Placebo response is not decreased by enrichment trial designs in randomized controlled trials of triptan medications in the paediatric age group Lawrence Richer MD, MSc 4th International Clinical Trials Methodology Conference 2017 Liverpool, United Kingdom

Background Migraine is a complex neurobiological disorder of recurring pain Among most significant causes of neurological morbidity worldwide Characterized by recurring moderate to severe headache with a pulsatile quality lasting 4 - 72 hours and associated with nausea, vomiting, photophobia and sonophobia

Treatment Simple analgesics commonly used Triptan medications (serotonin 1b/1d receptor agonists) RCT evidence for efficacy in children or adolescents inconsistent High placebo response is often implicated

Placebo response Complex neurobiological response associated with treatment expectation Mechanism? - activation of endogenous opioids, dopamine; cannabinoid receptors and genetic variants of COMT Can minimize – in order to maximize differentiation of drug Can maximize – in order to enhance clinical response

Objectives Evaluate the overall placebo response and compare enrichment versus non-enrichment designs in RCTs of migraine treatment with any triptan medication among children or adolescents

Methods Seven bibliographic databases, four clinical trial registers and grey literature searched through February 2016 All prospective RCTs of children and adolescents with migraine of symptom relieving drugs Co-primary outcomes Pain-free at 2 hours Headache relief at 2 hours

Meta-analysis Average effect  weighted mean Weights are the inverse variance of each study effect estimator Larger studies and studies with less random variation given greater weight over smaller studies Random effects model used

Results

Characteristics of included studies 25 randomized controlled trials (RCTs) of triptan medications in adolescents or children completed between 1992 and 2013 Adolescents and children were evaluated separately Characteristic N studies Study design Cross-over Parallel 9 16 Age group Adolescent Child 22 3 Route Oral Intranasal 17 8 Sponsor Pharmaceutical Unclear/Investigator 20 5

Triptan medications included Drug name No enrichment Enrichment Total Almotriptan 1 Eletriptan Naratriptan Rizatriptan 3 2 5 Sumatriptan 12 Sumatriptan/Naproxen Zolmitriptan 4 20 25

Pain-free by Enrichment Design 20 studies 5 studies N = 20 studies N = 5 studies N = 25 studies

Headache Relief by Enrichment Design 20 studies 5 studies

Placebo run-in (n=2 studies)

Non-responder (n=3 studies)

Performance of Enrichment Strategy Placebo run-in (2 studies reporting) 478 excluded of 2518 enrolled (19%) 1 of 2 met primary objective re: efficacy Non-responder (2 study reporting; one with two age groups) 100 excluded of 1382 enrolled (14%) 1 of 2 studies met primary objective re: efficacy

Subgroup and Sensitivity Analysis Pain-free Characteristic % (95% CI) %(95% CI) p Study Design Cross-over Parallel group 17% (14-21%) 22% (18-26%) 0.063 Age group Adolescents (12-17 yrs) Children (<12 yrs) 21% (17-24%) 26% (19-34%) 0.166 Route Oral Intranasal 21% (17-25%) 0.694 Sponsorship Pharmaceutical Unclear / Investigator 22% (19-26%) 19% (13-24%) 0.41

Placebo Response – Adult vs Pediatric Cameron C, et al. Headache. 2015 Jul;55 Suppl 4:221–35. 

Why is placebo response high? Suggestibility due to younger age Vigorous neurobiological response Patient reported outcomes / pain

Conclusions Placebo response is higher in pediatric RCTs of triptan medications Enrichment designs as a group did not significantly decrease the placebo response Significant variability between studies Placebo run-in enrichment design may be a more effective strategy Limited to two studies

Acknowledgements Lisa Hartling Ben Vandermeer Meghan Linsdell Ellen Crumley Lori Billinghurst Kelly Russell Ellen T Crumley Tamara Durec Terry P Klassen Funding: Stollery Children’s Hospital Foundation