Clinical Trials

Background In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest. However, the subgroup analysis required to investigate such associations remains controversial. Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredging.

Purpose As an alternative to hypothesis testing, the use of shrinkage estimation techniques is investigated in the context of an exploratory post hoc subgroup analysis. A range of models that have been suggested in the literature are reviewed. Building on this, we explore a general modeling strategy, considering various options for shrinkage of effect estimates. This is applied to a case-study, in which evidence was available from seven-phase II–III clinical trials examining a novel therapy, and also to two artificial datasets with the same structure.

Methods Emphasis is placed on hierarchical modeling techniques, adopted within a Bayesian framework using freely available software. A range of possible subgroup model structures are applied, each incorporating shrinkage estimation techniques.

Results The investigation of the case-study showed little evidence of subgroup effects. Because inferences appeared to be consistent across a range of well-supported models, and model diagnostic checks showed no obvious problems, it seemed this conclusion was robust. It is reassuring that the structured shrinkage techniques appeared to work well in a situation where deeper inspection of the data suggested little evidence of subgroup effects.

Limitations The post hoc examination of subgroups should be seen as an exploratory analysis, used to help make better informed decisions regarding potential future studies examining specific subgroups. To a certain extent, the degree of understanding provided by such assessments will be limited by the quality and quantity of available data.

Conclusions In light of recent interest by health authorities into the use of subgroup analysis in the context of drug development, it appears that Bayesian approaches involving shrinkage techniques could play an important role in this area. Hopefully, the developments outlined here provide useful methodology for tackling such a problem, in-turn leading to better informed decisions regarding subgroups.

Background Randomized controlled trials (RCTs) for the prevention of HIV heterosexual acquisition are usually conducted among adult African populations with high heterogeneity in individual risk of infection.

Purpose The objectives were to (a) review how this heterogeneity has been considered when designing and interpreting such RCTs, (b) evaluate its effect on the findings and the statistical power of these trials, and (c) assess the potential advantages of using the crossover design with single failure-time endpoint.

Methods Individual-level HIV prevention RCTs conducted in Africa and published in the period 1998–2008 were reviewed. Using Monte Carlo simulations and statistical calculations, we assessed the effect of heterogeneity on the findings and the statistical power of HIV prevention RCTs.

Results All reviewed RCTs used the parallel design. The heterogeneity in individual risk of infection within study sites was not used for stratification nor generally considered in the design and interpretation of RCTs. Simulations showed that in the context of high HIV incidence, high heterogeneity can lead to a substantial underestimation of the impact of an intervention and reduced statistical power. Calculations demonstrated that the crossover design allowed for similar or better estimation and statistical power. The crossover design has the ethical advantage of sharing the potential benefits and risks of the intervention between participants.

Limitations Only trials with two treatment arms and two follow-up periods were modeled. The baseline risk of infection of each participant was assumed to be constant over time and HIV status was assessed at the end of each follow-up period.

Conclusions The heterogeneity in individual risk of HIV infection is an underestimated problem which should be taken into account when designing and interpreting RCTs that test prevention methods of HIV heterosexual acquisition in adult African populations with high HIV incidence. When the effects of tested interventions are rapidly reversible, the use of the crossover design should be considered.

Background Objective measures are needed to quantify dietary adherence during caloric restriction (CR) while participants are freeliving. One method to monitor adherence is to compare observed weight loss to the expected weight loss during a prescribed level of CR. Normograms (graphs) of expected weight loss can be created from mathematical modeling of weight change to a given level of CR, conditional on the individual’s set of baseline characteristics. These normograms can then be used by counselors to help the participant adhere to their caloric target.

Purpose (1) To develop models of weight loss over a year of caloric restriction-given demographics, and well-defined measurements of body mass index, total daily energy expenditure (TDEE) and %CR. (2) To utilize these models to develop normograms, given the level of caloric restriction prescribed, and measures of these variables.

Methods Seventy-seven individuals completing a 6–12-month caloric restriction intervention (CALERIE) at three sites (Pennington Biomedical Research Center, Tufts University, and Washington University) and had body weight and body composition measured frequently. Energy intake (and %CR) was estimated from TDEE (by doubly labeled water) and body composition (by DXA) at baseline and months 1, 3, 6, and 12. Bodyweight was modeled to determine the predictors and distribution of the expected trajectory of percent weight change over 12 months of CR.

Results As expected, CR was related to change in body weight. Controlling for time-varying measures, initially simple models of the functional form indicated that the trajectory of percent weight change was predicted by a nonlinear function of age, TDEE, %CR, and sex. Using these estimates, normograms for the weight change were developed. Our model estimates that the mean weight loss (% change from baseline weight) for an individual adherent to a 25% CR regimen is −10.9 ± 6.3% for females and −13.9 + 6.4% for men after 12 months.

