Ayurvedic Medicine Offers a Good Alternative to Glucosamine and Celecoxib in the Treatment of Symptomatic Knee Osteoarthritis

A Randomized, Double-blind, Controlled Equivalence Drug Trial

Arvind Chopra; Manjit Saluja; Girish Tillu; Sanjeev Sarmukkaddam; Anuradha Venugopalan; Gumdal Narsimulu; Rohini Handa; Venil Sumantran; Ashwinikumar Raut; Lata Bichile; Kalpana Joshi; Bhushan Patwardhan

Disclosures

Rheumatology. 2013;52(8):1408-1417. 

In This Article

Patients and Methods

Patient enrolment began in January 2006 and the last follow-up was completed in August 2007. This trial was carried out at the All India Institute of Medical Sciences (New Delhi), Nizam Institute of Medical Sciences (Hyderabad) and Centre for Rheumatic Diseases (CRD, Pune). The ethics committee of each site (CRD Pune, AIIMS New Delhi, KEM Hospital Mumbai and NIMS Hyderabad) approved the study. Consent was obtained from each patient in the study and patients were suitably counselled before obtaining an informed consent. Several details of the NMITLI protocol and validation approach were published previously.[8]

This was a randomized, double-blind, parallel-efficacy, four-arm, multicentre non-commercial investigator-initiated drug trial of 24 weeks' duration comparing two standard Ayurvedic formulations, glucosamine and celecoxib, for equivalent effectiveness. Study evaluation visits were made at baseline and weeks 2, 4, 8, 12, 16, 20 and 24 (completion). The study was conducted in compliance with the Good Clinical Practice guidelines (ICH) and Declaration of Helsinki and national regulations.

Ayurvedic Formulations

(i)Selection: based on Ayurveda texts[6,9,10] and expert opinion, several anti-arthritis medicinal plants were short-listed and evaluated serially in exploratory clinical trials[8,11] and experimental studies.[12,13] Two shunthi-guduchi formulations (SGC and SGCG), each containing amalaki (Emblica officinalis), were identified for the current trial; in addition SGCG contained guggul (Boswellia serrata).

(ii)Test materials: after authentication by the National Institute of Science Communication and Information Resources (NISCAIR, New Delhi), all voucher samples (botanical materials) were deposited in the official herbarium (Agharkar Research Institute, Pune). Quality-certified standard generic forms of glucosamine sulphate and celecoxib were procured from a government (India)-accredited company (Natural Remedies, Bangalore, India).

(iii)Standardization and manufacture: traditional procedures[10] were used to extract plant material. At least one phytochemical reference marker (e.g. boswellic acid for B. s errata) was used to standardize each plant extract; other standard checks included assays for microbial load, heavy metals, pesticide residues and aflatoxins.

The total quantity of Ayurvedic formulations required for the trial was manufactured in a single batch. The detail ingredients of SGCG and SGC are shown in supplementary Table 1, available at Rheumatology Online. Each SGCG capsule (400 mg) contained Zingiber officinale, Tinospora cordifolia, Phyllanthus emblica and B. serrata. The SGC capsule (400 mg) was similar to SGCG (both for content and quantity) except for the absence of B. s errata extract and a higher quantity of excipients. The intervention study drug capsules were similar for physical appearance, size, taste and smell.

(iv) Safety and activity: Standard animal (mice) toxicity studies carried out as per current OECD guidelines[14] confirmed safety.

Patient Selection

Patients with chronic knee pain (Fig. 1) were screened in outpatient clinics and cost-free community arthritis camps as described elsewhere.[15]

Figure 1.

Flow of patients.
‡Other reasons include noncompliance and migration of patient to distant location. *Patients did not report for follow-up after randomization.

Inclusion Criteria

Patients of either sex in the age range 40–70 years with a diagnosis of knee OA as per modified ACR classification[16] criteria (the lower age limit was 40 years) and pain visual analogue scale (VAS) score ≥4 cm in one or both knees while performing a weight-bearing activity (e.g. walking, standing, climbing staircase) during the preceding 24 hours were included in the study; ambulant patients required frequent analgesics.

