Multiple Sclerosis
Conditions
Keywords
Multiple Sclerosis Relapsing-Remitting, Relapsing Multiple Sclerosis (RMS), Rebif, Vitamin D3, Cholecalciferol
Brief summary
The aim of this multicentre, randomised, double-blind, placebo-controlled study is to evaluate the efficacy and safety of supplementary treatment with cholecalciferol (vitamin D3) in subjects with relapsing multiple sclerosis (R MS) treated with subcutaneous (s.c.) interferon beta-1a 44 microgram (mcg) \[Rebif\] 3 times weekly. The subjects will be divided into 2 groups, one receiving cholecalciferol 100,000 IU twice monthly along with Rebif treatment and the other group will be on placebo along with Rebif treatment. A total of 200 subjects will be recruited in 20-30 centres in France.
Interventions
DIETARY_SUPPLEMENTCholecalciferol (Vitamin D3)
Subjects receive Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week.
DIETARY_SUPPLEMENTPlacebo
Subjects receive matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.
DRUGRebif
Subjects receive subcutaneous injection of Rebif 44 mcg 3 times weekly.
Sponsors
Merck Serono S.A.S, France
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of RRMS according to Poser criteria (clinically definite multiple sclerosis \[CDMS\] or laboratory supported definite multiple sclerosis \[LSDMS\]) or according to McDonald criteria (2005). * Subjects aged between 18 and 65 years. * Treated with interferon beta-1a 44 mcg (or 22 mcg in case of intolerance to 44 mcg) 3 times weekly subcutaneously for 4 months ± (2 months) at the randomization visit (V1). * Expanded disability status scale (EDSS) score between 0 and 5. * At least one documented episode during the last two year. * Stable disease with no episodes over the last 30 days. * Serum 25-hydroxyvitamin D less than (\<) 75 nanomolar per liter (nmol/l) at randomization visit. * Women must not be pregnant or breast-feeding, and women of childbearing age must meet the following criteria: * Surgically sterilised, or * Using a highly effective contraceptive method throughout the entire duration of the study. A highly effective contraceptive method is defined as a method with a very low failure rate (i.e. \< 1 % per year) with regular and appropriate use, e.g. implants, injectable contraceptives, combined oral contraceptives, coil, abstinence or vasectomised partner. * Menopausal women may be included. * Affiliated to French healthcare insurance. * Subjects must be ready and able to provide informed consent and comply with the protocol requirements.
Exclusion criteria
* Hormonal abnormalities associated with vitamin D other than low dietary intake or reduced exposure to sun, for example malabsorption (coeliac disease, Whipple's disease, inflammatory bowel disease, intestinal derivation, short bowel syndrome), cirrhosis, nephrotic syndrome, hyperthyroidism, rickets, hypoparathyroidism, cancer, granulomatous diseases (sarcoidosis, silicosis) and lymphomas known at the initial visit. * Patients with osteoporosis or known osteopenia. * Use of medicines affecting vitamin D metabolism other than corticosteroids, e.g. anticonvulsants (phenobarbital, primidone, phenytoin), rifampicin, isoniazid, ketoconazole, 5-FU and leucovorin, or thiazide diuretics. * Previous or ongoing hypercalcaemia. * Situations involving increased susceptibility to hypercalcaemia, e.g. known cardiac arrhythmia or cardiac disease, treatment with digitalis, renal lithiasis. * Any contraindication to the treatment (cholecalciferol) stated in the summary of product characteristics. * Moderate renal impairment defined as creatinine clearance between 30 and 60 ml/min. * An active episode during the month prior to inclusion in the study. * Inadequate liver function, defined as total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) or alkaline phosphatase greater than (\>) 2.5 \* upper limit of normal. * Severe renal impairment defined as creatinine clearance below 30 milliliter per minute (ml/min). * Inadequate marrow reserves, defined as white blood cells \< 0.5 \* lower limit of normal. * Serious or acute heart disease such as uncontrolled cardiac arrhythmia, uncontrolled angina, cardiomyopathy or uncontrolled congestive heart failure. * History of severe depression, or attempted suicide or ongoing suicidal ideation. * Epilepsy inadequately controlled by treatment. * Ongoing or previous alcohol or drug abuse (within the last two years). * Major medical or psychiatric disease which, in the opinion of investigator, would place the subject at risk or could adversely affect compliance with the study protocol. * Known hypersensitivity to gadolinium and/or known inability to undergo MRI. * Any medical condition requiring chronic treatment with systemic corticosteroids. * Participation in any other studies involving other study products over the 30 days prior to inclusion in this study. * Legal incapacity or limited legal capacity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate | 2 years post treatment (IMP) administration | The annualized relapse rate was calculated for each treatment group as follows: the number of relapses observed during the study period divided by the time spent in the study (in years). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Relapses Per Subject | 2 years post treatment (IMP) administration | Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Mean and standard deviation were reported. |
