Multiple SclerosisPhase 2CHOLINENCT01198132
A Multicentre Study of the Efficacy and Safety of Supplementary Treatment With Cholecalciferol in Patients With Relapsing Multiple Sclerosis Treated With Subcutaneous Interferon Beta-1a 44 µg 3 Times Weekly
A Phase 2 study testing Cholecalciferol (Vitamin D3) and Rebif in people with Multiple Sclerosis, run by Merck KGaA, Darmstadt, Germany at 1 site in France.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Cholecalciferol (Vitamin D3) and Rebif
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 129 participants
- Where
- 1 siteFrance
- Study dates
- Nov 2009to Nov 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 13Show fewer
- 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.
Who cannot join
- 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.
Show all 20Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Multicentre, Randomised, Double-blind, Placebo-controlled Study of the Efficacy of Supplementary Treatment With Cholecalciferol (Vitamin D3) in Patients With Relapsing- Multiple Sclerosis (RMS) Treated With Subcutaneous Interferon Beta-1a 44 µg 3 Times Weekly
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.
- Conditions
- Multiple Sclerosis
- Being tested
- Cholecalciferol (Vitamin D3), Placebo, Rebif
- Keywords
- Multiple Sclerosis Relapsing-Remitting, Relapsing Multiple Sclerosis (RMS), Rebif, Vitamin D3, Cholecalciferol
- Medical subject headings
- Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cholecalciferol (Vitamin D3)Dietary supplement
Also called 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.
PlaceboDietary supplement
Subjects receive matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.
RebifDrug
Also called Interferon beta-1a
Subjects receive subcutaneous injection of Rebif 44 mcg 3 times weekly.
| Study group | Role | What they receive |
|---|---|---|
| Cholecalciferol | Experimental | 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 3 times a week. Receives: Dietary Supplement: Cholecalciferol (Vitamin D3); Drug: Rebif |
| Placebo | Placebo comparator | Subjects receive matching placebo to Cholecalciferol once every two weeks along with subcutaneous injection of Rebif 3 times weekly. Receives: Dietary Supplement: Placebo; Drug: Rebif |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 2 years post treatment (IMP) administration
Secondary outcomes (9)
Time to First Documented Relapse
Time to First Documented Relapse was calculated using Kaplan-Meier survival methods.
Measured: 2 years post treatment (IMP) administration
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.
Measured: 2 years post treatment (IMP) administration
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.
Measured: 2 years post treatment (IMP) administration
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.
Measured: Baseline up to week 96
Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI)
Measured: 2 years post treatment (IMP) administration
Changes From Baseline in Measured Lesion Load (T2)
Baseline defined as last value recorded prior to first intake of study drug.
Measured: Baseline, Week 96
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.
Measured: Baseline, Week 96
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).
Measured: 2 years post treatment (IMP) administration
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.
Measured: Baseline up to end of treatment (week 96)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Sep 2010 (estimated)
- Study startNov 2009
- Primary completionMar 2015
- Study completionNov 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 129 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck KGaA, Darmstadt, Germany
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Serono S.A.S, France
- Responsible party
- Sponsor
- Investigators
- Medical Responsible, Study director, Merck KGaA, Darmstadt, Germany
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01198132
- Sponsor's protocol ID
- 701068-524
- Other IDs
- 2009-013695-46, 2009
- Acronym
- CHOLINE
- Status last verified
- May 2017
- First submitted
- 8 Sep 2010
- Last updated
- 14 Dec 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Camu W, Lehert P, Pierrot-Deseilligny C, Hautecoeur P, Besserve A, Jean Deleglise AS, Payet M, Thouvenot E, Souberbielle JC. Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE). Neurol Neuroimmunol Neuroinflamm. 2019 Aug 6;6(5):e597. doi: 10.1212/NXI.0000000000000597. Print 2019 Sep.
