Dietary Supplement of Curcumin in Subjects With Active Relapsing Multiple Sclerosis Treated With Subcutaneous Interferon Beta 1a

Study Overview
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Brief Summary
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This is a prospective, monocentric, double blind, placebo controlled, two arm study. Curcumin is derived from the rhizomes of the plant Curcuma longa (common name, turmeric) belonging to the Zingiberaceae family found in South Asian countries, especially India which is the largest producer. BCM95 (bioCurcumin) is a combination of a Curcumin extract and oil to enhance the bio-absorbability in humans. BCM95 may enhance and prolong the antioxidant and anti-inflammatory effects of the standard therapy maintaining a good safety profile.

Detailed Description
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The subjects must experience at least one Gadolinium (GD) enhancing Magnetic Resonance Imaging (MRI) lesion at the baseline visit or one Multiple Sclerosis (MS) relapse in the last 6 months before the screening visit. Randomization, in a 1:1 ratio, will be done with two arms: 40 subjects with Interferon (IFN) beta 1 a 44 mcg TIW + Curcumin (BCM 95) and 40 subjects with IFN beta-1a 44 mcg TIW + placebo. The study will last 42 months: 18 months of enrolment and 24 months of treatment period. The study consists of 6 visits per subject: screening visit (Visit 0), baseline (Visit 1), a visit 3 months after baseline (Visit 2), 6 months after baseline (Visit 3), 12 months after baseline (Visit 4) and 24 months after baseline (Visit 5).

