Glucosamine/chondroitin Arthritis Intervention Trial Research Articles

Glucosamine and Chondroitin Sulfate: What Has Been Learned Since the Glucosamine/chondroitin Arthritis Intervention Trial.

Glucosamine and chondroitin sulfate, alone or in combination, are used worldwide by individuals suffering from osteoarthritis pain. They are by prescription in some countries but are available as over-the-counter dietary supplements in other countries, such as the United States. The inconclusive results of the National Institutes of Health-sponsored Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) did little to clarify the efficacy of these agents. However, some newer studies have provided a better perspective on the potential benefits that they can offer. Because the 2 in combination showed a significant level of efficacy in the moderate-to-severe knee osteoarthritis subgroup of the GAIT, this review examines the randomized, controlled trials published from that time to the present. The findings of these studies are mixed, owing in some cases to the high rate of placebo response added to by the ethical incorporation of rescue analgesics into protocols designed to evaluate the slow-acting, subtle effects of glucosamine and chondroitin sulfate in combination. The strong influence of the placebo effect and confounding of results by rescue analgesics point to the importance of objective measurement tools such as osteoarthritis biomarker panels in long-term glucosamine/chondroitin sulfate clinical trials with less reliance on the subjective measurement tools commonly used in osteoarthritis trials of pharmaceuticals. [Orthopedics. 2018; 41(4):200-207.].

Is All Glucosamine Alike? Clarifying the Controversies for Product Selection and Clinical Research

In the United States, glucosamine is marketed as a dietary supplement therefore subject to less stringent manufacturing, labeling and marketing regulations than pharmaceuticals. The glucosamine product selected for the NIH-sponsored Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was required to satisfy Investigational New Drug (IND) application (and therefore pharmaceutical manufacturing requirements). This review describes the procedure that was developed by the authors to identify a high-quality glucosamine product for GAIT and to clarify confusing product information and nomenclature.Proprietary glucosamine products and bulk glucosamine powders of various salt forms were evaluated. Both the published literature and information provided by suppliers of bulk glucosamine powders were evaluated. No proprietary glucosamine product was selected due to manufacturing practices that did not meet the pharmaceutical standards mandated by GAIT; i.e., no practices that control and document the quality issues of product purity and content variability. At the time this study was initiated dietary supplements were not required to meet these standards. Other problems identified with proprietary products included the presence of other dietary supplements and/or trace elements and the inability of a manufacturer to provide the appropriate quality of product within the time constraints of the study. A bulk powder of glucosamine hydrochloride was identified and capsules were manufactured for the trial in compliance with pharmaceutical Good Manufacturing Practices.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.

Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.

Potential effects of chondroitin sulfate on joint swelling: a GAIT report

The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) was a randomized double-blind placebo and active comparator (celecoxib) controlled trial of 1583 persons with symptomatic osteoarthritis (OA) of the knee(1). Patients randomized to celecoxib had significant improvement in knee pain compared to those randomized to placebo. No statistically significant improvement in knee pain compared to placebo was seen among patients randomized to the dietary supplements, although a subset of patients with moderate-to-severe knee pain at entry who were assigned to the combination of glucosamine and chondroitin sulfate did seem to experience some improvement. Additionally, patients taking chondroitin sulfate were noted to have a statistically significant improvement in knee joint swelling. An exploratory post hoc analysis of GAIT patients suggested the effect of chondroitin sulfate on joint swelling occurred more often in patients with milder pain and lower Kellgren-Lawrence Grade at entry.