PubMed 31454777
Study at a glance
From the registry record, last updated by the sponsor on 14 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicentre, Randomised, Double-blind, Placebo-controlled Study of the Efficacy of Supplementary Treatment With Cholecalciferol (Vitamin D3) in Patients With Relapsing- Multiple Sclerosis (RMS) Treated With Subcutaneous Interferon Beta-1a 44 µg 3 Times Weekly
- ClinicalTrials.gov ID
- NCT01198132
- Acronym / sponsor ID
- CHOLINE / 701068-524
- Conditions
- Multiple Sclerosis
- Keywords
- Multiple Sclerosis Relapsing-Remitting, Relapsing Multiple Sclerosis (RMS), Rebif, Vitamin D3, Cholecalciferol
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 129 participants (actual)
- Lead sponsor
- Merck KGaA, Darmstadt, GermanyIndustry (pharma, biotech, devices)
- Collaborators
- Merck Serono S.A.S, France
- Study start
- Nov 2009 (actual)
- Primary completion
- Mar 2015 (actual)
- Study completion
- Nov 2015 (actual)
- First posted
- 9 Sep 2010 (estimated)
- Results
- Posted 14 Dec 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cholecalciferol | Experimental | Dietary Supplement: Cholecalciferol (Vitamin D3), Drug: RebifSubjects 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 3 times a week. |
| Placebo | Placebo comparator | Dietary Supplement: Placebo, Drug: RebifSubjects receive matching placebo to Cholecalciferol once every two weeks along with subcutaneous injection of Rebif 3 times weekly. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (20 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cholecalciferol (Vitamin D3)Also: Vitamin D3Subjects 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 supplement | Cholecalciferol |
| PlaceboSubjects receive matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly. | Dietary supplement | Placebo |
| RebifAlso: Interferon beta-1aSubjects receive subcutaneous injection of Rebif 44 mcg 3 times weekly. | Drug | Cholecalciferol, Placebo |
Primary outcome
Annualized Relapse Rate
Time frame: 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).
9 secondary outcomes
Time to First Documented Relapse
Time frame: 2 years post treatment (IMP) administration
Mean Number of Relapses Per Subject
Time frame: 2 years post treatment (IMP) administration
Number of Relapse-Free (Documented) Subjects
Time frame: 2 years post treatment (IMP) administration
Cumulative Probability of Progression of Disability (Kaplan-Meier Curves)
Time frame: Baseline up to week 96
Number of New or Extended Lesions by T1- and T2-Weighted Magnetic Resonance Imaging (MRI)
Time frame: 2 years post treatment (IMP) administration
Changes From Baseline in Measured Lesion Load (T2)
Time frame: Baseline, Week 96
Change From Baseline in Measurement and Evaluation of Cognitive Ability by Paced Auditory Serial Addition Task (PASAT) Total Score At Week 96
Time frame: Baseline, Week 96
Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L)
Time frame: 2 years post treatment (IMP) administration
Number of Subjects With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs and Abnormal Clinical Laboratory
Time frame: Baseline up to end of treatment (week 96)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Dec 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31454777Camu W, Lehert P, Pierrot-Deseilligny C, Hautecoeur P, Besserve A, Jean Deleglise AS, Payet M, Thouvenot E, Souberbielle JC. Cholecalciferol in relapsing-remitting MS: A randomized clinical trial (CHOLINE). Neurol Neuroimmunol Neuroinflamm. 2019 Aug 6;6(5):e597. doi: 10.1212/NXI.0000000000000597. Print 2019 Sep.
Related trials for Multiple Sclerosis
RecruitingPhase 2
Metformin as an add-on or Monotherapy in Treatment of Aging People With Multiple Sclerosis (MS)
Multiple Sclerosis
RecruitingObservational study
Pain Phenotypes in Individuals With Multiple Sclerosis
Multiple Sclerosis, Chronic Pain
Not yet recruiting
Evaluating the Effect of the Zeen Mobility Device on Clinical Practicality, Safety, and Impact (Via Assessments of Walking, Standing Tolerance, Balance, Endurance, Effort, and Participation in Daily Tasks) in an Outpatient Rehabilitation Setting for Individuals With Mobility Impairments.
Stroke, Parkinson's Disease (PD)
RecruitingPhase 3
Dalfampridine Combined With Physical Therapy for Mobility Impairment in Multiple Sclerosis
Multiple Sclerosis
RecruitingPhase 2
Targeting Agonists of Glucagon-like Peptide-1 Receptor for Multiple Sclerosis
Multiple Sclerosis
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Responsible study director
Merck KGaA, Darmstadt, Germany
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Cholecalciferol (Vitamin D3) and Rebif in people with Multiple Sclerosis, run by Merck KGaA, Darmstadt, Germany at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Dec 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Annualized Relapse Rate (time frame: 2 years post treatment (IMP) administration). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01198132, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Dec 2017.