Sickle Cell Disease Clinical Trials Research Articles

A Patient-Centric Approach to Sickle Cell Disease Clinical Trials: Integrating Patient Perspectives in the RISE UP Phase 2/3 Trial of Mitapivat for Informed Protocol Design and Associated Patient Community Benefit

Background: Sickle cell disease (SCD) is a genetic blood disorder that affects millions of people worldwide. There are currently limited treatment options and a high unmet need; new therapies - and therefore new trials - are essential. Although there is evidence of growing patient (pt) participation in the drug development processes, there is a lingering suspicion among the community that they are not treated as equal partners and too frequently regarded as mere data sources. Involving pts in planning and execution of clinical trials is essential to improve participation and meet the real needs of the patient community. Mitapivat is a first-in-class, oral, allosteric activator of pyruvate kinase (PK), approved by the United States Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, by the European Union European Medicines Agency, and the Medicines and Healthcare products Regulatory Agency in Great Britain for the treatment of PK deficiency in adults. The RISE UP phase 2/3 trial (NCT05031780) of mitapivat in pts with SCD was therefore devised to use a new approach to clinical trial design and recruitment that considered pt preferences wherever possible. Objective: Using the RISE UP Phase 2/3 trial, redefine best practices in clinical trial design by asking pts with SCD to describe what matters most to them in a trial setting and by involving them in decision making processes and trial awareness communications. Methods: Nine SCD pts and advocates (five from the US, one from Bahrain, one from France and two from the UK) took part in a series of clinical trial design workshops. Four remote advisory board interviews were held with pts (>16 years of age) and advocates to consult on the RISE UP Phase 2/3 clinical trial design. The insights gained from these consultations were incorporated into the proposed trial protocol design that was subsequently shared with Health Authorities (HAs) for their comment from a regulatory perspective. Once finalized, feedback from HAs was presented to the steering committee to determine whether changes requested by HAs met the needs and barriers-to-uptake expressed during partner consultations. In addition, a group of seven patients were involved in the development of the RISE UP phase 2/3 clinical trial awareness campaign, which sought to educate the community about the RISE UP clinical trial and value of pt participation. Results: Pt contributions to the protocol design included modified inclusion/exclusion criteria and the addition of pain (beyond pain crises) and fatigue as study outcomes. An overview of the community feedback is shown in Table 1. In response to pt input, monthly study visits were implemented for seven months, followed by visits every three months. An open label extension period was also added with visits on the second, fourth, eighth, and twelfth weeks of the extension period, followed by every 3 months up to 1.5 years and every six months thereafter. Taking additional pt input into account, the trial was adjusted to include a recommendation for tailored management of SCD pain crises using a daily diary. Additionally, following patient recommendations, the trial approved reimbursement for study-related travel, lodging, and specific non-study assessments. The RISE UP communications campaign was effective, with heightened interest in clinical trial participation generated within the community. Strong social media engagement and digital efforts resulted in increased trial website views, and community education and awareness efforts resulted in increased clinicaltrials.gov views to an average of 2-3 clicks per day. Approximately 278,000 users visited the RISE UP website and the campaign's YouTube video, which launched on World Sickle Cell Day has attracted 3 million views since Q4 2022. Conclusion: To meet the needs of the SCD pt and caregiver community and advance clinical trial research, we implemented a patient-centered approach to clinical trial protocol design and trial recruitment. Overall, this patient-centric approach could be useful in improving community engagement, designing trials that better reflect the needs and concerns of the pt population, and ultimately improving pt participation and diverse representation in clinical trials.

Motivators and Barriers for People with Sickle Cell Disease Participating in Clinical Trials: Global Findings from the LISTEN Survey

