TRANSPARENCY COMMITTEE OPINION. 26 November 2008

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 26 November 2008 CHONDROSULF 400 mg, capsule Box containing 84 capsules (CIP: ) CHONDROSULF 400 mg, granules for oral solution in sachet Box containing 84 x 2 g sachets (CIP: ) Applicant: GENEVRIER Chondroitin sulfate ATC Code: M01AX25 Date of Marketing Authorisation: 25 January 1993 (capsules) and 29 June 1993 (sachets) Amendment: 21 May 2008 (changes to wording of indication following re-assessment of the risk/benefit ratio of slow-acting osteoarthritis drugs) Social Security (35%) and Hospital Use Reason for request: Re-assessment of actual clinical benefit in line with article R of the French Social Security Code. Medical, Economic and Public Health Assessment Division 1

2 1.1. Active ingredient Chondroitin (sulfate) 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.2. Indication Former indication: "Delayed-action symptomatic treatment of functional manifestations of osteoarthritis of the knee and hip. " New indication: "Deferred-effect symptomatic treatment of osteoarthritis of the hip and knee " 1.3. Dosage 3 x 400 mg capsules or 3 x 400 mg sachets, giving 1200 mg per day, divided into 3 doses. The sachets or capsules should be taken with food ATC Classification (2008) 2 COMPARABLE MEDICINAL PRODUCTS M: Musculo-skeletal system M01: Anti-inflammatory and anti-rheumatic products M01A: Anti-inflammatory and anti-rheumatic products, non-steroids M01AX: Other anti-inflammatory and anti-rheumatic products, non-steroids M01AX25: Chondroitin sulfate 2.2. Medicines in the same therapeutic category Other symptomatic slow-action drugs for osteoarthritis : Active ingredient Proprietary product Presentation Indication Chondroitin (sodium sulfate) STRUCTUM 500 mg capsule Second-line treatment for joint pain Diacerhein ART 50 mg capsule Deferred-effect symptomatic treatment of osteoarthritis of the hip and knee Diacerhein ZONDAR 50 mg capsule Deferred-effect symptomatic treatment for osteoarthritis of the hip and knee Avocado and soy unsaponifiables PIASCLEDINE 300 mg capsule Deferred-effect symptomatic treatment for osteoarthritis of the hip and knee 2.3. Medicines with a similar therapeutic aim Other drug treatments for osteoarthritis: analgesics, oral and topical NSAIDs, intra-articular corticosteroids, hyaluronic acid (medicinal product or medical device) given as an intraarticular injection. 2

3 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy Clinical data provided in the dossier: - 2 placebo-controlled studies (Bourgeois and Pavelka ) - 1 study versus glucosamine and placebo (GAIT: Clegg, ) - 1 study versus NSAID (Morreale ) - 5 meta-analyses (Leeb 2000; McAlindon 2000; Pertuiset 2002; Richy- Reginster 2003; Reichenbach 2007) Placebo-controlled studies Bourgeois (1998) study Randomised double-blind study over 3 months, comparing CHONDROSULF oral gel sachet 1200 mg as a single daily dose and CHONDROSULF 400 mg capsule three times daily with placebo (double placebo, sachet + capsule) in 94 patients with osteoarthritis of the knee. Included patients had to have lateral or medial femorotibial osteoarthritis, defined using Altman's criteria, progressive for more than 6 months, characterised by functional pain for more than the past 3 months, with intensity measured on a visual analogue scale of 30 mm, a Lequesne 5 index on NSAID of 4, and who have needed to take NSAIDS for at least 1 month. Patients must have stopped taking any other symptomatic slow-action drugs for osteoarthritis at least 3 months before the study start date. The primary endpoint was change in Lequesne index after 3 months of treatment. Results: Patients included had a mean age of 63 years, and were mostly women (78%). Intensity of pain on inclusion, measured on a VAS, was 56 ± 14 mm in the CHONDROSULF sachet arm, 52 ± 12mm in the CHONDROSULF capsule arm and 54 ± 14 mm in the placebo arm. Some patients left the study prematurely: - 2/29 in the CHONDROSULF sachet arm, of whom 1 left because of adverse effects involving the skin, - 3/32 in the CHONDROSULF capsule arm, of whom 2 left because of adverse gastrointestinal effects, and - 8/33 in the placebo arm, 1 because of lack of efficacy and 3 because of adverse gastrointestinal effects (no reason stated for the other patients). During treatment, compliance was judged to be good or excellent in 75% of patients on CHONDROSULF sachet, 66% on CHONDROSULF capsules and 76% on placebo. 1 Bourgeois P et al. Efficacy and tolerability of chondroitin sulfate 1200 mg/day versus chondroitin sulfate 3 x 400 mg/day versus placebo. Osteoarthritis Cartilage 1998 May;6 Suppl A: Internal report. 3 Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8): Morreale P et al. Comparison of the anti-inflammatory efficacy of chondroitin sulfate and diclofenac sodium in patients with knee osteoarthritis. J. Rheumatology 1996;23: The Lequesne algofunctional index is expressed as a sum of scores relating to pain, maximum distance walked and activities of daily living, which provides a way of assessing disease progression and discomfort suffered by the patient. It is a scale from 0 to 24. 3

