Relapsing Remitting Multiple Sclerosis
Conditions
Keywords
Relapsing Remitting Multiple Sclerosis, Glatiramer Acetate
Brief summary
The study is designed to assess the efficacy of Glatiramer Acetate (GA) injection 40 mg administered three times a week compared to placebo in subjects with RRMS, as measured by the number of confirmed relapses during the 12 month placebo controlled period. The study has two periods: * Placebo Controlled Period: 12 months of 40 mg administered three times a week by subcutaneous injection or matching placebo. * Open Label Extension Period: All subjects will continue treatment with GA 40 mg administered three times a week, until this dose strength is commercially available for the treatment of relapsing remitting multiple sclerosis (RRMS) patients or until the development of this GA dose regimen is stopped by the Sponsor
Detailed description
Participants who were randomized to the GA 40 mg treatment arm in the Double-Blind Period, continue that treatment in the Open-Label Extension Period and are referred to as Early Start participants. Participants randomized to the Placebo arm in the Double-Blind Period and switched to GA 40 mg subcutaneous injections three times a week in the Open-Label Extension are referred to as Delayed Start participants.
Interventions
GA 40 mg/mL administered 3 times a week by subcutaneous injection for a period of 12 months for participants assigned to GA treatment in the Double-Blind Period, and GA 40 mg/mL administered 3 times a week by subcutaneous injection for all participants in the Open-Label Extension Period.
DRUGPlacebo
Placebo comparator administered by subcutaneous injection three times each week for 12 months during the Double-Blind Period.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria with a relapsing-remitting disease course. 2. Subjects must be ambulatory with an EDSS score of 0-5.5 in both screening and baseline visits. 3. Subjects must be in a relapse-free, stable neurological condition and free of corticosteroid treatment \[intravenous (IV), intramuscular (IM) and/or per os (PO)\] or ACTH 30 days prior to screening (month -1) and between screening and baseline (month 0) visits. 4. Subjects must have experienced one of the following: At least one documented relapse in the 12 months prior to screening, or At least two documented relapses in the 24 months prior to screening, or One documented relapse between 12 and 24 months prior to screening with at least one documented T1-Gd enhancing lesion in an MRI performed within 12 months prior to screening. 5. Subjects must be between 18 and 55 years of age, inclusive. 6. Women of child-bearing potential must practice an acceptable method of birth control. 7. Subjects must be able to sign and date a written informed consent prior to entering the study. 8. Subjects must be willing and able to comply with the protocol requirements for the duration of the study
Exclusion criteria
1. Subjects with progressive forms of MS. 2. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening. 3. Use of immunosuppressive (including Mitoxantrone and Fingolimod) or cytotoxic agents within 6 months prior to the screening visit. 4. Use of natalizumab (Tysabri®) or any other monoclonal antibodies within 2 years prior to screening. 5. Use of cladribine within 2 years prior to screening. 6. Previous treatment with immunomodulators (including IFNβ 1a and 1b, and IV Immunoglobulin (IVIg) within 2 months prior to screening. 7. Previous use of GA or any other glatiramoid. 8. Chronic (more than 30 consecutive days) systemic (IV, PO or IM) corticosteroid treatment within 6 months prior to screening visit. 9. Previous total body irradiation or total lymphoid irradiation. 10. Previous stem-cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. 11. Pregnancy or breastfeeding. 12. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical exams, ECG, abnormal laboratory tests and chest X-ray. Such conditions may include hepatic, renal or metabolic diseases, systemic disease, acute infection, current malignancy or recent history (5 years) of malignancy, major psychiatric disorder, history of drug and/or alcohol abuse and allergies that could be detrimental according to the investigator's judgment. 13. A known history of sensitivity to Gadolinium. 14. Inability to successfully undergo MRI scanning. 15. A known drug hypersensitivity to Mannitol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | Day 1 to 12 months | Relapses were monitored throughout the study. During the PC Period, two neurologists/physicians assessed subjects' general medical and neurological evaluations separately. A relapse was defined as the appearance of 1+ new neurological abnormalities or the reappearance of 1+ previously observed neurological abnormalities lasting \>= 48 hours and immediately preceded by an improving neurological state of at \>=30 days from onset of previous relapse. An event was counted as a relapse only when the subject's symptoms were accompanied by observed objective neurological changes, consistent with \>= one of the following: - An increase of \>= 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation. - An increase of one grade in the actual score of \>=2 of the 7 functional systems (FS), as compared to previous evaluation. - An increase of 2 grades in the actual score of one FS as compared to the previous evaluation. Adjusted mean values are displayed. |
| Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression | Day 1 up to 6.5 years | The annualized relapse rate (ARR) was calculated for the study by dividing the cumulative number of confirmed relapses by the number of person-years of exposure to treatment. The analysis of the annualized relapse rate is based on estimating a contrast (early start vs delayed start) derived from a baseline-adjusted, Negative Binomial Regression model to the number of confirmed relapses observed during study (post randomization) with an offset based on the log of exposure to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain Atrophy As Defined by the Percent of Change in Normalized Brain Volume From Baseline to Month 12 During the Placebo Controlled (PC) Treatment Period | Baseline (Day -7), Month 12 | The analysis of brain atrophy as defined by the percentage change in normalized brain volume from baseline to Month 12 was based on the outcome of a contrast (GA 40 mg TIW vs. placebo) derived from a baseline-adjusted ANCOVA. In addition to the treatment group, the model included the following covariates: - SIENAX normalized brain volume at baseline. - The number of enhancing lesions on T1-weighted images at baseline. - country or geographical region. Sienax estimates total brain tissue volume, from a single image, normalised for skull size. |
| The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Baseline (Day -7), Month 6, Month 12, Month 36 | All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The number of T2 lesions at Months 6, 12 and 36 that are new or enlarged as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates. An offset employing the log of the proportion of the number of the available post-placebo-controlled baseline (PCBL) scans was used to adjust for missing MRI scans. |
| The Cumulative Number of New/Enlarging T2 Lesions Taken at Month 6 and Month 12 During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | Baseline (Day -7), Month 6, Month 12 | T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The cumulative number of T2 lesions at Months 6 and 12 that are new or enlarged as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates. |
| Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Baseline (Day -7), Month 6, Month 12, Month 36 | The analysis of brain atrophy as defined by the percentage change in brain volume from baseline to Months 6, 12 and 36 was performed using mixed model for repeated measures (MMRM) with SIENAX normalized brain volume at baseline, number of Gd-enhancing lesions at baseline, and country or geographical region as fixed effects. Sienax estimates total brain tissue volume, from a single image, normalised for skull size. |
| Participants With Treatment-Emergent Adverse Events (TEAEs) | Early Start: Day 1 up to 6.5 years Delayed Start - Placebo: Day 1 up to Month 12 Delayed Start - GA: Month 13 up to 6.5 years | Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes. |
| The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Baseline (Day -7), Month 6, Month 12, Month 36 | All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6, 12 and 36 as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression The model was fit using an autoregressive covariance structure. Covariates used: number of enhancing lesions on T1-weighted images at placebo-controlled baseline and country or geographical region. The cumulative number is derived from all the data points before it. For example, if the participant skipped one time point in between the baseline and 36 months, then it cannot be calculated. |
| The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Month 6 and Month 12 of the Placebo-Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | Baseline (Day -7), Month 6, Month 12 | The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6 and 12 as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression with an offset employing the log of the proportion of the number of the available post-baseline scans to adjust for missing MRI scans (if any), adjusted for baseline number of enhancing lesions on T1-weighted images and country or geographical region as covariates. |
Countries
Bulgaria, Croatia, Czechia, Estonia, Georgia, Germany, Hungary, Israel, Italy, Lithuania, Poland, Romania, Russia, South Africa, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 1524 subjects were screened in this study, and 120 (7.9%) subjects failed screening. Of these, 69 did not meet inclusion or exclusion criteria, 30 withdrew from the study and 21 failed screening for other reasons.
