Jump to comment:

• What to conclude from the results of the LEGS study and what not?
  Andreas G. Helg
  Published on: 13 April 2016

• Published on: 13 April 2016

  What to conclude from the results of the LEGS study and what not?

  • Andreas G. Helg, PhD (Dr.sc.nat ETH Zurich), Business Unit Manager

  Dear Editor,

  Like probably many others, we have been waiting eagerly for the results of the LEGS study (1). The expectation was that this trial would bring light into the ongoing controversy about the value of chondroitin, glucosamine, and their combination in the treatment of osteoarthritis (OA) of the knee, and provide answers to several open questions. The LEGS study fully met this expectation as to the structure-...

  Show More

  Dear Editor,

  Like probably many others, we have been waiting eagerly for the results of the LEGS study (1). The expectation was that this trial would bring light into the ongoing controversy about the value of chondroitin, glucosamine, and their combination in the treatment of osteoarthritis (OA) of the knee, and provide answers to several open questions. The LEGS study fully met this expectation as to the structure-modifying effect of the combination of chondroitin sulphate and glucosamine sulphate. However, what do the results of this trial tell us about the structure-modifying effect of chondroitin sulphate or glucosamine sulphate alone or about the symptomatic effect of chondroitin sulphate, glucosamine sulphate, or the combination thereof? Unfortunately, the results of the LEGS study add very little to this question as we will point out subsequently.

  Symptomatic effect: The main symptomatic outcome measure in the LEGS study was changed from the use of NSAIDs to self-reported pain when the authors realized that only about 20 % of the patients recruited till that point in time were taking NSAIDs. The alternative primary outcome measure to assess the symptomatic effect was the maximum score of pain 'at its worst' recorded daily in a 7-day diary that the participants had to complete every two months. There are several problems with this alternative outcome measure: 1. It seems not to have been validated, i.e. we have not found any relevant validation study. 2. Experiences with it are lacking, i.e. we are not aware of any other trials in which this measure had been used. 3. Pain due to knee OA is activity- related (depending on the activity), i.e. a patient with knee OA may not suffer from pain while walking, but may does so when descending stairs. We do not know what activity caused 'pain at its worst' and how long that pain lasted. The activity that caused 'pain at its worst' likely was not always the same. Pain 'at its worst', therefore, may be largely an arbitrary measure. 4. Apart from being related to a very specific activity, pain 'at its worst' may lasted only seconds. Thus, potentially, this measure clinically may not be very relevant. 5. As 'average pain' - as opposed to 'pain at its worst' - decreases, patients may dare to indulge in more challenging activities. Such more challenging activities are likely to cause temporarily similar 'pain at its worst' even when 'average pain' decreases over time. Therefore, the alternative outcome measure actually may be more prone to a 'floor effect', i.e. contribute to what the authors wanted to avoid with its use. 6. We do not know how 'pain at its worst' correlates with 'average pain', pain on a standard visual analogue scale (VAS), or WOMAC pain, if at all. 7. As 'average' pain on a numerical rating scale is imperatively smaller than 'pain at its worst', the use of the alternative measure as an inclusion criterion (4 or more on a scale of 0-10) resulted in a very mildly symptomatic study population as documented by the WOMAC pain scores. These scores were between 6.5+/-3.4 (mean+/-SD) and 6.8+/-3.7 on a scale of 0-20 corresponding to 33+/-17 and 34+/-19, respectively, on a scale of 0-100. According to the EMA guideline CPMP/EWP/784/97 Rev. 1 (2) in order to assess the symptomatic effect of a drug, patients must have pain of at least 40 mm on a VAS of 100 mm. Judging on the basis of the above scores and SDs only about 30 % of the patients or about 50 patients per group met this criterion whereas about 100 are needed to observe statistically significant differences (3), not taking into account the dilution by those that are not sufficiently symptomatic.

  With respect to the assessment of the symptomatic effect we would like to note also that the information about co-medications as well as their cessation and washout provided in the publication is very scarce. From some statements and tables we conclude that there were no restrictions regarding co-medications. Patients could take paracetamol, NSAIDs, and opioids at their own discretion (as long as they had been prescribed such co-medications earlier or during the trial). About 30 % of the patients had been on a dietary supplement containing glucosamine during the month before enrolment. Data regarding the use of a dietary supplement containing chondroitin or a combination of the two before enrolment is lacking. Thus, most likely there was no washout of potential effects of such supplements, and it remains unclear whether the patients actually had been asked to stop taking such supplements during the trial. Assuming that chondroitin, glucosamine, and the combination of the two have a symptomatic and a structure-modifying effect, and also carry-over effects as described in the literature (4), i.e. effects that last to some extent at least 3 months beyond cessation of treatment, the lack of any appropriate washout and the possible intake of (additional) dietary supplements with chondroitin, glucosamine, or a combination of the two are likely to have influenced the results, particularly those of the placebo group, and, thus, contributed to a diminishment of the differences between the active treatment groups and the one with placebo. If so, then this affected the observation of the symptomatic as well as the structure- modifying effect. In any case, under the circumstances summarized above, the authors should not only have adjusted their analysis of the symptomatic effect for baseline pain and repeated measurements over time, but at least also for all pain-relevant co-medications and for exercise. Exercise was potentially a strong confounder, because, according to the data provided in Table 4, the number of participants with inadequate exercise decreased in the placebo group whereas it remained more or less stable in the glucosamine and the combination group, and increased in the one with chondroitin.

