The Effects of Interferon Beta Combined With Vitamin D on Relapsing Remitting Multiple Sclerosis Patients

September 2, 2012 updated by: Carmel Medical Center

A One Year Prospective, Randomized, Double Blind Interventional Study to Assess Tolerability, Quality of Life and Immunomodulation With Interferon Beta Combined With Vitamin D in Patients With Relapsing Remitting Multiple Sclerosis

The investigators hypothesize that vitamin D supplementation may ameliorate interferon beta-induced flu-like symptoms, owing to reduced release and activity of the cytokines that are in correlation with this adverse event. Vitamin D supplementation may also positively affect injection site reactions due to its immunomodulatory effects. Vitamin D may also augment the therapeutic efficacy of interferon beta among multiple sclerosis (MS) patients. Vitamin D intake may influence melatonin levels of MS patients as they share the same nuclear receptor.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Detailed Description of Study Evaluations

Adherence to treatment evaluation:

Patients will be asked to bring the empty packages of the IFN beta and Vitamin D that were used during the study.

Flu like symptoms and Injection site reactions evaluation:

Data regarding FLS and ISRs will be collected by means of a telephone interview every other week. The extent of FLS on the day of injection will be evaluated using a self-rating scale. A score from 0 (not at all) to 5 (very strong), will be given to each FLS component, i.e.: myalgia, chills, headache, malaise and fatigue, exacerbation of neurologic symptoms, sweating and difficulty to function compared to the time before injection. Patient will also record their oral temperature upon awakening as well as at their discretion. All patients will be provided with the same thermometer. Participants will be asked to report the frequency of Ibuprofen or Paracetamol use. and will be recommended not to exceed 800mg of Ibuprofen or 1000mg of Paracetamol per day, unless the symptoms are unbearable.

Patients will be inquired about the subjective degree of injection site pain for the first injections of every other week, by means of a 100 mm visual analogue scale (VAS scale). Patients will be seen at the clinic at 3 months intervals and in that visit the injection site will be inspected by the evaluating physician/ nurse and will be graded on a 0 to 3 scale: 0-none, 1- pain, itching or erythema, 2- swelling with inflammation and 3- ulceration and/or necrosis. Mode of application (manual or automatic injection) as well as needle size will be also recorded.

Patients will be instructed to refrain from reporting FLS and ISRs on the occasion of inter-current febrile illness or during and 4 weeks after corticosteroids treatment. In that case, patients will postpone the report by a week.

MS clinical parameters:

Patients will be clinically evaluated at enrollment and at 6 and 12 months for disease progression, by means of the EDSS score . The evaluating neurologist will be blinded to the patient's treatment.

Relapses, characterized by emergence of new symptoms or the worsening of existing ones for more than 24 hours in the absence of fever or infection ( McDonald et al., 2001) and severe enough to warrant corticosteroids treatment will be recorded.

Health related quality of life will be also evaluated at baseline and at the completion of the study, by means of a MS-specific validated questionnaire - FAMS (Functional Assessment of MS) (Miller A, 2006). (Attached)

Laboratory evaluation:

The following measurements will be obtained at the beginning of the study for the purpose of excluding patients with baseline impairment of mineral metabolism and at the end of the study to evaluate the resulting changes in mineral homeostasis consequent to vitamin D supplementation: blood levels of 25-OH- vitamin D, PTH, Magnesium, Calcium, Albumin, Creatinine, Urea, Phosphor, Alkaline phosphatase and 1-25- di-OH-D .

The following measurements will be assessed after 3, 6 and 12 months from study start for the purpose of 25-OH-D level monitoring and safety: Calcium, Phosphor, 25-OH-D , Albumin and creatinine. Laboratory evaluation required with IFN-beta safety will include: Complete blood count at baseline and after 3, 6, and 12 months from study start ; liver function tests at baseline and every 3 months, thyroid function tests at baseline, 6 months and by the end of the study or upon the emergence of symptoms suggestive of thyroid dysfunction.

Immunological markers:

Two venous blood samples will be drawn from a number of participants at Baseline and after 3 months of vitamin D supplementation . The first in the morning of IFN beta injection day and the second in the morning of the day after the injection. The percent rise after IFN beta injection of IL-6 and TRAIL will be assessed by commercial ELISA kits.

On visits baseline, 3 and 12 month, a venous blood portion will be stored at -80 oC within 30 min- 4 hour of blood withdrawal for MS related cytokines and proteins evaluation.

On visits baseline and 6 months another portion will be collected for immediately immune cell subset evaluation. PBMCs will isolated within 4 hour by Ficoll gradient centrifugation, stained with specific antibodies characterizing various immune cell subsets, and subset proportion determined by flow cytometry analysis.