Pre-assignment details
1404 subjects were enrolled and randomized in the placebo-controlled (PC) double-blind period. Participants were randomized 2:1 to the treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| Early Start: GA 40 mg / GA 40 mg Participants were administered glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week for 12 months during the double-blind Placebo-Controlled Period, and then continued that treatment in the Open-label Period from Month 13 up to Year 6.5 until the study ended. | 943 |
| Delayed Start: Placebo / GA 40 mg Participants were administered placebo subcutaneous injections three times a week for 12 months during the double-blind Placebo-Controlled Period. Participants were then switched to glatiramer acetate (GA) 40 mg/mL by subcutaneous injection three times a week during the Open-Label Period from Month 13 up to Year 6.5 until the study ended. | 461 |
| Total | 1,404 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Placebo-Controlled Period | Adverse Event | 29 | 6 |
| Double-Blind Placebo-Controlled Period | Death | 0 | 1 |
| Double-Blind Placebo-Controlled Period | Lost to Follow-up | 5 | 1 |
| Double-Blind Placebo-Controlled Period | Noncompliance with study drug | 2 | 0 |
| Double-Blind Placebo-Controlled Period | Physician Decision | 1 | 1 |
| Double-Blind Placebo-Controlled Period | Pregnancy | 7 | 4 |
| Double-Blind Placebo-Controlled Period | Protocol Violation | 2 | 0 |
| Double-Blind Placebo-Controlled Period | Refused to sign informed consent | 4 | 1 |
| Double-Blind Placebo-Controlled Period | Withdrawal by Subject | 34 | 17 |
| Open-Label Period | Adverse Event | 30 | 28 |
| Open-Label Period | Death | 3 | 1 |
| Open-Label Period | Lost to Follow-up | 21 | 20 |
| Open-Label Period | Non-compliance with study drug | 5 | 0 |
| Open-Label Period | Physician Decision | 13 | 11 |
| Open-Label Period | Pregnancy | 14 | 8 |
| Open-Label Period | Protocol Violation | 3 | 0 |
| Open-Label Period | Teva requested subject to be withdrawn | 5 | 2 |
| Open-Label Period | Withdrawal by Subject | 160 | 88 |
Baseline characteristics
| Characteristic | Total | Delayed Start: Placebo / GA 40 mg | Early Start: GA 40 mg / GA 40 mg |
|---|---|---|---|
| Age, Continuous | 37.61 years STANDARD_DEVIATION 9.346 | 38.12 years STANDARD_DEVIATION 9.222 | 37.36 years STANDARD_DEVIATION 9.401 |
| Body Mass Index (BMI) | 24.40 kg/m^2 STANDARD_DEVIATION 4.739 | 24.44 kg/m^2 STANDARD_DEVIATION 4.804 | 24.38 kg/m^2 STANDARD_DEVIATION 4.709 |
| Number of T1 Gadolinium (Gd)-Enhanced Lesions per Participant at Baseline | 1.6 lesions STANDARD_DEVIATION 4.39 | 1.4 lesions STANDARD_DEVIATION 3.69 | 1.7 lesions STANDARD_DEVIATION 4.7 |
| Number of T2 Lesions Per Participant at Baseline | 37.5 lesions STANDARD_DEVIATION 26.45 | 36.7 lesions STANDARD_DEVIATION 26.68 | 38.0 lesions STANDARD_DEVIATION 26.34 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 15 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 10 Participants | 1 Participants | 9 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 1394 Participants | 460 Participants | 934 Participants |
| Race/Ethnicity, Customized Other, not specified | 15 Participants | 3 Participants | 12 Participants |
| Race/Ethnicity, Customized White | 1371 Participants | 455 Participants | 916 Participants |
| Sex: Female, Male Female | 954 Participants | 313 Participants | 641 Participants |
| Sex: Female, Male Male | 450 Participants | 148 Participants | 302 Participants |
| Sienax Normalized Brain Volume at Baseline | 1535.206 mL STANDARD_DEVIATION 110.6347 | 1537.899 mL STANDARD_DEVIATION 110.7549 | 1533.888 mL STANDARD_DEVIATION 110.6107 |
| Time from First Symptom | 7.66 years STANDARD_DEVIATION 6.621 | 7.61 years STANDARD_DEVIATION 6.36 | 7.68 years STANDARD_DEVIATION 6.748 |
| Time from Multiple Sclerosis (MS) Diagnosis | 3.76 years STANDARD_DEVIATION 4.904 | 3.88 years STANDARD_DEVIATION 4.744 | 3.70 years STANDARD_DEVIATION 4.982 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 419 | 1 / 461 | 3 / 943 |
| other Total, other adverse events | 238 / 419 | 167 / 461 | 609 / 943 |
| serious Total, serious adverse events | 36 / 419 | 21 / 461 | 117 / 943 |
Outcome results
Primary
Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression
The annualized relapse rate (ARR) was calculated for the study by dividing the cumulative number of confirmed relapses by the number of person-years of exposure to treatment. The analysis of the annualized relapse rate is based on estimating a contrast (early start vs delayed start) derived from a baseline-adjusted, Negative Binomial Regression model to the number of confirmed relapses observed during study (post randomization) with an offset based on the log of exposure to treatment.
Time frame: Day 1 up to 6.5 years
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression | 0.2621 relapses per year | Standard Error 0.0189 |
| Delayed Start: Placebo / GA 40 mg | Annualized Rate of Confirmed Relapses Comparing Early Starters to Delayed Starters Estimated by Negative Binomial Regression | 0.3146 relapses per year | Standard Error 0.0279 |
Comparison: Entire Study The Negative Binomial Regression model covariates: • treatment group • PCBL (Placebo-Controlled Baseline) Kurtzke's Expanded Disability Status Scale (EDSS) score as 1 degree of freedom variable • Log of the # of relapses in the 2 years prior to PCBL • Volume of T2 lesions at PCBL • Status of Gd-enhancing T1 lesion activity at PCBL (=0 if no Gd-enhancing T1 lesions at PCBL; =1 if at least one Gd-enhancing T1 lesion at PCBL) • Country or Geographical Region (CGR)p-value: 0.040995% CI: [0.6995, 0.9925]Negative Binomial Regression
Primary
Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
Relapses were monitored throughout the study. During the PC Period, two neurologists/physicians assessed subjects' general medical and neurological evaluations separately. A relapse was defined as the appearance of 1+ new neurological abnormalities or the reappearance of 1+ previously observed neurological abnormalities lasting \>= 48 hours and immediately preceded by an improving neurological state of at \>=30 days from onset of previous relapse. An event was counted as a relapse only when the subject's symptoms were accompanied by observed objective neurological changes, consistent with \>= one of the following: - An increase of \>= 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation. - An increase of one grade in the actual score of \>=2 of the 7 functional systems (FS), as compared to previous evaluation. - An increase of 2 grades in the actual score of one FS as compared to the previous evaluation. Adjusted mean values are displayed.
Time frame: Day 1 to 12 months
Population: Intent To Treat (ITT) Analysis Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | 0.331 confirmed relapses | Standard Error 0.028 |
| Delayed Start: Placebo / GA 40 mg | Total Number of Confirmed Relapses During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | 0.505 confirmed relapses | Standard Error 0.049 |
Comparison: Relapses were estimated by a baseline-adjusted, Negative Binomial Regression with an offset based on the log of subject's exposure to treatment. The model included the following covariates: - Baseline EDSS score. - Log of the prior 2-year number of relapses. - Volume of T2 lesions at baseliner. - Status of Gd-enhancing T1 activity at baseline (=0 no Gd-enhancing T1 at baseline; =1 at least one Gd-enhancing T1 at baseline). - CGR.p-value: <0.000195% CI: [0.539, 0.799]Negative Binomial Regression
Secondary
Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures
The analysis of brain atrophy as defined by the percentage change in brain volume from baseline to Months 6, 12 and 36 was performed using mixed model for repeated measures (MMRM) with SIENAX normalized brain volume at baseline, number of Gd-enhancing lesions at baseline, and country or geographical region as fixed effects. Sienax estimates total brain tissue volume, from a single image, normalised for skull size.