4 After 3 months of treatment, reduction in the Lequesne index was greater for CHONDROSULF 1200 mg/day sachet and capsule than for placebo (the difference was statistically significant, see table 1). However, the difference between CHONDROSULF and placebo (-3 points) was modest. Table 1: change in Lequesne index (ITT population) - Bourgeois (1998) Lequesne index (mean ± standard deviation) Placebo (n=33) CHONDROSULF sachet 1200 mg/day (n=29) CHONDROSULF capsule 3 x 400 mg/day (n=32) Day 0 10 ± 3 11 ± 3 10 ± 3 Day 90 9 ± 4 7 ± 3 6 ± 3 Day 90 - day 0-1 ± 2-4 ± 3 * - 4 ± 3 * *: statistically significant difference versus placebo: p< NB: results of this study should be interpreted with care because of the small numbers in each treatment arm. Pavelka (1999) study Placebo-controlled randomised double-blind study over 3 months, with the aim of establishing a dose-effect curve by comparing 3 dosage levels in patients with osteoarthritis of the knee: CHONDROSULF in sachets of 200 mg, 800 mg and 1200 mg, 1 sachet per day (35 patients per arm). Patients could receive concomitant treatment with diclofenac 50 mg for the first 14 days and paracetamol as needed (max 4 g/day). Patients had to have osteoarthritis of the knee confirmed on X-ray, functional impairment and pain that had been stable for 3 months with a pain score of 40 mm on VAS (100 mm) and a Lequesne index of 8. The primary endpoints were Lequesne index and pain at rest (VAS of 100 mm). Results: Patients included had a mean age of approximately 65 years, and were mostly women (74%). Mean Lequesne index on inclusion was depending on treatment arm, and pain was mean mm on VAS. 1 patient in the placebo arm left the study prematurely (because of constipation), 1 in the CHONDROSULF 200 mg arm (allergic reaction) and 1 in the CHONDROSULF 1200 mg arm (fracture). After 3 months of treatment, reduction in the Lequesne index from baseline was greater for the CHONDROSULF 1200 mg/day arm (dosage recommended in the MA) than for the placebo arm (- 1.9 points; the difference was statistically significant, see table 2). Nonetheless, this difference was modest. Similarly, CHONDROSULF 1200 mg reduced pain more than placebo at day 90 (significant difference, see table 3). The difference between arms was around 25 mm. Table 2: Change in Lequesne index (ITT population) - Pavelka (1999) Lequesne index (mean ± standard deviation) Placebo CHONDROSULF 200 mg CHONDROSULF 800 mg CHONDROSULF 1200 mg 4

