Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the Chondroitin versus Celecoxib versus Placebo Trial (CONCEPT)
A 800 mg/day pharmaceutical-grade Chondroitin sulphate was found to be better than placebo and similar to celecoxib in alleviating pain and enhancing function in patients with symptomatic knee osteoarthritis (OA) over 6 months.
Osteoarthritis is one of the most common musculoskeletal disorders that significantly impact the quality of life of people suffering from it. It is known to be a chief cause of pain, loss of function and disability, and requires medical intervention. The various treatment approaches used for managing knee OA comprises both pharmacological and non-pharmacological modalities.
Osteoarthritis is one of the most common musculoskeletal disorders that significantly impact the quality of life of people suffering from it. It is known to be a chief cause of pain, loss of function and disability, and requires medical intervention. The various treatment approaches used for managing knee OA comprises both pharmacological and non-pharmacological modalities. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) have established a positive benefit-risk profile when used to treat symptoms of knee OA.
But, recent studies have violently challenged the use of paracetamol in treating symptomatic OA due to a lack of efficacy and a substantial degree of toxicity, particularly at the upper end of the standard analgesic dose. Likewise, another major concern is the safety profiles of oral NSAIDs. Thus, recent guidelines suggest maintenance therapy to be accompanied with symptomatic slow-acting drugs for OA (SYSADOAs), a class that offers a high degree of safety and tolerability. Although differences have been noted in the literature regarding references on SYSADOAs in managing knee OA, higher quality data appears to be provided for patented, prescription formulations of chondroitin sulfate (CS) and crystalline glucosamine sulfate (GS).
Chondroitin sulfate (CS) is a sulfated glycosaminoglycan that contain chains of alternating D-glucuronic acid and N-Acetyl-D-galactosamine. CS is available as pharmaceutical-grade and nutraceutical-grade products which makes it better in terms of preparation, composition, purity as well as clinical effects. In various studies, pharmaceutical-grade CS had shown to significantly improve pain and function and/or delay structural progression of knee OA as compared to lower grade formulations. A recent systematic review conducted by the Cochrane Collaborative Group concluded that CS alone or in combination with GS, is better than placebo in improving pain in OA patients, with CS offering lower risk of serious adverse events compared to controls.
Rationale behind research
As varying results were obtained from the previous studies of SYSADOAs due to idiosyncratic trial design, European Medicines Agency (EMA) produced a guideline which recommends testing the efficacy of chemical units in treating symptomatic OA according to a standard study design. The main parameters of the standard study design include a minimum 6-month study duration; a three-arm study design including a placebo and an active comparator (i.e., oral NSAID); and two co-primary endpoints evaluating pain and function, respectively. Therefore, the present study was the first one to be conducted according to EMA guideline.
The objective of the study was to test the efficacy of Chondroitin Sulfate 800mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the EMA guideline
- Primary outcomes: There were two co-primary endpoints
- First endpoint was the patient’s estimate of pain on a 100mm Visual Analogue Scale (VAS).
- The other endpoint was the Lequesne Index (LI), which integrates pain and function and results in a score from 0 to 24.
- Secondary outcomes: Secondary endpoints included the proportion of patients reaching the Minimal-Clinically Important Improvement (MCII), defined as the smallest change in measurement that signifies an important improvement in a patient’s symptom and the Patient Acceptable Symptom State (PASS), defined as the value of symptoms beyond which patients consider themselves well. Patient and investigator global assessment were scored on a 5-point Likert ordinal scale (excellent, good, fair, poor, none).
- Adverse events: All adverse events and abnormal laboratory test results were recorded.
Time Points: Baseline and at Day 30, day 91 and day 182
Baseline characteristics: Patients in the three groups had similar demographic and baseline characteristics
- Analysis of pain scores: There was a significant improvement in all three groups compared with baseline at day 30, 91 and 182 (all p<0.001). After Six months, a statistically greater reduction in pain was observed in both the CS and the celecoxib group as compared to the placebo group (p=0.001 for CS and p=0.009 for celecoxib.
Figure 1: Analysis of pain scores
- Analysis of LI scores: Significant improvement in all three groups was noted as compared to baseline at day 30, 91 and 182 (all p<0.001). Both CS and celecoxib made a significantly greater reduction in LI than placebo (p=0.050 for CS and p=0.027 for celecoxib at day 91, p=0.023 for CS and p=0.015 for celecoxib at day 182) while no difference was observed between CS and celecoxib (p=0.799 at day 91 and p=0.890 at day 182,). At day 30, the decrease in LI observed in the celecoxib group reached statistical significance in comparison to the placebo group (p=0.045) while it took the CS group until day 91 (p=0.050).
Figure 2: Analysis of LI scores
- Minimal-Clinically Important Improvement (MCII): A greater proportion of patients reached the MCII in the CS (68%) and celecoxib (69%) groups than in the placebo group (61%) after 6 months.
- PASS: The results similar to MCII were obtained for the proportion of patients reaching the PASS in the CS (57%), celecoxib (59%) and placebo (49%) groups. For the celecoxib–placebo comparison, the PASS data were significant (p=0.047) and for the CS–placebo comparison and the CS–celecoxib comparison, it was not significant (p=0.130 for CS-placebo, p=0.611 for CS-celecoxib).
- CS and celecoxib provided considerably more number of responders than placebo and no difference was observed between CS and celecoxib. At day 182, considerably more patients and more investigators notched the global assessment as excellent or good in the CS and celecoxib groups compared with the placebo.
Adverse events: There was no significant difference between CS, celecoxib or placebo usage in the rate of TEAEs, SAEs, ADRs and withdrawal related to TEAEs. Abdominal pain/discomfort was the most frequently reported ADR (2.5% in the CS group, 4.5% in the celecoxib group and 2.9% in the placebo group). There were no significant abnormalities in the CS or celecoxib groups.
This study (CONCEPT) provided strong evidence that daily administration of 800 mg of CS in patients with symptomatic knee OA improves pain and function better than placebo and similar to the NSAID celecoxib. Also, the present study has confirmed the excellent safety profile of CS which has been previously observed by others. This exemplary benefit-risk profile highlights the importance of pharmaceutical-grade CS in knee OA managemnet, particularly in those requiring long term treatment.
The study showed that CS is superior to placebo and similar to celecoxib in reducing pain and LI (co-primary endpoints), as well as in the proportion of patients experiencing MCII and patient/investigator global assessments. Before CONCEPT, there is only one study that evaluated the impact of a SYSADOA on knee OA in a three-arm design. It was the Glucosamine Unum-in-Die Efficacy (GUIDE) study which showed that patented crystalline glucosamine sulfate (GS) was better than placebo and equivalent to acetaminophen in reducing LI after 6 months of treatment. But, the present study (CONCEPT) was better as it utilised celecoxib as an active comparator, a NSAID that was recently shown to provide significantly greater clinical effectiveness than acetaminophen in knee OA
Therefore, this study supports the need for upcoming clinical guidelines on the pharmacological management of knee OA to reckon the study design, as well as the composition and quality of the test product, when assessing the effectiveness of SYSADOAs.