Multiple Sclerosis

The Food and Drug Administration’s evaluation of postmarketing adverse event reports for the multiple sclerosis drug dalfampridine indicate that the risk of seizures is highest soon after starting treatment with the recommended dose.

Seizures are a known risk of the drug, and the majority of them occurred within days to weeks of starting treatment. Seizures also occurred in patients without any history of them, according to the FDA statement issued on July 23.

The risk of seizures increases with higher blood levels of the drug, and because it is eliminated through the kidneys, the risk of seizures is higher in patients with kidney impairment, the agency said.

The sustained-release formulation of the potassium channel blocker dalfampridine, marketed as Ampyra by Acorda Therapeutics, was approved in January 2010 to improve walking in people with multiple sclerosis, at a dose of 10 mg twice a day. For more than 20 years before approval, a compounded formulation of the drug, called fampridine, was used off label to improve walking ability in people with different neurologic conditions. However, it was difficult to regulate blood levels of fampridine, which has a narrow therapeutic range, and the sustained formulation, dalfampridine, was developed to overcome this limitation.

The FDA statement provided the following recommendations aimed at clinicians, which includes information in the original label (now updated):

• Dalfampridine is contraindicated in patients with a history of seizures or who have moderate to severe renal impairment (a creatine clearance below 50 mL/min).

• The potential benefits of treatment with dalfampridine "should be carefully considered against the risk of seizures" before prescribing the drug to patients with mild renal impairment (creatine clearance 51 mL/min to 80 mL/min).

• Before starting treatment, a patient’s creatinine clearance level should be known (using the Cockroft-Gault equation), and should be checked annually during treatment, "even when serum creatinine levels appear to be normal."

• Patients should be advised not to take double or extra doses of dalfampridine if they miss a dose; and they should take the tablets whole, and not divide, crush, chew, or dissolve the tablets.

• Dalfampridine should be discontinued permanently if a patient has a seizure.

Seizures and other adverse events associated with dalfampridine should be reported to the FDA’s MedWatch program or at 800-332-1088.

The Food and Drug Administration’s evaluation of postmarketing adverse event reports for the multiple sclerosis drug dalfampridine indicate that the risk of seizures is highest soon after starting treatment with the recommended dose.

Seizures are a known risk of the drug, and the majority of them occurred within days to weeks of starting treatment. Seizures also occurred in patients without any history of them, according to the FDA statement issued on July 23.

The risk of seizures increases with higher blood levels of the drug, and because it is eliminated through the kidneys, the risk of seizures is higher in patients with kidney impairment, the agency said.

The sustained-release formulation of the potassium channel blocker dalfampridine, marketed as Ampyra by Acorda Therapeutics, was approved in January 2010 to improve walking in people with multiple sclerosis, at a dose of 10 mg twice a day. For more than 20 years before approval, a compounded formulation of the drug, called fampridine, was used off label to improve walking ability in people with different neurologic conditions. However, it was difficult to regulate blood levels of fampridine, which has a narrow therapeutic range, and the sustained formulation, dalfampridine, was developed to overcome this limitation.

The FDA statement provided the following recommendations aimed at clinicians, which includes information in the original label (now updated):

• Dalfampridine is contraindicated in patients with a history of seizures or who have moderate to severe renal impairment (a creatine clearance below 50 mL/min).

• The potential benefits of treatment with dalfampridine "should be carefully considered against the risk of seizures" before prescribing the drug to patients with mild renal impairment (creatine clearance 51 mL/min to 80 mL/min).

• Before starting treatment, a patient’s creatinine clearance level should be known (using the Cockroft-Gault equation), and should be checked annually during treatment, "even when serum creatinine levels appear to be normal."

• Patients should be advised not to take double or extra doses of dalfampridine if they miss a dose; and they should take the tablets whole, and not divide, crush, chew, or dissolve the tablets.

• Dalfampridine should be discontinued permanently if a patient has a seizure.

Seizures and other adverse events associated with dalfampridine should be reported to the FDA’s MedWatch program or at 800-332-1088.

The Food and Drug Administration’s evaluation of postmarketing adverse event reports for the multiple sclerosis drug dalfampridine indicate that the risk of seizures is highest soon after starting treatment with the recommended dose.

Seizures are a known risk of the drug, and the majority of them occurred within days to weeks of starting treatment. Seizures also occurred in patients without any history of them, according to the FDA statement issued on July 23.

The risk of seizures increases with higher blood levels of the drug, and because it is eliminated through the kidneys, the risk of seizures is higher in patients with kidney impairment, the agency said.

The sustained-release formulation of the potassium channel blocker dalfampridine, marketed as Ampyra by Acorda Therapeutics, was approved in January 2010 to improve walking in people with multiple sclerosis, at a dose of 10 mg twice a day. For more than 20 years before approval, a compounded formulation of the drug, called fampridine, was used off label to improve walking ability in people with different neurologic conditions. However, it was difficult to regulate blood levels of fampridine, which has a narrow therapeutic range, and the sustained formulation, dalfampridine, was developed to overcome this limitation.

The FDA statement provided the following recommendations aimed at clinicians, which includes information in the original label (now updated):

• Dalfampridine is contraindicated in patients with a history of seizures or who have moderate to severe renal impairment (a creatine clearance below 50 mL/min).

• The potential benefits of treatment with dalfampridine "should be carefully considered against the risk of seizures" before prescribing the drug to patients with mild renal impairment (creatine clearance 51 mL/min to 80 mL/min).

• Before starting treatment, a patient’s creatinine clearance level should be known (using the Cockroft-Gault equation), and should be checked annually during treatment, "even when serum creatinine levels appear to be normal."

• Patients should be advised not to take double or extra doses of dalfampridine if they miss a dose; and they should take the tablets whole, and not divide, crush, chew, or dissolve the tablets.

• Dalfampridine should be discontinued permanently if a patient has a seizure.

Seizures and other adverse events associated with dalfampridine should be reported to the FDA’s MedWatch program or at 800-332-1088.

Interferon-beta therapy did not slow the long-term progression of disability in adults with relapsing-remitting multiple sclerosis in a retrospective cohort study based on prospectively collected data.

Patients who took interferon-beta (IFN-beta) experienced rates of disease progression that were similar to a group of contemporaneous peers who did not take IFN-beta and a historical cohort of MS patients studied before IFN-beta therapy became available, Dr. Afsaneh Shirani of the Brain Research Centre at Vancouver (B.C.) Coastal Health Research Institute and her associates reported July 18 in JAMA.

These findings are consistent with those of the longer-term clinical trials that have examined IFN-beta’s efficacy in MS. They call into question the routine use of the drug to prevent or delay disability, the researchers noted.

Previous postmarketing studies have suggested that IFN-beta is beneficial in slowing the progression of MS, but many of those studies had methodologic flaws. For their study, Dr. Shirani and her colleagues used information from a province-wide database that is thought to cover 80% of the MS patients in British Columbia.

The investigators compared outcomes in 868 patients who took IFN-beta in 1995-2004 with 829 contemporaneous control patients who were eligible to take the drug during the same period but chose not to. They also assessed outcomes in a historical control group of 959 unexposed patients who were studied in 1985-1995 before IFN-beta was approved for use in Canada.

At baseline, the study subjects in all three groups had median scores of 2.0 on the 10-point Expanded Disability Status Scale (EDSS), in which higher scores indicate more-severe disability.

Most (76%) of the study subjects were women, and the mean age at onset of MS was 32 years. Median length of follow-up was 5 years for the group receiving IFN-beta, 4 years for their contemporaries who did not receive IFN-beta, and 11 years for the historical controls.

There was no evidence of an association between IFN-beta therapy and MS progression. A total of 94 patients in the treated group (11%), 44 (5%) in the contemporaneous control group, and 222 (23%) in the historical control group reached the main outcome of a sustained, irreversible EDSS score of 6. That score indicates "intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk about 100 meters, with or without resting," according to the investigators, who said that the differences between the groups were not significant (JAMA 2012;308:247-56).

