Addressing Recruitment Challenges in the Engage-HU Trial in Young Children with Sickle Cell Disease

Background: Sickle cell disease (SCD) is a genetic disorder that causes significant medical and neurologic morbidity in children. Hydroxyurea (HU) is the primary medication used to prevent these complications. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering HU to children as young as 9 months of age with SCD (HbSS or HbSB0 thalassemia) using a shared decision-making approach. Although HU has proven efficacious it remains underutilized and caregivers report that they are not always actively involved in the decision to initiate this therapy. Reasons for limited HU uptake likely include lack of clinician knowledge and training and negative caregiver perceptions. Thus, we developed the Engage-HU trial as a novel approach to address HU utilization barriers. A critical consideration for this trial was that SCD primarily affects individuals of African and Hispanic/Latino descent. In these minority populations, intervention trials are sometimes terminated early because of recruitment difficulties related to mistrust of research, caregiver burden, and transportation issues. As such, the Engage-HU trial design included best-practice strategies for recruiting people of color in research. This study describes these strategies, the initial recruitment plan, preliminary recruitment outcomes and strategies, and our procedural adaptations. Study Design and Methods: Engage-HU is a randomized control trial (NCT03442114) to assess how clinicians can engage caregivers in a shared discussion that considers their values and preferences and includes evidence that supports HU. Engage-HU compares two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD: 1) the American Society of Hematology Pocket Guide, and 2) the HU Shared-Decision Making (H-SDM) Toolkit. The study aims to recruit 174 caregivers and evaluate the effectiveness of the dissemination methods on patient-centered outcomes (caregiver confidence in decision-making and perceptions of experiencing shared decision-making) as well as HU uptake and child health outcomes. Eligible children are aged 0 to 5 years, candidates for HU, and their caregiver has not made a decision about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a stepped-wedge design. Data will be analyzed based on the intent-to-treat principle. All participants will remain in the arm of the study to which they were randomized, regardless of whether or not they receive the assigned dissemination method. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using a linear mixed effects regression model with a robust variance estimator and maximum likelihood estimation with observations clustered within site. The Engage-HU trial includes adaptations to increase recruitment such as tailored messaging, a relational recruitment approach, streamlined data collection, and a Stakeholder Advisory Committee. However, even with these adaptations, the first 6-months of the trial yielded lower than anticipated recruitment. Rather than terminate the trial or accept low enrollment, the research team implemented a series of recruitment strategies to address barriers including helping to improve research coordinator knowledge of the study purpose and adjusting no-show and follow-up procedures (e.g., calls to families after missed appointments and reminder calls before appointments). Site clinicians and clinic staff were provided with additional training so they could give more context about Engage-HU to caregivers and the study principal investigator led monthly "all coordinator" calls to provide support by sharing updates and experiences about successful recruitment. Implementation of these strategies resulted in triple the number of enrollments over the next 7-months compared to the previous 6-months (Table 1). Our goal in sharing this information is to provide lessons learned that can be implemented in future trials with the systematically underserved SCD population. It is also anticipated that methods described here may also inform clinical approaches to better engage caregivers of young children around critical clinical conversations, such as initiating medications like HU. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; Celgene: Consultancy; Tioma Therapuetics: Consultancy; Amphivena Therapeutics: Research Funding; WUGEN: Current equity holder in private company; Cell Works: Consultancy; Incyte: Consultancy. Smith-Whitley:Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Yates:Novartis: Research Funding. Thompson:Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; BMS: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. </jats:sec

Engaging Caregivers and Providers of Children With Sickle Cell Anemia in Shared Decision Making for Hydroxyurea: Protocol for a Multicenter Randomized Controlled Trial

