A phase I, first-in-human study investigating the safety, tolerability, and pharmacokinetics of the maturation inhibitor GSK3739937.

We report the safety and pharmacokinetic properties of the HIV-1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first-in-human, double-blind, randomized, placebo-controlled, single- (part 1) and multiple- (part 2) dose escalation study with an additional open-label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10-800 mg) in part 1, up to 18 once-daily 25- to 100-mg or 3 once-weekly 500-mg doses in part 2, and single 100-mg doses as powder-in-bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety-one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug-related AEs were gastrointestinal (14/17, 82%). The terminal phase half-life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose-proportional increases during part 1. Accumulation in exposure following repeat dosing was 6- to 7-fold with daily dosing and ~1.7-fold after weekly treatment, as expected due to the long half-life. Bioavailability of GSK'937 after a meal was 1.35- to 1.40-fold greater as a tablet versus powder-in-bottle and >2-fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose-limiting safety events occurred. Pharmacokinetic parameters of long half-life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684.

Lack of pharmacokinetic interaction between the HIV-1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women.

AIMS: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women. METHODS: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC0-t ), maximum observed concentration (Cmax ) and plasma concentration at the end of the dosing interval (Cτ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined. Adverse events were monitored. RESULTS: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC0-t , Cmax and Cτ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. CONCLUSION: Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol and levonorgestrel in healthy female participants. No major tolerability findings were reported. Elevated liver transaminase levels were probably due to ethinyl oestradiol/levonorgestrel.

Phase I evaluation of pharmacokinetics and tolerability of the HIV-1 maturation inhibitor GSK3640254 and dolutegravir in healthy adults.

AIMS: GSK3640254, a novel, next-generation maturation inhibitor effective against a range of HIV polymorphisms with no cross-resistance to current antiretroviral therapy, could potentially be coadministered with dolutegravir as a 2-drug regimen. In this phase I study, pharmacokinetics and tolerability of GSK3640254 plus dolutegravir were assessed. METHODS: Healthy participants received dolutegravir 50 mg once daily (QD) on Days 1-5 in period 1, GSK3640254 200 mg QD on Days 1-7 in period 2, and dolutegravir 50 mg plus GSK3640254 200 mg QD on Days 1-7 in period 3. All treatments were administered with a moderate-fat meal 30 minutes prior to dosing. Pharmacokinetics parameters were derived by noncompartmental methods, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed effects models. Adverse events, laboratory measurements, electrocardiography and vital signs were monitored. RESULTS: Sixteen participants completed the study. GMRs (90% CIs) for dolutegravir area under the plasma concentration-time curve from time 0 to the end of the dosing interval at steady state, maximum observed concentration and plasma concentration at the end of the dosing interval were 1.17 (1.118-1.233), 1.09 (1.044-1.138) and 1.24 (1.160-1.315), respectively. The GMRs (90% CIs) for GSK3640254 were 1.04 (0.992-1.094), 0.99 (0.923-1.065) and 0.10 (0.939-1.056), respectively. Dolutegravir plus GSK3640254 coadministration did not meaningfully alter steady-state exposure to dolutegravir or GSK3640254. No clinically significant trends in tolerability or safety were observed. CONCLUSION: Coadministration of GSK3640254 with dolutegravir did not result in clinically significant drug interaction and was well tolerated.

A machine learning compatible method for ordinal propensity score stratification and matching.

Although machine learning techniques that estimate propensity scores for observational studies with multivalued treatments have advanced rapidly in recent years, the development of propensity score adjustment techniques has not kept pace. While machine learning propensity models provide numerous benefits, they do not produce a single variable balancing score that can be used for propensity score stratification and matching. This issue motivates the development of a flexible ordinal propensity scoring methodology that does not require parametric assumptions for the propensity model. The proposed method fits a one-parameter power function to the cumulative distribution function (CDF) of the generalized propensity score (GPS) vector resulting from any machine learning propensity model, and is henceforth called the GPS-CDF method. The estimated parameter from the GPS-CDF method, ã , is a scalar balancing score that can be used to group similar subjects in outcome analyses. Specifically, subjects who received different levels of the treatment are stratified or matched based on their ã value to produce unbiased estimates of the average treatment effect (ATE). Simulation studies presented show remediation of covariate balance, minimal bias in ATEs, and maintain coverage probability. The proposed method is applied to the Mexican-American Tobacco use in Children (MATCh) study to determine whether an ordinal treatment of exposure to smoking imagery in movies causes cigarette experimentation in Mexican-American adolescents.