These results did not change appreciably when the data were adjusted to account for differences among the study groups in comorbidity and socioeconomic status, nor did they change in any of several sensitivity analyses.

The results were also similar for a secondary outcome measure, the attainment of an EDSS score of 4 (indicating "fully ambulatory without aid, up and about 12 hours a day despite relatively severe disability; able to walk without aid for 500 meters"). A total of 156 (18%) patients in the treated group, 68 (8%) in the contemporaneous control group, and 268 (28%) in the historical control group reached this end point. These differences also were not statistically significant.

The study is limited by the fact that factors other than IFN-beta treatment may have changed over time, which could bias the comparison with the historical control group. In addition, the decision to forgo IFN-beta therapy may have been related to several factors that could not be accounted for in this observational study, which could bias the comparison with the contemporaneous control group. For example, patients may have decided against IFN-beta therapy because they were in a stable phase of disease, had a needle phobia, were unable or unwilling to adhere to a noncurative treatment, wanted to become pregnant, or had personal or religious objections to using a drug that contains human albumin, Dr. Shirani and her associates said.

It is possible that a subgroup of relapsing-remitting MS patients may benefit from IFN-beta. "Further work is needed to identify these potential patients; perhaps through pharmacogenomic or biomarker studies, paving the way for a tailored, personalized medicine approach," they added.

This study was supported by the Canadian Institutes of Health Research, the National Multiple Sclerosis Society, the Multiple Sclerosis Society of Canada, the Michael Smith Foundation for Health Research, the Christopher Foundation, the University of British Columbia, the Medical Services Commission of British Columbia, the Natural Sciences and Engineering Research Council of Canada, and the United Kingdom Multiple Sclerosis Trust. Dr. Shirani’s associates reported numerous ties to industry sources.

Interferon-beta therapy did not slow the long-term progression of disability in adults with relapsing-remitting multiple sclerosis in a retrospective cohort study based on prospectively collected data.

Patients who took interferon-beta (IFN-beta) experienced rates of disease progression that were similar to a group of contemporaneous peers who did not take IFN-beta and a historical cohort of MS patients studied before IFN-beta therapy became available, Dr. Afsaneh Shirani of the Brain Research Centre at Vancouver (B.C.) Coastal Health Research Institute and her associates reported July 18 in JAMA.

These findings are consistent with those of the longer-term clinical trials that have examined IFN-beta’s efficacy in MS. They call into question the routine use of the drug to prevent or delay disability, the researchers noted.

Previous postmarketing studies have suggested that IFN-beta is beneficial in slowing the progression of MS, but many of those studies had methodologic flaws. For their study, Dr. Shirani and her colleagues used information from a province-wide database that is thought to cover 80% of the MS patients in British Columbia.

The investigators compared outcomes in 868 patients who took IFN-beta in 1995-2004 with 829 contemporaneous control patients who were eligible to take the drug during the same period but chose not to. They also assessed outcomes in a historical control group of 959 unexposed patients who were studied in 1985-1995 before IFN-beta was approved for use in Canada.

At baseline, the study subjects in all three groups had median scores of 2.0 on the 10-point Expanded Disability Status Scale (EDSS), in which higher scores indicate more-severe disability.

Most (76%) of the study subjects were women, and the mean age at onset of MS was 32 years. Median length of follow-up was 5 years for the group receiving IFN-beta, 4 years for their contemporaries who did not receive IFN-beta, and 11 years for the historical controls.

There was no evidence of an association between IFN-beta therapy and MS progression. A total of 94 patients in the treated group (11%), 44 (5%) in the contemporaneous control group, and 222 (23%) in the historical control group reached the main outcome of a sustained, irreversible EDSS score of 6. That score indicates "intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk about 100 meters, with or without resting," according to the investigators, who said that the differences between the groups were not significant (JAMA 2012;308:247-56).

These results did not change appreciably when the data were adjusted to account for differences among the study groups in comorbidity and socioeconomic status, nor did they change in any of several sensitivity analyses.

The results were also similar for a secondary outcome measure, the attainment of an EDSS score of 4 (indicating "fully ambulatory without aid, up and about 12 hours a day despite relatively severe disability; able to walk without aid for 500 meters"). A total of 156 (18%) patients in the treated group, 68 (8%) in the contemporaneous control group, and 268 (28%) in the historical control group reached this end point. These differences also were not statistically significant.

The study is limited by the fact that factors other than IFN-beta treatment may have changed over time, which could bias the comparison with the historical control group. In addition, the decision to forgo IFN-beta therapy may have been related to several factors that could not be accounted for in this observational study, which could bias the comparison with the contemporaneous control group. For example, patients may have decided against IFN-beta therapy because they were in a stable phase of disease, had a needle phobia, were unable or unwilling to adhere to a noncurative treatment, wanted to become pregnant, or had personal or religious objections to using a drug that contains human albumin, Dr. Shirani and her associates said.

It is possible that a subgroup of relapsing-remitting MS patients may benefit from IFN-beta. "Further work is needed to identify these potential patients; perhaps through pharmacogenomic or biomarker studies, paving the way for a tailored, personalized medicine approach," they added.

This study was supported by the Canadian Institutes of Health Research, the National Multiple Sclerosis Society, the Multiple Sclerosis Society of Canada, the Michael Smith Foundation for Health Research, the Christopher Foundation, the University of British Columbia, the Medical Services Commission of British Columbia, the Natural Sciences and Engineering Research Council of Canada, and the United Kingdom Multiple Sclerosis Trust. Dr. Shirani’s associates reported numerous ties to industry sources.

Interferon-beta therapy did not slow the long-term progression of disability in adults with relapsing-remitting multiple sclerosis in a retrospective cohort study based on prospectively collected data.

Patients who took interferon-beta (IFN-beta) experienced rates of disease progression that were similar to a group of contemporaneous peers who did not take IFN-beta and a historical cohort of MS patients studied before IFN-beta therapy became available, Dr. Afsaneh Shirani of the Brain Research Centre at Vancouver (B.C.) Coastal Health Research Institute and her associates reported July 18 in JAMA.

These findings are consistent with those of the longer-term clinical trials that have examined IFN-beta’s efficacy in MS. They call into question the routine use of the drug to prevent or delay disability, the researchers noted.

Previous postmarketing studies have suggested that IFN-beta is beneficial in slowing the progression of MS, but many of those studies had methodologic flaws. For their study, Dr. Shirani and her colleagues used information from a province-wide database that is thought to cover 80% of the MS patients in British Columbia.

The investigators compared outcomes in 868 patients who took IFN-beta in 1995-2004 with 829 contemporaneous control patients who were eligible to take the drug during the same period but chose not to. They also assessed outcomes in a historical control group of 959 unexposed patients who were studied in 1985-1995 before IFN-beta was approved for use in Canada.

At baseline, the study subjects in all three groups had median scores of 2.0 on the 10-point Expanded Disability Status Scale (EDSS), in which higher scores indicate more-severe disability.

Most (76%) of the study subjects were women, and the mean age at onset of MS was 32 years. Median length of follow-up was 5 years for the group receiving IFN-beta, 4 years for their contemporaries who did not receive IFN-beta, and 11 years for the historical controls.

There was no evidence of an association between IFN-beta therapy and MS progression. A total of 94 patients in the treated group (11%), 44 (5%) in the contemporaneous control group, and 222 (23%) in the historical control group reached the main outcome of a sustained, irreversible EDSS score of 6. That score indicates "intermittent or unilateral constant assistance (cane, crutch, or brace) required to walk about 100 meters, with or without resting," according to the investigators, who said that the differences between the groups were not significant (JAMA 2012;308:247-56).