Background: The success of clinical trials of new therapies for sickle cell disease (SCD) will depend on the recruitment and retention of a large and diverse group of people with SCD (PwS). Qualitative studies have reported barriers to participation in clinical trials, including the potential impact on health, unmanageable study demands, limited knowledge of trials, and lack of trust in healthcare(Patterson CA et al. J Pediatr Hematol Oncol 2015; Lee LH et al. Blood Adv 2021). The Learning and Insights into Sickle Cell Trial Experiences (LISTEN) Survey was developed to provide a robust and comprehensive understanding of the global barriers and motivators to participation in clinical trials for PwS. Aim: To present interim findings from the LISTEN Survey regarding participation and experiences of PwS in clinical trials, barriers and motivators to participation, and differences in responses from PwS compared with perspectives of healthcare professionals (HCPs) treating PwS. Methods: Between October 6, 2022 and June 22, 2023, a broad range of adults (≥18 years) with SCD and HCPs involved in the treatment and/or clinical research of SCD in 17 countries were asked to complete corresponding quantitative surveys. PwS were asked whether they had participated in a clinical trial and, if so, whether their experience had met their expectations. PwS were asked to rate on a 7-point scale (from not at all to extremely important) and rank (from most to least important) the importance of specified factors (grouped into five categories) when deciding whether to participate in a clinical trial for SCD. HCPs provided their perspectives on the importance of these factors to PwS. The results presented here include the total proportion of respondents who rated factors as extremely or very important and the proportion who ranked factors first or second. Results: Overall, 1028 PwS (57% female) with a median age (interquartile range) of 30 years (24-37) from 16 of the 17 countries and 361 HCPs (67% hematologists and/or SCD specialists) from 17 countries completed the survey. In total, 35% of PwS had been invited to participate in a clinical trial for SCD. In PwS who had taken part in a clinical trial (24%; n=249/1028), compared with their expectations, 36% reported a better experience, 36% the same as expected experience, 9% a worse experience, and 20% did not know what to expect. Extremely or very important factors that motivated PwS to participate in a clinical trial included the potential to better manage their symptoms (52%), the opportunity to try a new treatment that might work better (51%), and to increase their knowledge of SCD (51%; Figure 1). An important barrier to participation was the potential to experience different side effects (51%). In the trial information category, PwS ranked (first or second of five) safety measures (57%) and how the treatment works (49%) as the most important factors; these were considered to be significantly more important than who is leading (27%) or funding (24%) the trial; p<0.001 for all combinations. In the further considerations category, the majority of PwS ranked (first or second of five) speaking to other PwS involved in the trial (51%) and experts running the trial (50%) as the most important factors. HCPs overstated the potential practical barriers for PwS compared with responses from PwS, including missing school/work (50% vs 42%; p=0.009), the effort required to start the trial treatment (45% vs 32%; p<0.001), and travel requirements (52% vs 36%; p<0.001). HCPs understated the importance of wider clinical trial outcomes as motivators for PwS compared with responses from PwS, including supporting new treatment developments that may benefit them (41% vs 51%; p=0.001) or other PwS (38% vs 49%; p<0.001; Figure 2). Conclusions: Improving access and recruitment into clinical trials in SCD will require clear communication of the potential benefits to individuals and the wider SCD community, as well as potential safety and side effects. Findings from the LISTEN Survey highlight that those directly involved in the trial should deliver these messages, including other PwS who are involved in the trial. Given the disconnect between PwS and HCPs, shared decision-making may also improve understanding and increase participation in clinical trials. Further analyses of the survey results will be important to identify the differences in responses between regions, age groups, and other subpopulations.

Defining curative endpoints for sickle cell disease in the era of gene therapy and gene editing.

A growing number of gene therapy- and gene editing-based treatments for patients with sickle cell disease (SCD) are entering clinical trials. These treatments, designed to target the underlying cause of SCD, have the potential to provide functional cures, which until now were possible only through allogeneic hematopoietic stem cell transplant. However, as these novel approaches advance from early- to late-stage clinical trials, it is essential to identify physiologically and clinically relevant endpoints that can demonstrate the achievement of a functional cure for SCD. Here, we present an overview of the pathophysiology of SCD and current treatment options, review ongoing SCD clinical trials using gene therapy or gene editing approaches, and identify the most relevant endpoints for demonstrating the attainment of a functional cure for SCD.

