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Purpose: Gout in kidney transplant (KT) recipients can be severe and particularly challenging to manage. Pegloticase co-therapy with immunomodulators improved urate lowering therapy (ULT) response rates over phase 3 monotherapy trials by reducing anti-drug antibodies.1,2 This open-label trial (PROTECT NCT04087720) examined pegloticase safety and efficacy in KT patients with uncontrolled gout. Method(s): KT recipients with uncontrolled gout (serum urate [SU]>=7 mg/dL, intolerance/ inefficacy to ULT and >=1 of the following: tophi, chronic gouty arthritis, >=2 flares in past year) and functioning KT graft (eGFR>=15 ml/min/l.73m2) on stable immunosuppressive (IS) therapy (KT>l year earlier) received pegloticase (8 mg every 2 weeks for 24 weeks). SU response during Month 6 (SU <6 mg/dL for >=80% of time) and Health Assessment Questionnaire (HAQ) pain (most severe: 100) and Disability Index (HAQ-DI, max: 3) scores were evaluated. Patients discontinuing treatment before Month 6 were considered nonresponders. Patients discontinuing due to COVID-19 concerns were excluded from analysis if no data points were available in Month 6. Result(s): 20 patients enrolled (mean+/-SD;age: 53.9+/-10.9 years, 85% male, time since KT: 14.7+/-6.9 years, SU: 9.4+/-1.5 mg/dL, gout duration: 7.9+/-11.6 years;all on >=2 IS) and 14/20 completed treatment. 16/18 (88.9% [95% CI: 65.3, 98.6]) were SU responders vs 43.5% previously reported3 without immunomodulation. Substantial SU reductions during treatments were reported in 18/20 patients completing or discontinuing for non-SU monitoring rule reasons (pre-dose SU>6 mg/dL at 2 consecutive visits). No notable eGFR changes were observed up to 3 months follow-up. In patients completing treatment, HAQ-pain and HAQ-DI mean scores improved by 35.5+/-31.5 and 0.3+/-0.6, respectively, at Week 24 (n=13 and n=14). 7 serious adverse events, deemed unrelated to pegloticase, were reported in 5 patients. No anaphylaxis or infusion reaction events occurred. Conclusion(s): Pegloticase was safe and effective in treated KT patients with uncontrolled gout, achieving a higher durable response rate than in previously-reported patients not on IS therapy along with improved HAQ scores indicative of quality of life impact. These findings are consistent with other reports of immunomodulation with pegloticase.
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INTRODUCTION Under-representation in health-related research is one of a multitude of factors that contribute to cancer disparities experienced by African American and Latinx communities. Barriers to research participation stem from historical social injustices, are multi-faceted and include factors specific to the research process, research team members and community experiences and expectations about research participation. Informed consent is a longitudinal process and represents an opportunity to address these barriers and potentially improve access to research by individuals from underrepresented groups. The purpose of the Strengthening Translational Research in Diverse Enrollment (STRIDE) study was to develop and test an integrated, literacy- and culturally-sensitive, multi-component intervention that addresses barriers to research participation during the informed consent process. METHODS A multi-pronged community engaged approach was used to inform the development the three components of the STRIDE intervention. At each of the three study sites, Community Investigators, local community members of diverse racial/ethnic backgrounds, contribute to intervention development, pilot testing and dissemination activities. Community engagement studios provided a semi-structured opportunity to solicit feedback from community experts in a facilitated group regarding the relevance, usability and understandability of the STRIDE intervention components. Additionally, component-specific approaches to obtaining community input were utilized. RESULTS The three components were developed and refined with community input. The STRIDE intervention includes: (1) an electronic consent (eConsent) framework within the REDCap software platform that incorporates tools designed to facilitate material comprehension and relevance, (2) a storytelling intervention in which prior research participants from diverse backgrounds share their experiences, and (3) a simulation-based training program for research assistants that emphasizes cultural competency and communication skills for assisting in the informed consent process. CONCLUSIONS The STRIDE project had produced an integrated set of interventions that are available to support researchers across the CTSA hubs and beyond in efforts to enhance diversity in clinical research. Early dissemination of STRIDE intervention components include utilization in national COVID-19 trials and research networks.