These results did not change appreciably when the data were adjusted to account for differences among the study groups in comorbidity and socioeconomic status, nor did they change in any of several sensitivity analyses.

The results were also similar for a secondary outcome measure, the attainment of an EDSS score of 4 (indicating "fully ambulatory without aid, up and about 12 hours a day despite relatively severe disability; able to walk without aid for 500 meters"). A total of 156 (18%) patients in the treated group, 68 (8%) in the contemporaneous control group, and 268 (28%) in the historical control group reached this end point. These differences also were not statistically significant.

The study is limited by the fact that factors other than IFN-beta treatment may have changed over time, which could bias the comparison with the historical control group. In addition, the decision to forgo IFN-beta therapy may have been related to several factors that could not be accounted for in this observational study, which could bias the comparison with the contemporaneous control group. For example, patients may have decided against IFN-beta therapy because they were in a stable phase of disease, had a needle phobia, were unable or unwilling to adhere to a noncurative treatment, wanted to become pregnant, or had personal or religious objections to using a drug that contains human albumin, Dr. Shirani and her associates said.

It is possible that a subgroup of relapsing-remitting MS patients may benefit from IFN-beta. "Further work is needed to identify these potential patients; perhaps through pharmacogenomic or biomarker studies, paving the way for a tailored, personalized medicine approach," they added.

This study was supported by the Canadian Institutes of Health Research, the National Multiple Sclerosis Society, the Multiple Sclerosis Society of Canada, the Michael Smith Foundation for Health Research, the Christopher Foundation, the University of British Columbia, the Medical Services Commission of British Columbia, the Natural Sciences and Engineering Research Council of Canada, and the United Kingdom Multiple Sclerosis Trust. Dr. Shirani’s associates reported numerous ties to industry sources.

SAN DIEGO – Glatiramer acetate and interferon beta-1a used in combination were no more effective for patients with relapsing-remitting multiple sclerosis than were either agent alone in a 3-year, randomized trial.

On quality of life measures, monotherapy and combination therapy proved largely equal – and equally well tolerated – in the "CombiRx" study, in which half of the patients got the combination and a quarter got either glatiramer acetate (Copaxone) or interferon beta-1a (Avonex) alone plus a placebo.

CombiRx was conceived at time when interferon beta-1a (IFN-beta-1a) and glatiramer acetate (GA) were the only disease-modifying options for MS; investigators naturally wondered if they’d work better together, said Dr. Lael Stone, a CombiRx investigator and MS specialist at the Cleveland Clinic.

But with natalizumab and fingolimod now on the market, and dimethyl fumarate (also known as BG-12) in the Food and Drug Administration pipeline, times have changed.

It’s never been common to use GA and IFN-beta-1a together, and with newer agents available, "we look at [the CombiRx findings] in 2012 and say ‘that’s not very interesting.’ There were slight indications that" the combination, or one agent or the other, was "better in this respect and not so good in that respect, but it was relatively underwhelming," Dr. Stone said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The size of the study – 1,008 treatment-naive patients – and its duration are what remain important. "They can pull out all sorts of other types of data about what happens to MRIs and what happens to the quality of life" in MS. "They can also look at biomarkers [and genetics]. The database was just locked in April, so this is still going to be gone through in much more detail. What’s going to be most interesting are the other things that come out" of this study, she said.

Almost three-quarters of the CombiRx participants were women. They were 38 years old, on average, and 88% of them were white. Their mean baseline Expanded Disability Status Scale (EDSS) score was about 2.0, and mean disease duration 1.2 years.

Almost half the participants reported very good general health at baseline and 37% excellent general health. Most remained healthy throughout the study. "Everyone did very well. There were very minimal changes from baseline to the last observed MSQLI [Multiple Sclerosis Quality of Life Inventory]," the battery of scales used in CombiRx to see how participants fared, said investigator Stacey Cofield, Ph.D., a biostatician at the University of Alabama at Birmingham.

Mental health and perceived-support scores actually improved over the course of the study, she said, although fatigue, bladder, bowel, and cognitive impairment scores worsened slightly. Overall, "these were very small changes. None of them stand out as being very meaningful," Dr. Cofield said.

Combination therapy showed a half-point benefit on the 22-point bladder control scale, the only scale out of 11 that showed any significant difference between mono and combination therapy.

In the monotherapy groups, IFN-beta-1a patients fared slight better than GA patients on the mental health scale, with no change in the IFN-beta-1a group, but a 3.3 point drop in the 100-point scale in the GA group over 3 years. Conversely, GA patients fared slightly better on the bladder scale, with a 1.5 point improvement vs. a 0.6 point improvement in the IFN-beta-1a group.

Overall, CombiRx had "very low rates of progression and very low amounts of MRI activity," Dr. Cofield said at the meeting, sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee on Treatment and Research in Multiple Sclerosis.

Dr. Cofield reported financial ties to Teva Neuroscience and Centocor Ortho Biotech Services. Other investigators reported numerous ties to pharmaceutical companies, including Teva Neuroscience, which donated the Copaxone used in the trial, and Biogen Idec, which donated the Avonex.

SAN DIEGO – Glatiramer acetate and interferon beta-1a used in combination were no more effective for patients with relapsing-remitting multiple sclerosis than were either agent alone in a 3-year, randomized trial.

On quality of life measures, monotherapy and combination therapy proved largely equal – and equally well tolerated – in the "CombiRx" study, in which half of the patients got the combination and a quarter got either glatiramer acetate (Copaxone) or interferon beta-1a (Avonex) alone plus a placebo.

CombiRx was conceived at time when interferon beta-1a (IFN-beta-1a) and glatiramer acetate (GA) were the only disease-modifying options for MS; investigators naturally wondered if they’d work better together, said Dr. Lael Stone, a CombiRx investigator and MS specialist at the Cleveland Clinic.

But with natalizumab and fingolimod now on the market, and dimethyl fumarate (also known as BG-12) in the Food and Drug Administration pipeline, times have changed.

It’s never been common to use GA and IFN-beta-1a together, and with newer agents available, "we look at [the CombiRx findings] in 2012 and say ‘that’s not very interesting.’ There were slight indications that" the combination, or one agent or the other, was "better in this respect and not so good in that respect, but it was relatively underwhelming," Dr. Stone said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The size of the study – 1,008 treatment-naive patients – and its duration are what remain important. "They can pull out all sorts of other types of data about what happens to MRIs and what happens to the quality of life" in MS. "They can also look at biomarkers [and genetics]. The database was just locked in April, so this is still going to be gone through in much more detail. What’s going to be most interesting are the other things that come out" of this study, she said.

Almost three-quarters of the CombiRx participants were women. They were 38 years old, on average, and 88% of them were white. Their mean baseline Expanded Disability Status Scale (EDSS) score was about 2.0, and mean disease duration 1.2 years.

Almost half the participants reported very good general health at baseline and 37% excellent general health. Most remained healthy throughout the study. "Everyone did very well. There were very minimal changes from baseline to the last observed MSQLI [Multiple Sclerosis Quality of Life Inventory]," the battery of scales used in CombiRx to see how participants fared, said investigator Stacey Cofield, Ph.D., a biostatician at the University of Alabama at Birmingham.

Mental health and perceived-support scores actually improved over the course of the study, she said, although fatigue, bladder, bowel, and cognitive impairment scores worsened slightly. Overall, "these were very small changes. None of them stand out as being very meaningful," Dr. Cofield said.

Combination therapy showed a half-point benefit on the 22-point bladder control scale, the only scale out of 11 that showed any significant difference between mono and combination therapy.

In the monotherapy groups, IFN-beta-1a patients fared slight better than GA patients on the mental health scale, with no change in the IFN-beta-1a group, but a 3.3 point drop in the 100-point scale in the GA group over 3 years. Conversely, GA patients fared slightly better on the bladder scale, with a 1.5 point improvement vs. a 0.6 point improvement in the IFN-beta-1a group.

