences at the University of California, San Francisco. Patient-reported outcome measures are subject to recall bias and uneven perception of deficits. Remote ambulatory monitoring, on the other hand, could be a more objective measure that provides continuous information in the real-world setting, said Dr. Block. She and her colleagues have proposed remote ambulatory activity monitoring as an outcome measure for clinical trials.

The investigators chose this measure as an exploratory endpoint for SPI2, a phase 3 trial investigating the efficacy and safety of MD1003 (high-dose pharmaceutical-grade biotin) in patients with inactive primary progressive MS and secondary progressive MS. “To our knowledge, this is the first major clinical trial in progressive MS to include continuous remote step count monitoring as an exploratory endpoint,” said Dr. Block.

In the SPI2 study, patients received either MD1003 (300 mg/day) or placebo. To examine the relationship between ambulatory monitoring and clinical disability and MRI measures, the researchers remotely monitored participants’ ambulatory activity for 27 months using a fitness tracker. The investigators used the average daily step count from the first 30 days as the baseline activity measure. At first, they set a low daily step-count goal to minimize the influence of motivation on ambulatory activity. Participants later were taught how to change the goal independently.

Dr. Block and colleagues created LASSO subset selection regression models to correlate average daily step count with sex, age, disease duration, age at onset, disease course, and various MRI models (such as upper cervical cord area, gray matter volume, normalized brain volume, thalamic volume, and T1 and T2 lesion volumes). They performed least squares regression models on the subset selection results. Finally, the researchers calculated Spearman correlations between average daily step count and clinical disability, as measured by Expanded Disability Status Scale (EDSS) and timed 25-foot walk, and the Physical and Mental Health Composite measures of the MS Quality of Life scale (MSQoL-29).

As of April 23, 2019, the researchers had enrolled 492 patients (262 women) with full data at 90 centers (40 in the United States, 39 in Europe, 8 in Canada, and 3 in Australia). In all, 311 patients (63%) had secondary progressive MS, and 181 had primary progressive MS. Participants had moderate disability; the median EDSS score was 6.0. Median disease duration was 10.6 years. The mean daily step count during the first month was 3,699.

Greater step count was correlated with lower EDSS score, faster completion of the timed 25-foot walk, better Physical Health Composite score, better Symbol Digit Modalities Test score, and better Mental Health Composite score. Furthermore, greater mean daily step count also correlated with greater upper cervical cord area, greater normalized brain volume, greater gray matter volume, and lower T1 lesion volume. The correlations between step count and thalamic volume and T2 lesion volume were not significant. “These data support the study of steps as an exploratory outcome measure in clinical trials for progressive MS,” said Dr. Block.

Dr. Block received reimbursement for travel expenses related to this study from MedDay Pharmaceuticals. Coinvestigators received research support and compensation from companies such as Abbvie, Alexion, Biogen, Genentech, MedDay Pharmaceuticals, Novartis, and Sanofi Genzyme. One investigator is an employee of MedDay Pharmaceuticals.

egreb@mdedge.com

SOURCE: Block V et al. ECTRIMS 2019, Abstract 217.

STOCKHOLM – Among a cohort of patients with highly active multiple sclerosis (MS), MRI without gadolinium contrast still detected most lesions. Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.

“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.

The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.

For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.

The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.

The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.

In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.

Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”

In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.

The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.

Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.

Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.

koakes@mdedge.com

SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.

STOCKHOLM – Among a cohort of patients with highly active multiple sclerosis (MS), MRI without gadolinium contrast still detected most lesions. Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.

“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.

The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.

For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.

The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.

The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.

In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.

Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”

In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.

The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.

Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.

Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.

koakes@mdedge.com

SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.

STOCKHOLM – Among a cohort of patients with highly active multiple sclerosis (MS), MRI without gadolinium contrast still detected most lesions. Further, lesions missed by skipping gadolinium would have changed treatment course for just 1 of the 84 patients in the study, said Lucia Gentili, MD, a neurologist in the department of medicine, section of neurology, at the University of Perugia (Italy), in an interview at the annual congress of the European Committee on Treatment and Research in Multiple Sclerosis.

“Postcontrast MRI might not be mandatory to detect signs of disease activity in patients with active MS,” she observed.

The question of the long-term effects of gadolinium deposition from serial scans in patients with MS is a hot topic among both patients and those caring for people with MS, said Dr. Gentili, so she and her associates decided to see how avoiding gadolinium exposure would affect lesion detection and patient management among their patient population.

