Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
Multiple Sclerosis, Active Relapsing-Remitting Multiple Sclerosis
Brief summary
This was a Phase II, randomized, open-label, rater-blinded, three-arm study comparing two different doses of alemtuzumab (Lemtrada™) and one dose of subcutaneous (SC) interferon beta-1a (Rebif®) in participants with early, active relapsing-remitting multiple sclerosis (MS) who had not been previously treated with MS therapies other than steroids. The study was conducted for an initial period of 3 years and a follow-up to 5 years or more.
Detailed description
The aims of MS therapy are to prevent the progression of disease and accumulation of long-term disability. The hypothesis underlying this study was that aggressive treatment of inflammation in the brain early in the course of MS would protect the participant from disease progression and accumulating disability. This protocol compared two different doses of alemtuzumab and high-dose, high frequency of SC interferon beta-1a to evaluate the safety profiles of the respective treatments and to evaluate efficacy in terms of: * Slowing the sustained accumulation of disability in participant with MS; * Reducing the frequency of relapses experienced by participant with MS; and * Reducing the harmful effects of MS on the brain, as assessed by magnetic resonance imaging (MRI) Participants who received alemtuzumab during the initial 36-month treatment period may have been eligible for re-treatment with alemtuzumab in the extension study CAMMS03409 (NCT00930553) to evaluate: * How long the effects of prior alemtuzumab treatment lasted; * If additional treatments with alemtuzumab continued to reduce the effects of MS; and * What kind of side effects participants experienced upon retreatment with alemtuzumab
Interventions
BIOLOGICALInterferon beta-1a
Interferon beta-1a 44 microgram (mcg) subcutaneously 3-times weekly for 36 months.
BIOLOGICALAlemtuzumab 12 mg
Alemtuzumab 12 milligram per day (mg/day) was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the cluster of differentiation 4+ \[CD4+\] T-cell count was \>=100\*10\^6 cells per liter).
BIOLOGICALAlemtuzumab 24 mg
Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was \>=100\*10\^6 cells per liter).
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
* Signed informed consent form (ICF) * Male or non-pregnant, non-lactating female participants, 18 to 50 years of age (inclusive) as of signing the ICF * Diagnosis of MS per McDonald's update of the Poser criteria, including cranial MRI consistent with those criteria (McDonald, 2001, Ann Neurol) * Onset of first MS symptoms within 3 years prior to Screening as of signing the ICF * Expanded Disability Status Scale (EDSS) score 0.0 to 3.0 (inclusive) at the screening and Baseline visits * At least 2 completed clinical episodes of MS in the 2 years prior to study entry (that is, the initial event if within 2 years of study entry plus at least 1 relapse, or at least 2 relapses if the initial event was between 2 and 3 years prior to study entry) * In addition to the clinical criteria, at least 1 enhancing lesion on any 1 of up to 4 screening gadolinium-enhanced MRI brain scans during a maximum 3-month run-in period (inclusive of the Month 0 Baseline scan)
Exclusion criteria
* Previous immunotherapy for MS other than steroids, including treatment with interferons, intravenous immunoglobulin (IVIG), glatiramer acetate, and mitoxantrone * Personal history of thyroid autoimmune disease * Personal history of clinically significant autoimmune disease (for example, inflammatory bowel disease, diabetes, lupus, severe asthma) * History of thyroid carcinoma (previous thyroid adenoma was acceptable and was not considered an exclusion criterion) * History of malignancy (except for basal cell skin carcinoma if disease-free for at least 5 years) * Any disability acquired from trauma or another illness that, in the opinion of the Investigator, interfered with evaluation of disability due to MS * Previous treatment with alemtuzumab * History of anaphylaxis following exposure to humanized monoclonal antibodies * Inability to undergo MRI with gadolinium administration * Female participants of childbearing potential with a positive serum pregnancy test at screening or Baseline * Male and female participants who did not agree to use effective contraceptive method(s) during the study * Impaired renal function (that is, serum creatinine greater than or equal to 2 times the upper limit of normal \[ULN\]) * Untreated, major depressive disorder * Epileptic seizures that were not adequately controlled by treatment * Suicidal ideation * Major systemic disease or other illness that, in the opinion of the Investigator, have compromised participant safety or interfered with the