Overall, CombiRx had "very low rates of progression and very low amounts of MRI activity," Dr. Cofield said at the meeting, sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee on Treatment and Research in Multiple Sclerosis.

Dr. Cofield reported financial ties to Teva Neuroscience and Centocor Ortho Biotech Services. Other investigators reported numerous ties to pharmaceutical companies, including Teva Neuroscience, which donated the Copaxone used in the trial, and Biogen Idec, which donated the Avonex.

SAN DIEGO – Glatiramer acetate and interferon beta-1a used in combination were no more effective for patients with relapsing-remitting multiple sclerosis than were either agent alone in a 3-year, randomized trial.

On quality of life measures, monotherapy and combination therapy proved largely equal – and equally well tolerated – in the "CombiRx" study, in which half of the patients got the combination and a quarter got either glatiramer acetate (Copaxone) or interferon beta-1a (Avonex) alone plus a placebo.

CombiRx was conceived at time when interferon beta-1a (IFN-beta-1a) and glatiramer acetate (GA) were the only disease-modifying options for MS; investigators naturally wondered if they’d work better together, said Dr. Lael Stone, a CombiRx investigator and MS specialist at the Cleveland Clinic.

But with natalizumab and fingolimod now on the market, and dimethyl fumarate (also known as BG-12) in the Food and Drug Administration pipeline, times have changed.

It’s never been common to use GA and IFN-beta-1a together, and with newer agents available, "we look at [the CombiRx findings] in 2012 and say ‘that’s not very interesting.’ There were slight indications that" the combination, or one agent or the other, was "better in this respect and not so good in that respect, but it was relatively underwhelming," Dr. Stone said at the Fourth Cooperative Meeting on Multiple Sclerosis.

The size of the study – 1,008 treatment-naive patients – and its duration are what remain important. "They can pull out all sorts of other types of data about what happens to MRIs and what happens to the quality of life" in MS. "They can also look at biomarkers [and genetics]. The database was just locked in April, so this is still going to be gone through in much more detail. What’s going to be most interesting are the other things that come out" of this study, she said.

Almost three-quarters of the CombiRx participants were women. They were 38 years old, on average, and 88% of them were white. Their mean baseline Expanded Disability Status Scale (EDSS) score was about 2.0, and mean disease duration 1.2 years.

Almost half the participants reported very good general health at baseline and 37% excellent general health. Most remained healthy throughout the study. "Everyone did very well. There were very minimal changes from baseline to the last observed MSQLI [Multiple Sclerosis Quality of Life Inventory]," the battery of scales used in CombiRx to see how participants fared, said investigator Stacey Cofield, Ph.D., a biostatician at the University of Alabama at Birmingham.

Mental health and perceived-support scores actually improved over the course of the study, she said, although fatigue, bladder, bowel, and cognitive impairment scores worsened slightly. Overall, "these were very small changes. None of them stand out as being very meaningful," Dr. Cofield said.

Combination therapy showed a half-point benefit on the 22-point bladder control scale, the only scale out of 11 that showed any significant difference between mono and combination therapy.

In the monotherapy groups, IFN-beta-1a patients fared slight better than GA patients on the mental health scale, with no change in the IFN-beta-1a group, but a 3.3 point drop in the 100-point scale in the GA group over 3 years. Conversely, GA patients fared slightly better on the bladder scale, with a 1.5 point improvement vs. a 0.6 point improvement in the IFN-beta-1a group.

Overall, CombiRx had "very low rates of progression and very low amounts of MRI activity," Dr. Cofield said at the meeting, sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee on Treatment and Research in Multiple Sclerosis.

Dr. Cofield reported financial ties to Teva Neuroscience and Centocor Ortho Biotech Services. Other investigators reported numerous ties to pharmaceutical companies, including Teva Neuroscience, which donated the Copaxone used in the trial, and Biogen Idec, which donated the Avonex.

SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years

The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).

Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.

The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.

"The question [will] be, ‘Is it as good as promised?’ " she said.

The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.

About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.

The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.

About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.

About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.

Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.

No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.

SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years

The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).

Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.

The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.

"The question [will] be, ‘Is it as good as promised?’ " she said.

The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.

About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.

The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.

About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.

About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.

Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.

No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.

SAN DIEGO – Full results of the second phase III trial of dimethyl fumarate in patients with relapsing-remitting multiple sclerosis show that the investigational drug significantly reduces annualized relapse rates and MRI lesions over the course of 2 years

The results of the study, called CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis), are in line with those of an earlier phase III study called DEFINE. But unlike the earlier trial, CONFIRM did not demonstrate a statistically significant benefit for disease progression based on the Expanded Disability Status Scale (EDSS).

Even so, the two studies indicate that dimethyl fumarate, also known as BG-12, "has a future as an oral therapeutic option for patients with relapsing MS," said Dr. Theodore Phillips, an MS researcher at the Baylor Institute for Immunology Research and clinical professor in the neurology department at the University of Texas Southwestern Medical Center, both in Dallas.

The drug is under review by the Food and Drug Administration. "Hopefully, we won’t have to wait for a decision much past the first quarter of 2013," Dr. Phillips said at the Fourth Cooperative Meeting on Multiple Sclerosis.

"People are very excited about BG-12 because it’s a much better tolerated oral, we think, than fingolimod (Gilenya)," which it will compete against, Dr. Lael Stone, an MS specialist at the Cleveland Clinic, said about the study.

"The question [will] be, ‘Is it as good as promised?’ " she said.

The trial randomized 359 patients to BG-12 240 mg twice daily, 345 patients to BG-12 240 mg three times daily, 350 to subcutaneous glatiramer acetate (GA) 20 mg daily, and 363 to placebo.

About 70% of the subjects were women, with approximately 1.4 relapses in the prior year and a mean EDSS score of about 2.6. The average age in the trial was about 37 years.

The annualized relapse rate was 0.401 in the placebo group, 0.224 in the BG-12 twice-daily group (44% reduction versus placebo), 0.198 in the BG-12 three-times-daily group (51% reduction), and 0.286 in the GA group (29% reduction). These rates correspond to hazard ratios for relapse of 0.66, 0.55, and 0.71, respectively. The results were statistically significant.

About 17% of placebo, 13% of BG-12, and 15.6% of GA patients experienced disease progression in the trial. The differences did not reach significance, perhaps because progression rates overall were low, unlike the earlier trial, where 27% of placebo patients progressed, Dr. Phillips said.

About 140 patients in each arm were included in the MRI analysis. The placebo arm had an adjusted mean of 17.4 new or newly enlarging T2 hyperintense lesions and 7 new T1 hypointense lesions. Both BG-12 arms had a mean of about 5 new or newly enlarging T2 lesions and just under 3 T1 lesions. The GA group had a mean of 8 T2 lesions and 4.1 T1 lesions. The differences versus placebo were significant.

Flushing and gastrointestinal complaints were the most common side effects of BG-12, but they decreased after the first month of the trial. Mean lymphocyte counts fell during the first 6-12 months, but remained within normal limits throughout the study.

No opportunistic infections or malignancies were reported in the BG-12 groups. The twice-daily arm had two cellulitis cases, whereas the three-times-daily arm had one. No cellulitis was reported in the placebo and GA arms.

The meeting was sponsored by the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

The CONFIRM trial was funded by the maker of BG-12, Biogen Idec. Dr. Phillips reported financial relationships with Biogen, Avanir, Genzyme, Novartis, Teva, and Roche. Dr. Stone said she had no disclosures.

NEW ORLEANS—Exposure to disease-modifying multiple sclerosis (MS) drugs could adversely affect the fetus, according to a study that was presented at the 64th Annual Meeting of the American Academy of Neurology.