For the retrospective study, the investigators looked at the records of 84 patients with relapsing remitting MS at two Italian MS centers over a 5-year time span. This was a cohort enriched for patients with highly active disease, said Dr. Gentili. A total of 45 patients, or over half of the cohort, had experienced at least one relapse in the preceding year.

The study included patients who were being screened for a second-line treatment and had evidence of brain or spinal cord contrast-enhancing lesions on MRI, if they also had a previous MRI of the brain and spinal cord performed on the same scanner.

The uniform protocol used for all MRIs included axial T2-weighted, fluid attenuated inversion recovery (FLAIR), and pre- and postcontrast T1-weighted sequences.

In all, the reference MRI scans picked up 164 contrast-enhancing lesions; of these, 151 (92.1%) were also seen on the T2/FLAIR sequences, showing up as new or enlarging lesions. Thirteen lesions were not visible on T2/FLAIR sequences when compared with the previous MRI, said Dr. Gentili.

Almost all patients in the cohort – a group with highly active disease, Dr. Gentili emphasized – also had new or enlarging lesions visible in T2 sequences. “Only two patients with MRI evidence of contrast-enhancing lesions showed no new or enlarged lesions in T2/FLAIR images,” she added. “Therefore, without gadolinium administration, only two patients in our cohort would have been incorrectly classified as radiologically stable.”

In reality, though, one of the two subjects whose disease activity was missed without gadolinium contrast had a relapse in the preceding 12 months, so clinical evidence of disease activity prompted attention to this individual. “Thus, only one subject in the entire cohort would have been incorrectly classified as stable,” Dr. Gentili and coauthors reported.

The results of this small study do not represent a case for abandoning gadolinium, Dr. Gentili stressed. “In our study, active lesions detected only by gadolinium enhancement, that is, without any evidence of new or enlarged lesions on T2/FLAIR, occurred in a limited but significant portion of contrast-enhancing lesions,” occurring in about 8% of the total lesions.

Rather, this study and other ongoing work represents a basis for shared decision making between persons with MS and those caring for them. Particularly for patients with highly active MS who can anticipate receiving a high burden of contrast to track disease activity, physicians can consider presenting them with the option to omit gadolinium contrast, she said.

Dr. Gentili reported receiving a travel grant from the ECTRIMS scientific program committee, and several coauthors reported relationships with multiple pharmaceutical companies. One coauthor received research funding from the Italian Multiple Sclerosis Society, the Italian Ministry of health, and the Italian Ministry of Education.

koakes@mdedge.com

SOURCE: Gentili L et al. ECTRIMS 2019, Abstract P901.

STOCKHOLM – Radiologically isolated syndrome (RIS) converted to multiple sclerosis (MS) within 10 years of an initial abnormal MRI in 51% of patients in a large international cohort, Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Bruce Jancin/MDedge News

She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.

The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.

Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).

The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).

Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.

RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.

Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.

The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.

Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.

“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.

Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
 

bjancin@mdedge.com

SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.

STOCKHOLM – Radiologically isolated syndrome (RIS) converted to multiple sclerosis (MS) within 10 years of an initial abnormal MRI in 51% of patients in a large international cohort, Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Bruce Jancin/MDedge News

She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.

The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.

Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).

The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).

Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.

RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.

Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.

The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.

Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.

“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.

Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
 

bjancin@mdedge.com

SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.

STOCKHOLM – Radiologically isolated syndrome (RIS) converted to multiple sclerosis (MS) within 10 years of an initial abnormal MRI in 51% of patients in a large international cohort, Christine Lebrun-Frenay, MD, PhD, reported at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Bruce Jancin/MDedge News

She and her coinvestigators in the Radiologically Isolated Syndrome Consortium identified four significant risk factors for conversion. The likelihood of developing MS rose stepwise with the number of risk factors present at baseline such that patients possessing all four risk factors had an 87% conversion rate by 10 years.

The four significant risk factors that emerged from multivariate analysis were being age 37 years or younger at the time of the initial abnormal MRI, having spinal cord lesions on MRI, being cerebrospinal fluid positive for oligoclonal immunoglobulin bands and/or an elevated IgG index, and having infratentorial brain lesions on MRI.

Patients with none or one of the risk factors at baseline had a 29% conversion rate at 10 years. That risk climbed to 54% with two risk factors and 68% with any three, according to Dr. Lebrun-Frenay, head of the inflammatory neurologic disorders clinical research unit and MS Center at the University of Nice (France).

The new 10-year results expand upon the previously reported outcomes involving 5 years of prospective follow-up in the initial cohort of 451 RIS patients at participating MS centers in the United States, three European countries, and Turkey. At 5 years, 34% of subjects had converted to MS as defined by a first acute symptomatic clinical event involving CNS demyelination or 12 months of a progressive neurologic deficit (PLoS One. 2014 Mar 5;9[3]:e90509).