Opening a Crack in the Door: An Interview with Haydar Frangoul

Opening a Crack in the Door: An Interview with Haydar Frangoul

Democratizing Knowledge for Sickle Cell Disease Gene Therapy: A Community Based Model for Creating Patient Education Materials

Background: While the advancement of genetic therapy for hematological disorders provides tremendous therapeutic promise, it is not without risk. Sickle cell disease (SCD) is at the forefront of the development of novel, genetic therapies. The process of engaging individuals living with SCD to participate in gene therapy clinical trials requires building trust, respect, and partnership with the community, given the history of neglect towards this disease. With the growth of sickle cell disease gene therapy clinical trials and potential of FDA approval for gene therapy treatments, there is a need for understandable, accessible, and actionable patient education materials (PEMs) that are not sponsored by a specific clinical trial. An objective of the Democratizing Knowledge for Sickle Cell Disease Gene Therapy Project was to examine the process of engaging a diverse group of stakeholders representing different interests within the SCD community to develop open-source patient education materials for sickle cell disease gene therapy. Methods: For this project, we used a community-based dialogue model which incorporates participatory democracy with community based public health engagement approaches (Bonham et al PMID: 19451407). This approach was used to engage a multi-disciplinary group of patients, representatives of SCD advocacy groups, hematologists, gene therapy researchers, and industry and government stakeholders to purposefully work in teams over four workshops to create PEMs. Throughout this process, we recorded their deliberations, and collected survey data at three distinct stages of engagement. Results: We dichotomized the data on experiences and engagement levels into two categories: the Research Community, which includes individuals representing industry, research, government, healthcare, academia, and the Patient and Advocacy Community, which includes individuals living with SCD, parents of children with SCD, and individuals representing community-based SCD advocacy groups. Analysis of this longitudinal data from the three distinct points in time identified patterns across the stakeholder groups represented in these workshops. Of the participants in the research community, 68.3% attended all four workshops, while of those in the patient and advocacy community, 90.9% attended all four workshops (Table 1). In the research community, 95.1% expressed feeling satisfied with their participation in these workshops, and similarly, in the patient and advocacy community, 93.0% expressed feeling satisfied with their participation (Table 2). However, when surveyed about views on the role of power dynamics in this process, there were differing sentiments between these two groups. Amongst the research community, the majority felt power dynamics did not influence the workshops (59.3%). In contrast, amongst the patient and advocacy community, the majority felt power dynamics did influence the workshops (55.2%) (Table 2). In addition to this survey data, further data regarding the patient educational materials themselves and their dissemination will be reported. Conclusion: The data highlights differential engagement regarding the level of participation between the different stakeholders within the SCD community. It also reflects both similarities and differences with respect to satisfaction and perception of power dynamics in this process. With these results, we aim to introduce how a community-based dialogue approach can be used as a model for engagement for SCD clinical trials, for creation of stakeholder-informed patient education materials, and for other disease communities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical trial considerations in sickle cell disease: patient-reported outcomes, data elements, and the stakeholder engagement framework.

Patients with sickle cell disease (SCD) have significant impairment in their quality of life across the life span as a consequence of serious disease burden with several SCD-related complications. A number of disease-modifying therapies are currently available, yet long-term clinical benefits in real-world settings remain unclear. Over the past few years, a number of important initiatives have been launched to optimize clinical trials in SCD in different ways, including: (1) established panels through a partnership between the American Society of Hematology (ASH) and the US Food and Drug Administration; (2) the ASH Research Collaborative SCD Clinical Trials Network; (3) the PhenX Toolkit (consensus measures for Phenotypes and eXposures) in SCD; and (4) the Cure Sickle Cell Initiative, led by the National Heart, Lung, and Blood Institute. Electronic patient-reported outcomes assessment is highly recommended, and patient-reported outcomes (PROs) should be evaluated in all SCD trials and reported using Standard Protocol Items Recommendations for Interventional Trials guidelines. Patient-centered outcomes research (PCOR) approaches and meaningful stakeholder engagement throughout the process have the potential to optimize the execution and success of clinical trials in SCD with considerable financial value. This article reviews several clinical trial considerations in SCD related to study design and outcomes assessment as informed by recent initiatives as well as patient-centered research approaches and stakeholder engagement. A proposed hematology stakeholder-engagement framework for clinical trials is also discussed.

Bridging the implementation gap in medication adherence. If you build it, will they come?

Bridging the implementation gap in medication adherence. If you build it, will they come?