In addition, women with MS who took interferon beta before conception or during pregnancy had an increased risk of preterm birth (ie, at a gestational age of less than 37 weeks). Babies born to these women also had an increased risk of lower birth weight and shorter birth length. Both measures were still within the normal range for the general population, however.

In utero exposure to mitoxantrone, in particular, could harm offspring. Although no controlled human studies of mitoxantrone’s effects on unborn children have been performed to date, animal studies and human case reports suggest a risk of fetal harm after the mother or father is exposed to the drug, reported Ellen Lu, a PhD student at the University of British Columbia in Vancouver.

A Retrospective Evaluation of the Safety of MS Drugs for Fetuses
Ms. Lu and her colleagues reviewed the literature published before February 2012 to assess the effects of periconceptional or in utero exposure to interferon beta, glatiramer acetate, natalizumab, mitoxantrone, or fingolimod on perinatal and developmental outcomes in the children of patients with MS. The researchers evaluated the level and quality of evidence in the studies by examining their study designs and methods of data collection.

A total of 15 studies identified 761 pregnancies exposed to interferon beta, 97 exposed to glatiramer acetate, and 35 exposed to natalizumab. The quality of the studies ranged from poor to good. No study was considered excellent, and small sample sizes limited most of the studies. The researchers assigned each drug a Class of Recommendation regarding its use during pregnancy according to international guidelines.

Should MS Drugs Be Discontinued Before Conception?
The researchers concluded that mitoxantrone was harmful to the fetus during pregnancy, and that interferon beta may be harmful. Further studies of glatiramer acetate, natalizumab, and fingolimod are necessary because limited data were available for these drugs. In addition, no peer-reviewed studies on fingolimod have been published because the drug entered the market in 2011.

“Women with MS should be advised to discontinue disease-modifying drugs before conceiving,” said the researchers. Women also should consider discontinuing disease-modifying drugs if they are unintentionally exposed to them during pregnancy, they added.

Future research should explore birth outcomes following periconceptional exposure to disease-modifying drugs in fathers with MS and long-term development in offspring exposed to disease-modifying drugs, they concluded.   

NEW ORLEANS—Exposure to disease-modifying multiple sclerosis (MS) drugs could adversely affect the fetus, according to a study that was presented at the 64th Annual Meeting of the American Academy of Neurology.

In addition, women with MS who took interferon beta before conception or during pregnancy had an increased risk of preterm birth (ie, at a gestational age of less than 37 weeks). Babies born to these women also had an increased risk of lower birth weight and shorter birth length. Both measures were still within the normal range for the general population, however.

In utero exposure to mitoxantrone, in particular, could harm offspring. Although no controlled human studies of mitoxantrone’s effects on unborn children have been performed to date, animal studies and human case reports suggest a risk of fetal harm after the mother or father is exposed to the drug, reported Ellen Lu, a PhD student at the University of British Columbia in Vancouver.

A Retrospective Evaluation of the Safety of MS Drugs for Fetuses
Ms. Lu and her colleagues reviewed the literature published before February 2012 to assess the effects of periconceptional or in utero exposure to interferon beta, glatiramer acetate, natalizumab, mitoxantrone, or fingolimod on perinatal and developmental outcomes in the children of patients with MS. The researchers evaluated the level and quality of evidence in the studies by examining their study designs and methods of data collection.

A total of 15 studies identified 761 pregnancies exposed to interferon beta, 97 exposed to glatiramer acetate, and 35 exposed to natalizumab. The quality of the studies ranged from poor to good. No study was considered excellent, and small sample sizes limited most of the studies. The researchers assigned each drug a Class of Recommendation regarding its use during pregnancy according to international guidelines.

Should MS Drugs Be Discontinued Before Conception?
The researchers concluded that mitoxantrone was harmful to the fetus during pregnancy, and that interferon beta may be harmful. Further studies of glatiramer acetate, natalizumab, and fingolimod are necessary because limited data were available for these drugs. In addition, no peer-reviewed studies on fingolimod have been published because the drug entered the market in 2011.

“Women with MS should be advised to discontinue disease-modifying drugs before conceiving,” said the researchers. Women also should consider discontinuing disease-modifying drugs if they are unintentionally exposed to them during pregnancy, they added.

Future research should explore birth outcomes following periconceptional exposure to disease-modifying drugs in fathers with MS and long-term development in offspring exposed to disease-modifying drugs, they concluded.   

NEW ORLEANS—Exposure to disease-modifying multiple sclerosis (MS) drugs could adversely affect the fetus, according to a study that was presented at the 64th Annual Meeting of the American Academy of Neurology.

In addition, women with MS who took interferon beta before conception or during pregnancy had an increased risk of preterm birth (ie, at a gestational age of less than 37 weeks). Babies born to these women also had an increased risk of lower birth weight and shorter birth length. Both measures were still within the normal range for the general population, however.

In utero exposure to mitoxantrone, in particular, could harm offspring. Although no controlled human studies of mitoxantrone’s effects on unborn children have been performed to date, animal studies and human case reports suggest a risk of fetal harm after the mother or father is exposed to the drug, reported Ellen Lu, a PhD student at the University of British Columbia in Vancouver.

A Retrospective Evaluation of the Safety of MS Drugs for Fetuses
Ms. Lu and her colleagues reviewed the literature published before February 2012 to assess the effects of periconceptional or in utero exposure to interferon beta, glatiramer acetate, natalizumab, mitoxantrone, or fingolimod on perinatal and developmental outcomes in the children of patients with MS. The researchers evaluated the level and quality of evidence in the studies by examining their study designs and methods of data collection.

A total of 15 studies identified 761 pregnancies exposed to interferon beta, 97 exposed to glatiramer acetate, and 35 exposed to natalizumab. The quality of the studies ranged from poor to good. No study was considered excellent, and small sample sizes limited most of the studies. The researchers assigned each drug a Class of Recommendation regarding its use during pregnancy according to international guidelines.

Should MS Drugs Be Discontinued Before Conception?
The researchers concluded that mitoxantrone was harmful to the fetus during pregnancy, and that interferon beta may be harmful. Further studies of glatiramer acetate, natalizumab, and fingolimod are necessary because limited data were available for these drugs. In addition, no peer-reviewed studies on fingolimod have been published because the drug entered the market in 2011.

“Women with MS should be advised to discontinue disease-modifying drugs before conceiving,” said the researchers. Women also should consider discontinuing disease-modifying drugs if they are unintentionally exposed to them during pregnancy, they added.

Future research should explore birth outcomes following periconceptional exposure to disease-modifying drugs in fathers with MS and long-term development in offspring exposed to disease-modifying drugs, they concluded.   

Annualized relapse rate (ARR) in women with multiple sclerosis (MS) increased significantly in the period after in vitro fertilization (IVF), compared with the period immediately before fertilization and a control period, researchers reported in the June 11 online Journal of Neurology, Neurosurgery, and Psychiatry. The increase may be associated with treatment with gonadotrophin-releasing hormone agonists and failure of IVF.

Laure Michel, MD, a neurologist at the Centre Hospitalier Universitaire de Nantes in France, and colleagues analyzed data from 32 patients with MS who had undergone IVF. Patients’ mean age at MS onset was 26.3, and the mean disease duration at the first IVF was 6.6 years. Patients were followed up for a mean of 10.5 years. The investigators reviewed patient data to gather information about patients’ MS and about the treatments used for IVF. The association between IVF and MS relapse was analyzed using univariate and multivariate statistical tests.

Of the 32 patients, 19 had an MS relapse during the three months following IVF. In this period, mean ARR increased to 1.60 ± 2.40, compared with the three-month period before fertilization (mean ARR: 0.80 ± 1.61) and the control period one year earlier (mean ARR: 0.68 ± 1.51). When IVF failed, ARR increased to 1.96 ± 2, compared with 0.98 ± 1.74 before IVF.

