Simulation studies of phase III clinical trials to test the efficacy of a candidate HIV-1 vaccine.

One question of particular importance in phase III HIV vaccine trials is the choice of efficacy measure (EM) to validly and precisely estimate the true vaccinal efficacy. Traditional EMs, based on hazard rate ratio (HRR) or cumulative incidence ratio (CIR) are time-sensitive to mode of vaccine action and population heterogeneities. Through Monte-Carlo simulation, the performance of HRR and CIR based EMs are examined across different trial designs and vaccine and population characteristics. A new EM based on log-spline hazard regression (HARE) is proposed. Given that vaccinal properties (mode of action, time-lag, waning) are unknown a priori, appropriate selection of EM is problematic, and HRR and CIR can be unreliable to estimate the true maximum efficacy of candidate products. Non-random sexual mixing can exacerbate biases in HRR and CIR. HARE can offer valid estimation across different modes of vaccine action and in presence of frailty effects, contrary to its traditional counterparts. Our simulation studies highlight the weaknesses of widely used EMs while offering guidelines for trial design and suggesting new avenues for statistical analysis.

Some important issues in the planning of phase III HIV vaccine efficacy trials.

Given that interesting HIV vaccine candidates, including live preparations and DNA plasmids, exist and that the first phase III vaccine (AIDSVAX) testing is due to begin this summer, 1998, in the U.S., adequately addressing trial preparedness is a pressing issue. Despite double-blind randomized controlled clinical trial design, there may be difficulties with interpretation and use of the usual measures of vaccinal efficacy and calculation of sample size. Difficulties arise from vaccine characteristics (e.g. mode of action, time-lag, waning) and population heterogeneities (e.g. differences in susceptibility, sexual behaviour, mixing preferences) causing frailty effects that can exacerbate bias and time-dependent effects already known to exist in simple cases. Since vaccine properties, particularly mode of action, are unlikely to be known before the onset of clinical trials, choosing an efficacy measure and the associated analyses and sample size calculations will be problematic. Interim analyses designed to decide whether a study will be prolonged may be tenuous if based on a time-dependent measure and will influence sample size determination. Despite shortcomings, general recommendations can be made to minimise pernicious effects. The objectives of this paper are principally to review the current state of knowledge of the different stages in the preparation of large phase III HIV vaccine efficacy trials, the methodological difficulties related to their design, and the analysis of data collected from them. Mathematical models and trial simulations are used to demonstrate that further research is necessary to study the behaviour of vaccine efficacy measures under heterogeneous conditions of population, vaccine action, and trial design and identify a time-independent efficacy measure. Alternative methods to validate sample size calculations have to be developed in older to reduce the chances of unnecessary economic and human cost in phase III HIV vaccine trials.

Highlights of the sexual activity of the heterosexual population in the province of Quebec.

OBJECTIVES: To describe and quantify the level of sexual activity of the heterosexually active population of Quebec. METHODS: The data analysed included 2889 heterosexually active individuals aged 15-60 (agemed = 32) from a 1996-7 survey on the sexual lifestyles of the general population of Quebec. Various probability distributions were studied to assess their capacity to describe and quantify the lifetime and yearly numbers of sexual partners of the sampled population. To estimate the annual rates of new partner acquisition, a generalised linear model was fitted to the number of lifetime sexual partners as a function of age, years of sexual activity, and sex. RESULTS: The mean and variance of the number of lifetime sexual partners for men (mean = 11, s2 = 163) is higher than for women (mean = 6, s2 = 72). The negative binomial and lognormal probability distributions give the most adequate fit to the lifetime number of partners for both agglomerated and stratified (by sex and age) data. The estimated annual rates of new partner acquisition provide two important results for prevention: (1) the first year of sexual activity represents the highest annual rate of new partner acquisition independent of age, (2) annual rates of new partner acquisitions increase through mid-life (ages 40-50) combined with a decrease in condom use. CONCLUSION: Problems caused by the use of large categories in the estimation of mean and variance cannot totally be overcome by fitting probability distributions to the empirical data despite good fits. Furthermore, we believe that adequate estimates of the annual rate of new partner acquisition should be a better measure of the risk of HIV infection than the number of partners since the first is a measure of incidence while the second is a measure of prevalence.

Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion. Torsemide Investigators Group.

STUDY OBJECTIVE: To assess the effects of torsemide on the primary end point of change in body weight from baseline, and the following secondary end points: urinary sodium, potassium, and chloride excretion, and urine volume after the first dose of drug. DESIGN: Randomized, parallel, double-blind, multicenter study in patients treated with torsemide 5 mg (n = 19), 10 mg (n = 18), or 20 mg (n = 14), or placebo (n = 15) for 7 days. PATIENTS: Sixty-six patients with New York Heart Association class II or III congestive heart failure and edema. RESULTS: At the end of the study, patients treated with torsemide 10 and 20 mg demonstrated a significant reduction in body weight compared with those receiving placebo (-1.62 and -1.30 kg, respectively), and those treated with torsemide 5 mg did not (-0.60 kg). The severity of edema decreased with increasing torsemide dose. Torsemide caused no greater frequency of adverse effects with increasing dose. CONCLUSION: Orally administered torsemide 5, 10, and 20 mg once/day for 7 days were well tolerated. Doses of 10 and 20 mg were effective in producing weight loss.