Time frame: Baseline (Day -7), Month 6, Month 12, Month 36
Population: ITT population of participants with SIENEX brain scans at both baseline and the designated timeframes.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Month 6 | -0.429 percentage change | Standard Error 0.032 |
| Early Start: GA 40 mg / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Month 12 | -0.739 percentage change | Standard Error 0.035 |
| Early Start: GA 40 mg / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Month 36 | -1.935 percentage change | Standard Error 0.063 |
| Delayed Start: Placebo / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Month 6 | -0.345 percentage change | Standard Error 0.04 |
| Delayed Start: Placebo / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Month 12 | -0.653 percentage change | Standard Error 0.046 |
| Delayed Start: Placebo / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Brain Volume From Baseline to Months 6, 12 and 36 Estimated by a Mixed Model for Repeated Measures | Month 36 | -1.952 percentage change | Standard Error 0.09 |
Comparison: Month 6p-value: 0.042595% CI: [-0.166, -0.003]Mixed model for repeated measures (MMRM)
Comparison: Month 12p-value: 0.084495% CI: [-0.184, 0.012]Mixed model for repeated measures (MMRM)
Comparison: Month 36p-value: 0.870195% CI: [-0.91, 0.225]Mixed model for repeated measures (MMRM)
Secondary
Brain Atrophy As Defined by the Percent of Change in Normalized Brain Volume From Baseline to Month 12 During the Placebo Controlled (PC) Treatment Period
The analysis of brain atrophy as defined by the percentage change in normalized brain volume from baseline to Month 12 was based on the outcome of a contrast (GA 40 mg TIW vs. placebo) derived from a baseline-adjusted ANCOVA. In addition to the treatment group, the model included the following covariates: - SIENAX normalized brain volume at baseline. - The number of enhancing lesions on T1-weighted images at baseline. - country or geographical region. Sienax estimates total brain tissue volume, from a single image, normalised for skull size.
Time frame: Baseline (Day -7), Month 12
Population: ITT population of participants who had SIENEX brain volume estimates at both baseline and Month 12.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Normalized Brain Volume From Baseline to Month 12 During the Placebo Controlled (PC) Treatment Period | -0.706 percentage change | Standard Error 0.037 |
| Delayed Start: Placebo / GA 40 mg | Brain Atrophy As Defined by the Percent of Change in Normalized Brain Volume From Baseline to Month 12 During the Placebo Controlled (PC) Treatment Period | -0.645 percentage change | Standard Error 0.047 |
p-value: 0.205895% CI: [-0.154, 0.033]ANCOVA
Secondary
Participants With Treatment-Emergent Adverse Events (TEAEs)
Adverse events (AEs) summarized in this table are those that began or worsened after treatment with study drug (treatment-emergent AEs). An adverse event was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time frame: Early Start: Day 1 up to 6.5 years Delayed Start - Placebo: Day 1 up to Month 12 Delayed Start - GA: Month 13 up to 6.5 years
Population: Glatiramer Acetate (GA) - Treated Analysis Set The GA-Treated analysis set includes all subjects randomized into the study and treated with at least 1 dose of GA at any time during the study. Analyses includes data collected for these subjects from the first time GA was administered.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 777 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Mild | 698 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Moderate | 441 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Severe | 95 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 501 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 117 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 3 Participants |
| Early Start: GA 40 mg / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to treatment discontinuation | 63 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Moderate | 168 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 1 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Severe | 24 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 189 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 36 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 322 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Mild | 283 Participants |
| Delayed Start: Placebo / GA 40 mg | Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to treatment discontinuation | 28 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Moderate | 101 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Mild | 247 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 284 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Severity of TEAEs: Severe | 16 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Deaths | 1 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 21 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 73 Participants |
| Delayed Start: Placebo | Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to treatment discontinuation | 6 Participants |
Secondary
The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Month 6 and Month 12 of the Placebo-Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6 and 12 as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression with an offset employing the log of the proportion of the number of the available post-baseline scans to adjust for missing MRI scans (if any), adjusted for baseline number of enhancing lesions on T1-weighted images and country or geographical region as covariates.
Time frame: Baseline (Day -7), Month 6, Month 12
Population: ITT. When a subject had both Month 6 and Month 12 scans missing, the subject was excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Month 6 and Month 12 of the Placebo-Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | 0.905 lesions | Standard Error 0.087 |
| Delayed Start: Placebo / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Month 6 and Month 12 of the Placebo-Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | 1.639 lesions | Standard Error 0.194 |
p-value: <0.000195% CI: [0.436, 0.699]Negative Binomial Regression
Secondary
The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression
All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. The cumulative number of gadolinium (Gd)-enhanced lesions on T1-weighted images at Months 6, 12 and 36 as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression The model was fit using an autoregressive covariance structure. Covariates used: number of enhancing lesions on T1-weighted images at placebo-controlled baseline and country or geographical region. The cumulative number is derived from all the data points before it. For example, if the participant skipped one time point in between the baseline and 36 months, then it cannot be calculated.