Official Title
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ProspeCtive Study to Evaluate Efficacy, Safety and tOlerability of Dietary supplemeNT of Curcumin (BCM95) in Subjects With Active Relapsing MultIple Sclerosis Treated With subcutaNeous Interferon Beta 1a 44 mcg Three Times a Week (TIW)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: IFN beta 1a 44 mcg TIW
* Drug: Curcumin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with early diagnosis (no more than 3 years) of Relapsing Multiple Sclerosis according to the revised McDonald Criteria (2010) Subjects currently in treatment with IFN beta-1a 44 mcg TIW, having received this treatment a minimum of 6 months and for not longer than 12 months before enrollment. Subjects must experience at least one Gd-enhancing MRI lesion at baseline visit or one MS relapse in the last 6 months before screening visit. Males and females between 18 - 60 years of age Subjects with Expanded Disability Status Scale (EDSS) between 0-5.5 No use of oral or systemic corticosteroids or corticotropin (ACTH) within 30 days prior to Screening visit. No use of any Disease Modifying Drug (DMD) (other than IFN beta-1a 44 mcg) 12 months prior to Screening visit Be willing and able to comply with the protocol Signed informed consent Exclusion Criteria: Pregnancy and breast-feeding History of alcohol or drug abuse Serious psychiatric disorders History or presence of serious or acute gastrointestinal disease such as gastric or duodenal ulcer, ulcerative colitis and inflammatory bowel or Crohn's disease Subjects suffering by obstruction of the biliary tract Any major medical condition that in the opinion of the Investigator could create a risk to the subject or could affect adherence with the trial protocol. Subjects with inadequate haematological function (defined by leukocyte ≤ 2,0 x 10^9 ; platelets ≤ 100 x 10^9; haemoglobin ≤ 12 g/dl for female and ≤ 13 g/dl for male), liver function (defined by AST, ALT, alkaline phosphatase > 2.0 times upper limit of normal), thyroid function (In particular subjects with clinically overt hyperthyroidism or clinically overt hypothyroidism and in any case according to physician's discretion). Known hypersensitivity to gadolinium Any other condition that would prevent the subject from undergoing an MRI scan (impairment of Kidney function, metal prosthesis etc.) Immunosuppressive therapy 12 months before screening visit Use of some recognized drugs involved as enzyme substrates, inducers or inhibitors in P450 system Use of antiplatelet agents or antihyperlipidemics Any contra-indication according to IFN beta 1a 44 mcg Summary of Product Characteristics (SmPC)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IFN beta 1a 44 mcg TIW + curcumin (BCM95)<br> | Drug: IFN beta 1a 44 mcg TIW<br>* Subjects received IFN beta 1a 44 microgram (mcg) subcutaneously TIW for 24 months.<br>* Other names: Interferon beta 1a;Drug: Curcumin<br>* Subjects received 500 milligram (mg) curcumin orally twice a day for 24 months.<br>* Other names: BCM95;|
| Placebo Comparator: IFN beta 1a 44 mcg TIW + placebo<br> | Drug: IFN beta 1a 44 mcg TIW<br>* Subjects received IFN beta 1a 44 microgram (mcg) subcutaneously TIW for 24 months.<br>* Other names: Interferon beta 1a;Drug: Placebo<br>* Subjects received placebo matched to curcumin orally twice a day for 24 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Active (New or Enlarging) T2 Lesions Assessed by Magnetic Resonance Imaging (MRI) at Month 12 | A single T2 lesion was defined as an area of increased signal on a given 3-millimeters axial image that was not referable to normally hyperintense structures. New T2 lesions were those that appear in areas where on the previous scan no abnormality was detected. All T2 lesions were detected by an MRI scan. | Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hazard Ratio for Time to First Documented Relapse | Relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. Hazard ratio for time to first documented relapse was planned to be reported as per SAP. | Baseline up to Date at which first Relapse Occurs assessed up to 24 months | 
| Percentage of Subjects With Combined Unique Active (CUA) Lesions at Month 12 and 24 | CUA lesion was defined as new gadolinium (Gd)-enhancing lesions on T1-weighted, or new or enlarging lesions on T2-weighted MRI scans, without double counting. | Month 12 and 24 | 
| Mean Number of New Gadolinium (Gd)-Enhancing Lesions at Month 12 and 24 | New Gd-enhancing Lesions are a measure of inflammatory activity and were assessed using the Magnetic Resonance Imaging (MRI) scan. | Month 12 and 24 | 
| Mean Number of New T1 (Hypointense) Lesions at Month 12 and 24 | Mean number of new T1 (Hypointense) Lesions represents a measure of accumulation of inflammatory disease burden assessed on magnetic resonance imaging (MRI) scans. | Month 12 and 24 | 
| Cumulative Number of New T1 (Hypointense) Lesions | Cumulative number of new T1 (Hypointense) lesions were reported. | Baseline up to Month 24 | 
| Median Change From Baseline in Whole Brain Volume at Month 12 and 24 | Brain tissue volumes are inter-related and represent a measure of neurodegenerative aspects of the disease. | Baseline, Month 12 and 24 | 
| Median Change From Baseline in Regional Brain Volume at Month 12 and 24 | Brain tissue volumes are inter-related and represent a measure of neurodegenerative aspects of the disease. | Baseline, Month 12 and 24 | 
| Flu-like Symptoms (FLS) Assessed by FLS Scale Score | Flu-like symptoms were measured using FLS score in which subjects were scored as per the presence and intensity of muscle aches, chills, and weakness, each separately, on a scale of 0-3 as follows: 0 = absent; 1 = mild, do not interfere with daily activities; 2 = moderate, sufficient to interfere with daily activities; and 3 = severe, bed rest require. Body temperature also was also recorded to determine the presence of fever using the following scale: 0 (≤ 37.2 °C); 1 (≥ 37.3 °C but < 37.8 °C); 2 (≥ 37.8 but < 38.4 °C); and 3 (≥ 38.4 °C).The scores for each symptom (muscle aches, chills, weakness, body temperature) was added together to provide the combined flu-like symptom score ranging from 0 to 12 where 0 indicates absence of any symptom and 12 indicates the worst severity of the symptoms. | Screening, Baseline, Month 3, 6, 12 and 24 | 
| Number of Subjects With Treatment Emergent Adverse Event (TEAE), Serious AE (SAE), TEAE Leading to Death and Discontinuation | AE was defined as any untoward medical occurrence which does not necessarily have a causal relationship with the study drug. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE 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 or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug and up to 24 months. TEAEs include both Serious TEAEs and non-serious TEAEs. | Baseline up to Month 24 | 
| Number of Subjects With Clinical Significant Abnormality in Laboratory Parameters | Laboratory assessment included haematology, chemistry, and urinalysis. Clinical significance was determined by the investigator. | From screening up to Month 24 | 
| Number of Subjects With One Concomitant Medication From Baseline up to Month 24 | Number of subjects with at least one concomitant medication from baseline up to month 24 were reported. | Baseline up to Month 24 | 
| Time on Treatment (Adherence to Treatment) | Time up to which subjects were adhered to the treatment was reported. | Baseline up to 2.2 years | 
| Number of Subjects With Premature Termination From Treatment | Number of subjects with premature termination from treatment were reported. | Baseline up to Month 24 | 
| Percentage of Relapse-Free Subjects at Month 12 and Month 24 | Relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. | Month 12 and 24 | 
| Annualized Relapse Rate at Month 12 and 24 | Relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. Annualized relapse rate was calculated by dividing the total number of relapse events by the total number of days subjects participated in the study. This number was then multiplied by 365.25 to get an annualized rate. | Month 12 and 24 | 
| Total Number of Reported Relapses at Month 3, 6, 12 and 24 | Relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. | Month 3, 6, 12 and 24 | 
| Percentage of Subjects Treated With Glucocorticoids Due to Relapses During 24 Months | Relapse was defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, lasting for 24 hours and with a previous period for more than 30 days with a stable or an improving condition. Percentage of subjects treated with glucocorticoids due to relapses during 24 Months were reported here. | Baseline up to Month 24 | 
| Percentage of Subjects Free From Expanded Disability Status Scale (EDSS) Progression at Month 12 and 24 | Disability progression was assessed using EDSS. EDSS is based on a standardized neurological exam and focuses on symptoms that commonly occur in multiple sclerosis (MS) . Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS). Disability progression was defined as an increase of EDSS score of at least 1.0 point compared to baseline for subjects with an EDSS =< 4.0. For subjects with an EDSS= 0 at baseline, EDSS progression was defined as an increase of EDSS score of at least 1.5 point. Percentage of subjects free from EDSS progression at Month 12 and 24 were reported | Month 12 and 24 | 
| Hazard Ratio for Time to First Sustained Expanded Disability Status Scale (EDSS) Progression | EDSS progression is based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. Overall scores ranges from 0.0 (normal) to 10.0 (death due to MS). A sustained progression on EDSS score was defined as an EDSS progression confirmed into two consecutive assessment. EDSS values obtained during clinical attacks are not excluded for the assessment of EDSS progression. However, EDSS values obtained during MS attacks that are not confirmed after two consecutive assessments will be excluded from statistical analysis of confirmed EDSS progression. Hazard ratio for time to first sustained EDSS progression was planned to be reported as per SAP. | Baseline to date at which the first confirmed EDSS progression occurs, assessed up to 24 months | 
| Percentage of Subjects With Active (New/Enlarging) T2 Lesions at Month 24 | A single T2 lesion was defined as an area of increased signal on a given 3-millimeters axial image that was not referable to normally hyperintense structures. New T2 lesions were those that appear in areas where on the previous scan no abnormality was detected. All T2 lesions were detected by an MRI scan. | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Relapsing, Interferon beta 1a, Curcumin