Randomized Trials of Retosiban Versus Placebo or Atosiban in Spontaneous Preterm Labor.

OBJECTIVE: The aim of this study is to assess the efficacy and safety of retosiban in spontaneous preterm labor (sPTL). STUDY DESIGN: Two multicenter, randomized, and double-blind trials compared retosiban with placebo and retosiban with atosiban in women with a singleton pregnancy and intact membranes in sPTL at 24 to 336/7 weeks' gestation. Coprimary endpoints in the placebo-controlled trial were time to delivery (TTD) or treatment failure (whichever occurred first) and neonatal composite morbidity and mortality. The primary endpoint of the atosiban comparator trial was TTD. RESULTS: The trials were terminated early because of slow recruitment. The placebo-controlled trial enrolled 23 participants (February 2016-July 2017; 2.6% of target);the atosiban-comparator trial enrolled 97 (March 2015-August 2017; 29% of target). Baseline participant characteristics were similar between treatments. In the placebo-controlled trial, mean gestational ages at randomization were 30.8 (retosiban, n = 10) and 30.5 weeks (placebo, n = 13), and mean times to delivery/treatment failure were 18.9 days (retosiban) and 11.1 days (placebo). Two and four neonates in the retosiban and placebo groups, respectively, had ≥1 component of the neonatal composite endpoint. In the atosiban-comparator trial, mean gestational age at randomization was 31.5 weeks (for both retosiban, n = 47, and atosiban, n = 50), and adjusted mean TTDs were 32.51 days (retosiban) and 33.71 days (atosiban; p > 0.05). Adverse events were no more common with retosiban than placebo or atosiban. CONCLUSION: Despite considerable efforts to conduct two adequate and well-controlled studies in patients with sPTL, both studies were unable to recruit effectively and consequently terminated prematurely. Key factors negatively affecting participation were patient and physician resistance to use of a placebo comparator, lack of investigator consensus on diagnostic criteria and acceptance of protocol procedures, and ethics committee decisions. Meaningful cooperation between pharmaceutical companies, regulatory authorities, and the obstetric community is essential for future development of drugs to treat sPTL.

Better decision making in drug development through adoption of formal prior elicitation.

With the continued increase in the use of Bayesian methods in drug development, there is a need for statisticians to have tools to develop robust and defensible informative prior distributions. Whilst relevant empirical data should, where possible, provide the basis for such priors, it is often the case that limitations in data and/or our understanding may preclude direct construction of a data-based prior. Formal expert elicitation methods are a key technique that can be used to determine priors in these situations. Within GlaxoSmithKline, we have adopted a structured approach to prior elicitation on the basis of the SHELF elicitation framework and routinely use this in conjunction with calculation of probability of success (assurance) of the next study(s) to inform internal decision making at key project milestones. The aim of this paper is to share our experiences of embedding the use of prior elicitation within a large pharmaceutical company, highlighting both the benefits and challenges of prior elicitation through a series of case studies. We have found that putting team beliefs into the shape of a quantitative probability distribution provides a firm anchor for all internal decision making, enabling teams to provide investment boards with formally appropriate estimates of the probability of trial success as well as robust plans for interim decision rules where appropriate. As an added benefit, the elicitation process provides transparency about the beliefs and risks of the potential medicine, ultimately enabling better portfolio and company-wide decision making.

A Retrospective Database Analysis of Neonatal Morbidities to Evaluate a Composite Endpoint for Use in Preterm Labor Clinical Trials.

