Showing papers by "James D. Neaton published in 2020"

Natriuretic Peptide-Based Inclusion Criteria in a Heart Failure Clinical Trial: Insights From COMMANDER HF

Abstract: Objectives This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. Background Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide ≥200 ng/l or N-terminal pro–B-type natriuretic peptide ≥800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. Methods We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. Results A total of 5,022 patients with left ventricular ejection fraction ≤40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. Conclusions In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915)

Design and implementation of the multi-arm, multi-stage Therapeutics for Inpatients with COVID-19 (TICO) platform master protocol: An Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative.

Abstract: 1 Abstract Background The SARS-CoV-2 pandemic is a public health emergency. Safe and effective therapies are urgently needed. Methods Therapeutics for Inpatients with COVID-19 (TICO), is a global multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. The protocol design allows multiple therapeutic agents to be evaluated in an efficient and scientifically rigorous manner, with efficiencies delivered by the MAMS design, and began by studying neutralizing monoclonal antibodies. TICO employs an agile and robust approach to futility and safety evaluation at 300 patients enrolled (Stage 1), with subsequent expansion to full sample size and an expanded target population (Stage 2) if the agent shows an acceptable safety profile and evidence of efficacy. Two ordinal outcomes applied early (Day 5) determine the efficacy signals of the investigational agents(s) and progression to Stage 2. These ordinal outcomes assess both respiratory and other organ failure events, recognizing the broad range of COVID-19 morbidity. In Stage 2, overall efficacy is assessed using the primary outcome of ‘time to sustained recovery’ assessed over 90 days. This approach to early futility assessment using an early intermediate outcome and a primary endpoint out to 90 days allows the study team to make rapid decisions on safety and potential efficacy of novel agents while ultimately focusing on patient-centered, longer-term outcomes. The implementation of TICO across a global network allows for continued enrollment despite variations in geographic epidemiology. Study Status The TICO master protocol moved from conception to first patient enrolled in approximately 9 weeks, a testament to the expedited regulatory and ethics review, coupled with flexible and responsive study operations. The first agent to be tested using this protocol, LY-CoV-555, enrolled N=326 participants before undergoing Stage 1 futility and safety assessment. Two additional agents will enter the study in November 2020, with other agents planned. Conclusion The TICO MAMS platform trial has been implemented efficiently across a global network of sites and several trial networks. It will generate results rapidly for multiple novel neutralizing monoclonal antibodies and other therapeutics agents.

Adult and paediatric haematology and clinical chemistry laboratory reference limits for Liberia.

Abstract: Background As more research is conducted in Liberia, there is a need for laboratory reference limits for common chemistry and haematology values based on a healthy population. Reference limits from the United States may not be applicable. Objective The aim of this study was to present laboratory reference ranges from a Liberian population and compare them to United States ranges. Methods Serum chemistry and haematology values from 2529 adults and 694 children and adolescents obtained from two studies conducted in Liberia between 2015 to 2017 were used to determine reference limits. After removing outliers, the reference limits defined by the 2.5th and 97.5th percentiles were determined by sex in three age groups (6-11, 12-17, and 18+ years). Results The median (interquartile range) of adults was 29 (23, 37) years; 44% were female. The median (interquartile range) for children and adolescents was 12 (9, 15) years; 53% were female. Several reference ranges determined using Liberian participants differed from those in the US. For chemistries, a high percentage of both adults and children/adolescents had high serum chloride levels based on United States ranges. For haematology, a high percentage of Liberian participants had haemoglobin and related assays below the lower limit of United States ranges. Conclusion Chemistry and haematology reference intervals determined for a Liberian population of healthy individuals should be considered for establishing eligibility criteria and monitoring of laboratory adverse events for clinical trials as well as for use in clinical settings in Liberia and perhaps for other countries in Western Africa.