Glucosamine and Chondroitin Sulfate as Therapeutic Agents for Knee and Hip Osteoarthritis

Osteoarthritis (OA), the most common form of arthritis, is a public health problem throughout the world. Several entities have been carefully investigated for the symptomatic and structural management of OA. This review evaluates published studies of the effect of glucosamine salts and chondroitin sulfate preparations on the progression of knee or hip OA. Despite multiple double-blind, controlled clinical trials of the use of glucosamine and chondroitin sulfate in OA, controversy regarding the efficacy of these agents with respect to symptomatic improvement remains. Several potential confounders, including placebo response, use of prescription medicines versus over-the-counter pills or food supplements, or use of glucosamine sulfate versus glucosamine hydrochloride, may have relevance when attempting to interpret the seemingly contradictory results of different clinical trials. The National Institutes of Health-sponsored GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) compared placebo, glucosamine hydrochloride, chondroitin sulfate, a combination of glucosamine and chondroitin sulfate and celecoxib in a parallel, blinded 6-month multicentre study of patients with knee OA. This trial showed that glucosamine hydrochloride and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with OA of the knee. However, exploratory analyses suggest that the combination of glucosamine hydrochloride and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. For decades, the traditional pharmacological management of OA has been mainly symptomatic. However, in recent years, several randomised controlled studies have assessed the structure-modifying effect of glucosamine sulfate and chondroitin sulfate using plain radiography to measure joint space narrowing over years. There is some evidence to suggest a structure-modifying effect of glucosamine sulfate and chondroitin sulfate. On the basis of the results of recent randomised controlled trials and meta-analyses, we can conclude that glucosamine sulfate (but not glucosamine hydrochloride) and chondroitin sulfate have small-to-moderate symptomatic efficacy in OA, although this is still debated. With respect to the structure-modifying effect, there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA.

Glucosamine/Chondroitin

Results of the four-year study entitled the Glucosamine/ chondroitin Arthritis Intervention Trial (GAIT) provided partial answers to those seeking relief from arthritis pain. Scientists will continue studying the efficacy of these substances as pain remedy and cartilage rejuvenator.

Evidence‐based practice: Review of clinical evidence on the efficacy of glucosamine and chondroitin in the treatment of osteoarthritis

To evaluate past and current evidence from randomized controlled trials on the efficacy of glucosamine sulfate (GS), glucosamine hydrochloride (GH), and chondroitin sulfate (CS) for the treatment of osteoarthritis (OA). An extensive review of four meta-analyses and a review of the findings of the recently published Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) funded by the National Institutes of Health. Review of previous studies on the efficacy of GS, GH, and CS in the treatment of OA showed inconclusive results because of weak research design. The GAIT attempted to provide clarity on the use of GH and CS in treating knee pain from OA by using a rigorous research design to elicit cause and effect. The GAIT results showed that GH and CS were not effective in reducing knee pain in the study group overall; however, these may be effective in combination for patients with moderate-to-severe knee pain. There is now clinical evidence indicating that recommending GS, GH, and CS for the treatment of mild knee pain from OA is ineffective. Further research needs to be done to identify specific characteristics in patients that results in a positive response. Until the findings of the GAIT undergo further peer review, the results of the research needs to be interpreted with caution.

Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis

Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Chondroitin Product Selection for the Glucosamine/Chondroitin Arthritis Intervention Trial

To select a high-quality chondroitin dosage form and/or an appropriate source of sodium chondroitin for the National Institutes of Health's Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT). Controlled experimental trials. Laboratory. Not applicable. Commercially available chondroitin products were reviewed, and purified sodium chondroitin from two suppliers was evaluated through tests (infrared and near-infrared identification, moisture content, pH, optical rotation, color and clarity of aqueous solutions prepared from the powders, protein contamination, total residue following ignition and nitrogen content, determination of sodium chondroitin molecular weight, disaccharide analysis, and measurement of chondroitin, sodium, and total glycosaminoglycan content) and an onsite supplier audit. Purity, potency, and quality of sodium chondroitin powders. No commercially available chondroitin product was deemed appropriate for use in GAIT. Samples of sodium chondroitin powder from two suppliers exhibited similar disaccharide and glycosaminoglycan content. Each contained approximately 2% hyaluronic acid and 8%-9% unsulfated disaccharide. Potency was inconsistent across groups, which might have resulted from different analytical methods and choice of reference standard. Mean potency obtained by five separate methods ranged from 82.2% to 95.5% for one supplier, 92.5% to 110.1% for another, and 95.1% to 112.5% for a commercially obtained reference standard. Critical issues raised by the results include choice of reference standard, selection of assay method, and the consistent appearance of an unidentifiable contaminant present in all three lots from one supplier. This blinded study determined methods to identify acceptable agents and provided results, which, in addition to regulatory compliance supplier audits, formed the basis for chondroitin product selection in GAIT.

