Placebo and nocebo phenomena in anti- CGRP monoclonal antibody trials for migraine prevention: a meta-analysis
- 96 Downloads
High placebo and low nocebo phenomena mirror high positive expectations for a novel treatment, among other reasons. In a meta-analysis aimed to identify placebo and nocebo phenomena in the placebo-controlled randomized trials (RCTs) with the monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) all the placebo-treated patients were pooled and compared with the placebo-treated patients in RCTs with topiramate and onabotulinum toxin A (OBTA). In episodic migraine (EM), the proportion of placebo-treated patients who achieved the 50% responder rate (placebo) was 32.7% (95% CI 28.6%–37.0%) in anti-CGRP mAbs vs. 24.4% (95% CI 20.5%–28.5%) in topiramate trials. The proportion of dropouts due to adverse events in placebo-treated patients (nocebo) was 1.9% (95% CI 1.4%–2.6%) in anti-CGRP mAbs vs. 9.9% (95% CI 7.7%–12.3%) in topiramate RCTs. In chronic migraine (CM), the placebo 50% responder rate was 23.6% (95% CI 11.2%–38.8%) in anti-CGRP mAbs RCTs vs. 36.4% (95% CI 32.6%–39.3%) in RCTs with OBTA. The nocebo dropout in anti-CGRP mAbs and OBTA RCTs was 1.4% (95% CI 0.8%–2.1%) and 0.9 (95% CI 0.3%–1.7%), respectively. The stronger placebo and weaker nocebo phenomena in RCTs with anti-CGRP mAbs vs. those with topiramate in the prophylaxis of EM, may decisively determine anti-CGRP mAbs treatment success. No differences were detected between the anti-CGRP mAbs and OBTA in the treatment of CM.
KeywordsEpisodic migraine Chronic migraine Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies Treatment Topiramate Onabotulinum toxin A
The authors thank Mrs Evie Delicha, MSc, for her expert statistical advice.
All authors contributed to the study conception and design. Material preparation, literature search, data collection, and analysis were performed by KD and LK. The first draft of the manuscript was written by KD and LK and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Conceptualization: DDM; Methodology: DDM and DP; Formal analysis and investigation KD and LK; Writing—original draft preparation: KD and LK; Writing—review and editing: all authors; Funding acquisition: No founding; Supervision: DDM and DP.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with ethical standards
Conflicts of interest
Dr. L. Kokoti reports no disclosures. Dr. K. Drellia reports no disclosures. Dr. D. Papadopoulos has received consulting, speaking fees and travel grants from Bayer, Genesis Pharma, Merck, Novartis, Roche, Sanofi-Aventis, Specifar and Teva. Prof. D.D. Mitsikostas has received consulting, speaking fees and travel grants from Allergan, Amgen, Bayer, Biogen, Cefaly, ElectroCore, Genesis Pharma, Eli Lilly, Merck-Serono, Merz, Mylan, Novartis, Roche, Sanofi-Genzyme, Specifar and Teva.
No ethics approval or patient consent was obtained because all data used in this study were collected from previously published peer-reviewed articles.
- 10.Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, BIBN 4096 BS Clinical Proof of Concept Study Group (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 350:1104–1110PubMedCrossRefGoogle Scholar
- 25.Tassorelli C, Diener HC, Dodick DW, Silberstein SD, Lipton RB, Ashina M, Becker WJ, Ferrari MD, Goadsby PJ, Pozo-Rosich P, Wang SJ, International Headache Society (2018) Clinical trials standing committee. Guidelines of the international headache society for controlled trials of preventive treatment of chronic migraine in adults. Cephalalgia 38:815–832PubMedCrossRefGoogle Scholar
- 28.Lipton RB, Saper J, Ashina M et al (2018) A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of eptinezumab for the preventive treatment of chronic migraine: results of the PROMISE-2 (prevention of migraine via intravenous eptinezumab safety and efficacy-2) trial. Neurology 90:e2193–e2194Google Scholar
- 29.Saper J, Lipton R, Kudrow D, Hirman J, Dodick D, Silberstein S, Chakhava GJS (2018) Primary results of PROMISE-1 (prevention of migraine via intravenous eptinezumab safety and efficacy–1) trial: a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of eptinezumab for prevention of frequent episodic migraine. Neurology 90(15 Suppl):S20.001Google Scholar
- 40.Diener HC, Tfelt-Hansen P, Dahlöf C, Láinez MJ, Sandrini G, Wang SJ, Neto W, Vijapurkar U, Doyle A, JDM-003 SG (2004) Topiramate in migraine prophylaxis–results from a placebo-controlled trial with propranolol as an active control. J Neurol 251:943–950Google Scholar
- 54.Dodd S, Schacht A, Kelin K, Dueñas H, Reed VA, Williams LJ, Quirk FH, Malhi GS, Berk M (2015) Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry. 76:702–711PubMedCrossRefGoogle Scholar