A Double-blind double dummy prospective randomized study to evaluate the efficacy of classical Ayurveda management versus Methotrexate in Rheumatoid Arthritis (AMRA Study).
Trial Acronym
AMRA
Secondary IDs if Any
Secondary ID
Identifier
NIL
NIL
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Dr Shubhashree M N
Designation
Research Officer
Affiliation
Central Ayurveda Research Institute (CARI),
Address
Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109 Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109 Bangalore KARNATAKA 560109 India
Phone
9448016968
Fax
Email
shubhathejas@gmail.com
Details of Contact Person Scientific Query
Name
Dr Shubhashree M N
Designation
Research Officer
Affiliation
Central Ayurveda Research Institute (CARI),
Address
Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109 Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109 Koppal KARNATAKA 560109 India
Phone
9448016968
Fax
Email
shubhathejas@gmail.com
Details of Contact Person Public Query
Name
Dr Shubhashree M N
Designation
Research Officer
Affiliation
Central Ayurveda Research Institute (CARI),
Address
Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109 Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109 Koppal KARNATAKA 560109 India
Phone
9448016968
Fax
Email
shubhathejas@gmail.com
Source of Monetary or Material Support
Central Council for Research in Ayurvedic Science (CCRAS), 61-65, opp. DBlock, D Block, Janakpuri Institutional Area, Janakpuri, New Delhi, Delhi 110058
Primary Sponsor
Name
Central Council for Research in Ayurvedic Science CCRAS
Address
Jawahar Lal Nehru Bhartiya Chikitsa Avum Homeopathy Anusandhan Bhavan
No.61-65, Institutional Area, Opp. D Block, Janakpuri,
New Delhi - 110058 ( India )
Telephone : 91-011-28525862/28525897/28525852
Type of Sponsor
Government funding agency
Details of Secondary Sponsor
Name
Address
NIL
NIL
Countries of Recruitment
India
Sites of Study
No of Sites = 3
Name of Principal
Investigator
Name of Site
Site Address
Phone/Fax/Email
Dr K G Raveendran
AVP Research Foundation
136-137, Trichy Rd, Olymbus, Dhanvantri Nagar, Ramanathapuram, Tamil Nadu 641045 Coimbatore TAMIL NADU
9843199300
kgraveendran@gmail.com
Dr Shubhashree M N
Central Ayurveda Research Institute (CARI)
Uttarahalli Manavarthekaval , Uttarahalli (Hobli),Bangalore South (Tq) Kanakapura main road,Talaghattapura post, Bengaluru. 560109
Bangalore KARNATAKA
9448016968
amrabengaluru@gmail.com
Dr Manohar S Gundeti
Raja Ramdeo Anandilal Podar (RRAP) Central Ayurveda Research Institute for Cancer (CARIC),
Podar Medical Campus, Dr Annie Besant Rd, B Wing, BDD Chawls Worli, Worli, Mumbai, Maharashtra 400018 Mumbai MAHARASHTRA
9004960133
drmanoharccras@gmail.com
Details of Ethics Committee
No of Ethics Committees= 3
Name of Committee
Approval Status
Institutional ethical Committee, Bengaluru
Approved
Institutional ethical Committee,Mumbai
Approved
Institutional Ethics Committee, AVP Research Foundation
Approved
Regulatory Clearance Status from DCGI
Status
Not Applicable
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition:M056||Rheumatoid arthritis with involvement of other organs and systems. Ayurveda Condition: AMAVATAH,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Ayurveda along with Placebo Methotrexate
After randomization, 109 subjects will be administered with Ayurveda formulations along with Placebo methotrexate for a period of 36 weeks, with fixed scheduled visits during the entire course of trial.
The Ayurveda medicines are given orally through following dosage forms.
1) Kashayam (extract/decoction) is used for conditions involving any of the three doshas, no matter how vitiated, and regardless of digestive capacity. Dose: 15 ml of decoction mixed and stirred well with 60 ml of boiled water to which adjuvants are added if prescribed. Normally taken twice a day at 6 AM and 6 PM.
2) Choornam (herbal powder) potentiates the effect of other dosage forms. Compared with kashayams and gulikas, choorna is difficult to digest. It is less penetrative and is more localized in action. Dose: 5-10 grams to be consumed on an empty stomach before meals, after mixing with honey, warm water, or buttermilk.
3) Gutika (round pill) is easy to digest and has a broader effect than choornam. It enhances the bioavailability and the effect of combinations. Dose: 2-3 pills are to be taken on an empty stomach in the morning or at bedtime, followed by a glass of hot water or mixed with prescribed decoction.
4) Arishtam (self-fermented decoction) is mainly used for vata and kapha conditions and in mild pitta conditions. It is very fast acting and potent, and is well-tolerated. Dose: 25 ml twice daily after meals.
5) Lehyam (herbal "jam") has rejuvenating properties. It is very heavy to digest and generally adminis5ered only if the patients digestive capacity is good. Dose: 2-3 teaspoons to be taken on an empty stomach in the morning or at bedtime followed by a glass of hot water or mixed with prescribed decoction.
6) Thailam is medicated oil for external application. Dose: As directed by physician.
Comparator Agent
Methotrexate plus Ayurveda Placebo
After randomization, 109 subjects will be administered with Methotrexate along with placebo Ayurvedic formulations for a period of 36 weeks, with fixed scheduled visits during the entire course of trial.
The dosage of Methotrexate is given below.
MTX will be in the form of 2.5mg tablets given orally.
7.5 mg/week for 2 weeks
10 mg//week for 2 weeks
12.5 mg/week for 2 weeks
15 mg/week for 2 weeks
17.5 mg/week for 2 weeks
20 mg/week for 4 weeks
22.5 mg/week for 4 weeks
Then: 25 mg/week for the rest of the study.
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
1) Adult male or female aged between 18 and 65 years, inclusive.
2) Expected to survive more than or equal to 2 years from their inclusion in the protocol.
3) Able to give informed consent and able to read and/or understand instructions in English, Tamil, Malayalam, Kannada, Hindi, Marathi.
4) History of symptoms of RA for greater than 7 years and meets the 2010 ACR/EULAR diagnostic criteria at the time of study entry .
5) Rheumatoid Factor positivity or Anti-CCP positivity.
6). Active disease as defined by fulfillment of the following criteria at 2 visits that are at the most four weeks apart (i.e., at screening and baseline visits):
At least 9 of 68 joints assessed as painful or tender on motion.
7) Functional RA classes I, II, or III according to the 1991 ACR classification criteria. Functional RA class IV patients will be permitted if they are not wheelchair or bed bound.
ExclusionCriteria
Details
1. History of an acute inflammatory joint disease as defined by ACR/EULAR criteria other than RA which might interfere with the evaluation of the patient’s RA in this study (e.g., SLE, dermatomyositis/polymyositis,reactive arthritis, ankylosing spondylosis, vasculitis).
2. Significant symptomatic osteoarthritis.
3. Acute major trauma to joints within 1 year of study entry such that the joint is fused or non-functional.
4. Previous classic, complete Ayurvedic treatment for RA in the past 6 months, or have used OTC Ayurveda products within 1 month of entry into the study.
5. Currently enrolled in another clinical trial or received an investigational drug within 3 months(or 5 halflives, whichever is longer) prior to entry in the study.
6. Treatment with intra-articular corticosteroid injections in joint within 4 weeks of study entry.
7. Treatment with leflunomide (Arava) within 4 months before intake into study.
8. Previous treatment with methotrexate (greater than 4 doses).
9. Treatment with biologic or targeted synthetic DMARDS within the periods listed below before their baseline visit.
10. Treatment with any immunosuppressive agent (e.g., Azathioprine, Cyclosporine, etc.) within one month of study entry.
11. Chronic infections or a previous infection including intestinal ova and parasites requiring antimicrobial therapy within 1 month of study entry.
12. Concomitant disorders (e.g., diabetes mellitus, hypertension) which are poorly controlled.
13. Cardiac failure (stage III or IV according to the classification of the New York Heart Association, NYHA).
14. Uric acid >11mg/dL or well documented episode of gout according to ACR criteria for gout.
15. Impaired renal function, as shown by serum creatinine 1.5 times above the ULN of the laboratory.
16. Active liver disease OR previous liver disease that has not completely resolved, as shown by serum levels of alkaline phosphatase >2 times lab ULN; SGPT (ALT) >3 times the ULN of the lab; and/or a total bilirubin level less than 2.0 mg/dl 17. Active Hepatitis B or Hepatitis C positive by ELISA; HIV positive per previous screening.
18. Active Tuberculosis (TBC). Note. Can be treated and then started on study.
19. History of cancer or lymphoproliferative disease in the past 5 years.
20. White blood cell count less than 2000/ml, platelet count less than 100, 000/ml, or hemoglobin less than 8 g/L (5.27 mmol/L). If WBC less than 2000/ml but PMN greater than 1000, subject may still be included.