BACKGROUND: Sickle cell anemia (SCA) is a genetic blood disorder that puts children at a risk of serious medical complications, early morbidity and mortality, and high health care utilization. Until recently, hydroxyurea was the only disease-modifying treatment for this life-threatening disease and has remained the only option for children younger than 5 years. Evidence-based guidelines recommend using a shared decision-making (SDM) approach for offering hydroxyurea to children with SCA (HbSS or HbS/β0 thalassemia) aged as early as 9 months. However, the uptake remains suboptimal, likely because caregivers lack information about hydroxyurea and have concerns about its safety and potential long-term side effects. Moreover, clinicians do not routinely receive training or tools, especially those that provide medical evidence and consider caregivers' preferences and values, to facilitate a shared discussion with caregivers. OBJECTIVE: The aim of this study is to understand how best to help parents of young children with sickle cell disease and their clinicians have a shared discussion about hydroxyurea (one that considers medical evidence and parent values and preferences). METHODS: We designed our study to compare the effectiveness of two methods for disseminating hydroxyurea guidelines to facilitate SDM: a clinician pocket guide (ie, usual care) and a clinician hydroxyurea SDM toolkit (H-SDM toolkit). Our primary outcomes are caregiver reports of decisional uncertainty and knowledge of hydroxyurea. The study also assesses the number of children (aged 0-5 years) who were offered and prescribed hydroxyurea and the resultant health outcomes. RESULTS: The Ethics Committee of the Cincinnati Children's Hospital Medical Center approved this study in November 2017. As of February 2021, we have enrolled 120 caregiver participants. CONCLUSIONS: The long-term objective of this study is to improve the quality of care for children with SCA. Using multicomponent dissemination methods developed in partnership with key stakeholders and designed to address barriers to high-quality care, caregivers of patients with SCA can make informed and shared decisions about their health. TRIAL REGISTRATION: ClinicalTrials.gov NCT03442114; https://clinicaltrials.gov/ct2/show/NCT03442114. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27650

Dendritic Cell Based Tumor Vaccination in Prostate and Renal Cell Cancer: A Systematic Review and Meta-Analysis

BACKGROUND: More than 200 clinical trials have been performed using dendritic cells (DC) as cellular adjuvants in cancer. Yet the key question whether there is a link between immune and clinical response remains unanswered. Prostate and renal cell cancer (RCC) have been extensively studied for DC-based immunotherapeutic interventions and were therefore chosen to address the above question by means of a systematic review and meta-analysis. METHODOLOGY/PRINCIPAL FINDINGS: Data was obtained after a systematic literature search from clinical trials that enrolled at least 6 patients. Individual patient data meta-analysis was performed by means of conditional logistic regression grouped by study. Twenty nine trials involving a total of 906 patients were identified in prostate cancer (17) and RCC (12). Objective response rates were 7.7% in prostate cancer and 12.7% in RCC. The combined percentages of objective responses and stable diseases (SD) amounted to a clinical benefit rate (CBR) of 54% in prostate cancer and 48% in RCC. Meta-analysis of individual patient data (n = 403) revealed the cellular immune response to have a significant influence on CBR, both in prostate cancer (OR 10.6, 95% CI 2.5-44.1) and in RCC (OR 8.4, 95% CI 1.3-53.0). Furthermore, DC dose was found to have a significant influence on CBR in both entities. Finally, for the larger cohort of prostate cancer patients, an influence of DC maturity and DC subtype (density enriched versus monocyte derived DC) as well as access to draining lymph nodes on clinical outcome could be demonstrated. CONCLUSIONS/SIGNIFICANCE: As a 'proof of principle' a statistically significant effect of DC-mediated cellular immune response and of DC dose on CBR could be demonstrated. Further findings concerning vaccine composition, quality control, and the effect of DC maturation status are relevant for the immunological development of DC-based vaccines

Role of genetic polymorphisms in tumour angiogenesis

Angiogenesis plays a crucial role in the development, growth and spread of solid tumours. Pro- and anti-angiogenic factors are abnormally expressed in tumours, influencing tumour angiogenesis, growth and progression. Polymorphisms in genes encoding angiogenic factors or their receptors may alter protein expression and/or activity. This article reviews the literature to determine the possible role of angiogenesis-related polymorphisms in cancer. Further research studies in this potentially crucial area of tumour biology are proposed

Exploring Referral and Service Utilization Patterns Within an Outpatient Interdisciplinary Pediatric Chronic Pain Program