| Number of Relapse-Free (Documented) Subjects | 2 years post treatment (IMP) administration | The relapse-free patients after 2 years of treatment was calculated using Cochran-Mantel-Haenszel test using the site as control variable. |
| Cumulative Probability of Progression of Disability (Kaplan-Meier Curves) | Baseline up to week 96 | Disability progression was assessed using Expanded disability status scale (EDSS). EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A one-point increase on the EDSS scale was considered as a progression in disability. The time to disability progression was summarized using Kaplan-Meier survival methods. The cumulative probability of confirmed disease progression at each visit was obtained by applying a Kaplan-Meier method to the time to confirmed disease progression. |
| Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI) | 2 years post treatment (IMP) administration | — |
| Time to First Documented Relapse | 2 years post treatment (IMP) administration | Time to First Documented Relapse was calculated using Kaplan-Meier survival methods. |
| Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96 | Baseline, Week 96 | The Adapted Paced Auditory Serial Addition Task (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. The total score for PASAT is the total number of correct answers (out of 60, for a total possible score ranging from 0-60 with higher score indicates higher auditory processing speed) for each trial. Change from baseline in PASAT total score at Week 96 was summarized. |
| Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) | 2 years post treatment (IMP) administration | The EQ-5D health questionnaire is a generic self-reported health-related quality of life instrument that includes a 100 mm Visual Analog Scale (VAS) to measure the general health state, as well as 5 items corresponding to one dimension each: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In this study, the VAS scale is not collected and the version 3L of the scale was used: Each dimension had 3 possible levels: 1 = no problem, 2 = some problems and 3 = extreme problems. EQ-5D-3L weighted health state index exists that combines the score of the 5 dimensions and ranges from 0 to 1 (full health). The variables for the 5 dimensions of the EQ-5D descriptive system was named 'mobility','selfcare', 'activity', 'pain', and 'anxiety'. The 5 variables contained the values for the different dimensions in the EQ-5D health profile (i.e. 1, 2, or 3). |
| Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory | Baseline up to end of treatment (week 96) | A serious TEAE 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 and TEAE was defined as newly occurring or worsening after first dose. Clinical laboratory abnormalities are expected to be reported as adverse events if they met any criterion for seriousness, led to treatment discontinuation, required a medical intervention or were considered clinically significant by the investigator. |
| Changes From Baseline in Measured Lesion Load (T2) | Baseline, Week 96 | Baseline defined as last value recorded prior to first intake of study drug. |
Countries
France
Participant flow
Pre-assignment details
A total of 129 subjects were randomized. Out of which 126 subjects treated in the study and 90 subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Cholecalciferol Subjects received Cholecalciferol 100,000 IU one dose fortnightly (equivalent to a daily dose of approximately 7142 IU) for 96 weeks treatment period along with subcutaneous Rebif 44 mcg 3 times a week. | 63 |
| Placebo Subjects received matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly. | 66 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal/clinically significant biologic | 1 | 1 |
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 3 |
| Overall Study | Other Unspecified | 3 | 6 |
| Overall Study | Physician Decision | 5 | 4 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Sign/symptoms of underlying disease | 2 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 5 |
Baseline characteristics
| Characteristic | Cholecalciferol | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 38.5 years STANDARD_DEVIATION 9.29 | 36.9 years STANDARD_DEVIATION 8.34 | 37.7 years STANDARD_DEVIATION 8.81 |
| Sex: Female, Male Female | 50 Participants | 39 Participants | 89 Participants |
| Sex: Female, Male Male | 13 Participants | 27 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 61 | 31 / 65 |
| serious Total, serious adverse events | 11 / 61 | 10 / 65 |
Outcome results
Primary
Annualized Relapse Rate
The annualized relapse rate was calculated for each treatment group as follows: the number of relapses observed during the study period divided by the time spent in the study (in years).
