Relapsing-remitting Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis (MS), Relapsing-Remitting, Demyelinating Autoimmune Diseases, Disseminated sclerosis, Encephalomyelitis disseminate, Inflammatory disease, Demyelination, Auto-inflammatory disease, Devic's disease, Balo concentric sclerosis, Schilder's diffuse sclerosis
Brief summary
The purpose of this study was to determine the dose-response curve for the MRI-based efficacy of BAF312 compared with placebo in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), and to characterize its safety and tolerability for the selection of an optimal dose in a later phase III study. Study Design Rationale An adaptive design was chosen to characterize the dose response curve of BAF312. In a first period of study (Period 1), three doses of BAF312 and placebo were tested for MRI efficacy. Based on an interim analysis (IA) after 3 months of treatment, two additional active doses for period 2 wereselected , thus allowing to optimize the overall determination of the dose response curve with 5 data points of active treatment, and placebo. The doses were kept blinded. The use of Modeling and Simulation allowed to establish the full range and dynamics of the dose-response curve in silico, and hence the definition of the optimal dose for later phase III studies. The choice of placebo as treatment control was essential to obtain information on the specific compared to non-specific effects of active treatment and provides the best way of evaluating the efficacy and of assessing the true safety and tolerability profile of BAF312. Short-term placebo exposure (6 (Period 1) or 3 (Period 2) months, respectively) was unlikely to lead to longer term differences in outcomes \[Polman, 2008\]. The use of an adaptive design strategy contributed to a significant reduction of placebo exposure, both in terms of the number of patients and duration, as compared to conventional trial models. Patients having completed the study within the protocol might be eligible for the Extension Phase study where they receive long-term BAF312 treatment (a separate protocol).
Interventions
DRUGBAF312
DRUGPlacebo
Sponsors
Novartis Pharmaceuticals
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
Key inclusion Criteria: * Diagnosis of Multiple Sclerosis (MS) as defined by revised McDonald criteria. * A relapsing-remitting course of disease with at least 1 documented relapse during the previous year, or 2 documented relapses during the previous 2 years, or a positive gadolinium (Gd)-enhanced MRI scan at screening (in case the first MRI scan obtained at screening is negative, a second scan may be obtained 1 month later.) * An Expanded Disability Status Scale (EDSS) score of 0-5.0 inclusive at randomization. * Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to randomization. * Patients who decline initiation or continuation of treatment with available disease modifying drugs for MS, for whatever reason, after having been informed about their respective benefits and possible adverse events by the investigator. Key
Exclusion criteria
* A manifestation of another type of MS than RRMS * History of chronic disease of the immune system other than MS * Malignancies, diabetes, significant cardiovascular, pulmonary and hepatic diseases and conditions * Active infections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL) | 3 months of treatment | Combined unique active lesions (CUAL) were defined as new gadolinium \[Gd\]-enhanced lesions on T1-weighted MRI scans or new or enlarging lesions on T2-weighted MRI scans, without double-counting of lesions. ED50 is the dose that gives half of the asymptotic maximum change over placebo. ED90 is the dose that gives 90% of the asymptotic maximum change over placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 3 month | To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only) |
| Proportion of Participants With Relapse-free Patients - Period 1 Only | 6 months | To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only) |
| Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 3 months | Results for Month 1 through Month 3 inclusive include patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months | 6 months | Month 4 through Month 6 include patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 3 months | The results for Month 1 through Month 3 includes patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months | 6 months | The results for Month 4 through Month 6 inclusive includes patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 3 months | The results for Month 1 through Month 3 inclusive include patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of Confirmed Relapses - Period 1 | 6 months | confirmed relapse: A relapse was to be confirmed by the Independent Evaluating Physician (examining neurologist) performing the EDSS. It was recommended that this occurred within 7 days of the onset of symptoms. A relapse was confirmed when it was accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the Expanded Disability Status Scale (EDSS) or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS). |
| Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 3 months | The proportion of patients who were free of new Gd-enhanced T1 lesions, and/or free of new or enlarging T2 lesions, i.e. free of new MRI activity (CUAL). |
| Number of Patients Without Any New MRI Disease Activity - Period 1 Only | 6 months | The proportion of patients who were free of new Gd-enhanced T1 lesions, and/or free of new or enlarging T2 lesions, i.e. free of new MRI activity (CUAL). |
| Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 3 months | In patients with high baseline disease activity, the relative reduction in new Gd-enhanced T1 lesions compared to placebo at Month 3. High baseline disease activity is defined as \>=2 Gd-enhanced T1 lesions at baseline. The number of lesions of each type was available as such from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months | 6 months | In patients with high baseline disease activity, the relative reduction in new Gd-enhanced T1 lesions compared to placebo at Month 6. High baseline disease activity is defined as \>=2 Gd-enhanced T1 lesions at baseline. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
| Number of CUAL - Period 1 | 6 months | Combined unique active lesions (CUAL) are defined as new Gd-enhanced T1 lesions or new or enlarging T2 lesions, withput double counting of lesions at any specific point in time. |
| Geometric Mean BAF312 Plasma Trough Concentrations | Month 1, Month 3, Month 6 | Geometric mean BAF312 plasma concentrations by treatment and by visit |
| Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months | 6 months | Month 4 through Month 6 inclusive include patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link. |
Countries
Canada, Finland, Germany, Hungary, Italy, Norway, Poland, Russia, Spain, Switzerland, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was performed in 297 patients at 73 centers in 12 countries.
Pre-assignment details
One patient was misrandomized and never received study drug. Patient was included in Participant Flow and Baseline Characteristics but not included in actual enrollment count or Full Analysis Set..
Participants by arm
| Arm | Count |
|---|---|
| BAF312 10mg (Period 1) 10 mg of BAF given orally o.d. for a period of 6 months | 50 |
| BAF312 2 mg (Period 1) 2 mg of BAF given orally o.d. for a period of 6 months | 49 |
| BAF312 0.5 mg (Period 1) 0.5 mg of BAF given orally o.d. for a period of 6 months | 43 |
| Placebo (Period 1) Placebo given orally o.d. for a period of 3 months | 46 |
| BAF312 1.25 mg (Period 2) 1.25 mg of BAF given orally o.d. for a period of 3 months | 42 |
| BAF312 0.25 mg (Period 2) 0.25 mg of BAF given orally o.d. for a period of 3 months | 51 |
| Placebo (Period 2) Placebo given orally o.d. for a period of 6 months | 16 |
| Total | 297 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Abnormal laboratory value(s) | 3 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Administrative problems | 2 | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Adverse Event | 6 | 4 | 3 | 1 | 2 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | misrandomized (never received study med) | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 2 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | BAF312 10mg (Period 1) | BAF312 2 mg (Period 1) | BAF312 0.5 mg (Period 1) | Placebo (Period 1) | BAF312 1.25 mg (Period 2) | BAF312 0.25 mg (Period 2) | Placebo (Period 2) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 36.4 years STANDARD_DEVIATION 8.43 | 37.4 years STANDARD_DEVIATION 8.94 | 36.0 years STANDARD_DEVIATION 8.79 | 35.2 years STANDARD_DEVIATION 8.75 | 35.4 years STANDARD_DEVIATION 8.87 | 37.4 years STANDARD_DEVIATION 8.39 | 35.9 years STANDARD_DEVIATION 8.24 | 36.3 years STANDARD_DEVIATION 8.62 |
| Sex: Female, Male Female | 30 Participants | 34 Participants | 30 Participants | 36 Participants | 31 Participants | 42 Participants | 9 Participants | 212 Participants |
| Sex: Female, Male Male | 20 Participants | 15 Participants | 13 Participants | 10 Participants | 11 Participants | 9 Participants | 7 Participants | 85 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 50 | 0 / 49 | 1 / 42 | 0 / 43 | 0 / 51 | 0 / 61 |
| other Total, other adverse events | 46 / 50 | 42 / 49 | 26 / 42 | 34 / 43 | 34 / 51 | 45 / 61 |
| serious Total, serious adverse events | 3 / 50 | 4 / 49 | 2 / 42 | 8 / 43 | 0 / 51 | 0 / 61 |
Outcome results
Primary
Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL)
Combined unique active lesions (CUAL) were defined as new gadolinium \[Gd\]-enhanced lesions on T1-weighted MRI scans or new or enlarging lesions on T2-weighted MRI scans, without double-counting of lesions. ED50 is the dose that gives half of the asymptotic maximum change over placebo. ED90 is the dose that gives 90% of the asymptotic maximum change over placebo.