CoreSCD: multi-stakeholder consensus on core outcomes for sickle cell disease clinical trials

BackgroundWith the dramatic increase in the pipeline for new sickle cell disease (SCD) therapies in recent years, the time is ripe to ensure a robust body of evidence is available for decision making by regulators, payers, clinicians, and patients. Harmonization of the outcomes selected across interventional trials enables optimal post-trial appraisal and decision making through valid pooled analyses and indirect comparisons. We employed a structured, multi-stakeholder consensus process to develop core outcome sets (COS) for use in clinical trials of SCD interventions.MethodsCoreSCD utilized a modified Delphi method adapted from the standards recommended by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. An initial list of candidate outcomes was developed through a targeted literature review and input from an 11-member advisory committee. A 44-member multi-stakeholder Delphi Panel was established and included patients and family members, advocates, clinicians, researchers, payers, health technology assessors, representatives from government agencies, and industry representatives. Patients/advocates comprised 25% of the Delphi Panel and orientation and training was provided prior to the consensus process to ensure all were prepared to participate meaningfully. Panelists completed three rounds of an online survey to rate the importance of candidate outcomes for inclusion in the COS. Summary data was provided between each voting round and an in-person consensus meeting was held between the second and third round of voting. Consensus rules were applied following each round of voting to eliminate outcomes that did not meet predetermined criteria for retention.ResultsConsensus was reached for two core outcome sets. The final COS for trials of disease-modifying therapies includes ten outcomes and the COS for trials of acute interventions includes six outcomes. Both core sets include clinical outcomes as well as outcomes related to functioning/quality of life, resource utilization, and survival/mortality.ConclusionsUse of the COS in clinical development programs for SCD will help to ensure that relevant, consistent outcomes are available for decision making across the product lifecycle.

Defining Vaso-Occlusive Crises in Sickle Cell Disease from the Perspective of the Patient: Development of a New Toolbox to Measure Treatment Outcomes

Defining Vaso-Occlusive Crises in Sickle Cell Disease from the Perspective of the Patient: Development of a New Toolbox to Measure Treatment Outcomes

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

Clinical trials in sickle cell disease (SCD) often focus on health care utilization for painful vaso-occlusive crises (VOCs). 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 noninterventional, 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. Patients with SCD used an electronic patient-reported outcome (ePRO) tool to collect data on 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 end points 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 the 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-α, and thrombin–antithrombin. The Evaluation of Longitudinal Pain Study in Sickle Cell Disease (ELIPSIS) trial shows the feasibility of accurately monitoring out-of-hospital pain by using patient-reported VOC days as potential end points for clinical trials in SCD; it describes the changes in biomarkers and activity measured by actigraphy that may enable improved identification and assessment of VOCs.

A Patient-Centric Approach to Improve the Understanding of Sickle Cell Disease Using Real-World Data

