The 10-Item Sickle Cell Disease Severity Measure (SCDSM-10): A Novel Measure of Daily SCD Symptom Severity Developed to Assess Benefit of GBT440, an Experimental HbS Polymerization Inhibitor

Introduction and Objective: GBT440 inhibits HbS polymerization and reduces hemolysis, and is a promising treatment for Sickle Cell Disease (SCD). The traditional clinical endpoint, vaso-occlusive crisis (VOC) requiring healthcare utilization, is not a sensitive measure of the daily burden of symptoms in patients (the "tip of the iceberg" of severe symptom exacerbations) and poses a barrier to development of new treatments for SCD.

The objective was to develop a sensitive measure to detect treatment-related improvements in daily symptoms and exacerbations that define the disease. Existing SCD measures focus on distal impact, not on the core signs and symptoms of disease, and therefore not appropriate for meeting the regulatory standard to prove treatment benefit. Beginning with a hypothesized conceptual framework focused on pain and fatigue, rigorous qualitative and quantitative research was used to develop the content of the Sickle Cell Disease Severity Measure (SCDSM).

Methods: The content of the new measure was derived from 1-on-1 open-ended concept elicitation interviews in 56 adults and 10 adolescents with SCD in the US and UK. Participants were aged 12-63 years, 64% female, 44% currently on hydroxyurea treatment, 86% had 1 to 42 VOC in the previous year requiring urgent care. During the interview, 74% reported having a typical or "good" day versus 26% having a crisis or "bad" day.

Interview transcripts were coded to identify the most bothersome and frequently mentioned concepts related to both "good" and "bad" days. As hypothesized, patients reported having crisis days more frequently than those crises requiring healthcare utilization (traditional VOC endpoint). Interviews continued until saturation was demonstrated. How items worked individually and together were explored to quantify the full range of SCD severity. Both Classical Test Theory and Rasch Measurement Theory quantitative analyses supported the qualitative data to refine item content. To document content validity, the SCDSM content in its final electronic daily diary format will be evaluated in cognitive debriefing studies. Subsequently, longitudinal evaluation will occur in future clinical trials with GBT440. Translation and cultural adaptation is planned.

Results: After eliciting an initial pool of items using open-ended interviews, the items were administered to a small cohort of SCD patients. After analyses of the response data and re-examination of the qualitative data, revisions were made. The revised set was re-administered to a cohort of 50 SCD patients. Qualitative and quantitative analyses provided evidence that a set of 10-items demonstrated content validity in adult and adolescent SCD patients to produce a score which can measure the full range of sickle cell disease severity. The mixed methods process enabled streamlined decision-making concerning measure content. The final content includes items specific to pain, fatigue, concentration and breathlessness. Evidence supports the derived estimate as a reliable and valid measure of SCD symptom severity covering a wide range of experience and providing the ability to differentiate baseline symptoms from severe symptoms. Patient responses to the 10 SCDSM items are combined to generate a single daily estimate of SCD symptom severity. Two "scores" can be computed: an ordinal-level total score can be computed by summing item scores; an interval-level (linear) measure can be derived from item responses using RMT analysis.

Conclusions: SCD patients have a high burden of daily symptoms, with severe or "crisis" days occurring more frequently than traditionally defined VOC. The 10-item SCDSM is a promising new measure of daily SCD symptom severity developed to be fit for purpose in clinical trials to determine the treatment effect of new drugs on potential improvement in baseline symptoms and/or prevention of symptom exacerbations. SCDSM will soon be tested in a clinical trial setting to determine its longitudinal measurement characteristics, generate guidelines for measure interpretability, and to explore the clinical benefit of GBT440 in SCD. Qualitative and psychometric findings based on the SCD patient voice will be presented at the meeting to provide evidence of SCDSM validity, reliability, and usefulness in assessing symptom severity in a disease that has heretofore been poorly characterized on a daily basis.