Objective To propose and assess a composite endpoint (CE) of neonatal benefit based on neonatal mortality and morbidities by gestational age (GA) for use in preterm labor clinical trials. Study Design A descriptive, retrospective analysis of the Medical University of South Carolina Perinatal Information System database was conducted. Neonatal morbidities were assessed for inclusion in the CE based on clinical significance/risk of childhood neurodevelopmental impairment, frequency, and association with GA in a mother-neonate linked cohort, comprising women with uncomplicated singleton pregnancies delivered at ≥24 weeks' GA. Results Among 17,912 mother-neonate pairs, neonates were at a risk of numerous severe but infrequent morbidities. Clinically important, predominantly rare events were combined into a CE comprising neonatal mortality and morbidities, which decreased in frequency with increasing GA. The highest CE frequency occurred at <31 weeks. High frequency of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis drove the CE. Median length of hospital stay was longer at all GAs in those with the CE compared with those without. Conclusions Descriptive epidemiological assessment and clinical input were used to develop a CE to measure neonatal benefit, comprising clinically meaningful outcomes. These empirical data and CE allowed trials investigating tocolytics to be sized appropriately.

Assessing a composite end point for new tocolytics in clinical trials: Data from 4 US integrated delivery networks.

PURPOSE: A composite end point (CE) measuring neonatal benefit was created for use in tocolytic randomized controlled trials with rates assessed using data from one referral hospital. The goal of this study was to assess wider generalizability of the CE, using data from multiple integrated delivery networks, creating a cohort of linked mother-neonate pairs to understand neonatal outcomes in a broad population. METHODS: Retrospective data on births (2001-2012) were collected from 4 US integrated delivery networks in the COMparative effectiveness PAtient Safety and Surveillance (COMPASS) Research Network, and linked mother-neonate pairs were identified. The CE was analyzed for all in-hospital singleton neonates at ≥24 weeks of gestational age (GA) born to mothers aged ≤45 years at a referral hospital or hospital with >2000 annual births. RESULTS: The CE analyses included 56 485 eligible mother-neonate pairs; frequency of the CE decreased from 89% to 66% between GA weeks 24 and 29 and further decreased to <14% for infants born >34 weeks of GA. Composite end point rates were 20% to 30% lower at 24 to 30 weeks of GA in COMPASS compared with Medical University of South Carolina but were similar by 31 weeks. CONCLUSIONS: The COMPASS Network enabled evaluation of the CE across a large population demonstrating that the CE findings could be replicated beyond a single hospital and the potential for lower CE frequency. Based on this, an adaptive design was adopted for randomized controlled trials, specifically sample size reestimation to mitigate against the risk of lower outcome rates, highlighting the use of real-world data in drug development.

Treatment of spontaneous preterm labour with retosiban: a phase II pilot dose-ranging study.

AIMS: The aims of the present study were to investigate the maternal, fetal and neonatal safety and tolerability, pharmacodynamics and pharmacokinetics of intravenous (IV) retosiban in pregnant women with spontaneous preterm labour (PTL) between 340/7 and 356/7  weeks' gestation. METHODS: In parts A and B of a three-part, double-blind, placebo-controlled, multicentre study, women were randomized 3:1 (Part A) or 2:1 (Part B) to either 12-h IV retosiban followed by a single dose of oral placebo (R-P) or 12-h IV placebo followed by single-dose oral retosiban (P-R). RESULTS: A total of 29 women were randomized; 20 to R-P and nine to P-R. An integrated analysis found that adverse events were infrequent in mothers/newborns and consistent with events expected in the population under study or associated with confounding factors. Retosiban was rapidly absorbed after oral administration, with an observed half-life of 1.45 h. Efficacy analyses included 19 women. While not statistically significant, those receiving R-P more frequently achieved uterine quiescence in 6 h (R-P, 63%; 95% credible interval [CrI]: 38, 84; P-R, 43%; 95% CrI: 12, 78) and more achieved a reduction of ≥50% in uterine contractions in 6 h (R-P, 63%; 95% CrI: 38, 84; P-R, 29%; 95% CrI: 4, 64). The number of days to delivery was increased in women receiving R-P (median 26 days for R-P vs. 13 days for P-R). CONCLUSIONS: Intravenous retosiban has a favourable safety and tolerability profile and might prolong pregnancies in women with PTL. The study provides the rationale and dosing strategy for further evaluation of the efficacy of retosiban in the treatment of PTL.