Background: Sickle cell disease (SCD) comprises a group of inherited blood disorders, and is a complex, multi-system, disease. SCD is associated with a variety of clinical complications that affect multiple organ systems. These complications are driven primarily by vaso-occlusion and hemolytic anemia, and can result in end-organ damage and early death. Painful vaso-occlusive crises (VOCs) are a characteristic feature of SCD and can require healthcare intervention. Despite recent advances in the screening, management and treatment of SCD, gaps remain in our understanding of the disease in the real-world setting. These include how best to transition from pediatric to adult care and how to manage specific complications. Currently, most real-world evidence (RWE) is generated from information captured in payer databases, which is not as comprehensive as the information recorded in electronic medical records (EMRs). Despite being potentially valuable sources of real-world, clinical information, EMRs for individual patients in the USA are not centralized, often being held by multiple healthcare providers using different EMRs. This fragmented system prevents generation of clear, comprehensive RWE, both in general and for SCD specifically. Furthermore, there is a lack of harmonization between EMR companies/systems in the types of information included and how it's recorded. A separate approach that collates all available data from EMRs into a single, comprehensive record prior to RWE analysis would therefore greatly improve the accessibility of the available information and the quality of subsequent data analysis. Aims: In contrast to existing RWE, this study explores the value of collating EMRs for each patient into a single, consistently structured format, with the aim of developing richer RWE to complement existing data on SCD. It is hypothesized that the resulting longitudinal overview of each patient's care will contribute to an improved understanding of SCD in the real-world setting: firstly, by better capturing how many VOCs patients with SCD experience, with an indication of the proportion of VOCs that are being home-managed; secondly, by gaining deeper insights into the prevalence and progression of end-organ damage and any association with VOCs; and finally, by highlighting the type and site of care of SCD in the real world (eg medications, treating healthcare professional [HCP] specialties and the type of clinic visited). Study design: The study population will comprise 400 patients with SCD from the USA. Patient recruitment occurs directly via social media and indirectly through a variety of partnerships including HCPs and patient advocacy groups. To enroll, patients sign an informed consent form allowing their de-identified medical information to be shared with third-party organizations to advance SCD research. Enrolled patients gain access to their medical records via a dashboard. The key inclusion criteria are: a confirmed SCD diagnosis (irrespective of phenotype); aged ≥16 years at enrollment; and ≥1 inpatient admission for a VOC in the 12 months prior to enrollment. The key exclusion criterion is the absence of medical records. Components of EMRs collected include doctors' notes, laboratory and test results, clinical imaging and treatment records. Human-curated natural language processing and machine learning is used to extract, structure and code data from the structured sections and unstructured narrative text of the EMR. All medical records, from all visits, will be collected where possible and are expected to comprise ≥7 years of retrospective data for each patient. Results: Between 1 December 2019 and 24 June 2020, a total of 46 patients with a mean age of 36 years (SD 9.7) were enrolled. For each patient, a median of 6.8 years of data from a median of 32.5 providers were obtained. Conclusions: The evidence derived from this study aims to advance the understanding of real-world practices in the management of SCD. It may also provide further learnings regarding the prevalence of complications and any association between VOCs and end-organ damage. Generating a single, structured overview of all EMRs for each patient allows for richer insight generation and a more comprehensive analysis of RWE, compared with existing approaches. The insights gained from this RWE may inform future studies and clinical trials in SCD, with the ultimate aim of improving the quality of life of patients. Disclosures Clay: Novartis: Consultancy; GBT: Consultancy. Bailey:Novartis Pharmaceuticals Corporation: Current Employment. Drozd:F. Hoffmann-La Roche Ltd: Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; PicnicHealth: Current Employment, Current equity holder in private company. Paulose:Novartis Pharma AG: Current Employment. Ramscar:Novartis Pharma AG: Current Employment. Mace:Roche/Genentech: Ended employment in the past 24 months; PicnicHealth: Current Employment. Wormser:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company.

Mn porphyrins as a novel treatment targeting sickle cell NOXs to reverse and prevent acute vaso-occlusion in vivo

AbstractIn sickle cell disease (SCD), adhesion of sickle red blood cells (SSRBCs) and activated leukocytes in inflamed venules affects blood rheology, causing vaso-occlusive manifestations and vital reduction in microvascular blood flow. Recently, we found that NADPH oxidases (NOXs) create a vicious feedback loop within SSRBCs. This positive feedback loop mediates SSRBC adhesion to the endothelium. We show for the first time the therapeutic effectiveness of the redox-active manganese (Mn) porphyrins MnTnBuOE-2-PyP5+ (MnBuOE; BMX-001) and MnTE-2-PyP5+ (MnE; BMX-010, AEOL10113) to treat established vaso-occlusion in a humanized sickle mouse model of an acute vaso-occlusive crisis using intravital microscopy. These Mn porphyrins can suppress SSRBC NOX activity. Subcutaneous administration of only 1 dose of MnBuOE or MnE at 0.1 to 2 mg/kg after the inflammatory trigger of vaso-occlusion, or simultaneously, reversed and reduced leukocyte and SSRBC adhesion, diminished leukocyte rolling, restored blood flow, and increased survival rate. Furthermore, MnBuOE and MnE administered to sickle mice subcutaneously at 0.1 to 1 mg/kg for 28 days (except on weekends) did not exacerbate anemia, which seemed to be due to downregulation of both SSRBC reactive oxygen species production and exposure of the eryptotic marker phosphatidylserine. In addition, Mn porphyrins ameliorated leukocytosis, venous blood gases, endothelial activation, and organ oxidative damage. Our data suggest that Mn porphyrins, likely by repressing NOX-mediated adhesive function of SSRBCs and activated leukocytes, could represent a novel, safe therapeutic intervention to treat or prevent the establishment of acute pain crises. These NOX-targeted antioxidants merit further assessment in SCD clinical trials.

