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Correspondence
Comment on: ‘Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial’ by Qian-wen et al We have read the recent paper by Qian-Wen and colleagues on the efficacy of the traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF) alone and in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA).1 While we have great regard for all the efforts the authors have taken to investigate the efficacy and safety of this interesting compound in patients with RA, we fear that fundamental flaws in the design of the trial and the fallible reporting preclude a balanced interpretation of the otherwise remarkable results. Our concerns are twofold. First, it is not clear if the a priori hypothesis underlying this trial includes a non-inferiority comparison of TwHF and MTX, a superiority comparison of TwHF plus MTX versus TwHF or MTX alone, or maybe even both. Unfortunately, the authors do not report a public clinical trial register in which the trial protocol has been filed before the trial start, and which may serve as a reference for questions like these. While the very first sentence of the statistical analysis paragraph suggests a non-inferiority design, the wording dedicated to sample size calculation in the second sentence seems to be directly derived from wording used in a classical superiority designs: ‘A sample size of 207 subjects (69 patients in each group) was estimated to provide at least 80% power to detect a non-inferiority margin of 10% in the proportion of TwHF and MTX-treated patients achieving an ACR50 response at week 24, at a 5% level of significance’. In violation with common methodological guidelines,2 the authors do not explain how a non-inferiority margin as low as 10% has been justified up front, and which were the a priori expectations regarding American College of Rheumatology (ACR) 50% response rate (ACR50) responses. Such considerations are of utmost relevance for a reader to determine if a sample size of 69 patients per treatment arm is truly credible in order to allow a non-inferiority comparison with a claimed noninferiority margin of 10%. We expect the authors do understand that a non-inferiority comparison of TwHF and MTX allowing a between-group difference in response rate of 10% at most implies that the upper level of the 95% CI (one-sided testing is allowed in noninferiority comparisons) of the treatment effect (ie, expected ACR50 response in the MTX group minus expected ACR50 response in the TwHF group) excludes zero. At an expected rate of 40% ACR50 response in the MTX group (a reasonable expectation based on literature), we calculated a sample size of 279 per group instead of 69 (Zα=1.64; Zβ=0.84). A reasonable non-inferiority trial should have had a fourfold higher sample size! The results of this trial, therefore, by far do not allow the formal declaration of non-inferiority that the authors have claimed, even though the actually reported effects of TwHF and MTX indeed suggest ‘equivalence’ of TwHF and MTX.
Our second concern includes the lack of study drug blinding. As the authors have stated themselves, TwHF is very popular among patients and rheumatologists in China, implying that in a formal randomised controlled trial, expectations of patients and physicians regarding the efficacy of this drug alone and in combination with the anchor drug MTX will be sky-high and easily exaggerated. Every interpretation of drug efficacy (and drug safety) should be made in the context of this unblinded design. It should be added that—especially in case of a non-inferiority comparison—unblinded treatment allocation works tremendously in favour of demonstrating non-inferiority.2 3 Non-inferiority trials are popular, but unfortunately extremely difficult to design and conduct appropriately because they are so sensitive to inappropriate trial design and conduct. Apparently, authors as well as reviewers do not always realise the pitfalls associated with this type of research. Unless the authors are able to convince us that we have misinterpreted their trial report, we believe the bold conclusions of this trial regarding the efficacy and safety of TwHF should be interpreted with extreme caution. Robert B M Landewé,1,2 Désirée van der Heijde3 1 Departments of Rheumatology & Clinical Immunology, Academic Medical Center, Amsterdam, The Netherlands 2 Department of Rheumatology, Atrium Medical Center Heerlen, Heerlen, The Netherlands 3 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
Correspondence to Professor Robert BM Landewé, Rheumatology & Clinical Immunology, Academic Medical Center, Amsterdam, The Netherlands; [email protected] Contributors RBML and DvdH have both contributed to the design, content and writing of this eletter and have both approved the final version. Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed.
To cite Landewé RBM, van der Heijde D. Ann Rheum Dis 2014;73:e62. Received 20 June 2014 Accepted 25 June 2014 Published Online First 10 July 2014
▸ http://dx.doi.org/10.1136/annrheumdis-2014-206156 Ann Rheum Dis 2014;73:e62. doi:10.1136/annrheumdis-2014-206124
REFERENCES 1
2
3
Qian-wen LV, Zhang W, Shi Q, et al. Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial. Ann Rheum Dis 2014. Published Online First 14 Apr 2014. doi:10.1136/annrheumdis-2013-204807 Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 2012;308:2594–604. Pocock SJ, Piaggio G, Altman DG. Reporting noninferiority trials–reply. JAMA 2013;309:1585.