Is it time for more rheumatologists to embrace osteoarthritis?

There has been a degree of apathy or even antipathy towards osteoarthritis (OA) by UK rheumatologists, the origin of which is hard to elucidate. Clinical research in OA has historically not been regarded as the highest priority by UK funding bodies [1]. The paucity of evidence-based therapy, particularly diseasemodifying OA drugs (DMOADs), may have led to OA patients being a source of frustration for clinicians whose clinics are already bulging in addressing the challenges of inflammatory arthritis. The previous attempts of enthusiasts to nurture interest in OA have fallen by the wayside; for example, a previous incarnation of an OA Special Interest Group at the British Society for Rheumatology (BSR) Annual General Meeting was characterized by a small number of devotees and tumbleweed whistling through an otherwise deserted room. What, if anything, has changed? There are a number of answers to this question. Firstly, the Arthritis Research Campaign (arc) is taking a more progressive approach to clinical research, including OA: as much is now being directed towards projects for weight loss, exercise or rehabilitation, and vitamin D therapy for knee pain and hand OA as previously supported molecular studies [2]. Similarly, there are major initiatives in the USA, including the National Institutes for Health-funded Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) [3] and the $8.9 million Osteoarthritis Initiative, a 7-yr project to recruit 5000 people at risk of OA of the knee, examining predictors including biomarkers [4]. The controversy surrounding the two industry-sponsored trials suggesting glucosamine sulphate may be a DMOAD [5, 6] has certainly raised awareness among rheumatologists of the problem. The EULAR recommendations for the management of knee [7] and hip [8] OA and the MOVE consensus for the role of exercise in the management of OA of the hip or knee [9] have made the task of managing OA less daunting. Patients are also better informed, using resources like Arthritis Care’s OA Nation report [10] to understand the impact of their problems and the interventions available through conventional and complementary medicine. It is against this background that a group of OA enthusiasts met under the auspices of the BSR in Edinburgh 2004, including some who remembered the previous OA Special Interest Group, but came anyway. The event was notable not just for the eminence of the speakers and quality of the debate: rather it was the popularity of the session that overwhelmed. An equal number of putative attendees were turned away as were able to fit into a room of admittedly modest dimensions. The proceedings are reported elsewhere, but the initiative has been distilled by due democratic process into a discrete set of objectives for the OA Special Interest Group, to:

P164 Characteristics of patients who respond to placebo in the glucosamine/chondroitin arthritis intervention trial (GAIT)

P164 Characteristics of patients who respond to placebo in the glucosamine/chondroitin arthritis intervention trial (GAIT)

A Paradox®-based data collection and management system for multi-center randomized clinical trials

We have developed a Paradox®-based data collection and management system for large-scale multi-site randomized clinical trials. The system runs under Windows® operating system and integrates Symantec® pcAnywhere32® telecommunications software for data transmission and remote control sessions, PKZIP utility for the compression/decompression of transmitted data, and Stat/Transfer® for exporting the centralized Paradox database for analyses. We initially developed this system for VA Cooperative Study #399 ‘The Effect of Antiarrhythmic Therapy in Maintaining Stability of Sinus Rhythm in Atrial Fibrillation’, which collects over 1000 variables on 706 patients at 20 sites. Patient intake for this 5-year study began in March of 1998. We have also developed an enhanced version of this system, which is being used in the NIH-funded ‘Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT)’ that collects over 1200 variables on 1588 patients at 13 sites. Patient intake for this 4-year study began in October of 2000.