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| Clifton Bingham, M.D.
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Abstract 1203 Effects of Glucosamine Sulfate on 6-Month Control of Knee Osteoarthritis Symptoms vs Placebo and Acetaminophen: Results from the Glucosamine Unum in Die Efficacy (GUIDE) Trial Purpose: GUIDE was a double blind placebo controlled study performed in Europe with prescription glucosamine sulfate 1500 mg once-a-day vs acetaminophen for the treatment of knee osteoarthritis. Methods: 318 patients (88% women) with knee OA (ACR criteria) were randomised to double-dummy oral glucosamine sulfate soluble powder 1500 mg daily., or acetaminophen 1000 mg tablets t.i.d. (3 g/day, as recommended in Europe), or placebo, for 6 months. The rescue medication consisted of standardised use of ibuprofen 400 mg tablets (daily diary recording). The primary efficacy parameter was the 6-month change in the Lequesne index in the ITT population, using the LOCF approach for patients not completing the study according to the protocol (34 on placebo, 28 in each the acetaminophen and glucosamine sulfate groups, without differences in drop-out reasons). Secondary efficacy parameters included the changes in WOMAC and OARSI-A responder criteria. Statistical analysis on the indexes was performed by GLM-ANOVA, with Dunnetts pairwise comparisons vs placebo. The proportions of responders and patients using rescue medication were compared by chi-square. Results: The groups were comparable for demographics and baseline disease characteristics. The efficacy of Glucosamine sulfate efficacy vs placebo was significant on all parameters (table). Acetaminophen had more OARSI-A responders than placebo, but it failed to reach a significant difference on the Lequesne (p=0.18) and WOMAC (p=0.077) indexes.
More patients on placebo used rescue medication (p=0.027 and 0.045 vs glucosamine sulfate and acetaminophen, respectively). There were no differences among groups in safety. Conclusions: Glucosamine sulfate at the oral once-daily dose of 1500 mg demonstrated efficacy compared with placebo in relief of pain for osteoarthritis of the knee. Editorial comments: This study, sponsored by the manufacturers of the glucosamine compound, is similar to prior studies demonstrating an effect on OA signs and symptoms for glucosamine compared to placebo. Somewhat surprisingly the acetaminophen group, while showing directional improvements in Lequesne and WOMAC endpoints, did not reach significance compared to placebo, but was significant using the OMERACT OARSI response criteria. The reduction from baseline in WOMAC was 22% change from baseline in the placebo group compared to 31% and 34% decrease from baseline in the acetaminophen and glucosamine groups respectively. Perhaps the outcome measurements have poor performance in patients with lower levels of background pain as seen in this study. While the authors have suggested in their presentation that these results should prompt changes in treatment recommendations for OA, this study was neither designed or powered to detect differences between two active treatments. Abstract 622 The Efficacy of Glucosamine and Chondroitin Sulfate in Patients with Painful Knee Osteoarthritis (OA): The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) Purpose: GAIT was a multicenter, 5 arm placebo-controlled study conducted by the NIH at academic medical centers designed to rigorously assess the efficacy and safety of glucosamine and chondroitin sulfate, alone and in combination compared to placebo with a group of patients also receiving celecoxib. Methods: Patients were >40 years of age with knee pain (WOMAC Pain 125-400 mm) of at least 6 months duration and x-ray evidence of knee OA [Kellgren-Lawrence (KL) Grades 2 or 3]. Patients were randomly assigned double-blind to placebo (P); G (Glucosamine HCl 500 mg) tid; Sodium Chondroitin Sulfate (CS) 400 mg tid; G+CS at the above doses tid; or celecoxib (CE) 200 mg daily. All patients were allowed up to 4000 mg daily of acetaminophen (APAP) as rescue analgesia, except within 24 hours of study visits. Allocation was stratified by Center and by WOMAC Pain severity (125-300mm and 301-400mm). Patients were evaluated at baseline and weeks 4, 8, 16 and 24. The a priori primary outcome measure was a 20% improvement from baseline in WOMAC Pain at week 24. Adverse events were documented at each visit. Analysis was based on intention-to-treat. Results: 3238 patients were screened at 16 US academic rheumatology centers. 1583 were randomized and 1258 (80%) completed the study. Baseline characteristics were: mean age 58.6 years, BMI 31.7 kg/m2, OA symptoms 10 years, 64% female, summed mean WOMAC Pain 236+73mm (206mm for 125-300mm stratum, 341mm for 301-400mm stratum), 59% KL Grade 2, and 78% were in the 125-300mm WOMAC Pain stratum and were evenly distributed across all arms. The response rate for CE (70.1%) was higher than the response rate for P (60.1%) in the primary outcome analysis of all patients (p=0.008). In the 301-400 mm WOMAC pain stratum, the response rate for G+CS (79.2%) was higher than P (54.3%) (p=0.002). Secondary outcomes in the 301-400 mm stratum, including 50% WOMAC Pain response, WOMAC Stiffness, WOMAC Function, HAQ, patient assessments, and use of rescue APAP all demonstrated changes consistent with the primary outcome. Adverse events were generally mild and evenly distributed among the groups.
Conclusions: In the overall study population, when using a dichotomous outcome of response defined as a 20% reduction in WOMAC pain from baseline, very high placebo responses were seen with only celecoxib demonstrating significant differences compared to placebo, with smaller nonsignificant changes demonstrated for glucosamine, chondroitin, or the combination. All study agents were well tolerated. Editorial Comment: This is the largest study conducted to determine the effect of glucosamine and chondroitin sulfate in OA. It represents a major effort on the part of the investigators to adhere to the standards of a pharmaceutical study, without industry bias. The overall results of this study failed to demonstrate an effect of glucosamine or chondroitin sulfate alone or in combination. The extremely high placebo response resulted in a very small effect size even for the active celecoxib comparator. Only when stratified by patients with moderate to severe pain, who represented 22% of the overall patients, was a statistically significant difference noted for the supplements and only in combination. However in this group, the effect of the positive control celecoxib was not significant. This study has generated much discussion as to the conclusions that may be drawn. Evaluation of the other outcome measurements such as magnitude of WOMAC changes and other data anticipated in a manuscript will be helpful in putting the results in context. Given the magnitude of placebo improvements that were seen, and the small effect demonstrated for celecoxib, any positive findings demonstrated from a subset of patients must be interpreted with caution. The magnitude of the placebo benefit suggests that to demonstrate efficacy for any compound using this study design, an even larger number of patients would be required to demonstrate efficacy. It is important to note that this was not a flare design study and acetaminophen at doses of up to 4g/day were permitted as rescue analgesia. Perhaps the most important message that came out from this study in a large number of patients with rigorous monitoring was a lack of untoward side effects from the supplements such that while we continue to debate the merits of their efficacy, we have some assurance that we are not doing any harm when using pharmaceutically grade, quality controlled compounds as employed in this study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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