Time frame: 3 months of treatment
Population: Full analysis set (FAS) consisted of all patients who received at least one dose of study medication and had no protocol deviation with severity code 0 or 8. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BAF312/Placebo | Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL) | Dose achieving 50% reduction | 0.51 mg |
| BAF312/Placebo | Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL) | ED50 | 0.83 mg |
| BAF312/Placebo | Dose Responsiveness of BAF312 Based on the Number of Combined Unique Active MRI Lesions (CUAL) | ED90 | 7.46 mg |
Secondary
Geometric Mean BAF312 Plasma Trough Concentrations
Geometric mean BAF312 plasma concentrations by treatment and by visit
Time frame: Month 1, Month 3, Month 6
Population: The PK Analysis Set consisted of all patients who received at least one dose of active BAF 312 study medication. Patients were analyzed according to the treatment received.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BAF312/Placebo | Geometric Mean BAF312 Plasma Trough Concentrations | Month 1 | 127.9732 ng/ml | Standard Deviation 65.53329 |
| BAF312/Placebo | Geometric Mean BAF312 Plasma Trough Concentrations | Month 6 | 104.0332 ng/ml | Standard Deviation 75.60951 |
| BAF312/Placebo | Geometric Mean BAF312 Plasma Trough Concentrations | Month 3 | 127.4595 ng/ml | Standard Deviation 74.96856 |
| BAF312 2 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 3 | 23.5143 ng/ml | Standard Deviation 12.51344 |
| BAF312 2 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 1 | 25.1777 ng/ml | Standard Deviation 15.05116 |
| BAF312 2 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 6 | 23.4480 ng/ml | Standard Deviation 19.27251 |
| BAF312 0.5 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 3 | 11.8270 ng/ml | Standard Deviation 6.53977 |
| BAF312 0.5 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 1 | 14.0450 ng/ml | Standard Deviation 6.6103 |
| BAF312 0.5 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 6 | NA ng/ml | — |
| Placebo | Geometric Mean BAF312 Plasma Trough Concentrations | Month 1 | 6.9490 ng/ml | Standard Deviation 4.97572 |
| Placebo | Geometric Mean BAF312 Plasma Trough Concentrations | Month 6 | 5.307 ng/ml | Standard Deviation 2.75235 |
| Placebo | Geometric Mean BAF312 Plasma Trough Concentrations | Month 3 | 6.1075 ng/ml | Standard Deviation 3.89391 |
| BAF312 0.25 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 3 | 2.4897 ng/ml | Standard Deviation 1.64555 |
| BAF312 0.25 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 1 | 2.8167 ng/ml | Standard Deviation 1.17863 |
| BAF312 0.25 mg | Geometric Mean BAF312 Plasma Trough Concentrations | Month 6 | NA ng/ml | — |
Secondary
Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months
The results for Month 4 through Month 6 inclusive includes patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 6 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months | 0.3 Lesions | Standard Deviation 0.77 |
| BAF312 2 mg | Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months | 0.6 Lesions | Standard Deviation 1.37 |
| BAF312 0.5 mg | Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months | 1.1 Lesions | Standard Deviation 3.78 |
| Placebo | Number of All Gd-enhanced T1 Lesions - Period 1 Only at 6 Months | 3.0 Lesions | Standard Deviation 5.88 |
p-value: <0.00195% CI: [0.033, 0.273]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.069, 0.47]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.069, 0.434]Regression, Logistic
Secondary
Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3
The results for Month 1 through Month 3 includes patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 3 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 0.5 Lesions | Standard Deviation 0.99 |
| BAF312 2 mg | Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 0.8 Lesions | Standard Deviation 1.46 |
| BAF312 0.5 mg | Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 0.3 Lesions | Standard Deviation 0.68 |
| Placebo | Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 1.5 Lesions | Standard Deviation 3.92 |
| BAF312 0.25 mg | Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 1.0 Lesions | Standard Deviation 1.54 |
| Placebo | Number of All New Gd-enhanced T1 Lesions - Period 1 +2 at Month 3 | 2.0 Lesions | Standard Deviation 3.78 |
p-value: 0.00295% CI: [0.124, 0.628]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.01995% CI: [0.182, 0.861]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.059, 0.4]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.03595% CI: [0.219, 0.945]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.08796% CI: [0.283, 1.09]Regression, Logistic
Secondary
Number of Confirmed Relapses - Period 1
confirmed relapse: A relapse was to be confirmed by the Independent Evaluating Physician (examining neurologist) performing the EDSS. It was recommended that this occurred within 7 days of the onset of symptoms. A relapse was confirmed when it was accompanied by an increase of at least half a step (0.5) on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the Expanded Disability Status Scale (EDSS) or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS).
