Relapsing Multiple Sclerosis
Conditions
Keywords
interferon, injectable, MS, SC, PEGylated, Interferon beta-1a, relapsing, PEG, multiple sclerosis, subcutaneous
Brief summary
The primary objective of this study is to determine the efficacy of peginterferon beta-1a in reducing the annualized relapse rate (ARR) in participants with relapsing multiple sclerosis (RMS) at 1 year. The secondary objectives of this study are to determine whether peginterferon beta-1a, at 1 year when compared with placebo, is effective in reducing the total number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans, reducing the proportion of participants who relapse, and slowing the progression of disability.
Detailed description
This is a global multicenter, randomized, double-blind, parallel-group, placebo-controlled study. The treatment period is 96 weeks (2 years) in duration. Treatment Year 1 (Week 0 to Week 48) is referred to as the placebo-controlled treatment period of the study. At the beginning of Treatment Year 1, participants were randomized to receive placebo, peginterferon beta-1a 125 μg every 2 weeks, or peginterferon beta-1a 125 μg every 4 weeks. At the end of Treatment Year 1, participants in the placebo group were re-randomized to receive peginterferon beta-1a treatment so that during treatment Year 2 (Weeks 48 to Week 96) all participants received peginterferon beta-1a 125 μg every 2 or every 4 weeks. Per protocol, all primary and secondary endpoints pertain to Year 1 data.
Interventions
Supplied as a liquid in pre-filled syringes to deliver 0.5 mL of 0.25 mg/mL (125 µg dose), self-administered by subcutaneous injection.
DRUGPlacebo
Matched placebo provided in pre-filled syringes, to deliver 0.5 mL self-administered by subcutaneous injection.
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have a confirmed diagnosis of relapsing multiple sclerosis (RMS), as defined by McDonald criteria 1 through 4 (Polman, 2005) * Must have an EDSS score between 0.0 and 5.0. * Must have experienced at least 2 relapses that have been medically documented within the last 3 years with at least one occurring in the last 12 months Key
Exclusion criteria
* Other chronic disease of immune system, malignancies, urologic, pulmonary, gastrointestinal disease * Pregnant or nursing women * Prior treatment with interferon could not exceed 4 weeks and subjects must have discontinued interferon treatment 6 months prior to Baseline NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate (ARR) at 1 Year | 1 Year | A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by an independent neurology evaluation committee (INEC) are included in the analysis. Data after participants switched to alternative multiple sclerosis (MS) medications are excluded. Data were analyzed using negative binomial regression, adjusted for baseline Expanded Disability Status Scale (EDSS) score (\< 4 versus ≥ 4), baseline age (\< 40 versus ≥ 40 years), and baseline relapse rate (number of relapses in 3 years prior to study entry divided by 3). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year | 1 Year | Number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans. Data observed after participants switched to alternative MS medications are excluded. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions. |
| Proportion of Participants Relapsed at 1 Year | Year 1 | A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by INEC were included in the analysis. Estimated proportion of participants relapsed is based on the Kaplan-Meier product limit method. |
