Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
Multiple Sclerosis
Brief summary
The purpose of this study was to establish the efficacy and safety of alemtuzumab (Lemtrada™) as a treatment for relapsing-remitting multiple sclerosis (MS), in comparison with subcutaneous (SC) interferon beta-1a (Rebif®). The study had enrolled participants who had not previously received MS disease-modifying therapies. Participants had monthly laboratory tests and comprehensive testing every 3 months.
Detailed description
Every participant had received active treatment; there was no placebo. Participants who qualified were randomly assigned to treatment with either alemtuzumab or SC interferon beta-1a at a 2:1 ratio (that is, 2 given alemtuzumab for every 1 given interferon beta-1a). Alemtuzumab was administered in two annual courses, once at the beginning of the study and again 1 year later. Interferon beta-1a was self-injected 3 times per week for 2 years. All participants were required to return to their study site every 3 months for neurologic assessment. In addition, safety-related laboratory tests were performed at least monthly. Participation in this study ended 2 years after the start of treatment for each participant. Additionally, participants who received alemtuzumab might be followed in CAMMS03409 (NCT00930553) an extension study for safety and efficacy assessments. Participants who received interferon beta-1a and completed 2 years on study might be eligible to receive alemtuzumab on the extension study.
Interventions
BIOLOGICALAlemtuzumab
Alemtuzumab 12 milligram (mg) per day intravenous (IV) infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12.
BIOLOGICALInterferon beta-1a
Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion.
Sponsors
Bayer
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Given written/signed informed consent * Age 18 to 50 years old (inclusive) as of the date the informed consent form (ICF) was signed * Diagnosis of MS per updated McDonald criteria, and cranial magnetic resonance imaging (MRI) scan demonstrating white matter lesions attributable to MS within 5 years of screening * Onset of MS symptoms (as determined by a neurologist, either at screening or retrospectively) within 5 years of the date the ICF was signed * Expanded Disability Status Scale (EDSS) score 0.0 to 3.0 (inclusive) at screening * Greater than or equal to (\>=) 2 MS attacks (first episode or relapse) occurring in the 24 months prior to the date the ICF was signed, with \>=1 attack in the 12 months prior to the date the ICF was signed, with objective neurological signs confirmed by a physician, nurse practitioner, or other Genzyme-approved health-care provider and the objective signs could be identified retrospectively
Exclusion criteria
* Received prior therapy for MS other than corticosteroids, for example, alemtuzumab, interferons, intravenous immunoglobulin, glatiramer acetate, natalizumab, and mitoxantrone * Exposure to azathioprine, cladribine, cyclophosphamide, cyclosporine A, methotrexate, or any other immunosuppressive agent other than systemic corticosteroid treatment * Any progressive form of MS * History of malignancy (except basal skin cell carcinoma) * CD4 + , CD8 + count, B cell, or absolute neutrophil count less than (\<) lower limit of normal (LLN) at screening * Known bleeding disorder (for example, dysfibrinogenemia, factor IX deficiency, hemophilia, Von Willebrand's disease, disseminated intravascular coagulation, fibrinogen deficiency, or clotting factor deficiency) * Significant autoimmune disease including but not limited to immune cytopenias, rheumatoid arthritis, systemic lupus erythematosus, other connective tissue disorders, vasculitis, inflammatory bowel disease, severe psoriasis * Presence of anti-thyroid stimulating hormone (TSH) receptor (TSHR) antibodies (that is, above the LLN) * Active infection or at high risk for infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Accumulation of Disability (SAD) | Up to 2 years | EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score: 0 (normal neurological examination) to 10 (death due to MS). As measured by EDSS score, SAD was defined as increase of at least 1.5 points for participants with Baseline score of 0 and increase of at least 1.0 point for participants with a Baseline score of 1.0 or more; and the increase persisted for at least next 2 scheduled assessments, that is, 6 consecutive months. Onset date of SAD was date of first EDSS assessment that began 6 month consecutive period of SAD. Participants who did not reach SAD endpoint were censored at their last visit. Percentage of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported. |
| Annualized Relapse Rate | Up to 2 years | Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to multiple sclerosis that lasted for at least 48 hours, that were present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Annualized relapse rate was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region using observed number of relapses as dependent variable, the log total amount of follow-up from date of first study treatment for each participant as an offset variable, and treatment group and geographic region as model covariates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Were Relapse Free at Year 2 | Year 2 | Participants were considered relapse free at Year 2 if they did not experience a relapse from the date of first study treatment to study completion at 24 months. Percentage of participants who were relapse free at Year 2, estimated using the KM method, was reported. |
| Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2 | Baseline, Year 2 | EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Change was calculated by subtracting Baseline value from value at Year 2. |
| Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2 | Baseline, Year 2 | MSFC is a multidimensional measure consisting of quantitative tests of ambulation (Timed 25-Foot Walk), manual dexterity (9-Hole Peg Test; 9HPT), and cognitive function (Paced Auditory Serial Addition Test; PASAT). The MSFC score was calculated as the mean of the Z-scores of the 3 components. A Z-score was calculated by subtracting the mean of the reference population from the test result, then dividing by the standard deviation of the reference population. Higher Z-scores reflected better neurological function and a positive change from Baseline indicates improvement. An increase in score indicated an improvement (Z-score range: -3 to +3). Acquisition of disability was measured by change from Baseline in MSFC score at Year 2. |
| Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2 | Baseline, Year 2 | Percent change in MS lesion volume as measured by MRI-T2 scan was calculated from MRI-T2-weighted scans as the following: (lesion volume at 2 years - lesion volume at Baseline)\*100/ (lesion volume at Baseline). |
Countries
Argentina, Australia, Brazil, Canada, Croatia, Czechia, France, Germany, Mexico, Poland, Russia, Serbia, Sweden, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants were screened at 101 investigational sites in Argentina, Australia, Brazil, Canada, Croatia, the Czech Republic, France, Germany, Mexico, Poland, Russia, Serbia, Sweden, Ukraine, the United Kingdom (UK), and the United States (US) between August 28, 2007 and April 27, 2011.