Of note, 17% of patients were treated off label with MS disease-modifying therapies, including natalizumab, injectables, or fingolimod, while they still had RIS, she noted.

RIS was defined on the basis of an incidentally identified CNS white-matter lesion meeting the 2009 Okuda criteria (Neurology. 2009 Mar 3;72[9]:800-5), which remain the only validated criteria for RIS.

Fourteen patients converted from RIS to primary progressive MS, indicating the existence of a previously unrecognized presymptomatic phase for this form of the disease.

The mounting conversions from RIS to MS over time suggest that RIS is part of the MS spectrum. In light of the RIS Consortium’s 10-year findings, Dr. Lebrun-Frenay and colleagues strongly recommended yearly monitoring of patients with RIS via a clinical visit including a neurologic examination and possibly a cognitive evaluation, as well as brain and spinal cord MRI scans.

Based on the observed conversion trajectory between 5 and 10 years, Dr. Lebrun-Frenay speculated that with further prospective follow-up eventually all of the RIS patients will develop MS. Despite this, she did not recommend prescribing disease-modifying therapies for these asymptomatic RIS patients. Dr. Lebrun-Frenay noted that there are two ongoing major randomized, phase 3, placebo-controlled clinical trials addressing this very question: the ARISE study of dimethyl fumarate in the United States, and the TERIS study of teriflunomide in Europe.

“It hasn’t been demonstrated yet that to give an active drug at this early stage is useful, so we have to wait a little bit for the results of these ongoing trials. I think we have to believe in evidence-based medicine. After all, 5 or 6 years ago we didn’t have any diagnostic criteria for RIS. We didn’t have any knowledge of this syndrome. Now we have to wait for maybe 2 years. It’s not too long to wait for the answer,” she said.

Dr. Lebrun-Frenay serves as a consultant to more than a half-dozen pharmaceutical companies but reported having no financial conflicts regarding the RIS Consortium study, which is being conducted without commercial support.
 

bjancin@mdedge.com

SOURCE: Lebrun-Frenay C et al. ECTRIMS 2019, Abstract 97.

STOCKHOLM – The presence of an iron ring around a brain lesion suspicious for multiple sclerosis (MS) may provide a promising adjunct to evolving magnetic resonance imaging techniques to track disease activity and progression, according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Kari Oakes/MDedge News

Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.

“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”

Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”

It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.

koakes@mdedge.com

SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.

STOCKHOLM – The presence of an iron ring around a brain lesion suspicious for multiple sclerosis (MS) may provide a promising adjunct to evolving magnetic resonance imaging techniques to track disease activity and progression, according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Kari Oakes/MDedge News

Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.

“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”

Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”

It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.

koakes@mdedge.com

SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.

STOCKHOLM – The presence of an iron ring around a brain lesion suspicious for multiple sclerosis (MS) may provide a promising adjunct to evolving magnetic resonance imaging techniques to track disease activity and progression, according to research presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.

Kari Oakes/MDedge News

Using a conventional 3 Tesla magnetic resonance imaging (MRI) scanner, Margareta Clarke, PhD, and colleagues were able to identify iron rings (also called iron rims) and the central vein sign, and saw that both lesion characteristics were more common in MS patients than in those without MS.

“Routine two-dimensional 3 Tesla MRI with susceptibility weighting can be used to successfully visualize central veins and iron rims,” said Dr. Clarke, speaking at an imaging-focused young investigators’ session at the meeting. “Also, the central vein sign findings from previous 3T studies are confirmed.”

Dr. Clarke, a research fellow at the Vall d’Hebron Research Institute in Barcelona, explained that iron is stored within oligodendrocytes and myelin within the brain. In up to 56% of MS lesions, a rim of iron is visible with susceptibility weighted MRI imaging, she said, adding that the iron rings around the lesions “are likely caused by iron-laden activated microglia and macrophages that accumulate on the edges of lesions.”

It had been known that when lesions are surrounded by iron rings, they are more likely to enlarge and become increasingly hypointense on T1 weighted MRI. In addition, patients with more disability are more likely to have iron-rimmed brain lesions, said Dr. Clarke, and iron rings are associated with chronic disease activity. “Iron rings are a proposed marker of continuing inflammation and tissue loss,” she added.

koakes@mdedge.com

SOURCE: Clarke M et al. ECTRIMS 2019. Abstract 108.

STOCKHOLM – Ponesimod reduces annualized relapse rate, compared with teriflunomide, in adults with relapsing multiple sclerosis (MS), according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.

Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.

Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.

The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.

Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.

At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.

The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.

This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.

The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.

egreb@mdedge.com

SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.

STOCKHOLM – Ponesimod reduces annualized relapse rate, compared with teriflunomide, in adults with relapsing multiple sclerosis (MS), according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.

Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.

Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.

The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.

Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.

At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.

The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.

This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.

The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.

egreb@mdedge.com

SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.

STOCKHOLM – Ponesimod reduces annualized relapse rate, compared with teriflunomide, in adults with relapsing multiple sclerosis (MS), according to research presented at ECTRIMS 2019. Ponesimod also reduces fatigue and the number of active lesions, compared with teriflunomide.

Ponesimod selectively modulates the sphingosine-1-phosphate receptor 1 (S1P1). The drug is administered orally and reduces circulating lymphocyte counts by inducing a rapid, dose-dependent, and reversible sequestration of lymphocytes in lymphoid organs. This effect decreases the number of immune cells available for inflammatory attacks in the CNS, said Ludwig Kappos, MD, head of the department of neurology at University Hospital Basel (Switzerland). The drug has no active metabolites, and its effects on the immune system are reversible.

Dr. Kappos and colleagues conducted the OPTIMUM phase 3 study to assess the efficacy and safety of oral ponesimod, compared with those of teriflunomide. They enrolled patients between ages 18 and 55 years with an established diagnosis of MS according to the 2010 McDonald criteria with a relapsing course from onset into the multicenter, randomized, double-blind, superiority study. Eligible patients had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 inclusive and recent clinical or MRI disease activity. Dr. Kappos and colleagues randomized participants in equal groups to receive ponesimod (20 mg/day) or teriflunomide (14 mg/day) and the respective placebo for 108 weeks. To mitigate the potential effects on heart rate that are associated with S1P1 modulators, patients were titrated gradually from 2 mg/day to the target dose over 14 days.

The trial’s primary endpoint was the annualized relapse rate over 108 weeks. Secondary endpoints were the effect on fatigue-related symptoms, as assessed with Fatigue Symptom and Impact Questionnaire-Relapsing MS (FSIQ-RMS); active lesions on MRI to week 108; and time to 12- and 24-week confirmed disability accumulation to end of study. The investigators also assessed the drugs’ safety and tolerability.

Dr. Kappos and colleagues randomized 1,133 patients at 162 sites in 28 countries. They stratified randomization according to whether participants had received prior disease-modifying treatment in the previous 2 years (39.4% had, and 60.6% had not) and EDSS score at baseline (83.4% had a score of 3.5 or lower, and 16.6% had a score above 3.5). The population’s mean age was 36.7 years, and 65% of participants were female. Most patients were recruited in Europe, and 51% came from E.U. countries. Patients’ mean baseline EDSS score was 2.6, and mean disease duration was 7.6 years. The mean prestudy 12-month relapse rate was 1.3, and 483 (42.7%) patients had one or more gadolinium-enhancing T1 lesions on baseline MRI. The two treatment groups were well balanced. The rate of treatment discontinuation was 16.6% for ponesimod and 16.4% on teriflunomide.

At the end of the study, the annualized relapse rate was 0.202 in the ponesimod group and 0.290 in the teriflunomide group. Compared with teriflunomide, ponesimod significantly reduced the annualized relapse rate by 30.5%. Fatigue remained stable in the ponesimod group, but worsened in the teriflunomide group: The mean difference in FSIQ-RMS score between the arms at week 108 was 3.57, and this result was statistically significant. In addition, ponesimod significantly reduced the number of active lesions by 56%, compared with teriflunomide. The risk for 12- and 24- week confirmed disability were lower with ponesimod, compared with teriflunomide, but the difference was not statistically significant.

The rates of treatment-emergent adverse events were approximately 89% for the ponesimod arm and 88% for teriflunomide. The rates of serious adverse events were about 9% for ponesimod and about 8% for teriflunomide. Respiratory events and laboratory values prompted slightly more study discontinuations in the ponesimod group than in the teriflunomide group.

This research represents the first controlled study to show superior efficacy of oral ponesimod, compared with an approved oral compound, said Dr. Kappos. “The overall profile suggests that [ponesimod] may be a valuable addition to our armamentarium in treating patients with relapsing forms of MS,” he concluded.

The study was supported by Actelion Pharmaceuticals. University Hospital Basel, where Dr. Kappos works, received steering committee, advisory board, and consultancy fees from Actelion and other companies.

egreb@mdedge.com

SOURCE: Kappos L et al. ECTRIMS 2019, Abstract 93.