Time frame: 6 months
Population: Full analysis set in period I
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAF312/Placebo | Number of Confirmed Relapses - Period 1 | 9 Confirmed relapses |
| BAF312 2 mg | Number of Confirmed Relapses - Period 1 | 5 Confirmed relapses |
| BAF312 0.5 mg | Number of Confirmed Relapses - Period 1 | 13 Confirmed relapses |
| Placebo | Number of Confirmed Relapses - Period 1 | 13 Confirmed relapses |
p-value: 0.14895% CI: [0.219, 1.257]Mixed Models Analysis
p-value: 0.04195% CI: [0.121, 0.956]Mixed Models Analysis
p-value: 0.89995% CI: [0.486, 2.273]Mixed Models Analysis
Secondary
Number of CUAL - Period 1
Combined unique active lesions (CUAL) are defined as new Gd-enhanced T1 lesions or new or enlarging T2 lesions, withput double counting of lesions at any specific point in time.
Time frame: 6 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of CUAL - Period 1 | 0.4 lesions | Standard Deviation 1.04 |
| BAF312 2 mg | Number of CUAL - Period 1 | 0.4 lesions | Standard Deviation 1.26 |
| BAF312 0.5 mg | Number of CUAL - Period 1 | 0.9 lesions | Standard Deviation 3.42 |
| Placebo | Number of CUAL - Period 1 | 2.0 lesions | Standard Deviation 2.71 |
Secondary
Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months
The results for Month 1 through Month 3 inclusive include patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 3 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 0.4 Lesions | Standard Deviation 0.99 |
| BAF312 2 mg | Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 0.4 Lesions | Standard Deviation 1 |
| BAF312 0.5 mg | Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 0.2 Lesions | Standard Deviation 0.64 |
| Placebo | Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 1.0 Lesions | Standard Deviation 3.08 |
| BAF312 0.25 mg | Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 0.8 Lesions | Standard Deviation 1.39 |
| Placebo | Number of Monthly New/Enlarging T2 Lesions - Period 1 +2 at 3 Months | 1.5 Lesions | Standard Deviation 3.17 |
p-value: 0.00595% CI: [0.1, 0.67]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.00595% CI: [0.112, 0.676]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.034, 0.409]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.48595% CI: [0.234, 1.991]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.14295% CI: [0.292, 1.193]Regression, Logistic
Secondary
Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months
Month 4 through Month 6 inclusive include patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 6 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months | 0.4 Lesions | Standard Deviation 0.91 |
| BAF312 2 mg | Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months | 0.4 Lesions | Standard Deviation 1.18 |
| BAF312 0.5 mg | Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months | 0.9 Lesions | Standard Deviation 2.97 |
| Placebo | Number of Monthly New/Enlarging T2 Lesions - Period 1 Only at 6 Months | 2.1 Lesions | Standard Deviation 3.66 |
p-value: <0.00195% CI: [0.062, 0.421]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.00195% CI: [0.074, 0.527]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.13995% CI: [0.13, 1.331]Regression, Logistic
Secondary
Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months
In patients with high baseline disease activity, the relative reduction in new Gd-enhanced T1 lesions compared to placebo at Month 3. High baseline disease activity is defined as \>=2 Gd-enhanced T1 lesions at baseline. The number of lesions of each type was available as such from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 3 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 0.5 Lesions | Standard Deviation 0.93 |
| BAF312 2 mg | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 0.5 Lesions | Standard Deviation 1.09 |
| BAF312 0.5 mg | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 0.1 Lesions | Standard Deviation 0.53 |
| Placebo | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 1.5 Lesions | Standard Deviation 3.68 |