5 Day ± ± ± ± 2.1 Day 0 - day * Day 0 - day * -5.1* *: statistically significant difference versus placebo: p<0.01 Table 3: Change in pain evaluated on a VAS (ITT population) - Pavelka (1999) Pain (mm) (mean ± standard deviation) Placebo CHONDROSULF 200 mg CHONDROSULF 800 mg CHONDROSULF 1200 mg Day ± ± ± ± 10.8 Day 0 - day * ** Day 0 - day ** ** *: statistically significant difference versus placebo: p<0.05 **: statistically significant difference versus placebo: p<0.001 NB: results of this study should be interpreted with care because of the small numbers in each treatment arm NSAID-controlled study Morreale (1996) study Randomised double-blind study comparing, after 1 month of treatment, CHONDROSULF 400 mg 3/day with diclofenac 50 mg 3/day in 146 patients aged between 40 and 75 with osteoarthritis of the knee confirmed on X-ray, stage I or II on Kellgren-Lawrence classification. Included patients had to have stopped taking NSAID treatment at least 15 days previously, and symptomatic slow-action osteoarthritis drugs at least 30 days previously. Patients were treated according to the following regimen: CHONDROSULF arm: M1: mg sachet of CHONDROSULF x 3/day + diclofenac placebo M2 M3: mg sachet of CHONDROSULF x 3/day M4 M6: 1 sachet of CHONDROSULF placebo x 3/day Diclofenac arm: M1: 1 50 mg tablet of diclofenac x 3/day + CHONDROSULF placebo M2 - M3: CHONDROSULF placebo M4 - M6: CHONDROSULF placebo The primary endpoints were Lequesne index, pain at rest (100 mm VAS) and pain on movement (4-point scale: 0=absent, 3=intense) after 1 month of treatment (M1). Results: Patients included had a mean age of approximately 56 years, and 60% were women. Mean Lequesne index was 7.9, mean pain at rest 56.6 and mean pain on movement 2.5. Calculation of numbers required for this study showed that 80 patients were needed in each arm. In the event, 74 patients were randomised into the CHONDROSULF arm and 72 into the placebo arm. 9 patients from the CHONDROSULF arm and 11 from the diclofenac arm 5

6 left the study prematurely, the majority of whom were lost to follow-up. In total, 68 patients were included in the analysis for the CHONDROSULF arm and 65 for the placebo arm. Lequesne index: Lequesne index was evaluated after 1 month of treatment (primary endpoint) and had reduced for both CHONDROSULF and diclofenac arms, with a statistically significant difference in favour of diclofenac (see table 4). After stopping diclofenac and continuing CHONDROSULF treatment for the following 2 months, Lequesne index increased in the group that initially received diclofenac, while it continued to reduce in patients who received CHONDROSULF treatment. The difference between arms was statistically significant, in favour of CHONDROSULF. During the last 3 months of the study, during which CHONDROSULF was also stopped, the score increased in the CHONDROSULF arm but there was still a statistically significant difference in favour of CHONDROSULF (see table 4). Table 4: Change in Lequesne index - Morreale (1996) Lequesne index (mean ± standard deviation) CHONDROSULF 1200 mg/day (n=68) Diclofenac (n=65) Day ± ± 3.7 M1 4.9 ± ± 2.8 * M3 1.7 ± 2.2 * 4.9 ± 3.2 a M6 2.8 ± 2.2 * b 6.1 ± 3.4 *: statistically significant difference between treatment arms: p<0.01 a: diclofenac stopped after M1 and started on placebo b: CHONDROSULF stopped after M3 and started on placebo Pain at rest: The pain score (VAS), evaluated after 1 month of treatment (2nd primary endpoint) reduced in both groups, though there was no statistically significant difference. During the 2nd phase (after diclofenac was stopped), the reduction in score continued in both arms, with no statistically significant difference. At the end of the 3rd phase (during which both treatments were stopped), the pain score stayed at the same level in the CHONDROSULF arm, while it increased in the diclofenac arm, and the difference observed between the two arms was statistically significant (see table 5). 6