“To our knowledge and to date, this is the largest cohort analysis of the short-term relationship between IVF and the risk of relapse in MS patients,” said Dr. Michel. “MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy.”

Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012 Jun 11; [Epub ahead of print].

Annualized relapse rate (ARR) in women with multiple sclerosis (MS) increased significantly in the period after in vitro fertilization (IVF), compared with the period immediately before fertilization and a control period, researchers reported in the June 11 online Journal of Neurology, Neurosurgery, and Psychiatry. The increase may be associated with treatment with gonadotrophin-releasing hormone agonists and failure of IVF.

Laure Michel, MD, a neurologist at the Centre Hospitalier Universitaire de Nantes in France, and colleagues analyzed data from 32 patients with MS who had undergone IVF. Patients’ mean age at MS onset was 26.3, and the mean disease duration at the first IVF was 6.6 years. Patients were followed up for a mean of 10.5 years. The investigators reviewed patient data to gather information about patients’ MS and about the treatments used for IVF. The association between IVF and MS relapse was analyzed using univariate and multivariate statistical tests.

Of the 32 patients, 19 had an MS relapse during the three months following IVF. In this period, mean ARR increased to 1.60 ± 2.40, compared with the three-month period before fertilization (mean ARR: 0.80 ± 1.61) and the control period one year earlier (mean ARR: 0.68 ± 1.51). When IVF failed, ARR increased to 1.96 ± 2, compared with 0.98 ± 1.74 before IVF.

“To our knowledge and to date, this is the largest cohort analysis of the short-term relationship between IVF and the risk of relapse in MS patients,” said Dr. Michel. “MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy.”

Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012 Jun 11; [Epub ahead of print].

Annualized relapse rate (ARR) in women with multiple sclerosis (MS) increased significantly in the period after in vitro fertilization (IVF), compared with the period immediately before fertilization and a control period, researchers reported in the June 11 online Journal of Neurology, Neurosurgery, and Psychiatry. The increase may be associated with treatment with gonadotrophin-releasing hormone agonists and failure of IVF.

Laure Michel, MD, a neurologist at the Centre Hospitalier Universitaire de Nantes in France, and colleagues analyzed data from 32 patients with MS who had undergone IVF. Patients’ mean age at MS onset was 26.3, and the mean disease duration at the first IVF was 6.6 years. Patients were followed up for a mean of 10.5 years. The investigators reviewed patient data to gather information about patients’ MS and about the treatments used for IVF. The association between IVF and MS relapse was analyzed using univariate and multivariate statistical tests.

Of the 32 patients, 19 had an MS relapse during the three months following IVF. In this period, mean ARR increased to 1.60 ± 2.40, compared with the three-month period before fertilization (mean ARR: 0.80 ± 1.61) and the control period one year earlier (mean ARR: 0.68 ± 1.51). When IVF failed, ARR increased to 1.96 ± 2, compared with 0.98 ± 1.74 before IVF.

“To our knowledge and to date, this is the largest cohort analysis of the short-term relationship between IVF and the risk of relapse in MS patients,” said Dr. Michel. “MS patients should be aware of a possible increased risk of MS relapse after IVF, particularly if the procedure does not result in a pregnancy.”

Michel L, Foucher Y, Vukusic S, et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012 Jun 11; [Epub ahead of print].

The goal of the CombiRx study was to determine whether glatiramer acetate combined with interferon beta-1a was better than either drug alone. The study used “double-dummy” injections to blind participants to the study arm. Consequently, each patient was required to take eight injections per week for a minimum of three years. Including this feature was difficult but important in minimizing bias. The investigators and participants should be congratulated for completing a challenging study in an exemplary fashion.

The combination resulted in less MRI lesion activity than either drug alone. Also, the protocol-defined annualized relapse rate (ARR) was lower in the glatiramer acetate arm than in the interferon beta-1a arm. However, other important outcomes showed no differences between arms, thus raising doubts about the importance of the observed differences. For example, there were no between-arm differences in Expanded Disability Status Scale or Multiple Sclerosis Functional Composite worsening or in normalized CSF volume, a measure of brain atrophy. The magnitude of ARR difference between glatiramer acetate (0.10) and interferon beta-1a (0.15) was small.

Generally, the benefits of the combination, compared with monotherapy, seem insufficient to warrant changing clinical practice. Despite that result, there is still much to be learned from the trial. CombiRx is one of the largest cohorts of early relapsing-remitting MS patients studied rigorously for so many years. Data collected during the trial offer an opportunity to correlate biologic and imaging changes with subsequent MS progression. Those studies could provide crucial insights into the MS disease process.

The goal of the CombiRx study was to determine whether glatiramer acetate combined with interferon beta-1a was better than either drug alone. The study used “double-dummy” injections to blind participants to the study arm. Consequently, each patient was required to take eight injections per week for a minimum of three years. Including this feature was difficult but important in minimizing bias. The investigators and participants should be congratulated for completing a challenging study in an exemplary fashion.

The combination resulted in less MRI lesion activity than either drug alone. Also, the protocol-defined annualized relapse rate (ARR) was lower in the glatiramer acetate arm than in the interferon beta-1a arm. However, other important outcomes showed no differences between arms, thus raising doubts about the importance of the observed differences. For example, there were no between-arm differences in Expanded Disability Status Scale or Multiple Sclerosis Functional Composite worsening or in normalized CSF volume, a measure of brain atrophy. The magnitude of ARR difference between glatiramer acetate (0.10) and interferon beta-1a (0.15) was small.

Generally, the benefits of the combination, compared with monotherapy, seem insufficient to warrant changing clinical practice. Despite that result, there is still much to be learned from the trial. CombiRx is one of the largest cohorts of early relapsing-remitting MS patients studied rigorously for so many years. Data collected during the trial offer an opportunity to correlate biologic and imaging changes with subsequent MS progression. Those studies could provide crucial insights into the MS disease process.

The goal of the CombiRx study was to determine whether glatiramer acetate combined with interferon beta-1a was better than either drug alone. The study used “double-dummy” injections to blind participants to the study arm. Consequently, each patient was required to take eight injections per week for a minimum of three years. Including this feature was difficult but important in minimizing bias. The investigators and participants should be congratulated for completing a challenging study in an exemplary fashion.

The combination resulted in less MRI lesion activity than either drug alone. Also, the protocol-defined annualized relapse rate (ARR) was lower in the glatiramer acetate arm than in the interferon beta-1a arm. However, other important outcomes showed no differences between arms, thus raising doubts about the importance of the observed differences. For example, there were no between-arm differences in Expanded Disability Status Scale or Multiple Sclerosis Functional Composite worsening or in normalized CSF volume, a measure of brain atrophy. The magnitude of ARR difference between glatiramer acetate (0.10) and interferon beta-1a (0.15) was small.

Generally, the benefits of the combination, compared with monotherapy, seem insufficient to warrant changing clinical practice. Despite that result, there is still much to be learned from the trial. CombiRx is one of the largest cohorts of early relapsing-remitting MS patients studied rigorously for so many years. Data collected during the trial offer an opportunity to correlate biologic and imaging changes with subsequent MS progression. Those studies could provide crucial insights into the MS disease process.

NEW ORLEANS—A combination of interferon beta-1a and glatiramer acetate was not significantly better than glatiramer acetate alone at reducing the annualized relapse rate over three years in patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 64th Annual Meeting of the American Academy of Neurology. Glatiramer acetate reduced the annual relapse rate significantly more than interferon beta-1a did.

The percentage of patients relapsing over 36 months did not differ significantly between patients receiving interferon beta-1a, patients receiving glatiramer acetate, and those receiving a combination of the two drugs, said Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. The time to first relapse did not differ between the three groups, and the percentage with six-month confirmed Expanded Disability Status Scale (EDSS) progression was also similar in all three groups.