| BAF312 0.25 mg | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 1.5 Lesions | Standard Deviation 1.57 |
| Placebo | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 +2 at 3 Months | 2.7 Lesions | Standard Deviation 4.47 |
p-value: 0.00695% CI: [0.03, 0.561]Regression, Logistic
p-value: 0.00595% CI: [0.044, 0.578]Regression, Logistic
p-value: 0.00595% CI: [0.007, 0.405]Regression, Logistic
Comparison: Pairwise comparison of treatments are based on a negative binomial GEE regression model accounting for repeated measures on each patient, adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month (the month number of each lesion count measurement) interaction, using the log link.p-value: 0.01995% CI: [0.091, 0.807]Regression, Logistic
p-value: 0.16995% CI: [0.19, 1.337]Regression, Logistic
Secondary
Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months
In patients with high baseline disease activity, the relative reduction in new Gd-enhanced T1 lesions compared to placebo at Month 6. High baseline disease activity is defined as \>=2 Gd-enhanced T1 lesions at baseline. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 6 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months | 0.5 Lesions | Standard Deviation 0.69 |
| BAF312 2 mg | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months | 0.6 Lesions | Standard Deviation 1.16 |
| BAF312 0.5 mg | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months | 1.4 Lesions | Standard Deviation 4.26 |
| Placebo | Number of Monthly New Gd-enhanced T1 Lesions With High Baseline Disease Activity - Period 1 Only at 6 Months | 2.1 Lesions | Standard Deviation 2.42 |
p-value: <0.00195% CI: [0.091, 0.499]Regression, Logistic
p-value: 0.01895% CI: [0.074, 0.779]Regression, Logistic
p-value: 0.00695% CI: [0.081, 0.653]Regression, Logistic
Secondary
Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3
Results for Month 1 through Month 3 inclusive include patients from both Period 1 and Period 2. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 3 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 0.2 Lesion | Standard Deviation 0.61 |
| BAF312 2 mg | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 0.4 Lesion | Standard Deviation 1 |
| BAF312 0.5 mg | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 0.2 Lesion | Standard Deviation 0.48 |
| Placebo | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 0.9 Lesion | Standard Deviation 2.48 |
| BAF312 0.25 mg | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 0.6 Lesion | Standard Deviation 1.16 |
| Placebo | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 +2 at Month 3 | 1.4 Lesion | Standard Deviation 3.11 |
Comparison: Pairwise treatment comparison between different BAF312 dose groups and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.047, 0.408]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.01295% CI: [0.123, 0.771]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.036, 0.358]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.02195% CI: [0.163, 0.86]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.06295% CI: [0.22, 1.037]Regression, Logistic
Secondary
Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months
Month 4 through Month 6 include patients from Period 1 only. New lesions at a specific visit were assessed relative to the previous scheduled visit scan. The number of lesions of each type was available from the central MRI reader. No derivation was performed. Lesion ratio (and 95% CI) is set between the estimated number of lesions on active treatment compared to placebo. Estimates are computed at Month 3 and Month 6. New lesions at a specific visit were assessed relative to the previous visit. The computation was based upon the mean number of monthly new \[Gd\]- enhanced lesions. Month 3 and Month 6 results are based on two negative binomial GEE regression models accounting for repeated measures on a patient. Both models were adjusted for baseline number of Gd-enhanced T1 lesions and treatment group x month interaction, using the log link.
