Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
Subjects with relapsing remitting multiple sclerosis
Brief summary
General Note: throughout this record, Rebif® New Formulation is used for historical and consistency purposes. Objectives: Primary: To evaluate the efficacy of Rebif® New Formulation (Interferon-beta-1a \[IFN-beta-1a\], RNF), compared to placebo, in subjects with Relapsing Remitting Multiple Sclerosis and active disease by means of Magnetic Resonance Imaging (MRI) at the end of 16 weeks of treatment Secondary: To evaluate the efficacy of RNF by comparing the mean number of combined unique (CU) lesions per scan per subject between the initial 16 weeks of placebo treatment and 24 weeks of RNF treatment in the same subjects, originally randomized to placebo. Primary Endpoints: The primary endpoint is the difference between the number of CU active MRI lesions at Week 16 in the RNF group (Group 1) versus the placebo group (Group 2). Secondary Endpoints: The secondary endpoint is the difference in the mean number of CU active MRI lesions per scan per subject over the following treatment periods: Study Day 1 - Week 16 versus Weeks 17 - 40 for the subjects randomized to Group 2.
Interventions
DRUGRebif® New Formulation (IFN-beta-1a, RNF)
RNF will be administered at a dose of 44 mcg subcutaneously three times a week for 40 weeks.
DRUGPlacebo
Matching placebo will be administered subcutaneously three times a week for 16 weeks.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Males and females between 18 and 60 years of age * Female subjects must be neither pregnant nor breast-feeding and must lack child-bearing potential, as defined by either: post-menopausal or surgically sterile or use an effective method of contraception for the duration of the study * Have Relapsing Remitting Multiple Sclerosis (RRMS) according to the revised McDonald criteria 2005 * Have brain and/or spinal MRI with findings typical of Multiple Sclerosis (MS) * Have disease duration for more than 12 months * Have disease activity characterized by at least one clinical event and one or more Gadolinium-enhancing MRI lesions within the 6 months prior to randomization * Have score of \<=5.5 on the Expanded Disability Status Scale (EDSS) * Be willing and able to comply with the protocol for the duration of the study * Have given written informed consent prior to any study-related procedure not part of the normal medical practice
Exclusion criteria
* Have any disease other than MS that could better explain his/her signs and symptoms * Have complete transverse myelitis or bilateral optic neuritis * Have received or have used anytime monoclonal antibodies, mitoxantrone, cytotoxic or immunosuppressive therapy (excluding systemic steroids and adrenocorticotrophic hormone \[ACTH\]), or total lymphoid irradiation * Have received within 3 months prior to baseline any approved disease-modifying therapy for MS, cytokine or anti-cytokine therapy, intravenous immunoglobulin, plasmapheresis, any investigational drug, or experimental procedure * Have received within 30 days prior to baseline oral or systemic corticosteroids or ACTH * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Combined Unique (CU) Active Magnetic Resonance Imaging (MRI) Lesions at Week 16 | 16 Weeks | CU active lesions were defined as a unique newly active or persistently active lesion on the protocol density/time constant 2 (PD/T2) scan or the gadolinium (Gd-) enhanced time constant 1 (T1) scan (with a method to avoid double counting). |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Week 40 | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. AEs were categorized based upon the treatment period during which they occurred, that is, double-blind period (up to Week 16) and rater-blind period (Week 17 up to Week 40). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of CU Lesions Per Scan Between the Initial 16 Weeks of Placebo Treatment and 24 Weeks of RNF Treatment in the Same Participants, Originally Randomized to Placebo. | Day 1 up to Week 16 and Week 17 up to Week 40 | CU active lesions were defined as a unique newly active or persistently active lesion on the PD/T2 scan or the gadolinium enhanced T1 scan (with a method to avoid double counting). Only Placebo Followed by RNF arm was evaluable for this outcome measure. |
| Number of CU Active MRI Lesions | Up to Week 40 | CU active lesions were defined as a unique newly active or persistently active lesion on the PD/T2 scan or the gadolinium enhanced T1 scan (with a method to avoid double counting). |
Participant flow
Recruitment details
Date of first participant first visit: 15 Dec 2006. Date of last participant last visit: 28 Nov 2008. Twenty five trial centers enrolled participants in the following countries: Bulgaria (7), Canada(2), Estonia (2), Germany (1), Italy(2), Lithuania (1), Romania (1), Russian Federation (4), Serbia (2), and Spain (3).
Pre-assignment details
Participants meeting the eligibility criteria during screening period of up to 14 days were randomly assigned in a 2:1 ratio to receive either Rebif® New Formulation or matching placebo for 16 weeks. There were 33 screening failures: participants who did not meet all eligibility criteria (n=29), withdrawal of consent (n=3), and lost of view (n=1).