7 Table 5: Change in pain evaluated on a VAS - Morreale (1996) Pain (mm) (mean ± standard deviation) CHONDROSULF 1200 mg/day (n=68) Diclofenac (n=65) Day ± ± 18.7 M ± ± 15.0 M ± ± 13.0 a M ± 9.5 * b 36.2 ± 16.1 *: statistically significant difference between treatment arms: p<0.01 a: diclofenac stopped after M1 and started on placebo b: CHONDROSULF stopped after M3 and started on placebo Pain on movement: The pain on movement score, evaluated after 1 month of treatment (3rd primary endpoint) reduced in both groups, and there was a statistically significant difference in favour of diclofenac (see table 6). After stopping diclofenac and continuing CHONDROSULF treatment for the following 2 months, the score increased in the diclofenac arm, while it continued to reduce in patients who received CHONDROSULF treatment. The difference between the arms remained statistically significant. During the last 3 months of the study, during which CHONDROSULF was also stopped, the score increased in both arms but there was still a statistically significant difference in favour of CHONDROSULF (see table 6). Table 6: Change in pain on movement (scale from 0 to 3) - Morreale (1996) Pain (mm) (mean ± standard deviation) CHONDROSULF 1200 mg/day (n=68) Diclofenac (n=65) Day ± ± 0.6 M1 1.4 ± ± 0.7* M3 0.4 ± 0.6 * 1.3 ± 0.7 M6 1.1 ± 0.5 * 2.0 ± 0.5 *: statistically significant difference between treatment arms: p< Study versus glucosamine and placebo Clegg (2006) study: GAIT (glucosamine/chondroitin Arthritis Intervention Trial) Randomised double-blind study over 6 months, comparing glucosamine (hydrochloride, 1500 mg/day) with chondroitin (sulfate, 1200 mg/day) and with a combination of glucosamine + chondroitin in 1583 patients with symptomatic osteoarthritis of the knee. The study also included 2 control arms, of patients receiving placebo and celecoxib (200 mg/day). Patients had to have osteoarthritis grade II or III on the Kellgren/Lawrence classification, American Rheumatism Association functional class I, II or III and a pain score of between 125 and 400 on the WOMAC index (scale between 0 and 500). The primary endpoint was the percentage of patients with a 20% reduction in WOMAC pain score after 24 weeks of treatment. 7

8 Results: The patients included had a mean age of 58.6 years. The majority were women (64.1%). 58% of patients were in ARA functional class II, with 25% being in class I and 17% in class III. 55% of patients had osteoarthritis grade II on the Kellgren/Lawrence classification. WOMAC pain score on inclusion was around 236. The characteristics of each arm were comparable. After 24 weeks of treatment, no statistically significant difference was observed between the glucosamine, chondroitin or glucosamine/chondroitin combination arms and placebo. Celecoxib, the active comparator arm, was superior to placebo (see table 7). Comparisons were only made with placebo. Table 7: Percentage of patients with a 20% reduction in WOMAC pain score after 24 weeks (ITT) Glucosamine + Glucosamine Chondroitin Placebo Chondroitin Celecoxib (hydrochloride) (sulfate) (sulfate) n % responders P (versus placebo) The authors note that the absence of difference between placebo and glucosamine, chondroitin and a combination of both active substances could be explained by the significant treatment effect in the placebo arm (60.1% responded) which could be linked to the inclusion of a large number of patients who had few symptoms Meta-analyses Leeb (2000) This meta-analysis included 16 studies (done between 1986 and 1998) involving a total of 703 patients (372 treated with chondroitin sulfate and 331 with placebo) with osteoarthritis of the hip or knee, treated with chondroitin sulfate of various origins, at dosages of between 800 and 2000 mg/day. Evaluation of pain (VAS, 7 studies analysed): after 1 month of treatment, pain score was 65-80% of baseline score in the chondroitin arm, while it was 80% of baseline score in the placebo arm. After 3 months, the score was 57% of baseline, and after 6 months of treatment it was 42% (statistically significant difference versus placebo, p<0.005). This difference corresponds to a Glass score 6 of 0.9. Lequesne index (6 studies analysed): After 2 months of treatment, Lequesne index was 51% of baseline value in the chondroitin arm, while it was over 80% of baseline in the placebo arm (statistically significant difference, p<0.01). This difference corresponds to a Glass score of Note: The scope of these results is limited in that, although only controlled, randomised, double-blind, parallel-group studies involving homogeneous populations were included in the meta-analysis, the quality of these studies was not analysed, their heterogeneity was not tested and possible publication bias was not investigated. 6 Glass score: Study group mean - comparator group mean Standard deviation of two combined groups Score between -4 (inferior to comparator) to +4 (superior to comparator), with a score of 0.8 considered to be clinically relevant. 8