Time frame: 2 years post treatment (IMP) administration
Population: ITT set included all randomized subjects.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cholecalciferol | Annualized Relapse Rate | 0.45 Relapse per year |
| Placebo | Annualized Relapse Rate | 0.34 Relapse per year |
p-value: 0.379795% CI: [0.48, 1.32]Poisson log-linear model
Secondary
Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L)
The EQ-5D health questionnaire is a generic self-reported health-related quality of life instrument that includes a 100 mm Visual Analog Scale (VAS) to measure the general health state, as well as 5 items corresponding to one dimension each: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In this study, the VAS scale is not collected and the version 3L of the scale was used: Each dimension had 3 possible levels: 1 = no problem, 2 = some problems and 3 = extreme problems. EQ-5D-3L weighted health state index exists that combines the score of the 5 dimensions and ranges from 0 to 1 (full health). The variables for the 5 dimensions of the EQ-5D descriptive system was named 'mobility','selfcare', 'activity', 'pain', and 'anxiety'. The 5 variables contained the values for the different dimensions in the EQ-5D health profile (i.e. 1, 2, or 3).
Time frame: 2 years post treatment (IMP) administration
Population: ITT set included all randomized subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholecalciferol | Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) | Baseline (n=60, 63) | 0.7834 units on a scale | Standard Deviation 0.2409 |
| Cholecalciferol | Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) | Change at Week 96 (n=43, 45) | -0.0051 units on a scale | Standard Deviation 0.13742 |
| Placebo | Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) | Baseline (n=60, 63) | 0.7937 units on a scale | Standard Deviation 0.21447 |
| Placebo | Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) | Change at Week 96 (n=43, 45) | 0.0043 units on a scale | Standard Deviation 0.19654 |
Secondary
Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96
The Adapted Paced Auditory Serial Addition Task (PASAT) is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. The total score for PASAT is the total number of correct answers (out of 60, for a total possible score ranging from 0-60 with higher score indicates higher auditory processing speed) for each trial. Change from baseline in PASAT total score at Week 96 was summarized.
Time frame: Baseline, Week 96
Population: ITT set included all randomized subjects.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholecalciferol | Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96 | Baseline | 39.9 units on a scale | Standard Deviation 14.8 |
| Cholecalciferol | Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96 | Change at Week 96 | 6.4 units on a scale | Standard Deviation 8.49 |
| Placebo | Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96 | Baseline | 43.3 units on a scale | Standard Deviation 12.49 |
| Placebo | Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96 | Change at Week 96 | 6.0 units on a scale | Standard Deviation 8.02 |
Secondary
Changes From Baseline in Measured Lesion Load (T2)
Baseline defined as last value recorded prior to first intake of study drug.