Measuring success: utility of biomarkers in sickle cell disease clinical trials and care.

Progress in the care of sickle cell disease (SCD) has been hampered by the extreme complexity of the SCD phenotype despite its monogenic inheritance. While epidemiological studies have identified clinical biomarkers of disease severity, with a few exceptions, these have not been routinely incorporated in clinical care algorithms. Furthermore, existing biomarkers have been poorly apt at providing objective parameters to diagnose sickle cell crisis, the hallmark, acute complication of SCD. The repercussions of these diagnostic limitations are reflected in suboptimal care and scarcity of adequate outcome measures for clinical research. Recent progress in molecular and imaging diagnostics has heralded a new era of personalized medicine in SCD. Precision medicine strategies are particularly timely, since molecular therapeutics are finally on the horizon. This chapter will summarize the existing evidence and promising data on biomarkers for clinical care and research in SCD.

Middle Cerebral Artery Velocities Are Inversely Related to Hemoglobin Levels and Acutely Drop in Response to RBC Transfusion: Implications for Stroke Screening in SCD

INTRODUCTIONChronic red blood cell (RBC) transfusion therapy can prevent new and progressive stroke in Sickle Cell Disease (SCD), as shown by multiple clinical trials in SCD including the STOP 1&2, SIT, and SWITCH trials. Middle cerebral artery time-averaged mean velocity (MCA velocity), measured by Trans-cranial Doppler Ultrasound (TCD), is a clinical biomarker utilized to initiate chronic RBC transfusion to reduce stroke risk in children with SCD. However, MCA velocity measured by TCD lacks sensitivity and specificity in predicting stroke. Most SCD patients with high MCA velocity do not experience overt stroke, while 10-20% of SCD children will have new strokes on chronic RBC transfusion in spite of normalized MCA velocity.Prior studies showed an association with high MCA velocity and MCA narrowing when TCD and angiography were performed after RBC transfusion to target a hematocrit (HCT) > 30%. HCT adjustments addressed effects of anemia and higher cardiac output (Adams et al, 1992; Stroke PMID 1636180). Nevertheless, HCT adjustments may not always be used for routine TCD. Thus, despite the substantial decrease in strokes with TCD screening, there may be significant lack of specificity that leads to unnecessary RBC transfusion resulting from TCD screening in non-optimal conditions. Due to these concerns, we undertook a detailed study assessing MCA velocity by TCD immediately pre- and post-transfusion in SCD patients.METHODSThe study was approved by the Children's Hospital Los Angeles Institutional Review Board. SCD and thalassemia patients who receive chronic transfusion had pre- and post-transfusion blood laboratory tests and MCA velocity measurements by TCD (GE Vivid I, FE Medical Systems Ultrasound Israel Ltd., Israel). The TCD ultrasound probe was placed on left and right trans-temporal window, landmarks were visualized, and MCA velocity data were collected in 1.7mm depth increments from 65mm to 35mm depth. Magnetic resonance angiography was not done at the time of these measurements. Data was recorded and analyzed in JMP Pro Version 13.0.RESULTSSCD patients (n=24) had a median and interquartile range of 15 years & 14-18 years, with 18 females & 6 males, received 90 transfusions, and 70% of the patients had 3 transfusion events with repeat studies. Seventeen patients received simple RBC transfusion and 7 received red cell exchange. The thalassemia control population received simple transfusion (n=11; 48 transfusion events).Figure 1 shows the relation of MCA velocity compared to HCT in all subjects. There is a highly significant negative correlation showing lower HCT is associated with higher MCA velocity (Dots = TAMV measurements; lines = average TAMV measurements at different TCD depths; R2=0.12, F(1,4270)=556, p<.001). Figure 2 & 3 show that the MCA velocity measurement depends on depth of the TCD measurement. This accounts for a significant part of the variance evident in Figure 1. On average, a rise in HCT from a typical level in SCD of 21% to 31% would result in a 14% drop in TCD velocity. To illustrate the variable impact of acute PRBC transfusion among subjects, we show the MCA velocity response to RBC transfusion in two SCD patients (Figure 2&3: blue ♦=Pre-transfusion, red ♦=Post-transfusion). Patient 1 showed a 37% drop in MCA velocity following RBC transfusion on three occasions (∆HCT=7.5±1.7%; n=3; Figure 2) whereas Patient 2 showed only an 11% drop in MCA velocity following RBC transfusion (∆HCT=6.2±1.3%, n=5, Figure 3).DiscussionThese data show a striking relationship between anemia and TCD velocity, and that RBC transfusion can alter MCA velocity. Even an 11% increase in hemoglobin such as that seen in the low-responder in Figure 3 could change a patient classification from high-risk to conditional TCD. These data also show the significant sensitivity of MCA velocity to the depth of measurement (Figure 2 & 3). The investigators in the STOP study went to extreme ends to standardize these measurements. Nonetheless, TCD measures may not be done with such rigor in clinical settings. It is clear that standard TCD screening has been of tremendous benefit to SCD patients, and many enjoy a good quality of life as a result. Our data suggest that the specificity of TCD screening could be improved if testing was done at an HCT> 30%. Quantifiable blood, patient, and measurement factors can impact TCD MCA velocity and clinical decisions that commit children to years of RBC transfusions. [Display omitted] DisclosuresCoates:ApoPharma: Consultancy, Honoraria; Celgene Corp.: Consultancy; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria.