9 McAlindon (2000) This meta-analysis aimed to evaluate the benefits of preparations based on glucosamine and chondroitin. The meta-analysis involving chondroitin sulfate was carried out on 15 randomised double-blind placebo-controlled studies, carried out between 1994 and 1998, involving 759 patients with osteoarthritis of the knee or hip treated with various forms of oral or intramuscular chondroitin sulfate at unspecified dosages. The endpoints of these studies were Lequesne index, pain, WOMAC score, mobility and NSAID consumption. Effect size was calculated for each study using the following formula: difference in means by endpoint at final evaluation, divided by standard deviation for this criterion in the control group at the final evaluation. For all criteria, effect size was 0.78 (95% CI [0.6; 0.95]) in the chondroitin arm and 0.44 (95% CI = 0.24; 0.64]) in the glucosamine arm. Note: The scope of the results of this meta-analysis is limited because: - overall, the studies were of poor quality; quality score was between 12.3% and 55.4%, with a mean of 35.5% - publication bias was demonstrated - studies in which the medicinal product was administered intramuscularly were included - dosages were not specified - interpretation in terms of clinical relevance of the effect size was not stated. Pertuiset (2002) This meta-analysis involved 9 randomised, double-blind, placebo-controlled studies done between 1992 and 2001 (7 involving CHONDROSULF and 2 involving STRUCTUM) involving 988 patients with osteoarthritis of the knee. The following arms were distinguished on analysis: CHONDROSULF 800 mg/day, CHONDROSULF 1200 mg/day, STRUCTUM 1000 mg/day, STRUCTUM 2000 mg/day and placebo. In all trials, the use of NSAIDs was allowed. The endpoints used were Lequesne index (8 studies) and pain as measured on a VAS (100 mm, 9 studies), evaluated at 3 months. Evaluation of pain: CHONDROSULF 1200 mg/day was superior to placebo, with a mean intergroup difference at 3 months of mm (95% CI = [-15.88; -9.9]; the difference was statistically significant, no p-value provided). STRUCTUM was not shown to result in an improvement versus placebo (2 studies). Lequesne index: CHONDROSULF 1200 mg/day was superior to placebo, with a mean intergroup difference at 3 months of (95% CI = [-3.5; -2.54]; the difference was statistically significant, no p-value provided). STRUCTUM was not shown to result in an improvement versus placebo (2 studies). Note: The scope of the results of this meta-analysis is limited in that, although only controlled, randomised, double-blind studies were included in the meta-analysis, the quality of these studies was not analysed and possible publication bias was not investigated. In addition, heterogeneity of effects was not tested and the populations included in these studies were not homogeneous (male/female ratio, pain and Lequesne index at baseline and disease stage on X-ray). Richy (2003) This meta-analysis included randomised, double-blind studies involving glucosamine and chondroitin sulfate from different sources, all involving patients with osteoarthritis of the knee. The main objective was to analyse the efficacy of oral administration of chondroitin and glucosamine on osteoarthritis of the knee and, in particular, efficacy in the treatment of pain and functional impairment. 15 studies were analysed, involving 1775 patients (1020 patients treated with glucosamine and 755 treated with chondroitin). Quality score for the studies was between 60 and 100%, with a mean of 78.4 ±17.2%. Populations included were homogeneous between studies. The analysis enabled conclusions to be drawn as to the efficacy of chondroitin (all origins) on Lequesne index, pain on VAS, mobility and treatment response. 9