Participants by arm
| Arm | Count |
|---|---|
| Interferon Beta-1a Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 24 months. Dose adjustment was done as per Investigator's discretion. | 187 |
| Alemtuzumab Alemtuzumab 12 mg per day IV infusion on 5 consecutive days at Month 0, followed by alemtuzumab 12 mg per day IV infusion on 3 consecutive days at Month 12. | 376 |
| Total | 563 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Noncompliance with inclusion criterion 3 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Randomised in error | 1 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 12 |
Baseline characteristics
| Characteristic | Interferon Beta-1a | Alemtuzumab | Total |
|---|---|---|---|
| Age, Continuous | 33.2 years STANDARD_DEVIATION 8.48 | 33.0 years STANDARD_DEVIATION 8.03 | 33.1 years STANDARD_DEVIATION 8.18 |
| Expanded Disability Status Scale (EDSS) Score | 2.0 units on a scale STANDARD_DEVIATION 0.79 | 2.0 units on a scale STANDARD_DEVIATION 0.81 | 2.0 units on a scale STANDARD_DEVIATION 0.81 |
| Number of Relapse Episodes in the Preceding 2 Years 1 Relapse | 3 participants | 12 participants | 15 participants |
| Number of Relapse Episodes in the Preceding 2 Years 2 Relapses | 118 participants | 215 participants | 333 participants |
| Number of Relapse Episodes in the Preceding 2 Years Greater than or equal to 3 Relapses | 66 participants | 149 participants | 215 participants |
| Sex: Female, Male Female | 122 Participants | 243 Participants | 365 Participants |
| Sex: Female, Male Male | 65 Participants | 133 Participants | 198 Participants |
| Time Since First Relapse | 2.0 years STANDARD_DEVIATION 1.32 | 2.1 years STANDARD_DEVIATION 1.36 | 2.1 years STANDARD_DEVIATION 1.35 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 168 / 187 | 360 / 376 |
| serious Total, serious adverse events | 27 / 187 | 69 / 376 |
Outcome results
Primary
Annualized Relapse Rate
Relapse was defined as new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination, attributable to multiple sclerosis that lasted for at least 48 hours, that were present at normal body temperature, and that were preceded by at least 30 days of clinical stability. Annualized relapse rate was estimated through negative binomial regression with robust variance estimation and covariate adjustment for geographic region using observed number of relapses as dependent variable, the log total amount of follow-up from date of first study treatment for each participant as an offset variable, and treatment group and geographic region as model covariates.
Time frame: Up to 2 years
Population: FAS population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a | Annualized Relapse Rate | 0.39 relapses per participant per year |
| Alemtuzumab | Annualized Relapse Rate | 0.18 relapses per participant per year |
Comparison: Proportional means regression model with robust variance estimation and covariate adjustment for geographic region was used.p-value: <0.000195% CI: [0.32, 0.63]Proportional means regression
Primary
Percentage of Participants With Sustained Accumulation of Disability (SAD)
EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score: 0 (normal neurological examination) to 10 (death due to MS). As measured by EDSS score, SAD was defined as increase of at least 1.5 points for participants with Baseline score of 0 and increase of at least 1.0 point for participants with a Baseline score of 1.0 or more; and the increase persisted for at least next 2 scheduled assessments, that is, 6 consecutive months. Onset date of SAD was date of first EDSS assessment that began 6 month consecutive period of SAD. Participants who did not reach SAD endpoint were censored at their last visit. Percentage of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.
