Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain

Abstract

Many efficacy endpoints have been used in clinical trials of acute migraine pharmacotherapy. Headache response or headache relief (i.e., moderate/severe pain reduced to mild/no pain) at a single, specified time-point, traditionally the primary endpoint, and headache recurrence (i.e., return of pain after initial postdose relief) are inadequate. Headache relief does not provide information about pain-free response and counts a partial response as a treatment success. Headache recurrence can reflect sustained efficacy but is confounded by initial response to treatment, because ineffective drugs have low recurrence rates. The International Headache Society (IHS) guidelines state that 2 hour pain-free response and sustained pain-free response (i.e., freedom from pain with no recurrence or use of rescue or study medication 2-24 hours postdose) provide the most clinically relevant information about the efficacy of migraine pharmacotherapy. The pain-free criterion counts partial responses as failures and thus is a more rigorous test of therapeutic benefit than headache relief, and the two endpoints together incorporate the main treatment attributes that determine patient satisfaction. As an example, consider needle-free subcutaneous sumatriptan and oral triptan tablets. An open-label study of needle-free subcutaneous sumatriptan by Cady and colleagues found that 2 hour pain-free response and sustained pain-free response were 64% and 42% respectively. For oral triptan tablets, the 2001 metaanalysis by Ferrari and colleagues reported 2 hour pain-free response rates ranging from 23% to 38% and sustained pain-free response rates ranging from 11% to 26%. The measures of pain-free response 2 hours postdose and sustained pain-free response can differentiate among treatments and be used to guide therapeutic choices.

Patent Foramen Ovale and Migraine: Closing the Debate—A Review

“…Taken as a whole, the primary and secondary efficacy end points of these 3 studies are not remarkably different from the previously published clinical trials . However, one could argue that the primary efficacy end point in MIST study proposing complete resolution was unrealistic.…”

“…Two previous clinical trials of PFO closure in migraine were halted because of insufficient enrollment and financial constraints (ie, MIST‐II NCT00283738 43‐47 and ESCAPE [Effect of Septal Closure of Atrial PFO on Events of Migraine with Premere] NCT0267371) …”

“…Taken as a whole, the primary and secondary efficacy end points of these 3 studies are not remarkably different from the previously published clinical trials. 45,46 However, one could argue that the primary efficacy end point in MIST study proposing complete resolution was unrealistic. MIST also failed to achieve the secondary end points, such as significant change in intensity and frequency of migraine attacks, findings in line with the major clinical trials in migraine.…”

“…Two previous clinical trials of PFO closure in migraine were halted because of insufficient enrollment and financial constraints (ie, MIST-II NCT00283738 [43][44][45][46][47] and ESCAPE [Effect of Septal Closure of Atrial PFO on Events of Migraine with Premere] NCT0267371). [44][45][46][47][48] After the 3 randomized controlled trials of PFO closure in migraine patients failed to meet their primary end point, it seems prudent to no longer refer otherwise young, healthy migraine patients for invasive PFO closure, although one could argue that exceptions could be made, especially in older patients who have frequent aura, have significant disability from migraine, and who have failed known medical therapies. There are PAEs, post procedure complications, and after procedure care that includes 3-6 months of dual antiplatelet therapy and, in some cases, endocarditis prophylaxis.…”

Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies

“…Furthermore, the efficacy analysis was updated to reflect endpoints that have recently been recommended to better differentiate among treatments in clinical trials of TTH, i.e. pain-free after 2 h (Y/N) and headache response after 2 h (Y/N) [ 11 , 12 ]. These endpoints are particularly appropriate to guide therapeutic choices [ 11 ].…”