Citations

Abstract Interpreting cancer clinical trial results often depends on addressing issues of multiplicity. When testing multiple hypotheses, unreliable findings can occur by chance due to the inflation of the type I error rate, the probability of mistakenly rejecting the null hypothesis when the null hypothesis is true. In this setting, researchers may often set the type I error rate (or the alpha level) low to limit false positive findings and the interpretation of a causal relationship where none exists. Conversely, overly conservative type I error control may result in declaring findings, that do not meet multiplicity-adjusted alpha levels, as false when they are actually true, reducing opportunities for new discovery. This presentation focuses on multiplicity adjustment in the context of clinical trials conducted within the NCI’s Community Oncology Research Program (NCORP). Because federally sponsored trials often require long-term participation from patients and represent a substantial investment by taxpayers, striking the right balance between optimizing what is learned from these trials, while avoiding false positive results, should be a priority.

Abstract The intracluster correlation coefficient (ICC) measures the correlation of observations within clusters and is a key parameter for power and sample size calculations for cluster randomized trials (CRTs). To facilitate the design of future CRTs within the National Cancer Institute Community Oncology Research Program (NCORP), all studies from the NCORP website were reviewed to identify completed CRTs. ICCs for primary and secondary outcomes (when available) were ascertained from these trials and summarized in this article as a resource for future trial development. Although ICCs are relatively small for many outcome cluster combinations, that is not always the case, so consideration should always be given to the specific outcome of interest, trial design, and type of cluster when estimating an ICC to facilitate trial development.

Abstract Cancer care delivery research trials conducted within the National Cancer Institute (NCI) Community Oncology Research Program (NCORP) routinely implement interventions at the practice or provider level, necessitating the use of cluster randomized controlled trials (cRCTs). The intervention delivery requires cluster-level randomization instead of participant-level, affecting sample size calculation and statistical analyses to incorporate correlation between participants within a practice. Practical challenges exist in the conduct of these cRCTs due to unique trial network infrastructures, including the possibility of unequal participant accrual totals and rates and staggered study initiation by clusters, potentially with differences between randomized arms. Execution of cRCT designs can be complex, ie, if some clusters do not accrue participants, unintended cluster-level crossover occurs, how best to identify appropriate cluster-level stratification, timing of randomization, and multilevel eligibility criteria considerations. This article shares lessons learned with potential mitigation strategies from 3 NCORP cRCTs.

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

RATIONALE: Critically ill adults are at risk for a variety of distressing and consequential symptoms both during and after an ICU stay. Management of these symptoms can directly influence outcomes. OBJECTIVES: The objective was to update and expand the Society of Critical Care Medicine’s 2018 Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. PANEL DESIGN: The interprofessional inclusive guidelines task force was composed of 24 individuals including nurses, physicians, pharmacists, physiotherapists, psychologists, and ICU survivors. The task force developed evidence-based recommendations using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Conflict-of-interest policies were strictly followed in all phases of the guidelines, including task force selection and voting. METHODS: The task force focused on five main content areas as they pertain to adult ICU patients: anxiety (new topic), agitation/sedation, delirium, immobility, and sleep disruption. Using the GRADE approach, we conducted a rigorous systematic review for each population, intervention, control, and outcome question to identify the best available evidence, statistically summarized the evidence, assessed the quality of evidence, and then performed the evidence-to-decision framework to formulate recommendations. RESULTS: The task force issued five statements related to the management of anxiety, agitation/sedation, delirium, immobility, and sleep disruption in adults admitted to the ICU. In adult patients admitted to the ICU, the task force issued conditional recommendations to use dexmedetomidine over propofol for sedation, provide enhanced mobilization/rehabilitation over usual mobilization/rehabilitation, and administer melatonin. The task force was unable to issue recommendations on the administration of benzodiazepines to treat anxiety, and the use of antipsychotics to treat delirium. CONCLUSIONS: The guidelines task force provided recommendations for pharmacologic management of agitation/sedation and sleep, and nonpharmacologic management of immobility in critically ill adults. These recommendations are intended for consideration along with the patient’s clinical status.

