North Carolina GlaxoSmithKline Foundation

Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long-acting (LA) with live births, are presented. Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare-sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post-last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians. As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non-pregnant women. In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non-pregnant women. Pregnancy surveillance within ViiV Healthcare-sponsored clinical trials is ongoing, with dedicated pregnancy studies planned.

Background and AimsPatients with primary biliary cholangitis (PBC) often suffer with pruritus. We describe the impact of pruritus on quality of life and how it is managed in a real-world cohort.MethodsTARGET-PBC is a longitudinal observational cohort of patients with PBC across the USA. Data include information from medical records for three years prior to the date of consent up to 5 years of follow-up. Enrolled patients were asked to complete patient-reported outcome surveys: PBC-40, 5-D itch, and the PROMIS fatigue survey. Kruskal–Wallis tests were used to compare differences in symptoms between groups.ResultsA total of 211 patients with completed PRO surveys were included in the current study. PRO respondents were compared with non-respondents in the TARGET-PBC population and were broadly similar. Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. Patients reporting clinically significant pruritus were more likely to receive treatment, but 33% had never received treatment (no itch = 43.9%, mild itch = 38.3%).ConclusionsThe prevalence of pruritus was high in this population, and those reporting clinically significant pruritus had a higher likelihood of having advanced disease and worse quality of life. However, this study found that pruritus in PBC is under-treated. This may be due in part to ineffectiveness of current treatments, poor tolerance, or the lack of FDA-approved medications for pruritus.

The performances of three statistical approaches for assessing in vitro equivalence was evaluated with a set of 55 scenarios of realistic test (T) and reference (R) cascade impactor (CI) profiles (originally employed by the Product Quality Research Institute to evaluate the chi-square ratio statistic: CSRS) by comparing the outcomes against experts' opinion (surrogate for the truth). The three methods were (A) a stepwise aerodynamic particle size distribution (APSD) equivalence test integrating population bioequivalence (PBE) testing of impactor-sized mass (ISM) with the CSRS (PBE-CSRS approach), previously suggested by the USFDA; (B) the combination of PBE testing of single actuation content and ISM with the newly suggested modified CSRS (PBE-mCSRS approach), a method employing reference variance scaling; and (C) EMA's average bioequivalence (ABE approach). Based on Monte-Carlo simulations, both PBE-CSRS and ABE approaches resulted in high misclassification rates, the former with highest false-pass rate and the latter with highest false-fail rate at both ≥ 50% and ≥ 80% classification threshold values (the % of simulations or experts necessary to judge a given scenario as equivalent). Based on DeLong's tests, the PBE-mCSRS approach showed significantly better overall agreement with experts' opinion compared to the other approaches. Comparison of CSRS with mCSRS (both without PBE) suggested that the more discriminatory characteristics of the mCSRS method is based on the integration of variance scaling into the mCSRS method. Contrary to the ABE approach, the application of PBE-mCSRS approach for assessing APSD profiles of three dry powder inhaler (DPI) formulations supported the pharmacokinetic bioequivalence assessment of these formulations.

Sirtuin 1 influences gene expression and other cellular functions through deacetylation of histone and nonhistone proteins. We here sought to determine the effects of a small molecule sirtuin 1 activator, SRT2104, on inflammation and coagulation induced by lipopolysaccharide in humans. A randomized, double-blind, placebo-controlled study. An academic hospital. Twenty-four healthy humans. All subjects received an intravenous injection with lipopolysaccharide. Subjects were randomized to one of three groups (n=8 per group): 1) pretreatment with oral SRT2104 for 7 days (2 g/d), 2) pretreatment with a single SRT2104 dose (2 g), or 3) placebo. SRT2104 attenuated lipopolysaccharide-induced release of the cytokines interleukin-6 (mean peak levels of 58.8% [p<0.05] and 80.9% [p=0.078] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment) and interleukin-8 (mean peak levels of 57.0% [p<0.05 vs placebo] and 77.1% [p<0.05 vs placebo] after single and repeated SRT2104 ingestion, respectively, while not affecting tumor necrosis factor-α and interleukin-10 release). SRT2104 also reduced the lipopolysaccharide-induced acute phase protein response (C-reactive protein). SRT2104 inhibited activation of coagulation, as reflected by lower plasma levels of the prothrombin fragment F1+2 (mean peak levels 57.9% [p<0.05] and 64.2% [p<0.05] after single and repeated SRT2104 administration, respectively, relative to those measured after placebo treatment). Activation of the vascular endothelium (plasma von Willebrand levels) and the fibrinolytic system (plasma tissue-type plasminogen activator and plasminogen activator inhibitor type I) was not influenced by SRT2104. This is the first human study to demonstrate biological anti-inflammatory and anticoagulant responses consistent with the activation of sirtuin 1 by a small molecule.

Difficulties may be encountered when undertaking a benefit-risk assessment for an older product with well-established use but with a benefit-risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit-risk framework to assess the benefit-risk balance of warfarin for primary prevention of patients with atrial fibrillation. We used the qualitative framework BRAT as the starting point of the benefit-risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi-criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making. Our benefit-risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit-risk balance is fairly robust to differences in preferences. The probability of a favourable benefit-risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data. In this case study, we identified major challenges related to the identification of relevant benefit-risk criteria and taking into account the diversity and quality of evidence available to inform the benefit-risk assessment. The main challenges in applying formal methods for medical benefit-risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large.

To assess the effect of exposure to evidence-based medication after hospital discharge for Medicare beneficiaries with acute myocardial infarction (AMI). A discrete-time hazard model was used to estimate time to outcome associated with exposure to four drug classes (angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin-II receptor blockers (ARBs), beta-blockers (BBs), statins, and clopidogrel) used for post-AMI secondary prevention of cardiovascular events and mortality. Medicare administrative data for a 5% random sample of beneficiaries. Medicare beneficiaries (N=9,538) hospitalized for an AMI between April 1, 2006, and December 31, 2007, who survived for at least 30days after discharge. The cohort was followed until death or December 31, 2008. Time-varying exposure was measured as proportion of days covered (PDC) for each quarter during the follow-up period. PDC was classified into five categories (0-0.2, 0.2-0.4, 0.4-0.6, 0.6-0.8, 0.8-1.0). Outcomes were mortality and a composite outcome of death or post-AMI hospitalization. Over a median follow-up of 18months, mean PDC rates ranged from 0.37 (clopidogrel) to 0.50 (statins). When comparing the highest versus lowest categories of exposure, the hazard of the composite outcome was significantly lower for all drug classes except BBs (statins, adjusted hazard ratio (aHR)=0.71, ACEIs/ARBs, aHR=0.81, clopidogrel, aHR=0.85, BBs, aHR=0.93). All four drug classes were significantly associated with reductions in mortality; the magnitude of effect for the mortality outcome was largest for statins and smallest for BBs. Age modified the effect of statins on mortality. Use of evidence-based medications for secondary prevention after AMI is suboptimal in the Medicare population, and low exposure rates are associated with significantly higher risk for subsequent hospitalization and death.