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 (CHOLINE)

• ClinicalTrials.gov Identifier: NCT01198132
• Recruitment Status: Completed
• First Posted: September 9, 2010
• Results First Posted: December 14, 2017
• Last Update Posted: December 14, 2017
• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborator: Merck Serono S.A.S, France
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: September 8, 2010
• First Posted Date: September 9, 2010
• Results First Submitted Date: December 6, 2016
• Results First Posted Date: December 14, 2017
• Last Update Posted Date: December 14, 2017
• Actual Study Start Date: November 2009
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2017)

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).

Original Primary Outcome Measures (submitted: September 8, 2010)

Reduction in rate of relapse [ Time Frame: After 2 years of treatment ]

Relapse rate is expressed as percentage difference between the two groups

Current Secondary Outcome Measures (submitted: May 9, 2017)

• Time to First Documented Relapse [ Time Frame: 2 years post treatment (IMP) administration ]
  Time to First Documented Relapse was calculated using Kaplan-Meier survival methods.
• Mean Number of Relapses Per Subject [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 2 years post treatment (IMP) administration ]
• Changes From Baseline in Measured Lesion Load (T2) [ Time Frame: Baseline, Week 96 ]
  Baseline defined as last value recorded prior to first intake of study drug.
• 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 ]
  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) [ Time Frame: 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 [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: September 8, 2010)

• Time to First Documented Relapse [ Time Frame: After 2 years of treatment ]
• Mean number of relapses per subject per year [ Time Frame: After 2 years of treatment ]
• Number of Relapse-Free (Documented) Subjects [ Time Frame: after two years of treatment ]
• Cumulative Probability of Progression of Disability (Kaplan-Meier Curves) [ Time Frame: After 2 years of treatment ]
• Number of new or extended lesions by T1- and T2-weighted MRI [ Time Frame: After 2 years of treatment ]
• Changes in measured lesion load (T2), number of new lesions (T1 gadolinium activity and black holes) [ Time Frame: After 2 years of treatment ]
• Measurement and evaluation of cognitive ability by Paced auditory serial addition task (PASAT) [ Time Frame: After 2 years of treatment ]
• Change in quality of life (QoL) using EQ-5D (EuroQoL-5 dimension questionnaire) [ Time Frame: After 2 years of treatment ]
• Safety of the treatment assessed by recording of adverse events and clinical laboratory evaluations (blood biochemistry and urinalysis) [ Time Frame: After 2 years of treatment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Supportive Care
• Condition: Multiple Sclerosis

Intervention

• Dietary Supplement: Cholecalciferol (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.
  Other Name: Vitamin D3
• Dietary Supplement: Placebo
  Subjects receive matching placebo to Cholecalciferol once every two weeks orally along with subcutaneous injection of Rebif 44 mcg 3 times weekly.
• Drug: Rebif
  Subjects receive subcutaneous injection of Rebif 44 mcg 3 times weekly.
  Other Name: Interferon beta-1a

Study Arms

• Experimental: Cholecalciferol
  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.
  Interventions:

  • Dietary Supplement: Cholecalciferol (Vitamin D3)
  • Drug: Rebif
• Placebo Comparator: Placebo
  Subjects receive matching placebo to Cholecalciferol once every two weeks along with subcutaneous injection of Rebif 3 times weekly.
  Interventions:

  • Dietary Supplement: Placebo
  • Drug: Rebif

• 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). pii: e597. doi: 10.1212/NXI.0000000000000597. Print 2019 Sep. Erratum in: Neurol Neuroimmunol Neuroinflamm. 2019 Nov 15;7(1):.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 3, 2014): 129
• Original Estimated Enrollment (submitted: September 8, 2010): 250
• Actual Study Completion Date: November 2015
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT01198132
• Other Study ID Numbers: 701068-524; 2009-013695-46 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Merck KGaA, Darmstadt, Germany
• Study Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Serono S.A.S, France

Investigators

• Study Director: Medical Responsible; Merck KGaA, Darmstadt, Germany

• PRS Account: Merck KGaA, Darmstadt, Germany
• Verification Date: May 2017