Exclusion Criteria (Major)

Pregnant or lactating women or women with childbearing potential and not following adequate contraception; patients with non-degenerative joint disorders, severe disabling arthritis (including wheelchair bound) or a history of spine and lower limb surgery; patients on medication likely to influence efficacy evaluation (except paracetamol rescue); patients with a history of peptic ulcer bleed or recent active peptic ulcer and patients with any unstable severe medical disease were excluded.

Randomization

Patients were screened and randomized on a first-come, first-served basis. The study biostatistician (S.S.) used a standard software program to generate a randomized schedule of permuted block randomization with block size 4 for blinded (coded) drug allotment.

Washout Period

All patients taking NSAID analgesics prior to randomization underwent a washout period of 2–5 days.

Main Outcome Measures

Clinical Evaluation Active pain and WOMAC (version LK3)[17–19] pain score and functional difficulty score were the primary efficacy variables and were recorded at every visit. Maximum active pain on body weight-bearing activity (e.g. walking) during the preceding 24 hours was recorded for each knee on a horizontal 10 cm VAS (anchored at 0 for absent pain and 10 for maximum pain). A validated modified version of the WOMAC questionnaire[20] suitable for Indian patients and available in several Indian languages was used. Patients provided categorical answers for scoring (none = 0, mild = 1, moderate = 2, severe = 3, extreme = 4) and the maximum score (of 24 questions) was 96. Several secondary efficacy variables (clinical and laboratory) included pain VAS on rest and physician and patient global assessment (grades 1–5 corresponding to asymptomatic to very severe).

Intervention

The dose regimen for all study intervention drugs was two capsules three times a day taken with plain water after a meal or snack. Oral glucosamine sulphate (2 g daily) and celecoxib (200 mg daily) were administered in a similar manner (three times a day in equally divided doses).

A fixed quantity of paracetamol (500 mg tablet) was provided for emergency analgesic use. Ongoing concomitant medication for concurrent chronic illnesses was permitted. Patients were not allowed treatment with any other alternative medicinal system (such as homeopathy, acupuncture or acupressure). Patients could continue their regular exercise and/or physiotherapy programme begun prior to the current trial, but were discouraged from starting any new activity during the trial. Physical therapy and local applications of pain relieving ointments/gels were not permitted. Patients were not prescribed any instructions or advice regarding diet or other life style change as per standard Ayurveda practice.[10]

Laboratory Investigations Routine laboratory workup (haemogram and metabolic parameters including lipids, renal and hepatic function and urine analysis) was carried out at as per protocol. X-rays of knees were taken to confirm diagnosis. Commercially available ELISA kits were used to assay serum hyaluronic acid (Corgenix Inc. Broomfield, CO, USA) and urinary human type II collagen C-telopeptide (CTX-II) (Cartilaps, Nodic Biosciences, Denmark).

Adverse Event Patients were questioned at every visit for common drug-related symptoms as per a predetermined checklist and encouraged to add any other symptom they considered as a drug-related side effect.

Withdrawals Patients could withdraw voluntarily or at the discretion of the investigator.

Statistical Analysis

Equivalence ranges ( Table 1 ) for each of the three primary efficacy variables were selected a priori. The range (95% CI) of minimal clinically significant change in pain VAS was chosen from an equivalence study of topical diclofenac solution and oral diclofenac.[21] A similar range for WOMAC pain and WOMAC difficulty were adopted as recommended by Bellamy.[17] The trial was to be declared successful if equivalence was demonstrated for each of the primary efficacy variables.

The formula published by Jones et al.[22] was used to calculate the sample size of each intervention arm. Calculations were performed separately for each of the three primary efficacy variables (with usual standard type I error α = 0.05 and power = 80%) and the maximum sample size (out of the three variables) obtained was multiplied by four to calculate the sample size. The final sample size was adjusted for an expected 20% dropout rate.

Both intention-to-treat analysis with the last observation carried forward and per protocol analysis (completers) were carried out using analysis of variance (ANOVA). The trial was designed with 80% power and a two-sided P < 0.05 was considered significant in all statistical tests. Intervention groups were compared for efficacy after adjusting for baseline mean values [analysis of covariance (ANCOVA)] and P adjusted for multiple comparison (using Bonferroni's method). The 95% CIs were computed for mean change in efficacy variables between intervention groups. The statistical software program SPSS version 12.5 (SPSS, Chicago, IL, USA) was used.

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