10 No difference was demonstrated between chondroitin and glucosamine on any symptomatic criteria. Both products were found to have an overall effect 7 : (95% CI = [0.32; 0.54], p<0.001, 10 studies) for Lequesne index versus placebo, (95% CI = [0.11; 0.49], p<0.001, 2 studies) for reduction in total WOMAC score and WOMAC subscores for pain, function and mobility, (95% CI = [0.31; 0.67], p<0.001, 12 studies) for reduction in pain versus placebo. Reichenbach (2007) This meta-analysis included 22 studies (done between 1987 and 2006) in which patients with osteoarthritis of the knee or hip were treated with various forms of chondroitin sulfate given orally at dosages of between 800 and 2000 mg/day (the 1200 mg/day dosage was only used in 5 studies), or administered as an intramuscular treatment, for periods of between 13 and 132 weeks. The size of the effect on pain was assessed using the Glass score: (95% CI = [-0.99; -0.5]), corresponding to a difference of 16 mm (on a 100 mm VAS) between the chondroitin arm and the placebo arm. Note: The scope of the results of this meta-analysis is limited because of the use of dosages that do not conform to the marketing authorisation in most of the studies included Safety Adverse effects observed during CHONDROSULF treatment are: - skin effects: erythema, urticaria, eczema, maculopapular rash with or without associated itching and/or oedema have all been reported; - digestive effects: in rare cases, nausea, vomiting and possible digestive problems and diarrhoea (because of the sorbitol content); - nervous system effects: vertigo (frequency unknown, and this adverse effect was added following a re-evaluation by the marketing authorisation committee of the risk/benefit ratio for CHONDROSULF in 2007) Conclusion All studies provided were randomised, double-blind and comparative and were placebocontrolled (2 studies) or diclofenac-controlled (1 study), lasting between 3 and 6 months. Both placebo-controlled studies were carried out on patients with osteoarthritis of the knee, with, in the study by Bourgeois (1998) a mean Lequesne index of 8 and mean pain on VAS of around 55 mm, and in the study by Pavelka (1999) a mean Lequesne index of 11.5 and mean pain on VAS of around 70 mm. At a dose of 1200 mg/day, after 3 months of treatment, CHONDROSULF was significantly superior to placebo in terms of Lequesne index, with reduction versus placebo of 3 points in Bourgeois (1998) and 1.9 points in Pavelka (1999). In this study, the pain score was reduced further on CHONDROSULF than on placebo: mm versus mm, a difference of 25.3 mm. These results should be interpreted with care, as the studies involved small numbers (around thirty patients per arm). In a study that compared CHONDROSULF with glucosamine and placebo (GAIT: Clegg 2006) in patients with few symptoms, no difference was observed between the arms in terms of percentage of patients with a 20% improvement in WOMAC pain score. 7 Method for calculating effect size: Study group mean - comparator group mean Standard deviation of difference 10

11 A study comparing CHONDROSULF with diclofenac (Morreale 1996) was carried out in patients aged between 40 and 75 with stage I or II osteoarthritis of the knee on Kellgren/Lawrence classification with a mean Lequesne index of 7.9, mean pain at rest of 56.6 mm and pain on movement of 2.5 (scored between 0 and 4) After 1 month of treatment (the point at which the 3 endpoints were evaluated), results showed a statistically significant difference in favour of diclofenac above CHONDROSULF in terms of reduction in Lequesne index (2 points) and pain on movement. There were no differences between the arms in terms of pain at rest. Of the 5 meta-analyses provided, the analysis by Richy (2007) is the most methodologically sound. It showed that chondroitin sulfate had an effect compared to placebo, which can be considered to be weak, on symptomatic parameters (Lequesne index, WOMAC, pain) and that there was no difference versus glucosamine. The most commonly reported adverse effects of CHONDROSULF are digestive and skin effects (allergy). Two cases of vertigo, observed post-marketing, led to an amendment of the SPC. Overall, CHONDROSULF has a weak effect on symptomatic parameters and has a good safety profile Observational study 4 DATA CONCERNING MEDICINAL PRODUCT IN USE Begaud (2006) 8 : This study, which was previously examined by the Transparency Committee (opinion dated 8 and 22 January 1997), aimed to compare concomitant prescription of analgesics and antiinflammatories, according to duration of use of CHONDROSULF 400 mg. This was an observational study conducted on 199 pharmacists chosen at random from a sample of 1463 pharmacists in the Aquitaine region of France. Patients who presented with a prescription for CHONDROSULF 400 mg were included. Data collected were: socio-demographic characteristics, history of gastric or duodenal ulcer, current and past use of CHONDROSULF, other slow-action osteoarthritis drugs, NSAIDs and analgesics. Results were analysed by distinguishing recent users ( 3 months of continuous use) and long-term users (> 3 months of continuous use). Results: A total of 791 patients were included, of whom 401 were recent users and 390 long-term users. Mean patient age was 65 years. The majority were women (65%). It was observed that fewer NSAIDs were used (current or long-term treatment) in long-term users of CHONDROSULF than in recent users. Similarly, daily dosage of NSAIDs was lower in long-term users. A similar result was observed for consumption of analgesics and use of other slow-action osteoarthritis drugs (see table 8). The effect of CHONDROSULF on the consumption of NSAIDs can be described as weak. 8 Lagnaoui R, Baumevielle M, Begaud B, Pouyanne P, Maurice G, Depont F, Moore N. Less use of NSAIDs in long-term than in recent chondroitin sulfate users in osteoarthritis : a pharmacy-based observational study in France. Thérapie 2006 ; 61 :

