Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) by patient-reported outcomes, actigraphy, and biomarkers

Abstract

Clinical trials in sickle cell disease (SCD) often focus on health care utilization for painful vaso-occlusive crises (VOC). However, no objective, quantifiable pain biomarkers exist, pain is not specific to VOCs, health care utilization varies between patients, unreported at-home VOCs likely contribute to long-term outcomes, and patient-reported outcomes are seldom considered. This non-interventional, longitudinal, 6-month study aimed to develop tools to identify VOCs in SCD patients with or without health care utilization. Participants wore an actigraph device, tracking sleep and activity. SCD patients used an electronic patient-reported outcome (ePRO) tool collecting pain, medication, fatigue, and daily function. Patients self-reported when they experienced VOC pain (VOC day). Biomarkers were collected every 3 weeks (non-VOC). Self-reported VOCs triggered at-home or in-hospital blood collection. The study enrolled 37 participants with SCD; 35 completed the study. Participants reported 114 VOC events and 346 VOC days, of which 62.3% and 78.3%, respectively, were self-treated at home. The ePRO and actigraphy captured endpoints of pain, functionality, fatigue, activity, and sleep; each was significantly altered on VOC days compared with non-VOC days. Biomarkers collected at home or in hospital on VOC days were significantly altered compared with non-VOC baseline values, including leukocyte-platelet aggregates, microfluidic-based blood cell adhesion, interleukin-6, C-reactive protein, interleukin-10, tumor necrosis factor-alpha, and thrombin-antithrombin. ELIPSIS: demonstrates the feasibility of accurately monitoring out-of-hospital pain, using patient-reported VOC days as potential endpoints for clinical trials in SCD; showed changes in biomarkers and activity measured by actigraphy that may enable improved identification and assessment of VOCs.

A systematic literature review of frequency of vaso-occlusive crises in sickle cell disease

“…Among those studies in this SLR that included self-reported VOCs or those managed in a home setting, the mean annualized frequency was generally higher, ranging from 5.2 to 13.6 VOCs/year [ 19 – 21 ]. This is also consistent with a recent prospective cohort study published after the search period for this SLR, in which 35 U.S. patients were followed for 6 months and reported a median annualized frequency of 8 VOCs/year, with a mean duration of 2.7 days and 62.3% of VOC events self-managed at home [ 50 ]. Patients self-reported VOCs in their daily pain diary that were managed at home, in a clinic, in the emergency department, or in the hospital.…”

The Epidemiology of Neurological Complications in Adults With Sickle Cell Disease: A Retrospective Cohort Study

“…Therefore, at-home vaso-occlusive crises are underreported. The Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) trial has recently shown the feasibility of accurately monitoring out-of-hospital pain by using patient-reported vaso-occlusive crisis days as potential endpoints for clinical trials in SCD ( 42 ). The utilization of the quantifiable biomarker in future trials has the potential to improve this bias.…”

Longitudinal assessment of adhesion to vascular cell adhesion molecule‐1 at steady state and during vaso‐occlusive crises in sickle cell disease

“…VOC samples were collected within 24 h from report. This protocol was approved by the Wayne State University Human Investigation Committee Institutional Review Board and written informed consent was obtained from study participants, previously defined in detail 10 . Participants who were being treated with HU must have been on a stable dose for at least eight weeks prior to visit 1.…”

“…More than 100 biomarkers have been identified in SCD although none have been shown to reliably predict VOCs 1‐10 . Pathologic adhesive interactions of sickle erythrocytes (SSRBCs) to the vascular endothelium contribute to VOCs, resulting in impaired microvascular blood flow, tissue ischaemia, severe pain, and end‐organ damage.…”

“…More than 100 biomarkers have been identified in SCD although none have been shown to reliably predict VOCs. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 Pathologic adhesive interactions of sickle erythrocytes (SSRBCs) to the vascular endothelium contribute to VOCs, resulting in impaired microvascular blood flow, tissue ischaemia, severe pain, and end‐organ damage. Static and flow‐based adhesion assays have been used for decades to describe adhesion in SCD since earlier studies demonstrated that SSRBCs are more adherent than non‐sickle erythrocytes and observed a link between SSRBC adhesion and SCD severity.…”