Time frame: 6 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BAF312/Placebo | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months | 0.3 lesions | Standard Deviation 0.57 |
| BAF312 2 mg | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months | 0.4 lesions | Standard Deviation 0.96 |
| BAF312 0.5 mg | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months | 1.4 lesions | Standard Deviation 4.17 |
| Placebo | Number of New [Gd]-Enhanced T1 Lesions Monthly - Period 1 Only at 6 Months | 1.8 lesions | Standard Deviation 3.09 |
p-value: <0.00195% CI: [0.063, 0.376]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: 0.00595% CI: [0.081, 0.641]Regression, Logistic
Comparison: Pairwise treatment comparison between different BAF312 dose group and placebo used a two-sided significance level of 5% without adjusting for multiplicity.p-value: <0.00195% CI: [0.07, 0.509]Regression, Logistic
Secondary
Number of Patients Without Any New MRI Disease Activity - Period 1 +2
The proportion of patients who were free of new Gd-enhanced T1 lesions, and/or free of new or enlarging T2 lesions, i.e. free of new MRI activity (CUAL).
Time frame: 3 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAF312/Placebo | Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 15 Participants |
| BAF312 2 mg | Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 18 Participants |
| BAF312 0.5 mg | Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 20 Participants |
| Placebo | Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 13 Participants |
| BAF312 0.25 mg | Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 20 Participants |
| Placebo | Number of Patients Without Any New MRI Disease Activity - Period 1 +2 | 11 Participants |
p-value: 0.227Regression, Logistic
p-value: 0.02Regression, Logistic
p-value: 0.001Regression, Logistic
p-value: 0.122Regression, Logistic
p-value: 0.034Regression, Logistic
Secondary
Number of Patients Without Any New MRI Disease Activity - Period 1 Only
The proportion of patients who were free of new Gd-enhanced T1 lesions, and/or free of new or enlarging T2 lesions, i.e. free of new MRI activity (CUAL).
Time frame: 6 months
Population: Full analysis set One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BAF312/Placebo | Number of Patients Without Any New MRI Disease Activity - Period 1 Only | 12 Participants |
| BAF312 2 mg | Number of Patients Without Any New MRI Disease Activity - Period 1 Only | 16 Participants |
| BAF312 0.5 mg | Number of Patients Without Any New MRI Disease Activity - Period 1 Only | 11 Participants |
| Placebo | Number of Patients Without Any New MRI Disease Activity - Period 1 Only | 6 Participants |
p-value: 0.124Regression, Logistic
p-value: 0.335Regression, Logistic
p-value: 0.022Regression, Logistic
Secondary
Proportion of Participants With Relapse-free Patients - Period 1 + 2
To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only)
Time frame: 3 month
Population: Full analysis set - Period I and II
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAF312/Placebo | Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 0.87 Proportion of participants |
| BAF312 2 mg | Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 0.93 Proportion of participants |
| BAF312 0.5 mg | Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 0.93 Proportion of participants |
| Placebo | Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 0.79 Proportion of participants |
| BAF312 0.25 mg | Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 0.86 Proportion of participants |
| Placebo | Proportion of Participants With Relapse-free Patients - Period 1 + 2 | 0.88 Proportion of participants |
p-value: 0.87995% CI: [0.288, 2.925]Regression, Logistic
p-value: 0.39995% CI: [0.484, 7.167]Regression, Logistic
p-value: 0.45495% CI: [0.438, 8.296]Regression, Logistic
p-value: 0.22395% CI: [0.166, 1.511]Regression, Logistic
p-value: 0.66895% CI: [0.253, 2.392]Regression, Logistic
Secondary
Proportion of Participants With Relapse-free Patients - Period 1 Only
To explore the effect of BAF312 on the proportion of relapse-free patients (confirmed relapses only)
Time frame: 6 months
Population: Full analysis set - Period I One patient in the placebo group was misrandomized and never received study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BAF312/Placebo | Proportion of Participants With Relapse-free Patients - Period 1 Only | 0.84 proportion of participants |
| BAF312 2 mg | Proportion of Participants With Relapse-free Patients - Period 1 Only | 0.92 proportion of participants |
| BAF312 0.5 mg | Proportion of Participants With Relapse-free Patients - Period 1 Only | 0.77 proportion of participants |
| Placebo | Proportion of Participants With Relapse-free Patients - Period 1 Only | 0.72 proportion of participants |
p-value: 0.17895% CI: [0.731, 5.669]Regression, Logistic
p-value: 0.01495% CI: [1.328, 14.681]Regression, Logistic
p-value: 0.64295% CI: [0.468, 3.494]Regression, Logistic