| Estimated Proportion of Participants With Sustained Disability Progression at 1 Year | 1 Year | Sustained disability progression is defined as: at least a 1.0 point increase on the EDSS from baseline EDSS ≥ 1.0 that is sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks. The EDSS measures the disability status of people with MS on a scale that ranges from 0 to 10. The range of main categories include 0 (normal neurologic examination), to 5 (ambulatory without aid or rest for 200 meters/disability severe enough to impair full daily activities), to 10 (death due to MS). Estimated proportion of participants with progression based on the Kaplan-Meier product limit method. |
Countries
Belgium, Bulgaria, Canada, Chile, Colombia, Croatia, Czechia, Estonia, France, Georgia, Germany, Greece, India, Latvia, Mexico, Netherlands, New Zealand, Peru, Poland, Romania, Russia, Serbia, Spain, Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo every 2 weeks for 48 weeks | 500 |
| Peginterferon Beta-1a Q4W 125 µg peginterferon beta-1a subcutaneously every 4 weeks (Q4W) for 48 weeks. Participants received a placebo injection 2 weeks after each active injection (in order to maintain the blind with Q2W arm). | 500 |
| Peginterferon Beta-1a Q2W 125 µg peginterferon beta-1a subcutaneously every 2 weeks (Q2W) for 48 weeks | 512 |
| Total | 1,512 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Year 1 | Adverse Event | 4 | 22 | 24 | 0 | 0 | 0 | 0 |
| Year 1 | Death | 2 | 1 | 1 | 0 | 0 | 0 | 0 |
| Year 1 | Lost to Follow-up | 4 | 4 | 2 | 0 | 0 | 0 | 0 |
| Year 1 | Other | 4 | 2 | 7 | 0 | 0 | 0 | 0 |
| Year 1 | Physician Decision | 0 | 1 | 3 | 0 | 0 | 0 | 0 |
| Year 1 | Randomized But Not Treated | 0 | 1 | 3 | 0 | 0 | 0 | 0 |
| Year 1 | Withdrawal by Subject | 30 | 32 | 36 | 0 | 0 | 0 | 0 |
| Year 2 | Adverse Event | 0 | 0 | 0 | 9 | 8 | 11 | 6 |
| Year 2 | Death | 0 | 0 | 0 | 1 | 0 | 0 | 3 |
| Year 2 | Lost to Follow-up | 0 | 0 | 0 | 1 | 4 | 2 | 4 |
| Year 2 | Other | 0 | 0 | 0 | 2 | 3 | 1 | 0 |
| Year 2 | Physician Decision | 0 | 0 | 0 | 0 | 2 | 6 | 3 |
| Year 2 | Withdrawal by Subject | 0 | 0 | 0 | 17 | 18 | 27 | 13 |
Baseline characteristics
| Characteristic | Placebo | Peginterferon Beta-1a Q4W | Peginterferon Beta-1a Q2W | Total |
|---|---|---|---|---|
| Age, Continuous | 36.3 years STANDARD_DEVIATION 9.74 | 36.4 years STANDARD_DEVIATION 9.87 | 36.9 years STANDARD_DEVIATION 9.79 | 36.5 years STANDARD_DEVIATION 9.8 |
| Expanded Disability Status Scale (EDSS) | 2.44 units on a scale STANDARD_DEVIATION 1.18 | 2.48 units on a scale STANDARD_DEVIATION 1.244 | 2.47 units on a scale STANDARD_DEVIATION 1.255 | 2.46 units on a scale STANDARD_DEVIATION 1.226 |
| Sex: Female, Male Female | 358 Participants | 352 Participants | 361 Participants | 1071 Participants |
| Sex: Female, Male Male | 142 Participants | 148 Participants | 151 Participants | 441 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 378 / 499 | 466 / 500 | 472 / 513 | 190 / 227 | 206 / 228 | 373 / 439 | 367 / 438 |
| serious Total, serious adverse events | 76 / 499 | 70 / 500 | 55 / 513 | 42 / 227 | 36 / 228 | 67 / 439 | 39 / 438 |
Outcome results
Primary
Annualized Relapse Rate (ARR) at 1 Year
A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by an independent neurology evaluation committee (INEC) are included in the analysis. Data after participants switched to alternative multiple sclerosis (MS) medications are excluded. Data were analyzed using negative binomial regression, adjusted for baseline Expanded Disability Status Scale (EDSS) score (\< 4 versus ≥ 4), baseline age (\< 40 versus ≥ 40 years), and baseline relapse rate (number of relapses in 3 years prior to study entry divided by 3).
