Benefit-Risk Assessment of Galcanezumab Versus Placebo for the Treatment of Episodic and Chronic Migraine Using the Metrics of Number Needed to Treat and Number Needed to Harm

Leslie Citrome, Margarita Sánchez Del Rio, Yan Dong, Russell M Nichols, Antje Tockhorn-Heidenreich, Shonda A Foster, Virginia L Stauffer, Leslie Citrome, Margarita Sánchez Del Rio, Yan Dong, Russell M Nichols, Antje Tockhorn-Heidenreich, Shonda A Foster, Virginia L Stauffer

Abstract

Introduction: Subcutaneous galcanezumab was an effective, well-tolerated preventive treatment for adults with episodic (EM) or chronic migraine (CM) in 4 phase 3 randomized controlled trials: EVOLVE-1, EVOLVE-2, REGAIN, and CONQUER. Number needed to treat (NNT) and to harm (NNH) are metrics of effect size used to evaluate benefit-risk profiles. This study evaluated NNT, NNH, and benefit-risk profiles (measured as likelihood to be helped or harmed, LHH) of galcanezumab 120 mg versus placebo in patients with EM or CM.

Methods: Primary efficacy outcomes were responses defined as ≥ 30%, ≥ 50%, and ≥ 75% reductions from baseline in number of monthly migraine headache days in patients with EM (EVOLVE-1; EVOLVE-2; CONQUER) and CM (REGAIN; CONQUER); corresponding NNTs to achieve respective responses; and corresponding NNHs for discontinuations due to adverse events (DCAEs) among the safety population. Secondary efficacy outcomes were responses for patients with ≥ 2 failed prior preventive treatments due to lack of efficacy and/or for tolerability reasons. All LHHs were based on ≥ 50% response and DCAEs.

Results: During double-blind treatment periods with galcanezumab 120 mg, NNT to achieve ≥ 30% and ≥ 50% responses ranged from 4 to 10 and NNT to achieve ≥ 75% responses ranged from 5 to 23 in individual trials. NNH ranged from 93 to 1000, while LHH ranged from 18.6 to 104.6. NNTs were generally more robust among patients with EM than with CM; however, in patients with failure of ≥ 2 prior preventive treatments, NNTs to achieve ≥ 30% and ≥ 50% responses were similar between patients with CM and EM. NNHs were imputed as 1000 for both migraine types. Resulting LHHs were 178.8 (EM) and 127 (CM).

Conclusion: Across 4 trials, galcanezumab 120 mg demonstrated a favorable benefit-risk profile versus placebo, based on low NNTs to achieve response and high NNHs associated with DCAEs. LHH values consistently far exceeded 1.

Trial registration numbers: EVOLVE-1: ClinicalTrials.gov identifier, NCT02614183; EVOLVE-2: ClinicalTrials.gov identifier, NCT02614196; REGAIN: ClinicalTrials.gov identifier, NCT02614261; CONQUER: ClinicalTrials.gov identifier, NCT03559257.

Keywords: Benefit–risk profile; Chronic migraine; Effect size; Episodic migraine; Galcanezumab; Likelihood of help versus harm; Number needed to harm; Number needed to treat.

© 2021. The Author(s).

References

    1. Villalón CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther. 2009;124:309–323. doi: 10.1016/j.pharmthera.2009.09.003.
    1. American Headache Society The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59:1–18.
    1. Sacco S, Bendtsen L, Ashina M, et al. European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. J Headache Pain. 2019;20:6. doi: 10.1186/s10194-018-0955-y.
    1. Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885–892. doi: 10.1016/S1474-4422(14)70128-0.
    1. Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2018;75:187–193. doi: 10.1001/jamaneurol.2017.3859.
    1. Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38:1026–1037. doi: 10.1177/0333102418759786.
    1. Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123–2132. doi: 10.1056/NEJMoa1705848.
    1. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425–434. doi: 10.1016/S1474-4422(17)30083-2.
    1. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319:1999–2008. doi: 10.1001/jama.2018.4853.
    1. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377:2113–2122. doi: 10.1056/NEJMoa1709038.
    1. Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia. 2020;40:935–948. doi: 10.1177/0333102420905321.
    1. Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381:132–141. doi: 10.1056/NEJMoa1813440.
    1. Silberstein SD, Stauffer VL, Day KA, Lipsius S, Wilson MC. Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2) J Headache Pain. 2019;20:75. doi: 10.1186/s10194-019-1024-x.
    1. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1) Cephalalgia. 2020;40:241–254. doi: 10.1177/0333102420905132.
    1. Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020;94:e1365–e1377. doi: 10.1212/WNL.0000000000009169.
    1. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018;91:e2211–e2221. doi: 10.1212/WNL.0000000000006640.
    1. Mulleners WM, Kim BK, Láinez MJA, et al. Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): a multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol. 2020;19:814–825. doi: 10.1016/S1474-4422(20)30279-9.
    1. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38:1442–1454. doi: 10.1177/0333102418779543.
    1. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75:1080–1088. doi: 10.1001/jamaneurol.2018.1212.
    1. Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117:412–419. doi: 10.1111/j.1600-0447.2008.01194.x.
    1. Citrome L, Ketter TA. When does a difference make a difference? Interpretation of number needed to treat, number needed to harm, and likelihood to be helped or harmed. Int J Clin Pract. 2013;67:407–411. doi: 10.1111/ijcp.12142.
    1. Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998;17:873–890. doi: 10.1002/(SICI)1097-0258(19980430)17:8<873::AID-SIM779>;2-I.
    1. Vo P, Wen S, Martel MJ, Mitsikostas D, Reuter U, Klatt J. Benefit-risk assessment of erenumab and current migraine prophylactic treatments using the likelihood of being helped or harmed. Cephalalgia. 2019;39:608–616. doi: 10.1177/0333102418801579.
    1. Andrade C. Likelihood of being helped or harmed as a measure of clinical outcomes in psychopharmacology. J Clin Psychiatry. 2017;78:e73–e75. doi: 10.4088/JCP.16f11380.
    1. Akobeng AK. Communicating the benefits and harms of treatments. Arch Dis Child. 2008;93:710–713. doi: 10.1136/adc.2008.137083.
    1. Pinson L, Gray GE. Psychopharmacology: number needed to treat: an underused measure of treatment effect. Psychiatr Serv. 2003;54(145–6):154.
    1. Straus SE. Individualizing treatment decisions. The likelihood of being helped or harmed. Eval Health Prof. 2002;25:210–224.
    1. Dalton GW, Keating JL. Number needed to treat: a statistic relevant for physical therapists. Phys Ther. 2000;80:1214–1219. doi: 10.1093/ptj/80.12.1214.
    1. Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. BMJ. 1995;310:452–454. doi: 10.1136/bmj.310.6977.452.
    1. Straus SE, Glasziou P, Richardson WS, Haynes RB. Evidence-based medicine: how to practice and teach EBM. 5. Elsevier; 2018.
    1. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ. 1996;13(312):71–72. doi: 10.1136/bmj.312.7023.71.
    1. Schoenen J, Manise M, Nonis R, Gérard P, Timmermans G. Monoclonal antibodies blocking CGRP transmission: an update on their added value in migraine prevention. Revue Neurolog. 2020;176:788–803. doi: 10.1016/j.neurol.2020.04.027.
    1. Drellia L, Kokoti L, Deligianni CI, Papadopoulos D, Mitsikostas DD. Anti-CGRP monoclonal antibodies for migraine preventions: a systemic review and likelihood to help or harm analysis. Cephalalgia. 2021;41:851–864. doi: 10.1177/0333102421989601.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi