The Short‐Term Effects and Unintended Long‐Term Consequences of Binge Drinking in College: A 10‐Year Follow‐Up Study

This study addresses binge drinking in college as a risk factor for heavy drinking and alcohol dependence after college. A national probability sample of 1972 college students from the National Longitudinal Surveys of Youth (NLSY79) was interviewed in 1984 and reinterviewed again as adults in 1994. The short‐term effects of binge drinking in college were assessed as well as the extent to which experiences of negative effects in college predicted patterns of alcohol use across the transition from college into postcollege years. As expected, college binge drinkers were comparatively more likely than nonbinge drinkers to experience one or more alcohol‐related problems while in college. In addition, weighted estimates of DSM‐IV‐defined diagnostic criteria in logistic regression models indicated that the binge drinking patterns exhibited during the college years, for some former college students of both genders, posed significant risk factors for alcohol dependence and abuse 10 years after the initial interview, in conjunction with evidence of academic attrition, early departure from college and less favorable labor market outcomes.     

Clinical Trial Simulation To Assist In COPD Trial Planning And Design With A Biomarker-Based Diagnostic: When To Pull The Trigger?

Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with a wide range of clinical phenotypes that vary from predominantly airway disease (chronic bronchitis) to predominantly parenchymal disease (emphysema). Current advances for the treatment of COPD are increasingly focused on targeted treatments and development of novel biomarker-based diagnostics (Dx)'s to select the patients most likely to benefit. Clinical trial planning and design with biomarkers includes additional considerations beyond those for conventional trials in un-selected populations, e.g., the heterogeneity of COPD phenotypes in the population, the ability of a biomarker to predict clinically meaningful phenotypes that are differentially associated with the response to a targeted treatment, and the data needed to make Go/No Go decisions during clinical development.

We developed the Clinical Trial Object Oriented Research Application (CTOORA), a computer-aided clinical trial simulator of COPD patient outcomes, to inform COPD trial planning with biomarkers. CTOORA provides serial projections of trial success for a range of hypothetical and plausible scenarios of interest. In the absence of data, CTOORA can identify characteristics of a biomarker-based Dx needed to provide a meaningful advantage when used in a clinical trial. We present a case study in which CTOORA is used to identify the scenarios for which a biomarker may be used successfully in clinical development. CTOORA is a tool for robust clinical trial planning with biomarkers, to guide early-to-late stage development that is positioned for success.     

Comparison of Oral and Depot Intra‐muscular Steroids in Assessing Steroid‐Responsiveness in COPD

Non‐compliance or euphoria may limit the usefulness of prednisolone tablets in assessing steroid‐responsiveness in chronic obstructive pulmonary disease (COPD). Depot intra‐muscular methyl‐prednisolone (imMP), producing a plateau steroid effect over two weeks, may be more reliable. Following two weeks of placebo, twenty‐seven COPD patients (mean FEV₁ 43% predicted) participated in a two‐week randomised, double‐blind, placebo‐controlled, parallel‐design trial taking either 120 mg imMP with placebo tablets or placebo injection with prednisolone 30 mg daily. After each period, post‐bronchodilator FEV₁, forced vital capacity (FVC), inspiratory capacity (IC) and six‐minute walking distance (6MWD) were assessed and patients completed both quality‐of‐life scores (St. George's 30 and Short Form 36) and mood scores (Hospital Anxiety and Depression scores and Altman's Self‐rating Mania Scale). There were no significant changes in 6MWD, quality of life or mood scores after either type of steroids and no change in lung function after imMP. By contrast, there were small mean improvements in lung function on oral prednisolone (mean FEV₁, FVC and IC increased by 100, 320 and 150 ml, respectively). Only the improvement in FVC was significantly greater after prednisolone compared with imMP. Single depot intra‐muscular injections of steroids have no advantage over oral daily prednisolone in testing steroid‐responsiveness in COPD patients.     

Clinical Trial Design in Contemporary Device Studies in Heart Failure: Is There a Gold Standard?

The assessment of the efficacy and safety of implantable cardiac devices used for the management of heart failure is complicated by procedural challenges. We present an overview of the advantages and disadvantages of different clinical trial designs, and discuss investigator and patient blinding. We conclude that blinding is optimal, but methodologically difficult. Until rules for and assessment of blinding are developed or surrogate measures are considered to be acceptable from a regulatory standpoint, an open-label design with objective end points is an unavoidable default standard.     

Effectiveness of Long‐Term Residential Substance Abuse Treatment for Women: Findings from Three National Studies

The effectiveness of residential substance abuse treatment for women was examined using data from the Center for Substance Abuse Treatment's Residential Women and Children/Pregnant and Postpartum Women (RWC/PPW) Cross‐Site Study and two other recent national studies. Treatment success was defined as posttreatment abstinence from further drug or alcohol use, measured through in‐person follow‐up interviews conducted 6–12 months after each client's discharge. Despite differences in treatment programs, client profiles, follow‐up intervals, data collection methods, and other factors, all three studies found high treatment success rates—ranging narrowly from 68% to 71% abstinent—among women who spent six months or more in treatment. Success rates were lower, and between‐study differences were larger, for clients with shorter stays in treatment. Controlling for salient client and treatment project characteristics, strong associations between length of stay in treatment and posttreatment abstinence rate were found in all three studies, suggesting that women's length of stay in residential treatment is a major determinant of treatment effectiveness. In further analysis of RWC/PPW data, treatment completion was also found to be an important outcome factor. Among clients who remained in treatment for at least three months, those who achieved their treatment goals in three to five months abstinence outcomes were as good as those for clients who took more than six months to complete their treatment (76%–78% abstinent) and substantially better than those for clients who did not complete treatment (51%–52% abstinent). Notably, however, most of the RWC/PPW clients who successfully completed treatment (71%) required six months or more to do so.     

Adaptive Trial Design: Could We Use This Approach to Improve Clinical Trials in the Field of Global Health?

We need more clinical trials in the world''s poorest regions to evaluate new drugs and vaccines, and also to find better ways to manage health issues. Clinical trials are expensive, time consuming, and cumbersome. However, in wealthier regions these limiting factors are being addressed to make trials less administrative and improve the designs. A good example is adaptive trial design. This innovation is becoming accepted by the regulators and has been taken up by the pharmaceutical industry to reduce product development times and costs. If this approach makes trials easier and less expensive surely we should be implementing this approach in the field of tropical medicine and international health? As yet this has rarely been proposed and there are few examples. There is a need for raising the awareness of these design approaches because they could be used to make dramatic improvements to clinical research in developing countries.     

Bronchodilators in Heart Failure Patients With COPD: Is It Time for a Clinical Trial?

Chronic heart failure (HF) and chronic obstructive pulmonary disease (COPD) commonly coexist, and patients with both diseases fare worse than those with either disease alone. Several factors may contribute to worse outcomes, including an increased burden of care related to greater disease complexity, an overlap of symptoms resulting in misapplication of therapy, and the adverse effects of treatment for one disease on the symptoms and outcomes related to the other. For example, there are conflicting data about the cardiovascular risks of bronchodilators in HF patients who may experience worse outcomes with inhaled beta-2 agonists via arrhythmogenesis, ischemia, and/or attenuation of beta-blocker benefits. In contrast, the long-acting anticholinergic class of bronchodilators has a more reassuring safety profile. Anticholinergic bronchodilators may be the preferred first-line agents for COPD patients with comorbid HF, yet data supporting these recommendations are limited. Therapeutic trials in COPD patients have generally excluded patients with significant HF and vice-versa. This paper reviews bronchodilator therapy in HF and proposes a randomized trial designed to enroll patients with significant COPD and HF to determine the risks and/or benefits of adding a long-acting beta-2 agonist to patients currently taking a long-acting anticholinergic agent.     

The Impact of the ISCHEMIA Trial on Clinical Practice: an Interventionist’s Perspective

Cardiovascular Drugs and Therapy - The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial is the latest in a series of studies evaluating...     

OPPORTUNITY?: A Randomized Clinical Trial of Growth Hormone on Outcome in Hemodialysis Patients

Background: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY™ Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients.Hypothesis: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile.Design/Measurements: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 μg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V ≥1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy.Conclusions: The OPPORTUNITY™ Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.Adult end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (MHD) experience high mortality and morbidity with diminished quality of life (1,2). Death and hospitalization rates in MHD patients correlate strongly with indicators of low protein mass, as indicated by low serum albumin and decreased fat-free, edema-free body mass (i.e., lean body mass [LBM]), as well as chronic inflammation (3,4). This is an important association because protein-energy wasting (PEW) occurs in approximately 40% of MHD patients (5). The possibility that improved measures of PEW may lead to decreased mortality or morbidity was recently underscored by several cross-sectional and longitudinal evaluations of cohorts containing up to 58,000 MHD patients who were followed for up to 2 yr. These studies showed that both higher serum albumin and body weight and an increase in these measures are strongly associated with greater survival (6,7). However, there are no prospective, randomized, clinical trials (RCTs) that have confirmed or even assessed whether a pharmacologic intervention that improves indicators of PEW prolongs survival and/or reduces morbidity, including hospitalization, in MHD patients. Thus, major unmet medical needs and important questions exist concerning whether PEW causes mortality and morbidity in MHD patients and whether a treatment that reduces PEW will reduce their high mortality and morbidity.Growth hormone (GH) has extensive metabolic and, in particular, protein anabolic effects (8), a number of which have also been demonstrated in MHD or chronic peritoneal dialysis patients (9–23). Most of these studies were performed on small numbers of patients. A recent phase 2 RCT involving 139 MHD patients indicated that the GH-treated patients underwent improvement in LBM, serum transferrin, exercise capacity, and a tendency (P = 0.076) for serum albumin to rise (9). Based on these data, a decision was made to conduct a more definitive prospective RCT in hypoalbuminemic MHD patients.     

Assessing Adherence in the CAPRISA 004 Tenofovir Gel HIV Prevention Trial: Results of a Nested Case–Control Study

Adherence undeniably impacts product effectiveness in microbicide trials, but the connection has proven challenging to quantify using routinely collected behavioral data. We explored this relationship using a nested case–control study in the CAPRISA 004 Tenofovir (TFV) gel HIV prevention trial. Detailed 3-month recall data on sex events, condom and gel use were collected from 72 incident cases and 205 uninfected controls. We then assessed how the relationship between self-reported adherence and HIV acquisition differed between the TFV and placebo gel groups, an interaction effect that should exist if effectiveness increases with adherence. The CAPRISA 004 trial determined that randomization to TFV gel was associated with a significant reduction in risk of HIV acquisition. In our nested case–control study, however, we did not observe a meaningful decrease in the relative odds of infection—TFV versus placebo—as self-reported adherence increased. To the contrary, exploratory sub-group analysis of the case–control data identified greater evidence for a protective effect of TFV gel among participants reporting less than 80 % adherence to the protocol-defined regimen (odds ratio (OR) 0.30; 95 % CI 0.11–0.78) than among those reporting ≥80 % adherence (Odds Ratio 0.81; 95 % CI 0.34–1.92). The small number of cases may have inhibited our ability to detect the hypothesized interaction between adherence and effectiveness. Nonetheless, our results re-emphasize the challenges faced by investigators when adherence may be miss-measured, miss-reported, or confounded with the risk of HIV.