Blood sampling will be postponed in case of a known condition that may possibly influence the expression of the studied cytokines. Namely, suspicion of a new or ongoing relapse within 30 days before or during the date of blood sampling; Clinical or paraclinical signs of acute infectious disease 48 hrs prior to blood sampling (leukocyte count > 10,000/mcl and /or CRP >2 mg/dl); Clinical signs of allergy within 7 days before participation; corticosteroids within 30 days before participation.

Melatonin:

Urine will be collected during 12-hour nighttime (20:00-08:00) at baseline, 3 months and by the end of the study. Levels of the melatonin metabolite (6-sulphatoxy-melatonin) will be assessed using a highly specific ELISA assay.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
45

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Israel
      • Haifa, Israel
        • MS Clinic, Carmel Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male and female patients with a diagnosis of RRMS according to the McDonald criteria (2005)
  • At least 18 years of age
  • Patients are treated with IFN-beta for RRMS. The decision to treat with IFN beta will be independent from this study protocol.
  • Patients will be either newly diagnosed, who are going to start IFN beta therapy for the first time or RRMS patients who suffer from FLS while being treated with IFN beta.
  • Insufficient blood levels of 25-hydroxy-vitamin D (below 75nmol/l according to current definitions.
  • EDSS score up to 7
  • Willing and able to give informed consent

Exclusion Criteria:

  • Patients having abnormalities of vitamin D related hormonal system other than low dietary intake or decreased sun exposure will be excluded. Namely, malabsorption [Celiac, Whipple, Inflammatory bowl disease, Intestinal bypass surgery, Short bowel syndrome, Cirrhosis, Nephrotic syndrome, Hyperthyroidism, Renal failure [creatinine clearance of less than 40 ml/min], Rickets, Hypoparathyroidism, Hypercalcemia at baseline, known malignancy, granulomatous disorders (Sarcoidosis, Tuberculosis, Silicosis) and Lymphomas.
  • Patients who take medications that influence vitamin D metabolism, other than corticosteroids, will be also excluded. Namely, Orlistat, Anticonvulsants [Phenobarbital, Primidone, Phenytoin], Rifampin, Isoniazide, ketoconazole, 5FU and Leucovorin
  • Patients with conditions with increased susceptibility to hypercalcemia will be excluded too: known arrhythmia or heart disease, treatment with Digitalis, or Hydrochlorothiazide.and those who suffer from nephrolithiasis.
  • Other Central Nervous System disorders than RRMS
  • Psychiatric disorders such as psychosis, bipolar disorder or substance abuse
  • Pregnancy
  • Contra-indication to treatment with IFN-beta

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: High dose vitamin D
800 IU of Vitamin D3 by tablets plus a bottle of 75,000 IU vitamin D3 solution every 3 weeks
Dietary supplement: Vitamin D3
Patients will be treated daily with 800 IU of Vitamin D3 by tablets plus a bottle of 75,000 IU vitamin D3 solution every 3 weeks
Dietary supplement: Vitamin D3
Patients will receive 800 IU of vitamin D3 by tablets plus a 3 weekly placebo solution
Active Comparator: Low dose vitamin D
800 IU of vitamin D3 by tablets plus a 3 weekly placebo solution
Dietary supplement: Vitamin D3
Patients will be treated daily with 800 IU of Vitamin D3 by tablets plus a bottle of 75,000 IU vitamin D3 solution every 3 weeks
Dietary supplement: Vitamin D3
Patients will receive 800 IU of vitamin D3 by tablets plus a 3 weekly placebo solution

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Occurrence and severity of Interferon beta related Flu Like Symptoms and Injection Site Reactions.
Time Frame: One year
One year

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Time Frame
Quality of life
Time Frame: 1 year
1 year
Relapse rate
Time Frame: 1 year
1 year
Expanded Disability Status Scale (EDSS) progression
Time Frame: 1 year
1 year
Change in serum levels of cytokines and proteins involved in MS pathogenesis
Time Frame: 12 months
12 months
Immune cells subsets
Time Frame: 6 months
6 months
Night time Urine levels of 6-sulphatoxy-melatonin
Time Frame: 1 year
1 year
Percent rise of IL6 and TRAIL levels following IFN-beta injection
Time Frame: 3 months
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Carmel Medical Center

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ariel Miller, Prof, Multiple Sclerosis Center Carmel Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2010

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
April 1, 2012

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
April 1, 2012

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 29, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 29, 2009

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 30, 2009

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 5, 2012

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 2, 2012

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2012

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • RNFVD0209

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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