Propensity score stratification methods for continuous treatments.

Continuous treatments propensity scoring remains understudied as the majority of methods are focused on the binary treatment setting. Current propensity score methods for continuous treatments typically rely on weighting in order to produce causal estimates. It has been shown that in some continuous treatment settings, weighting methods can result in worse covariate balance than had no adjustments been made to the data. Furthermore, weighting is not always stable, and resultant estimates may be unreliable due to extreme weights. These issues motivate the current development of novel propensity score stratification techniques to be used with continuous treatments. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) and the nonparametric GPS-CDF approaches are introduced. Empirical CDFs are used to stratify subjects based on pretreatment confounders in order to produce causal estimates. A detailed simulation study shows superiority of these new stratification methods based on the empirical CDF, when compared with standard weighting techniques. The proposed methods are applied to the "Mexican-American Tobacco use in Children" study to determine the causal relationship between continuous exposure to smoking imagery in movies, and smoking behavior among Mexican-American adolescents. These promising results provide investigators with new options for implementing continuous treatment propensity scoring.

Phase I evaluation of the safety, tolerability, and pharmacokinetics of GSK3640254, a next-generation HIV-1 maturation inhibitor.

Despite advances in HIV-1 management with antiretroviral therapy, drug resistance and toxicities with multidrug regimens can result in treatment failure. Hence, there is a continuing demand for antiretroviral agents (ARVs) with novel mechanisms of action. Maturation inhibitors inhibit HIV-1 replication via a unique mechanism of action and can be combined with other ARVs. Two phase I randomized clinical trials were conducted for a maturation inhibitor, GSK3640254, to determine safety, pharmacokinetics (NCT03231943), and relative bioavailability (NCT03575962) in healthy adults. The first trial was conducted in two parts. Part 1 was conducted in a two-cohort, interlocking, eight-period fashion in 20 participants with single ascending doses of GSK3640254 (1-700 mg) or placebo. In Part 2, 58 participants were randomized to receive GSK3640254 (n = 44) or placebo (n = 14). Four participants reported adverse events (AEs) leading to study discontinuation, with one adverse drug reaction (maculopapular rash). There was no relationship between frequency or severity of AEs and dose. Pharmacokinetic assessments showed that GSK3640254 was slowly absorbed, with time to maximum concentration (tmax) occurring between 3.5 and 4 hours and half-life of ~24 hours. In the relative bioavailability study of GSK3640254 mesylate salt vs bis-hydrochloride salt capsules in 14 healthy adults, the mesylate salt performed slightly better than the bis-hydrochloride formulation (12%-16% increase in area under the concentration-time curve and maximum concentration); tmax (5 hours) was similar between the formulations. Initial pharmacokinetic and safety data from these healthy-participant studies informed further development of GSK3640254 for once-daily dosing for the treatment of HIV-1 infection.

A novel approach for propensity score matching and stratification for multiple treatments: Application to an electronic health record-derived study.

Currently, methods for conducting multiple treatment propensity scoring in the presence of high-dimensional covariate spaces that result from "big data" are lacking-the most prominent method relies on inverse probability treatment weighting (IPTW). However, IPTW only utilizes one element of the generalized propensity score (GPS) vector, which can lead to a loss of information and inadequate covariate balance in the presence of multiple treatments. This limitation motivates the development of a novel propensity score method that uses the entire GPS vector to establish a scalar balancing score that, when adjusted for, achieves covariate balance in the presence of potentially high-dimensional covariates. Specifically, the generalized propensity score cumulative distribution function (GPS-CDF) method is introduced. A one-parameter power function fits the CDF of the GPS vector and a resulting scalar balancing score is used for matching and/or stratification. Simulation results show superior performance of the new method compared to IPTW both in achieving covariate balance and estimating average treatment effects in the presence of multiple treatments. The proposed approach is applied to a study derived from electronic medical records to determine the causal relationship between three different vasopressors and mortality in patients with non-traumatic aneurysmal subarachnoid hemorrhage. Results suggest that the GPS-CDF method performs well when applied to large observational studies with multiple treatments that have large covariate spaces.