12 Table 8: Results for concomitant prescriptions Criterion Recent users (n=401) Long-term users (n=390) Current NSAID usage (%) <0.05 > 3 months of NSAID use (%) <0.01 Dosage (ketoprofen mg equivalent) 188 ± ± 72 <0.001 Painkiller usage (%) <0.001 Use of other slow-action osteoarthritis drugs (%) <0.002 NB: Previous Committee opinion, dated 8 and 22 January 1997: "There is a non-negligible selection bias (comparison of subjects starting treatment with CHONDROSULF with subjects for whom the treatment has been judged to be sufficiently efficacious to follow it up for more than 3 months) which means that no definitive conclusions can be drawn as to the link between treatment with CHONDROSULF for more than 3 months and a reduction in NSAID consumption. " In addition, these data are old and have not been updated, and this study was only carried out in the Aquitaine region, which is not representative of the wider French population. p 5 TRANSPARENCY COMMITTEE CONCLUSIONS 5.1. Actual benefit Symptomatic osteoarthritis of the hip and knee cause pain and functional impairment, which can develop into chronic disease. The condition can require surgical intervention with insertion of prosthesis. These products are symptomatic treatments with a deferred effect. Public health benefit: Osteoarthritis of the knee and hip together represent a significant public health burden. Reduction in functional impairment and disability caused by osteoarthritis, and improvement in the quality of life of those affected, is a public health need. Responses to this need do not consist only of drug treatments. Available data concerning pain and algofunctional indices do not enable conclusions to be drawn as to the impact of chondroitin sulfate on quality of life and functional impairment: there are no data concerning quality of life, and there is a weak effect on symptoms. The theoretical benefit to public health of slow-action osteoarthritis drugs is the potential reduction in NSAID consumption, which could reduce the frequency of digestive system adverse effects, which are particularly harmful in older subjects. Convincing studies involving chondroitin sulfate have not shown such a benefit. As a result, CHONDROSULF 400 mg is not expected to benefit public health. These products are not very efficacious in improving the symptoms of osteoarthritis. The efficacy/adverse effect ratio is modest. Management of osteoarthritis is primarily based on lifestyle and diet measures (weight loss, regular physical exercise) and non-pharmacological methods (e.g. physiotherapy, orthotics, walking sticks). Treatment of symptoms primarily involves analgesics and oral NSAIDs. These proprietary products have a limited role to play in the therapeutic strategy. 12

13 The actual clinical benefit provided by CHONDROSULF 400 mg, capsule and granules for oral solution (sachet) is low Therapeutic use The first measures to take when treating symptomatic osteoarthritis of the lower limbs are diet and lifestyle measures (losing weight, regular physical activity except during painful or inflammatory flare-ups during which reduction in activity is necessary) and nonpharmacological methods (e.g. physiotherapy, orthotics, walking sticks). During symptomatic phases, treatment consists mainly of analgesics, starting with paracetamol, and during acute flare-ups, oral NSAIDs in short courses at the minimal effective dose. Topical treatments can also be used, such as topical NSAIDS, intra-articular injections of corticosteroids, particularly during inflammatory phases, or hyaluronic acid. Slow-action osteoarthritis drugs (chondroitin sulfate CHONDROSULF, avocado and soya unsaponifiables, diacerhein and glucosamine) have modest efficacy in terms of pain and functional disability and it has not been shown that these agents can lead to a substantial reduction in the consumption of NSAIDs. For this reason, they have a limited role to play in the therapeutic strategy. Surgery (arthroplasty, insertion of prosthesis) is reserved for cases of osteoarthritis that are advanced on X-ray, that cause pain and disability, and that do not respond to the usual therapeutic methods Transparency Committee recommendations The Transparency Committee approves maintaining inclusion of CHONDROSULF 400 mg on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services. This approval is conditional on the establishment within 2 years of a study designed to show the impact of the prescription of CHONDROSULF 400 mg on consumption of NSAIDs. Packaging: Appropriate for the prescription conditions Reimbursement rate: 35% 13