Defining Sickle Cell Disease Acute Painful Episodes: The Pisces Project

Background: For research purposes, painful crises in sickle cell disease (SCD) have either been self-defined by patients, or adjudicated by research experts, most often based on whether urgent care or hospital care was sought for pain related to SCD. The Pain in Sickle Cell Epidemiology Study (PiSCES) determined that three-fourths of self-defined crises days were not managed in urgent or hospital care. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (AAPT) published a taxonomy of chronic SCD pain, defined as pain on most days of 6 months duration, along with at least one clinical sign, and no better explanation for the pain. We served on a similar SCD consensus panel to propose a more expansive taxonomy of acute sickle cell pain or painful episodes, informed by the PiSCES dataset (manuscript under review). Here we present three PiSCES-derived definitions of acute painful episodes, and we analyze the impact of various definitions on pain outcome results potentially useful for research.Methods: PiSCES Patients (N=81) who completed at least 5 out of the expected 6 months of daily diaries and did not have gaps in their daily diary of 4 days or more were included. Patients self-reported their worst sickle cell pain intensity on a scale from 0 (none) to 9 (unbearable), and independently self-reported whether they were having a crisis that day, whether they went for an unscheduled physician visit, an Emergency Department visit, or whether they were hospitalized for sickle cell pain. Definitions of acute pain episodes compared here include self-reported crisis days, days with pain ≥ 5, and days with utilization of the ED or overnight hospitalization (other potential definitions not shown). To meet any definition, a crisis day (pain≥ 5, utilization) had to be reported for 2 or more consecutive days. Non-crisis intervals were 2 or more consecutive days without a self-reported crisis (pain ≥ 5, utilization). The average length of non-crisis intervals was considered to represent the time between crisis episodes. For <4 consecutive missing days, imputations were performed using non-missing data to calculate the probability that missing days were crisis days. We used PiSCES data to compare various pain outcomes (see Table) for patients with and without AAAPT-defined chronic pain, for the three definitions of an acute painful episode. We note that episode length, intensity, time between episodes and intensity of non-episodes were all estimated using only patients who had an acute painful episode.Results: (Table)For each definition of an acute painful episode, a larger percentage of patients with chronic pain had acute episodes than patients without chronic pain. Similarly, chronic pain patients had statistically significantly more episodes and higher mean pain intensity on non-episode days. For 2 of 3 definitions (but not ED or hospitalization use), chronic pain patients had longer episodes and shorter time between episodes. Only for the self-reported crisis definition, patients had higher mean pain intensity during episodes. Raising the pain intensity threshold from 5 to 6 to define an acute episode slightly decreased the absolute percentage with acute episodes, the number of episodes, and the length of episodes, but did not affect the relationships between outcomes for patients with and without chronic pain (results not shown in table).Conclusions: A comparison of various definitions of acute painful episodes using the PiSCES dataset yields slightly different pain outcome results. However, these differences are intuitive. For example, chronic pain patients still have more intense and more frequent acute painful episodes regardless of the definition used. The finding of more frequent acute pain in SCD adults with chronic pain has important implications for treatment and the design of SCD clinical trials. [Display omitted] DisclosuresField:Ironwood: Consultancy, Research Funding; Prolong: Research Funding; Incyte: Research Funding. Dampier:Pfizer: Research Funding.