Aimee K Hildenbrand,1– 3 Christina M Amaro,1,4 Benjamin Bear,1 Catherine M Soprano,3,5 Katherine S Salamon2,3 1Center for Healthcare Delivery Science, Nemours Children’s Health, Wilmington, DE, USA; 2Division of Behavioral Health, Nemours Children’s Hospital Delaware, Wilmington, DE, USA; 3Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; 4Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; 5Division of Diagnostic Referral, Nemours Children’s Hospital Delaware, Wilmington, DE, USACorrespondence: Aimee K Hildenbrand, Nemours Center for Healthcare Delivery Science, 1600 Rockland Road, RC-1, Suite 160, Wilmington, DE, 19803, USA, Tel +1 302 298 7874, Email [email protected]: We examine referral sources and clinical characteristics for youth presenting to an outpatient interdisciplinary pediatric chronic pain program.Patients and Methods: Referral data were extracted from the electronic health record. PROMIS Pediatric Anxiety and Pain Interference Scales were administered at an initial evaluation visit.Results: The program received 1488 referrals between 2016 and 2019, representing 1338 patients, with increasing volume of referrals over time. Referrals were primarily from orthopedics (19.6%), physical medicine and rehabilitation (18.8%), neurology (14.4%), and rheumatology (12.6%). Patients referred were primarily female (75.4%), White (80.1%), English-speaking (98.4%) adolescents (median=15.0 years). Of those referred, 732 (54.7%) attended an interdisciplinary evaluation (ie, with ≥ 2 disciplines). Adolescent anxiety was within the expected range by self-report (N=327, MT-score=55.67) and parent proxy-report (N=354, MT-score=57.70). Pain interference was moderately elevated by self-report (N=323, MT-score=61.52) and parent proxy-report (N=356, MT-score=64.02). There were no differences between patients referred who attended versus did not attend an interdisciplinary evaluation based on age, sex, ethnicity, or language. A smaller than expected proportion of referred Black patients (44%, P=0.02) and patients referred from orthopedics (40%) or pulmonology (11%) attended an evaluation, whereas a larger than expected proportion of those referred from physical medicine and rehabilitation (78%) were evaluated (P< 0.001).Conclusion: Results highlight the demand for outpatient interdisciplinary pediatric chronic pain treatment. Findings can inform decisions related to staffing and service design for pediatric hospitals that aim to establish or grow outpatient pediatric chronic pain programs.Keywords: chronic pain, interdisciplinary, pediatric, referral, treatmen

Feasibility of Electronic Medication Monitoring Among Adolescents and Emerging Adults with Sickle Cell Disease

Aimee K Hildenbrand,1– 3 Katherine M Kidwell,4 Meghan E McGrady,5,6 Constance A Mara,5,6 Charles T Quinn,6,7 Lori E Crosby5,6 1Center for Healthcare Delivery Science, Nemours Children’s Health, Wilmington, DE, USA; 2Division of Behavioral Health, Nemours Children’s Hospital Delaware, Wilmington, DE, USA; 3Department of Pediatrics, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; 4Department of Psychology, Syracuse University, Syracuse, NY, USA; 5Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 7Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Aimee K Hildenbrand, Nemours Center for Healthcare Delivery Science, 1600 Rockland Road, RC-1, Suite 160, Wilmington, DE, 19803, USA, Tel +1-302-298-7874, Email [email protected]: To examine the feasibility of using MEMS® bottles to assess adherence among adolescents and emerging adults with sickle cell disease.Patients and Methods: Eighteen non-Hispanic Black participants with HbSS (M = 17.8 years; 61% male) were given a MEMS® bottle to store hydroxyurea (n = 14) or deferasirox (n = 4).Results: One hundred percent initiated MEMS® use and 61% sustained use through the 18-week study; at follow-up, only 11% returned their bottle on time. Barriers to MEMS® use included medication changes and transition to adult care; facilitators included tip sheets and reminders.Conclusion: While MEMS® is acceptable to this population, ensuring sustained use and timely provision of bottles will require additional supports.Keywords: adherence, MEMS, medicine, sickle cell anemi