Ann Rheum Dis October 2014 Vol 73 No 10
e62
Downloaded from http://ard.bmj.com/ on December 24, 2014 - Published by group.bmj.com
Comment on: 'Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial' by Qian-wen et al Robert B M Landewé and Désirée van der Heijde Ann Rheum Dis 2014 73: e62 originally published online July 10, 2014
doi: 10.1136/annrheumdis-2014-206124 Updated information and services can be found at: http://ard.bmj.com/content/73/10/e62
These include:
References Email alerting service
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Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Correspondence
Comment on: ‘Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial’ by Qian-wen et al We have read the recent paper by Qian-Wen and colleagues on the efficacy of the traditional Chinese medicine Tripterygium wilfordii Hook F (TwHF) alone and in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA).1 While we have great regard for all the efforts the authors have taken to investigate the efficacy and safety of this interesting compound in patients with RA, we fear that fundamental flaws in the design of the trial and the fallible reporting preclude a balanced interpretation of the otherwise remarkable results. Our concerns are twofold. First, it is not clear if the a priori hypothesis underlying this trial includes a non-inferiority comparison of TwHF and MTX, a superiority comparison of TwHF plus MTX versus TwHF or MTX alone, or maybe even both. Unfortunately, the authors do not report a public clinical trial register in which the trial protocol has been filed before the trial start, and which may serve as a reference for questions like these. While the very first sentence of the statistical analysis paragraph suggests a non-inferiority design, the wording dedicated to sample size calculation in the second sentence seems to be directly derived from wording used in a classical superiority designs: ‘A sample size of 207 subjects (69 patients in each group) was estimated to provide at least 80% power to detect a non-inferiority margin of 10% in the proportion of TwHF and MTX-treated patients achieving an ACR50 response at week 24, at a 5% level of significance’. In violation with common methodological guidelines,2 the authors do not explain how a non-inferiority margin as low as 10% has been justified up front, and which were the a priori expectations regarding American College of Rheumatology (ACR) 50% response rate (ACR50) responses. Such considerations are of utmost relevance for a reader to determine if a sample size of 69 patients per treatment arm is truly credible in order to allow a non-inferiority comparison with a claimed noninferiority margin of 10%. We expect the authors do understand that a non-inferiority comparison of TwHF and MTX allowing a between-group difference in response rate of 10% at most implies that the upper level of the 95% CI (one-sided testing is allowed in noninferiority comparisons) of the treatment effect (ie, expected ACR50 response in the MTX group minus expected ACR50 response in the TwHF group) excludes zero. At an expected rate of 40% ACR50 response in the MTX group (a reasonable expectation based on literature), we calculated a sample size of 279 per group instead of 69 (Zα=1.64; Zβ=0.84). A reasonable non-inferiority trial should have had a fourfold higher sample size! The results of this trial, therefore, by far do not allow the formal declaration of non-inferiority that the authors have claimed, even though the actually reported effects of TwHF and MTX indeed suggest ‘equivalence’ of TwHF and MTX.
Our second concern includes the lack of study drug blinding. As the authors have stated themselves, TwHF is very popular among patients and rheumatologists in China, implying that in a formal randomised controlled trial, expectations of patients and physicians regarding the efficacy of this drug alone and in combination with the anchor drug MTX will be sky-high and easily exaggerated. Every interpretation of drug efficacy (and drug safety) should be made in the context of this unblinded design. It should be added that—especially in case of a non-inferiority comparison—unblinded treatment allocation works tremendously in favour of demonstrating non-inferiority.2 3 Non-inferiority trials are popular, but unfortunately extremely difficult to design and conduct appropriately because they are so sensitive to inappropriate trial design and conduct. Apparently, authors as well as reviewers do not always realise the pitfalls associated with this type of research. Unless the authors are able to convince us that we have misinterpreted their trial report, we believe the bold conclusions of this trial regarding the efficacy and safety of TwHF should be interpreted with extreme caution. Robert B M Landewé,1,2 Désirée van der Heijde3 1 Departments of Rheumatology & Clinical Immunology, Academic Medical Center, Amsterdam, The Netherlands 2 Department of Rheumatology, Atrium Medical Center Heerlen, Heerlen, The Netherlands 3 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
Correspondence to Professor Robert BM Landewé, Rheumatology & Clinical Immunology, Academic Medical Center, Amsterdam, The Netherlands; [email protected] Contributors RBML and DvdH have both contributed to the design, content and writing of this eletter and have both approved the final version. Competing interests None. Provenance and peer review Not commissioned; internally peer reviewed.
To cite Landewé RBM, van der Heijde D. Ann Rheum Dis 2014;73:e62. Received 20 June 2014 Accepted 25 June 2014 Published Online First 10 July 2014
▸ http://dx.doi.org/10.1136/annrheumdis-2014-206156 Ann Rheum Dis 2014;73:e62. doi:10.1136/annrheumdis-2014-206124
REFERENCES 1
2
3
Qian-wen LV, Zhang W, Shi Q, et al. Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial. Ann Rheum Dis 2014. Published Online First 14 Apr 2014. doi:10.1136/annrheumdis-2013-204807 Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 2012;308:2594–604. Pocock SJ, Piaggio G, Altman DG. Reporting noninferiority trials–reply. JAMA 2013;309:1585.
Ann Rheum Dis October 2014 Vol 73 No 10
e62
Downloaded from http://ard.bmj.com/ on December 24, 2014 - Published by group.bmj.com
Comment on: 'Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): a randomised, controlled clinical trial' by Qian-wen et al Robert B M Landewé and Désirée van der Heijde Ann Rheum Dis 2014 73: e62 originally published online July 10, 2014
doi: 10.1136/annrheumdis-2014-206124 Updated information and services can be found at: http://ard.bmj.com/content/73/10/e62
These include:
References Email alerting service
This article cites 2 articles, 0 of which you can access for free at: http://ard.bmj.com/content/73/10/e62#BIBL Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