  Structure-modifying effect: The authors decided, a priori, that for valid estimates of joint space narrowing (JSN), a medial tibial inter-rim distance (TIRD) of <= 1.7 mm at each time point was required for an X-ray to be included in the analysis. Furthermore, they limited their analysis to pairs of X-rays with a difference in TIRD of <= 0.2 mm between the two X-rays. The first criterion was adopted from work by Vignon et al., 2010 (5). The LEGS study was registered with ClinicalTrials.gov (NCT00513422) on August 7, 2007, thus before the publication by Vignon et al., 2010. With 'a priori' the authors, therefore, mean that their decision to apply the above criterion had been taken prior to the data analysis. Nevertheless, the application of this criterion represents a deviation from the original protocol. The authors, therefore, first should have carried out the analysis according to the protocol, and also should have published the results of that analysis. The analysis actually carried out and presented in the publication could then have served as a sensitivity analysis to consolidate or question the results obtained according to the protocol and for discussion.

  The protocol allowed a single repeat of each X-ray if the TIRD was > 2.0 mm. Thus, the limitation of the analysis to X-rays with a TIRD of <= 1.7 mm is largely redundant. Therefore, it is likely that the reduction of the number of 'valid' pairs of X-rays predominantly can be attributed to the application of the second criterion, a difference of TIRD of <= 0.2 mm between pairs of X-rays. This second criterion is not only too severe - Vignon et al., 2010 set the cut-point at 0.5 mm and not at 0.2 mm -, it is also unnecessary: Vignon and co-workers only applied the second criterion to pairs of X-rays in which both TIRDs were > 1.7 mm. They, however, did not investigate any subgroup of pairs of X-rays meeting both of the above criteria. In fact, the first criterion is already sufficient to guarantee a high accuracy and the best responsiveness. They found a JSN of 0.13+/-0.51 mm (mean+/-SD) over one year and a standardized response mean (SRM) of 0.25 for all pairs of X- rays (n=590) as well as a JSN of 0.15+/-0.43 mm and a SRM of 0.34 for all pairs of X-rays with a TIRD of <= 1.7 mm in both of them (n=256). All other results in their publication refer to situations where one or both of the two X-rays of a pair had a TIRD > 1.7 mm. Their results clearly indicate that the application of the first criterion is absolutely adequate, and, furthermore, that the gain in accuracy and responsiveness disproportionately is at the expense of statistical power. Again, as the loss of 'valid' pairs of X-rays by the application of the first criterion had not been accounted for in the sample size calculation, the authors should have carried out the analysis of the X-rays according to the protocol and then applied the first criterion for sensitivity analysis. As for the second criterion, there is no evidence that it contributes anything when applied to pairs of X-rays in which both TIRDs are <= 1.7 mm, with the exception of an unacceptable loss of statistical power.

  In summary: Symptomatic effect: The inclusion of very little symptomatic patients, the switch of the primary symptomatic endpoint to an unusual, unpredictable, and not validated alternative outcome measure, and the lack of exclusion or control of confounding factors do not allow to draw any substantial conclusions regarding the symptomatic effects of chondroitin sulphate, glucosamine sulphate or the combination of the two.

  Structure-modifying effect: With only about 50 % of valid pairs of X- rays, i.e. about 75 per group and one third less than required according to the sample size calculation, the results of the LEGS study as presented in the publication do by no means exclude a structure-modifying effect of chondroitin sulphate or glucosamine sulphate alone.

  Several characteristics of the LEGS study discussed above are suited to underestimate or impede the detection of the investigated effects. The fact, however, that the combination of chondroitin sulphate and glucosamine sulphate nevertheless did achieve a meaningful reduction in JSN over 2 years, compared with placebo, in patients with mostly early radiographic knee OA in this study adds even more weight and importance to this finding.

  References

  1. Fransen M, Agaliotis M, Nairn L, et al. Glucosamine and chondroitin for knee osteoarthritis: a double-blind randomised placebo- controlled clinical trial evaluating single and combination regimens. Ann Rheum Dis Published Online First: January 6, 2014. doi:10.1136/annrheumdis -2013-203954.

  2. EMA guideline CPMP/EWP/784/97 Rev. 1. EMA European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on Clinical Investigation of Medicinal Products Used in the Treatment of Osteoarthritis. London, January 20, 2010.

  3. Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 2007;146:580-90.

  4. Uebelhart D, Malaise M, Marcolongo R, et al. Intermittent treatment of knee osteoarthritis with oral chondroitin sulfate: a one- year, randomized, double-blind, multicenter study versus placebo. Osteoarthritis Cart 2004;12:269-276.

  5. Vignon E, Brandt KD, Mercier C, et al. Alignment of the medial tibial plateau affects the rate of joint space narrowing in the osteoarthritic knee. Osteoarthritis Cart 2010;18:1436-40.

  Conflict of Interest:

  Andreas G. Helg is employed by IBSA Institut Biochimique SA, a Swiss manufacturer and distributor of a chondroitin sulphate prescription drug and a glucosamine sulphate dietary supplement. Analysis of the publication of the LEGS study and the preparation of this letter were carried out on behalf of IBSA.

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top