Optimal adaptive sequential designs for crossover bioequivalence studies.

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at ≥ 80%, their average sample sizes were similar to or less than those of conventional single stage designs.

Treatment of spontaneous preterm labour with retosiban: a phase 2 proof-of-concept study.

AIM: The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour. METHODS: This was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 30(0/7) and 35(6/7) weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety. RESULTS: Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups. CONCLUSIONS: Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile.

Re-introduction of a novel approach to the use of stable isotopes in pharmacokinetic studies.

The purpose of this investigation is to evaluate the scientific benefits of a novel approach in using stable isotopes to reduce the number of subjects needed to perform relative bioavailability and bioequivalence pharmacokinetic studies for formulations that are qualitatively and quantitatively the same and quality by design (QbD) pharmacokinetic studies. The stable isotope approach was investigated using simulations to determine the impact this approach would have on the estimation of variability and, subsequently, the sample size for a bioequivalence study. A biostudy was conducted in dogs in a two period crossover to explore the viability of the stable isotope approach. For a drug product with within-subject variability (CV(w)) of 50% and assuming a correlation of 0.95 between the enriched and non-enriched pharmacokinetics (PK), simulations showed that the variability can be reduced by 70% and the required sample size can be reduced by 90% while maintaining 90% power to demonstrate bioequivalence. The dog study showed a strong correlation (R(2), > 0.99) between the enriched and non-enriched area under the curve and maximum observed concentration, and a significant reduction in the variability (reduction in % coefficient of variation from 79.9% to 6.3%). Utilization of a stable isotope approach can markedly improve the efficiency and accuracy of bioavailability and bioequivalence studies particularly for highly variable drugs in formulations that are qualitatively and quantitatively the same and for studies designed for QbD investigations.

Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'.

In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright © 2011 John Wiley & Sons, Ltd.

Evaluation of vardenafil and sildenafil on cardiac repolarization.

This novel study evaluated the effects of vardenafil and sildenafil on QT and corrected QT (QTc) duration using a model that minimizes experimental error to obtain the most accurate assessment of observed QTc effects. A placebo-controlled and positive-controlled, period-balanced, double-blinded, 6-way crossover study evaluated therapeutic and supratherapeutic oral doses of vardenafil (10 and 80 mg, respectively) and sildenafil (50 and 400 mg, respectively), therapeutic doses of moxifloxacin (400 mg), and a placebo in 58 healthy men (mean age 53 years), with dosing every 3 days. Six replicate, 12-lead, digital electrocardiograms (ECGs) were recorded at 3 time points before and 5 time points after dosing to cover the time course of maximum exposure to study drugs and their metabolites. An independent laboratory blindly analyzed approximately 17,000 ECGs. For the placebo, mean change in QTcF (Fridericia) duration 1 hour after dose (approximate Tmax of vardenafil and sildenafil) was 0 ms (+/-0.7 SD). QT/QTc variability was small across regimens, indicating statistically powerful results. Moxifloxacin demonstrated an expected 8-ms mean change and was the only drug to prolong absolute QT. Placebo-corrected mean changes in QTcF duration (90% confidence interval) at 1 hour after dose were 8 ms (range 6 to 9) for vardenafil 10 mg and 6 ms (range 5 to 8) for sildenafil 50 mg. QTci (linear and nonlinear per patient) yielded similar trends: 4 ms (range 3 to 6) for vardenafil 10 mg and 4 ms (range 2 to 5) for sildenafil 50 mg. Dose response demonstrated very shallow QTc relations for study drugs. Therapeutic and supratherapeutic doses produced only small increases in the QTcF interval, which were considered to be clinically irrelevant. This well-controlled, statistically powerful study in middle-aged men demonstrated that vardenafil and sildenafil produced no increase of absolute QT and only similar, small increases of the QTc interval, with a shallow dose-response curve. The study design and conduct may serve as a guide for future QT assessment of new drugs.