The CombiRx Trial
These results were drawn from the CombiRx trial, a multicenter, double-blind, randomized study that Dr. Lublin and his colleagues conducted to determine whether interferon beta-1a and glatiramer acetate in combination were more effective than either drug alone in treating relapsing-remitting MS. The study’s primary end point was the annualized relapse rate over three years. The researchers enrolled 1,008 patients with relapsing-remitting MS at 68 clinical sites between January 2008 and April 2009.

Half the participants were randomized to receive interferon beta-1a and glatiramer acetate. One quarter of patients received interferon beta-1a and placebo, and 25% received glatiramer acetate and placebo. The study lasted for 36 months, and, during a blinded extension, participants stayed on their assigned treatment until the last patient had completed 36 months of therapy.

Eligible patients were ages 18 to 60, had not used either of the two drugs previously, and had an EDSS score of 5.5 or less. Approximately 81% of patients completed the 36-month trial. “This is a very good retention rate for an MS study,” said Dr. Lublin. “The usual MS phase 3 trial reports on 24-month information.”

Drug Combination Reduces T2 Lesions More Than Either Agent Alone
When the researchers examined the percentage of patients who had no relapse activity and no confirmed change in EDSS, they saw no difference between the three treatment groups. “However, when you go to a full definition of disease-activity–free status—meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions—the combination group is significantly better than either of the two treatment groups,” observed Dr. Lublin.

Patients who entered the study with an EDSS score of 0 had a ninefold greater risk of confirmed disease progression than patients with an EDSS score higher than 0. “We’ve not seen this sort of data before, and we’re studying it now to see what was driving those changes,” said Dr. Lublin. The researchers will analyze the longer-term extension phase of the CombiRx study to examine if the differences between patient groups observed by MRI will predict later clinical differences.   

NEW ORLEANS—A combination of interferon beta-1a and glatiramer acetate was not significantly better than glatiramer acetate alone at reducing the annualized relapse rate over three years in patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 64th Annual Meeting of the American Academy of Neurology. Glatiramer acetate reduced the annual relapse rate significantly more than interferon beta-1a did.

The percentage of patients relapsing over 36 months did not differ significantly between patients receiving interferon beta-1a, patients receiving glatiramer acetate, and those receiving a combination of the two drugs, said Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. The time to first relapse did not differ between the three groups, and the percentage with six-month confirmed Expanded Disability Status Scale (EDSS) progression was also similar in all three groups.

The CombiRx Trial
These results were drawn from the CombiRx trial, a multicenter, double-blind, randomized study that Dr. Lublin and his colleagues conducted to determine whether interferon beta-1a and glatiramer acetate in combination were more effective than either drug alone in treating relapsing-remitting MS. The study’s primary end point was the annualized relapse rate over three years. The researchers enrolled 1,008 patients with relapsing-remitting MS at 68 clinical sites between January 2008 and April 2009.

Half the participants were randomized to receive interferon beta-1a and glatiramer acetate. One quarter of patients received interferon beta-1a and placebo, and 25% received glatiramer acetate and placebo. The study lasted for 36 months, and, during a blinded extension, participants stayed on their assigned treatment until the last patient had completed 36 months of therapy.

Eligible patients were ages 18 to 60, had not used either of the two drugs previously, and had an EDSS score of 5.5 or less. Approximately 81% of patients completed the 36-month trial. “This is a very good retention rate for an MS study,” said Dr. Lublin. “The usual MS phase 3 trial reports on 24-month information.”

Drug Combination Reduces T2 Lesions More Than Either Agent Alone
When the researchers examined the percentage of patients who had no relapse activity and no confirmed change in EDSS, they saw no difference between the three treatment groups. “However, when you go to a full definition of disease-activity–free status—meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions—the combination group is significantly better than either of the two treatment groups,” observed Dr. Lublin.

Patients who entered the study with an EDSS score of 0 had a ninefold greater risk of confirmed disease progression than patients with an EDSS score higher than 0. “We’ve not seen this sort of data before, and we’re studying it now to see what was driving those changes,” said Dr. Lublin. The researchers will analyze the longer-term extension phase of the CombiRx study to examine if the differences between patient groups observed by MRI will predict later clinical differences.   

NEW ORLEANS—A combination of interferon beta-1a and glatiramer acetate was not significantly better than glatiramer acetate alone at reducing the annualized relapse rate over three years in patients with relapsing-remitting multiple sclerosis (MS), researchers reported at the 64th Annual Meeting of the American Academy of Neurology. Glatiramer acetate reduced the annual relapse rate significantly more than interferon beta-1a did.

The percentage of patients relapsing over 36 months did not differ significantly between patients receiving interferon beta-1a, patients receiving glatiramer acetate, and those receiving a combination of the two drugs, said Fred Lublin, MD, Saunders Family Professor of Neurology at Mount Sinai School of Medicine in New York City. The time to first relapse did not differ between the three groups, and the percentage with six-month confirmed Expanded Disability Status Scale (EDSS) progression was also similar in all three groups.

The CombiRx Trial
These results were drawn from the CombiRx trial, a multicenter, double-blind, randomized study that Dr. Lublin and his colleagues conducted to determine whether interferon beta-1a and glatiramer acetate in combination were more effective than either drug alone in treating relapsing-remitting MS. The study’s primary end point was the annualized relapse rate over three years. The researchers enrolled 1,008 patients with relapsing-remitting MS at 68 clinical sites between January 2008 and April 2009.

Half the participants were randomized to receive interferon beta-1a and glatiramer acetate. One quarter of patients received interferon beta-1a and placebo, and 25% received glatiramer acetate and placebo. The study lasted for 36 months, and, during a blinded extension, participants stayed on their assigned treatment until the last patient had completed 36 months of therapy.

Eligible patients were ages 18 to 60, had not used either of the two drugs previously, and had an EDSS score of 5.5 or less. Approximately 81% of patients completed the 36-month trial. “This is a very good retention rate for an MS study,” said Dr. Lublin. “The usual MS phase 3 trial reports on 24-month information.”

Drug Combination Reduces T2 Lesions More Than Either Agent Alone
When the researchers examined the percentage of patients who had no relapse activity and no confirmed change in EDSS, they saw no difference between the three treatment groups. “However, when you go to a full definition of disease-activity–free status—meaning no relapse activity, no progression on EDSS, no new T2 lesions, and no new gadolinium-enhancing lesions—the combination group is significantly better than either of the two treatment groups,” observed Dr. Lublin.

Patients who entered the study with an EDSS score of 0 had a ninefold greater risk of confirmed disease progression than patients with an EDSS score higher than 0. “We’ve not seen this sort of data before, and we’re studying it now to see what was driving those changes,” said Dr. Lublin. The researchers will analyze the longer-term extension phase of the CombiRx study to examine if the differences between patient groups observed by MRI will predict later clinical differences.   

NEW ORLEANS—Performance Scale Severity Score (PSSS) tables may allow patients and their physicians to easily compare  functional impairment of a patient with multiple sclerosis (MS) to that of other patients with similar MS duration, according to research presented at the 64th Annual Meeting of the American Academy of Neurology.   

“PSSS tables provide a snapshot of perceived disease impact on 11 neurologic domains across disease lifespan,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University (NYU) Langone Medical Center, New York City, and colleagues.

“[The tables] could assist clinicians and patients in choosing the disease-modifying therapy commensurate with relative disease severity,” he added.

Scoring Domain-Specific Impairment
The study’s reference population derives from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,  which collects self-reported data from 29,904 patients in 11 neurologic domains—cognition, depression, pain, fatigue, vision, hand function, mobility, spasticity, bowel/bladder, sensory, and tremor. A domain-specific, six- or seven-grade Performance Scale is used to score impairment in each of the domains.