21. Any condition that would, in the investigators opinion, compromise the subjects ability to absorb, tolerate, metabolize, or excrete the study medication or could cause unacceptable risk to the patient.
22. History of recent, clinically significant drug or alcohol abuse (eg, drug seeking behaviour which intereferes with family or work), in the past six months.
23. Mental condition rendering the subjects unable to understand the nature, scope and possible consequence of the study.
24. Subject unlikely to comply with protocol (e.g., non-compliance, inability to return for follow-up visits, and likelihood of not completing the study).
25. If the patient requires more than 3 g per day acetaminophen or whose NSAID intake is more than the maximum dose allowed in the package insert.
26. Pregnant.
27. Lactating.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Pharmacy-controlled Randomization
Blinding/Masking
Double Blind Double Dummy
Primary Outcome
Outcome
TimePoints
Disease activity score (DAS 28-C-Reactive protein CRP),The American college Of Rheumatology Response criteria 20%,50%,70%(ACR 20/50/70)ACR
the Primary outcome will be assessed at 12th, 24th and 36th week.
the secondary outcome will be assessed at oth week and 36th week.
Secondary Outcome
Outcome
TimePoints
American College of Rheumatology Response Criteria 20%,50%, 70%(A CR20/50/70)responses and its components.
Immunological response to ayurvedic treatment and cytokine response at selected points during the study
To assess the clinical safety(Biochemical parameter viz LFT and KFT adverse effects and ECG)
Quality of life measure HAQ-DI
8TH,16TH ,24TH AND 36TH WK
Target Sample Size
Total Sample Size="240" Sample Size from India="240" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This Phase III clinical trial uses a randomized, placebo-controlled, double blind, double-dummy design to compare classical Ayurvedic outpatient treatment to the allopathic standard of care treatment (methotrexate) for rheumatoid arthritis (RA). At three centers, 218 subjects with active RA will be randomized into two groups of 109 subjects each to receive either: (1) methotrexate plus Ayurvedic placebo or (2) classic Ayurveda plus methotrexate placebo. Treatment duration will be 36 weeks; recruitment will be spread equally across the three centers.
Primary Objective: To compare DAS28-CRP responses among RA patients treated with Ayurvedic therapy or methotrexate.
Secondary Objectives:
1. To compare the two groups in terms of:
a) ACR20/50/70) responses and its components
b) RA remission as defined by DAS28-CRP and CDAI criteria
c) Immunological response to Ayurvedic treatment by examining generalized measures of inflammation and cytokine response at selected points during the study
2. To compare the adverse effects among patients treated with classical Ayurveda vs. methotrexate.
Exploratory Objective: To demonstrate the sensitivity to change of DAS28-CRP and HAQ-DI; andQuality of Life questionnaires in the Indian population.
Study Timeline:
Total number of months = 24
Duration of subject participation: 9 months
Data cleaning and analysis: 6 months.
Protocol
Once every four weeks: Study visits; CBC, Chemistry, and urinalysis; dispensation of Medicine/placebo.
Once every 12 weeks: Full rheumatologic evaluations
Safety: Hematology, chemistry battery, and urinalysis; open-ended questions on adverse events; Medical Safety Officer (unblinded); Ayurvedic medicines tested for heavy metal and microbial content; Data Safety Monitoring Board.
Randomization will be done by the Central Study Pharmacist, using random permuted block design with varying block sizes implementedon a Web-based data management system by the Study Statistician. Once a patient is determined to be eligible, based on definitive inclusion and exclusion criteria, the patient can be randomized at the Baseline visit.
The Study Pharmacy at each center will be responsible for proper preparation and dispensing of the study medication and placebo within the randomization protocol.
Blinding: Only the Central Study Pharmacist, who will be a specialist in Ayurvedic pharmacology, will be the only unblinded person for the entire duration of the trial.
When changes in medication are made in the Ayurvedic treatment group, corresponding changes will be made to the prescriptions in the methotrexate group which would be receiving Ayurvedic placebo, so that unblinding will not occur during the course of the study. All subjects, regardless of treatment group, will receive the same amount of attention and have the same assessments done at each visit. Both Ayurvedic physician and allopathic physician will see subjects at each visit.
Statistical Analysis (will be described fully before the start of the study)
Descriptive analysis
ANOVA or ANCOVA for parametrically distributed data
Chi-Square or Wilcoxon Test for non-parametric data
Adverse events described and tested as appropriate
Exploratory endpoints tested as appropriate
Ancillary analyses including Success of double-blinding; Compliance.