Improved conditional imputation for linear regression with a randomly censored predictor.

This article describes a nonparametric conditional imputation analytic method for randomly censored covariates in linear regression. While some existing methods make assumptions about the distribution of covariates or underestimate standard error due to lack of imputation error, the proposed approach is distribution-free and utilizes resampling to correct for variance underestimation. The performance of the novel method is assessed using simulations, and results are contrasted with methods currently used for a limit of detection censored design, including the complete case approach and other nonparametric approaches. Theoretical justifications for the proposed method are provided, and its application is demonstrated through a study of association between lipoprotein cholesterol in offspring and parental history of cardiovascular disease.

Utilizing Propensity Score Analyses in Prehospital Blood Product Transfusion Studies: Lessons Learned and Moving Toward Best Practice.

Recently, observational studies analyzing prehospital blood product transfusions (PHT) for trauma have become more widespread in both military and civilian communities. Due to these studies' non-random treatment assignment, propensity score (PS) methodologies are often used to determine an intervention's effectiveness. However, there are no guidelines on how to appropriately conduct PS analyses in prehospital studies. Such analyses are complicated when treatments are given in emergent settings as the ability to administer treatment early, often before hospital admission, can interfere with assumptions of PS modeling. This study conducts a systematic review of literature from military and civilian populations to assess current practice of PS methodology in PHT analyses. The decision-making process from the multicenter Prehospital Resuscitation on Helicopter Study (PROHS) is discussed and used as a motivating example. Results show that researchers often omit or incorrectly assess variable balance between treatment groups and include inappropriate variables in the propensity model. When used correctly, PS methodology is an effective statistical technique to show that aggressive en route resuscitation strategies, including PHT, can reduce mortality in individuals with severe trauma. This review provides guidelines for best practices in study design and analyses that will advance trauma care.

Abnormalities of laboratory coagulation tests versus clinically evident coagulopathic bleeding: results from the prehospital resuscitation on helicopters study (PROHS).

BACKGROUND: Laboratory-based evidence of coagulopathy (LC) is observed in 25-35% of trauma patients, but clinically-evident coagulopathy (CC) is not well described. METHODS: Prospective observational study of adult trauma patients transported by helicopter from the scene to nine Level 1 trauma centers in 2015. Patients meeting predefined highest-risk criteria were divided into CC+ (predefined as surgeon-confirmed bleeding from uninjured sites or injured sites not controllable by sutures) or CC-. We used a mixed-effects, Poisson regression with robust error variance to test the hypothesis that abnormalities on rapid thrombelastography (r-TEG) and international normalized ratio (INR) were independently associated with CC+. RESULTS: Of 1,019 highest-risk patients, CC+ (n=41, 4%) were more severely injured (median ISS 32 vs 17), had evidence of LC on r-TEG and INR, received more transfused blood products at 4 hours (37 vs 0 units), and had greater 30-day mortality (59% vs 12%) than CC- (n=978, 96%). The overall incidence of LC was 39%. 30-day mortality was 22% vs 9% in those with and without LC. In two separate models, r-TEG K-time >2.5 min (RR 1.3, 95% CI 1.1-1.7), r-TEG mA <55 mm (RR 2.5, 95% CI 2.0-3.2), platelet count <150 x 109/L (RR 1.2, 95% CI 1.1-1.3), and INR >1.5 (RR 5.4, 95% CI 1.8-16.3) were independently associated with CC+. A combined regression model was not generated because too few patients underwent both r-TEG and INR. CONCLUSION: CC was rare compared to LC. CC was associated with poor outcomes and impairment of both clotting factor and platelet-mediated coagulation components.

Multicenter retrospective study of noncompressible torso hemorrhage: Anatomic locations of bleeding and comparison of endovascular versus open approach.