Time frame: 1 Year
Population: Intent-to-treat (ITT) population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Year 1: Placebo | Annualized Relapse Rate (ARR) at 1 Year | 0.397 relapses per person-years |
| Year 1: Peginterferon Beta-1a Q4W | Annualized Relapse Rate (ARR) at 1 Year | 0.288 relapses per person-years |
| Year 1: Peginterferon Beta-1a Q2W | Annualized Relapse Rate (ARR) at 1 Year | 0.256 relapses per person-years |
p-value: 0.011495% CI: [0.565, 0.93]Negative Binomial Regression
p-value: 0.000795% CI: [0.5, 0.831]Negative Binomial Regression
Secondary
Estimated Proportion of Participants With Sustained Disability Progression at 1 Year
Sustained disability progression is defined as: at least a 1.0 point increase on the EDSS from baseline EDSS ≥ 1.0 that is sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS = 0 that is sustained for 12 weeks. The EDSS measures the disability status of people with MS on a scale that ranges from 0 to 10. The range of main categories include 0 (normal neurologic examination), to 5 (ambulatory without aid or rest for 200 meters/disability severe enough to impair full daily activities), to 10 (death due to MS). Estimated proportion of participants with progression based on the Kaplan-Meier product limit method.
Time frame: 1 Year
Population: ITT population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo). Participants were censored at the time of withdrawal/switch if they withdrew from study or switched to alternative MS medication without a progression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Year 1: Placebo | Estimated Proportion of Participants With Sustained Disability Progression at 1 Year | 0.105 proportion of participants |
| Year 1: Peginterferon Beta-1a Q4W | Estimated Proportion of Participants With Sustained Disability Progression at 1 Year | 0.068 proportion of participants |
| Year 1: Peginterferon Beta-1a Q2W | Estimated Proportion of Participants With Sustained Disability Progression at 1 Year | 0.068 proportion of participants |
p-value: 0.03895% CI: [0.4, 0.97]Cox Proportion Hazards model
p-value: 0.038395% CI: [0.4, 0.97]Cox Proportion Hazards model
Secondary
Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year
Number of new or newly enlarging T2 hyperintense lesions on brain magnetic resonance imaging (MRI) scans. Data observed after participants switched to alternative MS medications are excluded. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions.
Time frame: 1 Year
Population: ITT population, with at least 1 post-baseline assessment. Missing data prior to alternative MS medications and visits after participants switched to alternative MS medications imputed based on previous visit data assuming the constant rate of lesion development or group mean at same visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Year 1: Placebo | Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year | 10.9 lesions | 95% Confidence Interval 19.51 |
| Year 1: Peginterferon Beta-1a Q4W | Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year | 7.9 lesions | 95% Confidence Interval 15.84 |
| Year 1: Peginterferon Beta-1a Q2W | Number of New Or Newly Enlarging T2 Hyperintense Lesions at 1 Year | 3.6 lesions | 95% Confidence Interval 8.55 |
p-value: 0.000895% CI: [0.6, 0.87]Negative Binomial Regression
p-value: <0.000195% CI: [0.27, 0.4]Negative Binomial Regression
Secondary
Proportion of Participants Relapsed at 1 Year
A relapse is defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting for at least 24 hours, and accompanied by new objective neurologic findings. Only relapses confirmed by INEC were included in the analysis. Estimated proportion of participants relapsed is based on the Kaplan-Meier product limit method.
Time frame: Year 1
Population: ITT population: participants who were randomized and received at least 1 dose of study treatment (peginterferon beta-1a or placebo). Participants who did not experience a relapse prior to switching to alternative MS medications or withdrew from study were censored at the time of switch/withdrawal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Year 1: Placebo | Proportion of Participants Relapsed at 1 Year | 0.291 proportion of participants |
| Year 1: Peginterferon Beta-1a Q4W | Proportion of Participants Relapsed at 1 Year | 0.222 proportion of participants |
| Year 1: Peginterferon Beta-1a Q2W | Proportion of Participants Relapsed at 1 Year | 0.187 proportion of participants |
p-value: 0.0295% CI: [0.57, 0.95]Cox Proportion Hazards model
p-value: 0.000395% CI: [0.47, 0.8]Cox Proportion Hazards model