Abstract Context Lipodystrophy syndromes are rare disorders characterized by deficient adipose tissue, leading to insulin resistance, dyslipidemia, and organ system abnormalities. Objective Our goal was to develop a lipodystrophy severity score (LDS) to holistically capture the diverse manifestations of lipodystrophy into a numerical score to aid in prediction of clinical outcomes and/or treatment impact. Design An 8-domain LDS was developed by 8 disease experts in consultation with patient organizations. The LDS was rated for feasibility and content validity by 28 additional clinicians and 9 patient representatives. LDS was compared to the Clinical Global Impression (CGI) of severity for 20 putative patient profiles, each at 2 different time points, and by comparing change in LDS to global impression of change. For external validation, LDS was calculated in 2 cohorts of patients with lipodystrophy treated with metreleptin. Results LDS domains include Diabetes/Insulin Resistance, Microvascular Complications of Diabetes, Lipids, Cardiovascular, Liver, Kidney, Reproductive, and Other. Each domain is assessed by 1 or more questions assessing both lifetime and recent complications of lipodystrophy. The LDS had high content validity and feasibility and high reliability by intraclass correlation coefficients (>0.95). Global and domain-specific LDS were strongly correlated with CGI, as were changes in scores across visits (R = 0.79-0.99, P < .001 for all). In generalized lipodystrophy, metreleptin significantly reduced LDS (from 46 to 26 at 12 months, P < .001). The reductions were smaller in partial lipodystrophy (from 65 to 61 at 12 months, P = .04). Conclusion The LDS can reflect the severity of diverse manifestations of lipodystrophy and monitor changes following interventions.

Abstract Rationale Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. The extent of medication nonadherence in PAH is uncertain and may be linked to adverse outcomes. There has been a lack of multicenter, registry-based studies assessing medication nonadherence and patient-centered outcomes in PAH. Objectives To determine the prevalence of self-reported nonadherence in Pulmonary Hypertension Association Registry (PHAR) participants with PAH or chronic thromboembolic pulmonary hypertension and the relationship of nonadherence with several patient-centered outcomes (mortality, hospitalization rates, emergency department visits, and health-related quality of life). Methods Self-reported PAH medication nonadherence was captured at PHAR enrollment and during follow-up visits. Predictors of nonadherence were modeled using generalized estimating equations assuming a binary distribution. Outcomes associated with nonadherence were modeled using generalized estimating equations with a Poisson distribution. Results A total of 1,543 patients were included, of whom 1,092 (70.8%) were female and 1,340 (86.8%) had PAH. The overall rate of any self-reported nonadherence was 6.1% (95% confidence interval [CI], 5.3–6.9). Predictors of nonadherence included self-reported male sex at birth (odds ratio [OR], 1.4; 95% CI, 1.0–1.9; P = 0.02), poverty (OR, 1.6; 95% CI, 1.2–2.3; P = 0.01), not being married or partnered (OR, 1.5; 95% CI, 1.1–1.9; P = 0.01), having Medicaid or no health insurance (OR, 2.1; 95% CI, 1.5–2.9; P < 0.001), and having completed high school but not having a college degree (OR, 1.7; 95% CI, 1.1–2.9; P < 0.001). PHAR participants who reported any nonadherence had 50.0% more emergency department visits (P < 0.001), 13.3% more hospital admissions (P = 0.03), and 61.9% more days hospitalized (P = 0.01). No relationship was observed between nonadherence and the type or number of PAH therapies or all-cause mortality. Participants reporting nonadherence had worse mean Short Form-12 scores (P < 0.001) and worse emPHasis-10 scores (P = 0.02). Conclusions The rate of self-reported nonadherence in PHAR registrants was low but was associated with male sex and several social determinants of health. Although the complexity or type of PAH regimen did not appear to influence nonadherence, nonadherence was associated with numerous adverse patient-centered outcomes, including greater healthcare use and worse health-related quality of life. Because of limitations in the structure of the gathered data, relationships between exposure and outcomes were not temporally definitive; these observations warrant additional prospective studies.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR <1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510

ImportanceAmyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention.ObjectiveTo determine the effects of pridopidine, a σ1-receptor agonist, in ALS.Design, Settings, and ParticipantsPridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses.InterventionsEligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation.ResultsAmong 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively).Conclusions and RelevanceIn this 24-week study, pridopidine did not impact the progression of ALS.Trial RegistrationClinicalTrials.gov Identifiers: NCT04297683, NCT04615923