In Phase 2 and Phase 3 Trials, Broadening the Definition of Acute Vaso-Occlusive Pain to Include at Least One Episode of Pain Requiring Nsaids, Opioids, or Both Treatments at Home within 30 Days of a Physician Visit

Introduction:Despite the high incidence of acute painful events in children and adults with SCD, there is a lack of consensus on the acute pain definition in controlled clinical trials. To address this limitation, we elected to have three definitions of acute vaso-occlusive pain based on the setting for the pain location: inpatient, outpatient, ED, or at home. Based on the results of the SPRING Trial, the primary stroke prevention trial in children with SCD conducted in Nigeria (The Lancet Haematol. 2022 Jan 1;9(1):e26-37), and the PISCES study (Annals of internal medicine. 2008 Jan 15;148(2):94-101), most acute pain events in low-middle and high-income countries occur at home. We tested the hypothesis that the majority of negative phase 2 and phase 3-controlled trials for SCD failed to consider acute pain events in all four settings.

Methods: To identify the relevant Phase II and III trials with acute pain as an outcome, we conducted a literature review using the website clinicaltrials.gov with the following key terms: “Sickle Cell Disease,” and “Vaso-occlusive.”. Studies that were not Phase II or Phase III were excluded from our search.

We identified Phase 2 or 3 SCD pain trials published between 2015 and 2023. Inclusion criteria: definitions in the clinicaltrials.gov trial page, protocol, or method section. An inclusive, consensus definition for vaso-occlusive pain was chosen from the SPRING Trial. This definition was compared to the acute vaso-occlusive pain definitions of both SCD Phase 2 and 3 trials, with vaso-occlusive pain as a primary or secondary outcome. Based on the SPRING Trial and the results of the PISCES study, we elected to have three definitions of acute vaso-occlusive pain: 1. inpatient uncomplicated pain that excludes a concomitant diagnosis of acute chest syndrome; 2. Pain that required either an inpatient or outpatient visit and opioid treatment; and 3. An acute pain event at home requiring NSAIDs, opioids, or both. Only uncomplicated pain events were included to avoid double counting participants who developed acute chest syndrome or strokes that may have preceded the vaso-occlusive pain event.

Results: We identified 35 articles based on our criteria. Our study sample included 3 clinical trials that led to the FDA approval for therapy to prevent acute vaso-occlusive pain events (FDA-approved therapy trials). Among these 35 trials, 32 clinical trials did not provide any evidence of the therapeutic benefits of the experimental agent (negative controlled trials).

The three randomized controlled trials that led to FDA approval for therapy to prevent acute pain were: Hydroxyurea, L-Glutamine, and Crizanlizumab. Hospitalization for pain was included in all three FDA-approved therapy trials and 34.4% (11/32) of negative controlled trials. The ED visits in the pain definition were included in all 3 FDA-approved therapy trials and 28.1% (9/32) of negative controlled trials. Outpatient visits in the pain definition were included in all 3 FDA-approved therapy trials and 21.9% (7/32) of negative controlled trials. Home pain episodes were included in none of the FDA-approved therapy trials and 9.4% (3/32) of negative controlled trials. Finally, 43.8% (14/32) negative controlled trials were excluded as they failed to define vaso-occlusive pain in their methods or definition section and 15.6% (5/32) negative controlled trials did not have a publication.

Conclusion: Most controlled trials designed to evaluate the efficacy of new treatment did not include the setting where pain occurs most frequently, at home. For future therapeutic trials designed to address whether a new therapy decreases the incidence rate of acute pain, we recommend an assessment of pain in all 4 four settings (Hospitalization, ED, Outpatient, and Home).