ABSTRACT
Background: The prevalence of gout is high in kidney transplant (KT) recipients (up to 13%), largely because of decreased kidney function and calcineurin inhibitor use.1 Residual chronic kidney disease (CKD) leading to decreased urate lowering therapy clearance and drug interactions make managing gout in KT recipients challenging. Studies show that successful treatment with pegloticase, a pegylated uricase, leads to marked reductions in serum uric acid (sUA)2 and a subsequent decrease in overall urate load and tophi burden.3 However, pegloticase use in solid organ transplant recipients has not been systematically studied or well-characterized in the literature.4,5 Objectives: To examine the safety and efficacy of pegloticase in KT recipients with uncontrolled gout. Methods: This ongoing multicenter, open-label, efficacy and safety study of pegloticase in KT recipients (NCT04087720) included patients with uncontrolled gout sUA ≥7 mg/dL, urate lowering therapy [ULT] contraindication/inefficacy, and with either visible tophi, chronic gouty arthritis, or ≥2 flares in past year, who were KT recipients (KT >1 year prior), had a functioning graft (estimated glomerular filtration rate [eGFR] ≥15 ml/min/1.73m2), and were on a stable immunosuppressant regimen. Pegloticase (8 mg infusion) was administered biweekly for 24 weeks (12 infusions) followed by a safety visit 30 days after the last infusion and 3-month post-treatment follow up visit. The primary endpoint was proportion of patients who were serum uric acid responders during Month 6 (sUA <6 mg/dL for ≥80% of time). Change from baseline (CFB) at 24 weeks was also evaluated for sUA, renal function, and health assessment questionnaire (HAQ) disability index (DI, maximum = 3) and pain (maximum = 100). Results: Preliminary findings of this study included 15 patients (12 male, 53.5±11.0 years of age) with uncontrolled gout (6.2±6.0 years since diagnosis) who had received a donor kidney 15.1±6.6 years earlier. At the time of analysis, 5 patients had completed the 24-week treatment period and 8 remained on therapy (last visit sUA <0.1 mg/dL in 6 patients, 1 had sUA of 7.4 mg/dL, 1 only received first infusion), and 2 had discontinued treatment (sUA rise [n=1], COVID-19 concerns [n=1]). Of the 5 patients who completed 24 weeks of therapy, all met response criteria and sUA was below detection limits (CFB: -10.2±1.3 mg/dL, baseline [BL]: 10.2±1.3 mg/dL). Patients also had less pain (HAQ-pain CFB: -33.6±22.2, BL: 35.9±22.0;n=5) and disability (HAQ-DI CFB: -0.3±0.6, BL: 0.7±0.8;n=5) at 24 weeks compared to BL. eGFR remained stable during 24 week treatment (eGFR CFB: -0.2±6.3 ml/min/1.73 m2, BL: 40.9±14.4 ml/min/1.73 m2;n=5). Urine albumin-to-creatinine ratio showed improvement at 24 weeks (CFB: -223±405 mg/g, BL: 664±870 mg/g;n=5). 80% of patients experienced an AE, and 4 SAEs (duodenal ulcer, cellulitis, dyspnea, skin bacterial infection) deemed unrelated to pegloticase were reported. AEs that occurred in >1 patient included gout flare, pyrexia, arthralgia, and nasal congestion. No anaphylaxis or infusion reactions occurred. Conclusion: Initial findings suggest that pegloticase therapy is effective at reducing sUA in most KT recipients while preserving renal function. Results suggest that in the setting of profound urate lowering with pegloticase in KT patients, eGFR remains stable and patients experience clinically beneficial reductions in pain and disability with an absence of unexpected safety findings.