interpretation of study results * Abnormal CD4 count or significantly abnormal thyroid function; presence of anti-thyroid stimulating hormone (TSH) receptor antibodies; known seropositivity for human immunodeficiency (HIV) * Intolerance of pulsed corticosteroids, especially a history of steroid psychosis * Presence of a monoclonal paraprotein * Participants who had any form of MS other than relapsing-remitting * Participants currently participating in a clinical study of an experimental or unapproved/unlicensed therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Participants With Sustained Accumulation of Disability (SAD) | Up to 3 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 Baseline score of 1.0 or more; and the increase persisted for at least next the 2 scheduled assessments, that is, 6 consecutive months. The 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. Probability of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported. |
| Annualized Relapse Rate | Up to 3 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 using a Poisson regression model with observed number of relapses as a dependent variable, the log total amount of follow-up from date of randomization for each participant as an offset variable and treatment group indicator as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment | Year 3 | Participants were considered relapse free at Year 3 if they did not experience a relapse between randomization and study completion at 36 months. Participants who discontinued early were considered relapse free if they did not experience a relapse prior to discontinuation. Probability of participants who were relapse free at Year 3, estimated using the KM method, was reported. |
| Percent Change From Baseline in T1 Cerebral Volume at Year 3 | Baseline, Year 3 | Magnetic resonance imaging (MRI) T1 was used to determine rate of cerebral atrophy (decrease in cerebral/brain volume). Partial brain volumes were measured using the technique of Losseff et al. (1996). Percent change in cerebral volume at Year 3 was calculated from MRI-T1-weighted scans as: 100\*(\[brain volume at Year 3\] minus \[brain volume at Baseline\]) divided by \[brain volume at Baseline\]). |
| Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 | Baseline, Year 3 | Percent change in lesion volume at Year 3 was calculated from MRI-T2-weighted scans as: 100\*(\[lesion volume at Year 3\] minus \[lesion volume at Baseline\]) divided by \[lesion volume at Baseline\]). |
Countries
Croatia, Poland, Russia, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 49 investigational sites in the United States, United Kingdom, and Eastern Europe between December 04, 2002 and January 12, 2010.
Participants by arm
| Arm | Count |
|---|---|
| Interferon Beta-1a Interferon beta-1a 44 mcg subcutaneously 3-times weekly for 36 months. | 111 |
| Alemtuzumab 12 mg Alemtuzumab 12 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was \>=100\*10\^6 cells per liter). | 112 |
| Alemtuzumab 24 mg Alemtuzumab 24 mg/day was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24 (the latter at the treating physicians' discretion if the CD4+ T-cell count was \>=100\*10\^6 cells per liter). | 110 |
| Total | 333 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 3 | 2 |
| Overall Study | Death | 0 | 1 | 1 |
| Overall Study | Familial and personal reasons | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 16 | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 2 | 4 |
| Overall Study | Physician Decision | 3 | 0 | 2 |
| Overall Study | Protocol Violation | 2 | 0 | 1 |
| Overall Study | Randomized but not treated | 4 | 5 | 2 |
| Overall Study | Withdrawal by Subject | 6 | 8 | 4 |
Baseline characteristics
| Characteristic | Total | Alemtuzumab 12 mg | Alemtuzumab 24 mg | Interferon Beta-1a |
|---|---|---|---|---|
| Age, Continuous | 32.3 years STANDARD_DEVIATION 8.52 | 31.9 years STANDARD_DEVIATION 8.01 | 32.2 years STANDARD_DEVIATION 8.76 | 32.8 years STANDARD_DEVIATION 8.82 |
| Expanded Disability Status Scale (EDSS) Score | 1.9 units on a scale STANDARD_DEVIATION 0.76 | 2.0 units on a scale STANDARD_DEVIATION 0.73 | 2.0 units on a scale STANDARD_DEVIATION 0.73 | 1.9 units on a scale STANDARD_DEVIATION 0.81 |
| Number of Relapse Episodes in the Preceding 2 Years 0 Relapse | 3 participants | 2 participants | 1 participants | 0 participants |
| Number of Relapse Episodes in the Preceding 2 Years 1 Relapse | 26 participants | 5 participants | 13 participants | 8 participants |
| Number of Relapse Episodes in the Preceding 2 Years 2 Relapses | 187 participants | 58 participants | 56 participants | 73 participants |
| Number of Relapse Episodes in the Preceding 2 Years Greater than or equal to 3 Relapses | 117 participants | 47 participants | 40 participants | 30 participants |
