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

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ClinicalTrials.gov Identifier: NCT01514370
Recruitment Status : Completed
First Posted : January 23, 2012
Results First Posted : January 21, 2019
Last Update Posted : January 21, 2019
Sponsor:
Collaborator:
Merck Serono S.P.A., Italy
Information provided by (Responsible Party):
Merck KGaA, Darmstadt, Germany

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: IFN beta 1a 44 mcg TIW Drug: Curcumin Drug: Placebo Phase 2

Detailed Description:

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).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : April 30, 2012
Actual Primary Completion Date : March 31, 2016
Actual Study Completion Date : March 31, 2016


Arm Intervention/treatment
Experimental: IFN beta 1a 44 mcg TIW + curcumin (BCM95) Drug: IFN beta 1a 44 mcg TIW
Subjects received IFN beta 1a 44 microgram (mcg) subcutaneously TIW for 24 months.
Other Name: Interferon beta 1a

Drug: Curcumin
Subjects received 500 milligram (mg) curcumin orally twice a day for 24 months.
Other Names:
  • Rebif
  • BCM95

Placebo Comparator: IFN beta 1a 44 mcg TIW + placebo Drug: IFN beta 1a 44 mcg TIW
Subjects received IFN beta 1a 44 microgram (mcg) subcutaneously TIW for 24 months.
Other Name: Interferon beta 1a

Drug: Placebo
Subjects received placebo matched to curcumin orally twice a day for 24 months.




Primary Outcome Measures :
  1. Number of Subjects With Active (New or Enlarging) T2 Lesions Assessed by Magnetic Resonance Imaging (MRI) at Month 12 [ Time Frame: 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.


Secondary Outcome Measures :
  1. Percentage of Relapse-Free Subjects at Month 12 and Month 24 [ Time Frame: 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.

  2. Annualized Relapse Rate at Month 12 and 24 [ Time Frame: 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.

  3. Total Number of Reported Relapses at Month 3, 6, 12 and 24 [ Time Frame: 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.

  4. Percentage of Subjects Treated With Glucocorticoids Due to Relapses During 24 Months [ Time Frame: Baseline up to 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. Percentage of subjects treated with glucocorticoids due to relapses during 24 Months were reported here.

  5. Percentage of Subjects Free From Expanded Disability Status Scale (EDSS) Progression at Month 12 and 24 [ Time Frame: 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

  6. Hazard Ratio for Time to First Sustained Expanded Disability Status Scale (EDSS) Progression [ Time Frame: Baseline to date at which the first confirmed EDSS progression occurs, assessed up to 24 months ]
    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.

  7. Percentage of Subjects With Active (New/Enlarging) T2 Lesions at Month 24 [ Time Frame: 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.

  8. Percentage of Subjects With Combined Unique Active (CUA) Lesions at Month 12 and 24 [ Time Frame: 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.

  9. Mean Number of New Gadolinium (Gd)-Enhancing Lesions at Month 12 and 24 [ Time Frame: Month 12 and 24 ]
    New Gd-enhancing Lesions are a measure of inflammatory activity and were assessed using the Magnetic Resonance Imaging (MRI) scan.

  10. Mean Number of New T1 (Hypointense) Lesions at Month 12 and 24 [ Time Frame: 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.

  11. Cumulative Number of New T1 (Hypointense) Lesions [ Time Frame: Baseline up to Month 24 ]
    Cumulative number of new T1 (Hypointense) lesions were reported.

  12. Median Change From Baseline in Whole Brain Volume at Month 12 and 24 [ Time Frame: Baseline, Month 12 and 24 ]
    Brain tissue volumes are inter-related and represent a measure of neurodegenerative aspects of the disease.

  13. Median Change From Baseline in Regional Brain Volume at Month 12 and 24 [ Time Frame: Baseline, Month 12 and 24 ]
    Brain tissue volumes are inter-related and represent a measure of neurodegenerative aspects of the disease.

  14. Flu-like Symptoms (FLS) Assessed by FLS Scale Score [ Time Frame: Screening, Baseline, Month 3, 6, 12 and 24 ]
    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.

  15. Number of Subjects With Treatment Emergent Adverse Event (TEAE), Serious AE (SAE), TEAE Leading to Death and Discontinuation [ Time Frame: Baseline up to Month 24 ]
    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.

  16. Number of Subjects With Clinical Significant Abnormality in Laboratory Parameters [ Time Frame: From screening up to Month 24 ]
    Laboratory assessment included haematology, chemistry, and urinalysis. Clinical significance was determined by the investigator.

  17. Number of Subjects With One Concomitant Medication From Baseline up to Month 24 [ Time Frame: Baseline up to Month 24 ]
    Number of subjects with at least one concomitant medication from baseline up to month 24 were reported.

  18. Time on Treatment (Adherence to Treatment) [ Time Frame: Baseline up to 2.2 years ]
    Time up to which subjects were adhered to the treatment was reported.

  19. Number of Subjects With Premature Termination From Treatment [ Time Frame: Baseline up to Month 24 ]
    Number of subjects with premature termination from treatment were reported.

  20. Hazard Ratio for Time to First Documented Relapse [ Time Frame: Baseline up to Date at which first Relapse Occurs assessed up to 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. Hazard ratio for time to first documented relapse was planned to be reported as per SAP.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01514370


Locations
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Italy
Investigational Site
Naples, Italy, 80131
Sponsors and Collaborators
Merck KGaA, Darmstadt, Germany
Merck Serono S.P.A., Italy
Investigators
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Study Director: Medical Responsible Merck Serono S.P.A., Italy

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Responsible Party: Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier: NCT01514370     History of Changes
Other Study ID Numbers: EMR200136-549
First Posted: January 23, 2012    Key Record Dates
Results First Posted: January 21, 2019
Last Update Posted: January 21, 2019
Last Verified: August 2018
Keywords provided by Merck KGaA, Darmstadt, Germany:
Multiple Sclerosis
Relapsing
Interferon beta 1a
Curcumin
Additional relevant MeSH terms:
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Curcumin
Multiple Sclerosis
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Interferons
Interferon-beta
Interferon beta-1a
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Adjuvants, Immunologic