Time frame: Baseline, Week 96
Population: ITT set included all randomized subjects. Here n signifies those subjects who were evaluable for this outcome measure at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholecalciferol | Changes From Baseline in Measured Lesion Load (T2) | Baseline (n=49, 43) | 5305.4 cubic millimeter (mm^3) | Standard Deviation 10858.86 |
| Cholecalciferol | Changes From Baseline in Measured Lesion Load (T2) | Change at Week 96 (n=44, 38) | -315.0 cubic millimeter (mm^3) | Standard Deviation 2523.97 |
| Placebo | Changes From Baseline in Measured Lesion Load (T2) | Baseline (n=49, 43) | 3520.1 cubic millimeter (mm^3) | Standard Deviation 4954.44 |
| Placebo | Changes From Baseline in Measured Lesion Load (T2) | Change at Week 96 (n=44, 38) | 596.3 cubic millimeter (mm^3) | Standard Deviation 2034.8 |
Secondary
Cumulative Probability of Progression of Disability (Kaplan-Meier Curves)
Disability progression was assessed using Expanded disability status scale (EDSS). EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. A one-point increase on the EDSS scale was considered as a progression in disability. The time to disability progression was summarized using Kaplan-Meier survival methods. The cumulative probability of confirmed disease progression at each visit was obtained by applying a Kaplan-Meier method to the time to confirmed disease progression.
Time frame: Baseline up to week 96
Population: ITT set included all randomized subjects. Here Number of participant analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cholecalciferol | Cumulative Probability of Progression of Disability (Kaplan-Meier Curves) | 12.7 percentage of subjects |
| Placebo | Cumulative Probability of Progression of Disability (Kaplan-Meier Curves) | 9.1 percentage of subjects |
Secondary
Mean Number of Relapses Per Subject
Relapse was defined as new, worsening or recurrent neurological symptoms attributed to multiple sclerosis that last for at least 24 hours without fever or infection, or adverse reaction to prescribed medication, preceded by a stable or improving neurological status of at least 30 days. Mean and standard deviation were reported.
Time frame: 2 years post treatment (IMP) administration
Population: ITT set included all randomized subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cholecalciferol | Mean Number of Relapses Per Subject | 0.5 relapses | Standard Deviation 0.78 |
| Placebo | Mean Number of Relapses Per Subject | 0.5 relapses | Standard Deviation 0.75 |
Secondary
Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI)
Time frame: 2 years post treatment (IMP) administration
Population: ITT set included all randomized subjects. Here Number of participant analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cholecalciferol | Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI) | T1-weighted MRI | 0.4 lesions | Standard Deviation 0.76 |
| Cholecalciferol | Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI) | T2-weighted MRI | 0.5 lesions | Standard Deviation 0.79 |
| Placebo | Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI) | T1-weighted MRI | 1.9 lesions | Standard Deviation 3.76 |
| Placebo | Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI) | T2-weighted MRI | 2.0 lesions | Standard Deviation 4.71 |
Secondary
Number of Relapse-Free (Documented) Subjects
The relapse-free patients after 2 years of treatment was calculated using Cochran-Mantel-Haenszel test using the site as control variable.
Time frame: 2 years post treatment (IMP) administration
Population: ITT set included all randomized subjects. Here Number of participants analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cholecalciferol | Number of Relapse-Free (Documented) Subjects | 35 subjects |
| Placebo | Number of Relapse-Free (Documented) Subjects | 27 subjects |
Secondary
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory
A serious TEAE 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 and TEAE was defined as newly occurring or worsening after first dose. Clinical laboratory abnormalities are expected to be reported as adverse events if they met any criterion for seriousness, led to treatment discontinuation, required a medical intervention or were considered clinically significant by the investigator.
Time frame: Baseline up to end of treatment (week 96)
Population: Safety set included all subjects who receive at least one administration of trial medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cholecalciferol | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory | TEAEs | 43 subjects |
| Cholecalciferol | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory | Serious TEAEs | 11 subjects |
| Placebo | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory | TEAEs | 35 subjects |
| Placebo | Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory | Serious TEAEs | 10 subjects |
Secondary
Time to First Documented Relapse
Time to First Documented Relapse was calculated using Kaplan-Meier survival methods.
Time frame: 2 years post treatment (IMP) administration
Population: ITT set included all randomized subjects. Here Number of participant analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cholecalciferol | Time to First Documented Relapse | NA weeks |
| Placebo | Time to First Documented Relapse | NA weeks |