Participants by arm
| Arm | Count |
|---|---|
| Rebif® New Formulation (IFN-beta-1a, RNF) RNF 44 mcg administered subcutaneously three times a week for 40 weeks. | 120 |
| Placebo/RNF Matching placebo administered subcutaneously three times a week for 16 weeks, followed by RNF 44 mcg administered subcutaneously three times a week for subsequent 24 weeks. | 60 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease Progression | 2 | 0 |
| Overall Study | Inclusion criteria absent | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Non-compliant | 0 | 1 |
| Overall Study | Participant decided to stop | 0 | 1 |
| Overall Study | Participant decided to withdraw | 1 | 0 |
| Overall Study | Participant refused MRI | 1 | 0 |
| Overall Study | Participant's reason | 0 | 1 |
| Overall Study | Participant unable to use Rebiject II | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Rebif® New Formulation (IFN-beta-1a, RNF) | Placebo/RNF | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 120 Participants | 60 Participants | 180 Participants |
| Age, Continuous | 34.0 years STANDARD_DEVIATION 7.8 | 35.2 years STANDARD_DEVIATION 10.5 | 34.4 years STANDARD_DEVIATION 8.8 |
| Region of Enrollment Bulgaria | 40 participants | 12 participants | 52 participants |
| Region of Enrollment Canada | 3 participants | 3 participants | 6 participants |
| Region of Enrollment Estonia | 8 participants | 5 participants | 13 participants |
| Region of Enrollment Germany | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Italy | 7 participants | 4 participants | 11 participants |
| Region of Enrollment Lithuania | 5 participants | 3 participants | 8 participants |
| Region of Enrollment Romania | 11 participants | 8 participants | 19 participants |
| Region of Enrollment Russian Federation | 20 participants | 12 participants | 32 participants |
| Region of Enrollment Serbia | 20 participants | 9 participants | 29 participants |
| Region of Enrollment Spain | 5 participants | 4 participants | 9 participants |
| Sex: Female, Male Female | 88 Participants | 42 Participants | 130 Participants |
| Sex: Female, Male Male | 32 Participants | 18 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 100 / 120 | 39 / 60 |
| serious Total, serious adverse events | 4 / 120 | 3 / 60 |
Outcome results
Primary
Number of Combined Unique (CU) Active Magnetic Resonance Imaging (MRI) Lesions at Week 16
CU active lesions were defined as a unique newly active or persistently active lesion on the protocol density/time constant 2 (PD/T2) scan or the gadolinium (Gd-) enhanced time constant 1 (T1) scan (with a method to avoid double counting).
Time frame: 16 Weeks
Population: ITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rebif® New Formulation (IFN-beta-1a, RNF) | Number of Combined Unique (CU) Active Magnetic Resonance Imaging (MRI) Lesions at Week 16 | 0.9 lesions | Standard Deviation 1.4 |
| Placebo/RNF | Number of Combined Unique (CU) Active Magnetic Resonance Imaging (MRI) Lesions at Week 16 | 3.0 lesions | Standard Deviation 4.1 |
p-value: <0.001ANOVA
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. AEs were categorized based upon the treatment period during which they occurred, that is, double-blind period (up to Week 16) and rater-blind period (Week 17 up to Week 40).
Time frame: Baseline up to Week 40
Population: Safety population included all randomized participants who received at least one dose of study drug. Here, 'n' signifies those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rebif® New Formulation (IFN-beta-1a, RNF) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs during double-blind period (n = 120, 60) | 100 participants |
| Rebif® New Formulation (IFN-beta-1a, RNF) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs during rater-blind period (n = 112, 57) | 72 participants |
| Rebif® New Formulation (IFN-beta-1a, RNF) | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs during overall period (n = 120, 60) | 4 participants |
| Placebo/RNF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs during double-blind period (n = 120, 60) | 39 participants |
| Placebo/RNF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs during rater-blind period (n = 112, 57) | 43 participants |
| Placebo/RNF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs during overall period (n = 120, 60) | 3 participants |
Secondary
Mean Number of CU Lesions Per Scan Between the Initial 16 Weeks of Placebo Treatment and 24 Weeks of RNF Treatment in the Same Participants, Originally Randomized to Placebo.
CU active lesions were defined as a unique newly active or persistently active lesion on the PD/T2 scan or the gadolinium enhanced T1 scan (with a method to avoid double counting). Only Placebo Followed by RNF arm was evaluable for this outcome measure.
Time frame: Day 1 up to Week 16 and Week 17 up to Week 40
Population: ITT population included all randomized participants who received at least one dose of study drug. Here, N (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rebif® New Formulation (IFN-beta-1a, RNF) | Mean Number of CU Lesions Per Scan Between the Initial 16 Weeks of Placebo Treatment and 24 Weeks of RNF Treatment in the Same Participants, Originally Randomized to Placebo. | Day 1 up to Week 16 | 2.31 lesions | Standard Deviation 2.63 |
| Rebif® New Formulation (IFN-beta-1a, RNF) | Mean Number of CU Lesions Per Scan Between the Initial 16 Weeks of Placebo Treatment and 24 Weeks of RNF Treatment in the Same Participants, Originally Randomized to Placebo. | Week 17 up to Week 40 | 0.65 lesions | Standard Deviation 0.95 |
Comparison: Mean difference was calculated by subtracting 'Day 1 up to Week 16' from 'Week 17 up to Week 40' and analyzed using Wilcoxon signed-rank test.p-value: <0.001Wilcoxon signed-rank test
Secondary
Number of CU Active MRI Lesions
CU active lesions were defined as a unique newly active or persistently active lesion on the PD/T2 scan or the gadolinium enhanced T1 scan (with a method to avoid double counting).
Time frame: Up to Week 40
Population: ITT population included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rebif® New Formulation (IFN-beta-1a, RNF) | Number of CU Active MRI Lesions | 0.62 lesions | Standard Deviation 1.29 |
| Placebo/RNF | Number of CU Active MRI Lesions | 1.27 lesions | Standard Deviation 1.33 |