BACKGROUND: Rational development of technology for rapid control of noncompressible torso hemorrhage (NCTH) requires detailed understanding of what is bleeding. Our objectives were to describe the anatomic location of truncal bleeding in patients presenting with NCTH and compare endovascular (ENDO) management versus open (OPEN) management. METHODS: This is a retrospective study of adult trauma patients with NCTH admitted to four urban Level I trauma centers in the Houston and San Antonio metropolitan areas in 2008 to 2012. Inclusion criteria include named axial torso vessel disruption, Abbreviated Injury Scale chest or abdomen score of 3 or higher with shock (base excess, <-4) or truncal operation in 90 minutes or less, or pelvic fracture with ring disruption. Exclusion criteria include isolated hip fractures, falls from standing, or prehospital cardiopulmonary resuscitation. After dichotomizing into OPEN, ENDO, and resuscitative thoracotomy (RT) groups based on the initial approach to control NCTH, a mixed-effects Poisson regression with robust error variance (controlling for age, mechanism, Injury Severity Score, shock, hypotension, and severe head injury as fixed effects and site as a random effect) was used to test the hypothesis that ENDO was associated with reduced in-hospital mortality in NCTH patients. RESULTS: Five hundred forty-three patients with NCTH underwent ENDO (n = 166, 31%), OPEN (n = 309, 57%), or RT (n = 68, 12%). Anatomic bleeding locations were 25% chest, 41% abdomen, and 31% pelvis. ENDO was used to treat relatively few types of vascular injuries, whereas OPEN and RT injuries were more diverse. ENDO patients had more blunt trauma (95% vs. 34% vs. 32%); severe injuries (median Injury Severity Score, 34 vs. 27 vs. 21), and increased time to intervention (median, 298 vs. 92 vs. 51 minutes) compared with OPEN and RT. Mortality was 15% versus 20% versus 79%. ENDO was associated with decreased mortality compared to OPEN (relative risk, 0.58; 95% confidence interval, 0.46-0.73). CONCLUSION: Although ENDO may reduce mortality in NCTH patients, significant group differences limit the generalizability of this finding. LEVEL OF EVIDENCE: Therapeutic, level V.

Multicenter observational prehospital resuscitation on helicopter study.

BACKGROUND: Earlier use of in-hospital plasma, platelets, and red blood cells (RBCs) has improved survival in trauma patients with severe hemorrhage. Retrospective studies have associated improved early survival with prehospital blood product transfusion (PHT). We hypothesized that PHT of plasma and/or RBCs would result in improved survival after injury in patients transported by helicopter. METHODS: Adult trauma patients transported by helicopter from the scene to nine Level 1 trauma centers were prospectively observed from January to November 2015. Five helicopter systems had plasma and/or RBCs, whereas the other four helicopter systems used only crystalloid resuscitation. All patients meeting predetermined high-risk criteria were analyzed. Patients receiving PHT were compared with patients not receiving PHT. Our primary analysis compared mortality at 3 hours, 24 hours, and 30 days, using logistic regression to adjust for confounders and site heterogeneity to model patients who were matched on propensity scores. RESULTS: Twenty-five thousand one hundred eighteen trauma patients were admitted, 2,341 (9%) were transported by helicopter, of which 1,058 (45%) met the highest-risk criteria. Five hundred eighty-five of 1,058 patients were flown on helicopters carrying blood products. In the systems with blood available, prehospital median systolic blood pressure (125 vs 128) and Glasgow Coma Scale (7 vs 14) was significantly lower, whereas median Injury Severity Score was significantly higher (21 vs 14). Unadjusted mortality was significantly higher in the systems with blood products available, at 3 hours (8.4% vs 3.6%), 24 hours (12.6% vs 8.9%), and 30 days (19.3% vs 13.3%). Twenty-four percent of eligible patients received a PHT. A median of 1 unit of RBCs and plasma were transfused prehospital. Of patients receiving PHT, 24% received only plasma, 7% received only RBCs, and 69% received both. In the propensity score matching analysis (n = 109), PHT was not significantly associated with mortality at any time point, although only 10% of the high-risk sample were able to be matched. CONCLUSION: Because of the unexpected imbalance in systolic blood pressure, Glasgow Coma Scale, and Injury Severity Score between systems with and without blood products on helicopters, matching was limited, and the results of this study are inconclusive. With few units transfused to each patient and small outcome differences between groups, it is likely large, multicenter, randomized studies will be required to detect survival differences in this important population. LEVEL OF EVIDENCE: Level II.