For each of the 11 Performance Scales, Dr. Kister and his colleagues from the NYU School of Medicine and the University of Alabama at Birmingham School of Public Health calculated the percent of patients in each impairment grade for each of the first 30 years of disease.

Tracking Increasing Disease Severity
In the first 15 years following symptom onset, the percentage of patients in the more severe grades continued to increase across all 11 neurologic domains as disease duration increased.

The domains of cognition, depression, and pain had little change in severity during the last 15 years of observation, while the domains of mobility, spasticity, bowel/bladder, hand function, and fatigue showed a shift to the more severe grades throughout the observation period.

The researchers noted that the prevalence of severe impairment in patients with MS was probably underestimated, as patients with the most severe disease are less likely to self-register into the NARCOMS registry.

However, the NARCOMS cohort exhibits similar mobility impairment to that of most published cohorts (greater than 50% of patients needed to use a cane on a daily basis after approximately 15 years of disease).

Prevalence Tables May Enhance Understanding
Dr. Kister believes that the prevalence tables may be a useful tool for clinicians and patients. “Our data provide a ‘natural history’ of MS symptoms in a large database,” he told Neurology Reviews. “This information is not available elsewhere.

“[Our data] give patients and doctors a sense of how MS affects patients throughout the disease and allow a patient to see how well he or she is doing, relative to other patients who had disease for the same duration,” Dr. Kister concluded.   

NEW ORLEANS—Performance Scale Severity Score (PSSS) tables may allow patients and their physicians to easily compare  functional impairment of a patient with multiple sclerosis (MS) to that of other patients with similar MS duration, according to research presented at the 64th Annual Meeting of the American Academy of Neurology.   

“PSSS tables provide a snapshot of perceived disease impact on 11 neurologic domains across disease lifespan,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University (NYU) Langone Medical Center, New York City, and colleagues.

“[The tables] could assist clinicians and patients in choosing the disease-modifying therapy commensurate with relative disease severity,” he added.

Scoring Domain-Specific Impairment
The study’s reference population derives from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,  which collects self-reported data from 29,904 patients in 11 neurologic domains—cognition, depression, pain, fatigue, vision, hand function, mobility, spasticity, bowel/bladder, sensory, and tremor. A domain-specific, six- or seven-grade Performance Scale is used to score impairment in each of the domains.

For each of the 11 Performance Scales, Dr. Kister and his colleagues from the NYU School of Medicine and the University of Alabama at Birmingham School of Public Health calculated the percent of patients in each impairment grade for each of the first 30 years of disease.

Tracking Increasing Disease Severity
In the first 15 years following symptom onset, the percentage of patients in the more severe grades continued to increase across all 11 neurologic domains as disease duration increased.

The domains of cognition, depression, and pain had little change in severity during the last 15 years of observation, while the domains of mobility, spasticity, bowel/bladder, hand function, and fatigue showed a shift to the more severe grades throughout the observation period.

The researchers noted that the prevalence of severe impairment in patients with MS was probably underestimated, as patients with the most severe disease are less likely to self-register into the NARCOMS registry.

However, the NARCOMS cohort exhibits similar mobility impairment to that of most published cohorts (greater than 50% of patients needed to use a cane on a daily basis after approximately 15 years of disease).

Prevalence Tables May Enhance Understanding
Dr. Kister believes that the prevalence tables may be a useful tool for clinicians and patients. “Our data provide a ‘natural history’ of MS symptoms in a large database,” he told Neurology Reviews. “This information is not available elsewhere.

“[Our data] give patients and doctors a sense of how MS affects patients throughout the disease and allow a patient to see how well he or she is doing, relative to other patients who had disease for the same duration,” Dr. Kister concluded.   

NEW ORLEANS—Performance Scale Severity Score (PSSS) tables may allow patients and their physicians to easily compare  functional impairment of a patient with multiple sclerosis (MS) to that of other patients with similar MS duration, according to research presented at the 64th Annual Meeting of the American Academy of Neurology.   

“PSSS tables provide a snapshot of perceived disease impact on 11 neurologic domains across disease lifespan,” said Ilya Kister, MD, Assistant Professor of Neurology at New York University (NYU) Langone Medical Center, New York City, and colleagues.

“[The tables] could assist clinicians and patients in choosing the disease-modifying therapy commensurate with relative disease severity,” he added.

Scoring Domain-Specific Impairment
The study’s reference population derives from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry,  which collects self-reported data from 29,904 patients in 11 neurologic domains—cognition, depression, pain, fatigue, vision, hand function, mobility, spasticity, bowel/bladder, sensory, and tremor. A domain-specific, six- or seven-grade Performance Scale is used to score impairment in each of the domains.

For each of the 11 Performance Scales, Dr. Kister and his colleagues from the NYU School of Medicine and the University of Alabama at Birmingham School of Public Health calculated the percent of patients in each impairment grade for each of the first 30 years of disease.

Tracking Increasing Disease Severity
In the first 15 years following symptom onset, the percentage of patients in the more severe grades continued to increase across all 11 neurologic domains as disease duration increased.

The domains of cognition, depression, and pain had little change in severity during the last 15 years of observation, while the domains of mobility, spasticity, bowel/bladder, hand function, and fatigue showed a shift to the more severe grades throughout the observation period.

The researchers noted that the prevalence of severe impairment in patients with MS was probably underestimated, as patients with the most severe disease are less likely to self-register into the NARCOMS registry.

However, the NARCOMS cohort exhibits similar mobility impairment to that of most published cohorts (greater than 50% of patients needed to use a cane on a daily basis after approximately 15 years of disease).

Prevalence Tables May Enhance Understanding
Dr. Kister believes that the prevalence tables may be a useful tool for clinicians and patients. “Our data provide a ‘natural history’ of MS symptoms in a large database,” he told Neurology Reviews. “This information is not available elsewhere.

“[Our data] give patients and doctors a sense of how MS affects patients throughout the disease and allow a patient to see how well he or she is doing, relative to other patients who had disease for the same duration,” Dr. Kister concluded.   

Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.

Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.

A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.

In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.

It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).

Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.

Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.

A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.

In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.

It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).

Two randomized, double-blind clinical trials of oral laquinimod in relapsing–remitting multiple sclerosis (MS) have been completed. The BRAVO study failed to meet its primary end point, a significant decrease in annualized relapse rate (ARR), until a prespecified readjustment was carried out because of an imbalance in baseline characteristics. The ALLEGRO study, however, satisfied this end point.

Despite the adjustments, the effect of laquinimod on a reduction in ARR was only 21.3%, its effect on decrease in Expanded Disability Status Scale (EDSS) was 33.5%, and its effect on decrease in brain volume loss was 27.5%. No significant decrease in ARR or disability progression was found comparing placebo to interferon b-1a. Comparisons between interferon and laquinimod have not yet been published.

A post hoc analysis of the combined studies yielded results similar to those of the individual studies. Although it is dangerous to do a cross-study comparison, the laquinimod results compared unfavorably to those of other phase 3 trials in effect on ARR reduction, or decrease in Gad+ or new T2 lesions. The major positive findings were the effects of laquinimod in reducing sustained EDSS progression and loss of brain volume. This result raises the possibility that laquinimod may have a mechanism of action other than as an anti-inflammatory agent.

In considering any drug in MS, assessment of progression can be difficult. Progression may occur slowly and may be secondary to clinical or MRI relapses. Even sustained progression is difficult to assess and may reverse itself after study completion.

It is of interest that comparing decrease in three-month EDSS progression in all completed phase III oral trials (ie, of five drugs), a mean clustering of decrease in sustained three-month disease progression was found in a fairly narrow range between 30% and 34%. Measurements of brain-volume loss can also be confounded by the degree and timing of inflammation. If inflammation occurs later in a study, there can be an impression that brain-volume loss is lessened due to an increase in brain volume seen with inflammation (ie, pseudohypertrophy).