| Sex: Female, Male Female | 214 Participants | 72 Participants | 71 Participants | 71 Participants |
| Sex: Female, Male Male | 119 Participants | 40 Participants | 39 Participants | 40 Participants |
| Time Constant 1 (T1) Cerebral Volume | 319.6 cubic centimeter STANDARD_DEVIATION 25.61 | 320.8 cubic centimeter STANDARD_DEVIATION 27.15 | 320.5 cubic centimeter STANDARD_DEVIATION 24.99 | 317.5 cubic centimeter STANDARD_DEVIATION 24.7 |
| Time Constant 2 (T2) Lesion Volume | 17.0 cubic centimeter STANDARD_DEVIATION 19.19 | 17.2 cubic centimeter STANDARD_DEVIATION 23.84 | 17.8 cubic centimeter STANDARD_DEVIATION 17.45 | 15.8 cubic centimeter STANDARD_DEVIATION 15.23 |
| Time Since First Relapse | 1.3 years | 1.3 years | 1.2 years | 1.4 years |
| Total Number of Relapses | 884 relapses | 301 relapses | 290 relapses | 293 relapses |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 106 / 107 | 108 / 108 | 108 / 108 | 216 / 216 |
| serious Total, serious adverse events | 29 / 107 | 30 / 108 | 33 / 108 | 63 / 216 |
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 using a Poisson regression model with observed number of relapses as a dependent variable, the log total amount of follow-up from date of randomization for each participant as an offset variable and treatment group indicator as a covariate.
Time frame: Up to 3 years
Population: FAS population included all randomized participants who had correct diagnosis of MS at entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a | Annualized Relapse Rate | 0.37 relapses per participant per year |
| Alemtuzumab 12 mg | Annualized Relapse Rate | 0.12 relapses per participant per year |
| Alemtuzumab 24 mg | Annualized Relapse Rate | 0.09 relapses per participant per year |
| Alemtuzumab (Pooled) | Annualized Relapse Rate | 0.11 relapses per participant per year |
Comparison: Treatment effects were estimated using an Anderson-Gill multiplicative intensity model with robust variance estimation. Covariates included treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country).p-value: <0.000195% CI: [0.126, 0.431]Andersen-Gill Model
Comparison: Treatment effects were estimated using an Anderson-Gill multiplicative intensity model with robust variance estimation. Covariates included treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country).p-value: <0.000195% CI: [0.176, 0.441]Andersen-Gill Model
Comparison: Treatment effects were estimated using an Anderson-Gill multiplicative intensity model with robust variance estimation. Covariates included treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country).p-value: <0.000195% CI: [0.196, 0.552]Andersen-Gill Model
Primary
Probability 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 Baseline score of 1.0 or more; and the increase persisted for at least next the 2 scheduled assessments, that is, 6 consecutive months. The 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. Probability of participants with SAD, estimated by Kaplan-Meier (KM) method, was reported.
Time frame: Up to 3 years
Population: Full Analysis Set (FAS) population included all randomized participants who had correct diagnosis of MS at entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a | Probability of Participants With Sustained Accumulation of Disability (SAD) | 0.27 probability of participants with SAD |
| Alemtuzumab 12 mg | Probability of Participants With Sustained Accumulation of Disability (SAD) | 0.08 probability of participants with SAD |
| Alemtuzumab 24 mg | Probability of Participants With Sustained Accumulation of Disability (SAD) | 0.09 probability of participants with SAD |
| Alemtuzumab (Pooled) | Probability of Participants With Sustained Accumulation of Disability (SAD) | 0.09 probability of participants with SAD |
Comparison: Cox proportional hazards (PH) regression model using treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country) as covariates was used.p-value: 0.000695% CI: [0.11, 0.545]Cox Proportional Hazards Regression
Comparison: Cox PH regression model using treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country) as covariates was used.p-value: 0.002195% CI: [0.151, 0.658]Cox Proportional Hazards Regression
Comparison: Cox PH regression model using treatment group, Baseline EDSS group (grouped by less than or equal to 1.5 and greater than 1.5), and country (investigative center grouped by country) as covariates was used.p-value: <0.000195% CI: [0.152, 0.515]Cox Proportional Hazards Regression
Secondary
Percent Change From Baseline in MRI T2 Lesion Volume at Year 3
Percent change in lesion volume at Year 3 was calculated from MRI-T2-weighted scans as: 100\*(\[lesion volume at Year 3\] minus \[lesion volume at Baseline\]) divided by \[lesion volume at Baseline\]).
