Measurement of Sickle Cell Disease Symptoms from the Patient Perspective: Considerations for Clinical Trials
Authors: Ojo Funke , Litcher-Kelly Leighann , Mazar Iyar , Klooster Brittany , Ollis Sarah , Chaston Emily , Roeder Adam , Treadwell Marsha J. , Reasner David 
Published: October 2019

Abstract
OBJECTIVES: Sickle cell disease (SCD), a group of inherited blood disorders, can impact multiple organs and can lead to variable clinical presentations. In addition to severe pain crises, patients may experience chronic symptoms (e.g. pain, tiredness). Assessing treatment benefit using a patient-reported outcome (PRO) measurement strategy can be critical for supporting clinical SCD research. We conducted qualitative research activities to inform considerations for PRO measurement strategies to assess daily chronic symptoms in regulated SCD clinical trials in patients 16 years and older.
METHODS: Research activities aimed to identify the relevant and important signs/symptoms of SCD and determine their potential for measurement via existing PRO instruments. A literature review, meetings with clinical experts (N=5), and interviews with adolescent and adult SCD patients (N=20) were conducted. Trained researchers conducted semi-structured qualitative interviews. Results were analyzed to develop a synthesized SCD conceptual model describing the literature, expert, and patient perspectives of SCD.
Five instruments used in SCD research were selected for review: Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-MeSM), Pediatric Quality of Life Inventory (PedsQL™) sickle cell disease module, the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue and Pediatric Pain Interference measures, and Scribe Sickle Cell Record of Daily Symptom Burden™ (SSCRDSB). Signs/symptoms in the SCD conceptual model were compared to those assessed in these instruments and measurement properties were reviewed. Considerations for concept selection (e.g. suitability of measuring a symptom via PRO instrument) and item development (e.g. selection of recall period) in developing a PRO measurement strategy were evaluated. Instruments developed to assess SCD concepts should have documented evidence of content validity (i.e., qualitative data confirming the instrument measures concepts important, relevant and understandable to the target patient population) and should include clear instructions, a short recall period, items that measure dimensions of importance to patients (e.g., symptom intensity), and well-defined response options that are sufficiently sensitive to detect change.
RESULTS: Patients reported 22 signs/symptoms that they experienced generally with SCD and/or during pain episodes, which were largely endorsed by the literature and/or clinical experts. Pain was reported by all patients and tiredness was reported by 80.0% of patients; both were cited as the most important to improve with treatment. Patients reported 29 impacts of SCD across 9 domains.
Across the 5 instruments, pain was the most frequently measured SCD symptom concept, measured in different ways by 3 instruments. None of the reviewed instruments assessed more than 5 of the signs/symptoms included in our SCD conceptual model with the SSCRDSB assessing the greatest number of signs/symptoms (n=5/22 concepts, 22.7%). The remaining 4 instruments assessed 3 or fewer of the signs/symptoms reported by patients. Physical impacts were the most frequently measured impact domain, assessed to varying degrees by all 5 instruments evaluated. The PedsQL™ SCD module assessed the greatest number of impact domains in our SCD conceptual model (n=7/9 domains, 77.8%). The reviewed instruments were determined to have limitations in the context of assessing SCD signs/symptoms daily as part of regulated clinical trials.
CONCLUSIONS: The research activities conducted as part of this work suggest that (1) patients experience numerous SCD signs/symptoms regularly and intermittently and (2) existing instruments, while perhaps suitable for other contexts of use or in conjunction with other tools, may be inadequate for evaluating the most important symptoms in a way that can demonstrate treatment benefit when measured daily in regulated clinical research. A de novo instrument developed for these purposes may better assess treatment benefit from the patient perspective in the context of measuring variable SCD symptoms daily in a regulated clinical trial setting.

Disclosures
Ojo: Ironwood Pharmaceuticals: Employment. Litcher-Kelly:Ironwood Pharmaceuticals: Consultancy. Mazar:Ironwood Pharmaceuticals: Consultancy. Klooster:Ironwood Pharmaceuticals: Consultancy. Ollis:Ironwood Pharmaceuticals: Consultancy. Chaston:Ironwood Pharmaceuticals: Consultancy. Roeder:Ironwood Pharmaceuticals: Consultancy. Treadwell:Global Blood Therapeutics: Consultancy; Ironwood Pharmaceuticals: Consultancy; Pfizer: Consultancy. Reasner:Ironwood Pharmaceuticals: Employment, Equity Ownership.