Impact of Different Definitions of Vaso-Occlusion on Efficacy Assessments in Sickle Cell Disease Clinical Trials.

IF 3.4 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Haydar Frangoul, Franco Locatelli, Michael J Eckrich, Suzan Imren, Nanxin Li, Fengjuan Xuan, Stephan A Grupp
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引用次数: 0

Abstract

Introduction: Patients with sickle cell disease (SCD) experience recurrent, severe pain events due to vaso-occlusion. Eliminating these acute pain events is a key outcome in SCD clinical trials; however, the definition of a vaso-occlusive crisis (VOC) or a vaso-occlusive event (VOE) has not been consistently applied, hampering comparisons of treatment efficacy between different therapeutic approaches. We have examined the degree to which differing definitions of vaso-occlusion in clinical trial endpoints impact efficacy outcomes.

Methods: Descriptions of clinical endpoints related to vaso-occlusion and pain events were reviewed from trials of exagamglogene autotemcel (exa-cel), lovotibeglogene autotemcel (lovo-cel), renizgamglogene autogedtemcel (reni-cel), hydroxyurea, L-glutamine, voxelotor, and crizanlizumab. Patient-level data from the published exa-cel Phase 3 pivotal trial (CLIMB SCD-121; data cut 14 Jun 2023) was used to evaluate efficacy outcomes based on differing endpoint definitions of vaso-occlusion.

Results: In the seven clinical trials reviewed, definitions of vaso-occlusion and/or pain events varied by care setting, duration of care, treatments used, and associated complications, with the frequency and duration of medical facility visits for acute pain events being most dissimilar between trials. Definitions of severe VOCs (exa-cel), VOC (voxelotor), and sickle cell-related pain crises (SCPCs; crizanlizumab and L-glutamine) included pain events requiring a medical facility visit of any duration, whereas the definition of painful crises (hydroxyurea) required a medical facility visit of > 4 h and the definition of severe vaso-occlusive events (VOEs; lovo-cel and reni-cel) required a hospital or emergency room (ER) observation unit visit lasting ≥ 24 h or ≥ 2 visits to a day unit or ER over a 72-h period. Based on the definition of severe VOCs, 29/30 patients [96.7%; 95% confidence interval (CI): 82.8, 99.9] in the CLIMB SCD-121 trial were considered free from severe VOCs for ≥ 12 consecutive months, whereas when the severe VOEs definition was applied to the same data, all patients (30/30; 100.0%; 95% CI: 88.4, 100.0) were considered free from severe VOEs for ≥ 12 consecutive months.

Conclusion: Differences exist in definitions of vaso-occlusion and pain events used in SCD clinical trials. Severe VOCs (exa-cel), VOC (voxelotor), and SCPCs (crizanlizumab and L-glutamine) were more broadly inclusive than severe VOEs (lovo-cel and reni-cel) or painful crisis (hydroxyurea). Clinically, these differences resulted in differing numbers of patients being considered free from vaso-occlusion pain events, underscoring the challenge in comparing frequencies of pain events across SCD clinical trials.

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来源期刊
Advances in Therapy
Advances in Therapy 医学-药学
CiteScore
7.20
自引率
2.60%
发文量
353
审稿时长
6-12 weeks
期刊介绍: Advances in Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all therapeutic areas. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Advances in Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research.
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