Measurement of Sickle Cell Disease Symptoms from the Patient Perspective: Considerations for Clinical Trials

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. DisclosuresOjo: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.

Challenges to Management of Pain in Sickle Cell Disease

Sickle Cell Disease (SCD) is one of the most common blood disorders in the world. Pain is the primary reason for which individuals with SCD interact with the healthcare system. Generally speaking, there are two types of SCD pain: vaso-occlusive pain (or sickle cell disease crisis) and chronic pain caused by an accumulation of organ and tissue damage over time. However, despite its frequency, we have limited understanding about what causes pain in sickle cell disease, how best to manage pain in SCD and (most importantly) how to prevent pain in SCD. For medical providers, pain is also an elusive target due to the difficulty in objectively measuring pain and the importance of relying on patient reported outcomes. To face the challenges in managing pain in SCD, we will review the current understanding of the pathophysiology of vaso-occlusion, the multiple dimensions of the pain experience, and the current methods of measuring and managing pain. We will also review new pharmacologic agents undergoing clinical trials in SCD that will help to prevent pain and improve outcomes in SCD.

Sickle Cell Disease Clinical Trials and Phenotypes.

Sickle cell disease, one of the world’s most common genetic disorders is prevalent in sub-Saharan Africa. The trans-Atlantic slave trade accounted for the gene movement from Africa to the Caribbean and United States of America and lately, migration has resulted in the introduction of the gene to the United Kingdom and other parts of Europe. Different haplotypes exist, however the differences in these haplotypes are not sufficient to explain the different clinical variations within the same region or different settings.

Elipsis: A Longitudinal Study of Electronic Patient-Reported Outcomes, Actigraphy and Biomarkers to Identify and Assess at-Home Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease

Elipsis: A Longitudinal Study of Electronic Patient-Reported Outcomes, Actigraphy and Biomarkers to Identify and Assess at-Home Vaso-Occlusive Crises in Adults and Adolescents with Sickle Cell Disease

Mistrust of Pediatric Sickle Cell Disease Clinical Trials Research.

Sickle cell disease (SCD) research is hampered by disparities in participation due in part to mistrust of research among racial/ethnic minorities. Beyond the historic context of research misconduct, little is known about the associations of social ecologic factors with mistrust and of mistrust with SCD clinical trials enrollment. This study evaluated proximal (age, gender, disease severity, perceived stress, SES) and distal (religious beliefs, social support, instrumental support) factors related to mistrust of research among caregivers of children with SCD and adolescents and young adults (AYAs) with SCD. Over an 18-month period (2009-2010), participants completed questionnaires of perceived barriers and benefits to clinical trials enrollment, perceived stress, and self-reported demographic and disease-related information. Analyses (January-June 2015) used multivariable linear regressions to evaluate predictors of mistrust. Data were analyzed for 154 caregivers (mean age, 38.75 years; SD=9.56 years; 90.30% female) and 88 AYAs (mean age, 24.76 years; SD=7.25 years; 46.40% female). Among caregivers (full model, R(2)=0.14, p≤0.001), greater mistrust was explained by higher perceived stress (β=0.04, p=0.052); religious beliefs (β=0.61, p≤0.001); and greater instrumental support (β=0.07, p=0.044). Among AYAs (full model, R(2)=0.18, p≤0.001), higher mistrust was explained by being male (β=-0.56, p≤0.001) and lower instrumental support (β=-0.11, p=0.016). Mistrust was significantly greater among caregivers that reported no prior involvement in medical research (p=0.003). By understanding the complexity through which social ecologic factors contribute to mistrust, researchers may create targeted strategies to address mistrust and increase engagement in SCD research for caregivers and AYAs.