Time frame: Baseline, Year 3
Population: Analysis population included participants in the FAS population (randomized with a correct diagnosis of MS) who had an evaluable scan for MRI-T2 lesion volume at Baseline and Year 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Beta-1a | Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 | 23.4 percent change | Standard Deviation 134.3 |
| Alemtuzumab 12 mg | Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 | -11.4 percent change | Standard Deviation 38.8 |
| Alemtuzumab 24 mg | Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 | -8.9 percent change | Standard Deviation 41.1 |
| Alemtuzumab (Pooled) | Percent Change From Baseline in MRI T2 Lesion Volume at Year 3 | -10.1 percent change | Standard Deviation 39.9 |
Comparison: Ranked ANCOVA model using Baseline MRI-T2 lesion volume, EDSS group, country, and treatment as covariates was used.p-value: 0.3077ANCOVA
Comparison: Ranked ANCOVA model using Baseline MRI-T2 lesion volume, EDSS group, country, and treatment as covariates was used.p-value: 0.3632ANCOVA
Comparison: Ranked ANCOVA model using Baseline MRI-T2 lesion volume, EDSS group, country, and treatment as covariates was used.p-value: 0.2758ANCOVA
Secondary
Percent Change From Baseline in T1 Cerebral Volume at Year 3
Magnetic resonance imaging (MRI) T1 was used to determine rate of cerebral atrophy (decrease in cerebral/brain volume). Partial brain volumes were measured using the technique of Losseff et al. (1996). Percent change in cerebral volume at Year 3 was calculated from MRI-T1-weighted scans as: 100\*(\[brain volume at Year 3\] minus \[brain volume at Baseline\]) divided by \[brain volume at Baseline\]).
Time frame: Baseline, Year 3
Population: Analysis population included participants in the FAS population (randomized with a correct diagnosis of MS) who had an evaluable scan for MRI-T1 brain volume at Baseline and Year 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Interferon Beta-1a | Percent Change From Baseline in T1 Cerebral Volume at Year 3 | -1.9 percent change | Standard Deviation 4.48 |
| Alemtuzumab 12 mg | Percent Change From Baseline in T1 Cerebral Volume at Year 3 | -0.8 percent change | Standard Deviation 3.66 |
| Alemtuzumab 24 mg | Percent Change From Baseline in T1 Cerebral Volume at Year 3 | -0.4 percent change | Standard Deviation 4.27 |
| Alemtuzumab (Pooled) | Percent Change From Baseline in T1 Cerebral Volume at Year 3 | -0.6 percent change | Standard Deviation 3.99 |
Comparison: Ranked analysis of covariance (ANCOVA) model using Baseline MRI-T1 brain volume, EDSS group, country, and treatment as covariates was used.p-value: 0.0885ANCOVA
Comparison: Ranked ANCOVA model using Baseline MRI-T1 brain volume, EDSS group, country, and treatment as covariates was used.p-value: 0.0195ANCOVA
Comparison: Ranked ANCOVA model using Baseline MRI-T1 brain volume, EDSS group, country, and treatment as covariates was used.p-value: 0.0215ANCOVA
Secondary
Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment
Participants were considered relapse free at Year 3 if they did not experience a relapse between randomization and study completion at 36 months. Participants who discontinued early were considered relapse free if they did not experience a relapse prior to discontinuation. Probability of participants who were relapse free at Year 3, estimated using the KM method, was reported.
Time frame: Year 3
Population: FAS population included all randomized participants who had correct diagnosis of MS at entry.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Interferon Beta-1a | Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment | 0.50 probability of participants |
| Alemtuzumab 12 mg | Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment | 0.76 probability of participants |
| Alemtuzumab 24 mg | Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment | 0.84 probability of participants |
| Alemtuzumab (Pooled) | Probability of Participants Who Were Relapse Free at 3 Years After Initial Treatment | 0.80 probability of participants |
Comparison: Cox PH regression model with treatment group indicator, Baseline EDSS and country as covariates was used.p-value: 0.0001Cox Proportional Hazards Regression
Comparison: Cox PH regression model with treatment group indicator, Baseline EDSS and country as covariates was used.p-value: <0.0001Cox Proportional Hazards Regression
Comparison: Cox PH regression model with treatment group indicator, Baseline EDSS and country as covariates was used.p-value: <0.0001Cox Proportional Hazards Regression