Time frame: Baseline (Day -7), Month 6, Month 12, Month 36
Population: ITT population of participants with MRIs at both baseline and the designated timeframes, inclusive of the proceeding post-baseline timeframes.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 6 | 0.629 lesions | Standard Error 0.072 |
| Early Start: GA 40 mg / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 12 | 1.054 lesions | Standard Error 0.115 |
| Early Start: GA 40 mg / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 36 | 1.501 lesions | Standard Error 0.168 |
| Delayed Start: Placebo / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 6 | 1.131 lesions | Standard Error 9.186 |
| Delayed Start: Placebo / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 12 | 2.051 lesions | Standard Error 0.282 |
| Delayed Start: Placebo / GA 40 mg | The Cumulative Number of Gadolinium (Gd)-Enhanced Lesions on T1-Weighted Images At Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 36 | 2.265 lesions | Standard Error 0.278 |
Comparison: Month 6p-value: 0.000595% CI: [0.4, 0.773]Negative Binomial Regression
Comparison: Month 12p-value: <0.000195% CI: [0.388, 0.679]Negative binomial regression
Comparison: Month 36p-value: 0.001595% CI: [0.514, 0.854]Negative binomial regression
Secondary
The Cumulative Number of New/Enlarging T2 Lesions Taken at Month 6 and Month 12 During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression
T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The cumulative number of T2 lesions at Months 6 and 12 that are new or enlarged as compared to the baseline MRI are offered. Note that the two timeframes (Months 6 and 12) are combined. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates.
Time frame: Baseline (Day -7), Month 6, Month 12
Population: ITT. When a subject had both Month 6 and Month 12 scans missing, the subject was excluded from the analysis. When the Month 12 scan was missing, data from Month 6 was used and an offset of log (0.5) introduced. When the Month 6 scan was missing, data from Month 12 was used with an offset of 0.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | The Cumulative Number of New/Enlarging T2 Lesions Taken at Month 6 and Month 12 During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | 3.650 lesions | Standard Error 0.259 |
| Delayed Start: Placebo / GA 40 mg | The Cumulative Number of New/Enlarging T2 Lesions Taken at Month 6 and Month 12 During the Placebo Controlled (PC) Treatment Period Estimated by Negative Binomial Regression | 5.592 lesions | Standard Error 0.49 |
Comparison: Negative binomial regressionp-value: <0.000195% CI: [0.546, 0.78]Negative binomial regression
Secondary
The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression
All data accumulated from screening, the PC Treatment period up to the end of the Open Label (OL) period are combined and referred to as the Long Term Period. T2 lesions are hyperintense brain lesions that show on magnetic resonance imaging (MRI) and are associated with multiple sclerosis. The number of T2 lesions at Months 6, 12 and 36 that are new or enlarged as compared to the baseline MRI are offered. Adjusted mean is based on negative binomial regression, adjusted for baseline number of T2 lesions and country or geographical region as covariates. An offset employing the log of the proportion of the number of the available post-placebo-controlled baseline (PCBL) scans was used to adjust for missing MRI scans.
Time frame: Baseline (Day -7), Month 6, Month 12, Month 36
Population: ITT population of participants with MRIs at both baseline and the designated timeframes.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Early Start: GA 40 mg / GA 40 mg | The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 6 | 2.872 lesions | Standard Error 0.214 |
| Early Start: GA 40 mg / GA 40 mg | The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 12 | 4.484 lesions | Standard Error 0.318 |
| Early Start: GA 40 mg / GA 40 mg | The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 36 | 5.836 lesions | Standard Error 0.41 |
| Delayed Start: Placebo / GA 40 mg | The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 6 | 3.902 lesions | Standard Error 0.43 |
| Delayed Start: Placebo / GA 40 mg | The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 12 | 7.086 lesions | Standard Error 0.699 |
| Delayed Start: Placebo / GA 40 mg | The Number of New/Enlarging T2 Lesions at Months 6, 12 and 36 Estimated by Negative Binomial Regression | Month 36 | 8.759 lesions | Standard Error 0.82 |
Comparison: Month 6 Negative binomial regressionp-value: 0.005695% CI: [0.592, 0.914]Negative binomial regression
Comparison: Month 12 Negative binomial regressionp-value: <0.000195% CI: [0.524, 0.765]Negative binomial regression
Comparison: Month 36 Negative binomial regressionp-value: <0.000195% CI: [0.557, 0.797]Negative binomial regression