Time frame: Up to 2 years
Population: FAS population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a | Percentage of Participants With Sustained Accumulation of Disability (SAD) | 11.12 percentage of participants with SAD |
| Alemtuzumab | Percentage of Participants With Sustained Accumulation of Disability (SAD) | 8.00 percentage of participants with SAD |
Comparison: Cox proportional hazards (PH) regression model with robust variance estimation using treatment group and geographic region as covariates was used.p-value: 0.217395% CI: [0.4, 1.23]Cox Proportional Hazards Regression
Secondary
Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2
EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Change was calculated by subtracting Baseline value from value at Year 2.
Time frame: Baseline, Year 2
Population: FAS population included all randomized participants who received at least 1 dose of study drug. Here, number of participants analyzed was subset of FAS who had EDSS assessment at both Baseline and end-of-study (Year 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Beta-1a | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2 | -0.2 units on a scale | Standard Deviation 1.05 |
| Alemtuzumab | Change From Baseline in Expanded Disability Status Scale (EDSS) Score at Year 2 | -0.2 units on a scale | Standard Deviation 0.87 |
Comparison: The analysis was performed using Wei-Lachin method for non-parametric analysis of repeated measures. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by multiple sclerosis functional composite. Each endpoint could only be formally tested if prior endpoint was significant.p-value: 0.4188Wei-Lachin
Secondary
Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2
MSFC is a multidimensional measure consisting of quantitative tests of ambulation (Timed 25-Foot Walk), manual dexterity (9-Hole Peg Test; 9HPT), and cognitive function (Paced Auditory Serial Addition Test; PASAT). The MSFC score was calculated as the mean of the Z-scores of the 3 components. A Z-score was calculated by subtracting the mean of the reference population from the test result, then dividing by the standard deviation of the reference population. Higher Z-scores reflected better neurological function and a positive change from Baseline indicates improvement. An increase in score indicated an improvement (Z-score range: -3 to +3). Acquisition of disability was measured by change from Baseline in MSFC score at Year 2.
Time frame: Baseline, Year 2
Population: FAS population included all randomized participants who received at least 1 dose of study drug. Here, number of participants analyzed signifies subset of FAS who had MSFC score assessment at Baseline; 'n' signifies participants who had MSFC score assessment at Baseline (for Baseline) and at both Baseline and Year 2 (for change at Year 2).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Interferon Beta-1a | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2 | Baseline (n=186, 375) | 0.05 Z-score | Standard Deviation 0.629 |
| Interferon Beta-1a | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2 | Change at Year 2 (n=172, 362) | 0.07 Z-score | Standard Deviation 0.45 |
| Alemtuzumab | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2 | Baseline (n=186, 375) | -0.02 Z-score | Standard Deviation 0.695 |
| Alemtuzumab | Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Score at Year 2 | Change at Year 2 (n=172, 362) | 0.15 Z-score | Standard Deviation 0.516 |
Comparison: Change at Year 2: analysis was performed using Wei-Lachin method for non-parametric analysis of repeated measures. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by MSFC. Each endpoint could only be formally tested if prior endpoint was significant.p-value: 0.0115Wei-Lachin
Secondary
Percentage of Participants Who Were Relapse Free at Year 2
Participants were considered relapse free at Year 2 if they did not experience a relapse from the date of first study treatment to study completion at 24 months. Percentage of participants who were relapse free at Year 2, estimated using the KM method, was reported.
Time frame: Year 2
Population: FAS population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a | Percentage of Participants Who Were Relapse Free at Year 2 | 58.69 percentage of participants |
| Alemtuzumab | Percentage of Participants Who Were Relapse Free at Year 2 | 77.59 percentage of participants |
Comparison: Cox PH regression model with robust variance estimation, covariate adjustment for geographic region, was used. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by multiple sclerosis functional composite. Each endpoint could only be formally tested if prior endpoint was significant.p-value: <0.000195% CI: [0.33, 0.61]Cox Proportional Hazards Regression
Secondary
Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2
Percent change in MS lesion volume as measured by MRI-T2 scan was calculated from MRI-T2-weighted scans as the following: (lesion volume at 2 years - lesion volume at Baseline)\*100/ (lesion volume at Baseline).
Time frame: Baseline, Year 2
Population: FAS population included all randomized participants who received at least 1 dose of study drug. Here, number of participants analyzed was subset of FAS who had assessment for T2 volume at both Baseline and end-of-study (Year 2).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Beta-1a | Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2 | -6.68 percent change | Standard Deviation 32.44 |
| Alemtuzumab | Percent Change From Baseline in Magnetic Resonance Imaging Time Constant 2 (MRI-T2) Hyperintense Lesion Volume at Year 2 | -10.28 percent change | Standard Deviation 22.58 |
Comparison: Ranked ANCOVA models with covariate adjustment for geographic region and baseline T2 lesion volume was used. Secondary endpoints were analyzed sequentially as: Proportion of participants relapse free at Year 2, Change from baseline in EDSS, Percent change from Baseline in magnetic resonance imaging-T2 hyperintense lesion volume at Year 2, Acquisition of disability measured by multiple sclerosis functional composite. Each endpoint could only be formally tested if prior endpoint was significant.p-value: 0.308Ranked ANCOVA