Limitations There are several limitations. Sample sizes are small (n = 77), and, by design, the protocols, including prescribed CR, for the interventions differed by site, and not all subjects completed a year of follow-up. In addition, the inclusion of subjects by age and initial BMI was constricted, so that these results may not generalize to other populations including older and obese subjects.

Conclusions The trajectory of percent weight change during CR interventions in the presence of well-measured covariates can be modeled using simple nonlinear functions, and is related level of CR, the percent change in TDEE, gender, and age. Displayed on a normogram, individually tailored trajectories can be used by counselors and participants to monitor weight loss and adherence to a CR regimen.

Background Chronic kidney disease is associated with a marked increase in risk for left ventricular hypertrophy and cardiovascular mortality compared with the general population. Therapy with vitamin D receptor activators has been linked with reduced mortality in chronic kidney disease and an improvement in left ventricular hypertrophy in animal studies.

Purpose PRIMO (Paricalcitol capsules benefits in Renal failure Induced cardia MOrbidity) is a multinational, multicenter randomized controlled trial to assess the effects of paricalcitol (a selective vitamin D receptor activator) on mild to moderate left ventricular hypertrophy in patients with chronic kidney disease.

Methods Subjects with mild-moderate chronic kidney disease are randomized to paricalcitol or placebo after confirming left ventricular hypertrophy using a cardiac echocardiogram. Cardiac magnetic resonance imaging is then used to assess left ventricular mass index at baseline, 24 and 48 weeks, which is the primary efficacy endpoint of the study. Because of limited prior data to estimate sample size, a maximum information group sequential design with sample size re-estimation is implemented to allow sample size adjustment based on the nuisance parameter estimated using the interim data. An interim efficacy analysis is planned at a pre-specified time point conditioned on the status of enrollment. The decision to increase sample size depends on the observed treatment effect. A repeated measures analysis model, using available data at Week 24 and 48 with a backup model of an ANCOVA analyzing change from baseline to the final nonmissing observation, are pre-specified to evaluate the treatment effect. Gamma-family of spending function is employed to control family-wise Type I error rate as stopping for success is planned in the interim efficacy analysis.

Limitations If enrollment is slower than anticipated, the smaller sample size used in the interim efficacy analysis and the greater percent of missing week 48 data might decrease the parameter estimation accuracy, either for the nuisance parameter or for the treatment effect, which might in turn affect the interim decision-making.

Conclusions The application of combining a group sequential design with a sample-size re-estimation in clinical trial design has the potential to improve efficiency and to increase the probability of trial success while ensuring integrity of the study.

Background In 2009, the Safety Planning, Evaluation and Reporting Team gave detailed recommendations for a well-planned and systematic approach for safety data collection and analysis. Important aspects of this approach included regular reviews of aggregate data by a multidisciplinary team focusing on safety.

Purpose This article provides information to facilitate the planning and implementation of aggregate data reviews.

Methods Our recommendations are based on experience of the authors and review of relevant literature.

Results We present information regarding the planning of aggregate data reviews as well as examples of data displays that are useful for many different compounds. A subset of these data displays could form a set of ‘core’ analyses to be generated for aggregate data reviews.

Background Clinical trials are widely considered the gold standard in comparative effectiveness research (CER) but the high cost and complexity of traditional trials and concerns about generalizability to broad patient populations and general clinical practice limit their appeal. Unsuccessful implementation of CER results limits the value of even the highest quality trials. Planning for a trial comparing two standard strategies of insulin administration for hospitalized patients led us to develop a new method for a clinical trial designed to be embedded directly into the clinical care setting thereby lowering the cost, increasing the pragmatic nature of the overall trial, strengthening implementation, and creating an integrated environment of research-based care.

Purpose We describe a novel randomized clinical trial that uses the informatics and statistics infrastructure of the Veterans Affairs Healthcare System (VA) to illustrate one key component (called the point-of-care clinical trial – POC-CT) of a ‘learning healthcare system,’ and settles a clinical question of interest to the VA.

Methods This study is an open-label, randomized trial comparing sliding scale regular insulin to a weight-based regimen for control of hyperglycemia, using the primary outcome length of stay, in non-ICU inpatients within the northeast region of the VA. All non-ICU patients who require in-hospital insulin therapy are eligible for the trial, and the VA’s automated systems will be used to assess eligibility and present the possibility of randomization to the clinician at the point of care. Clinicians will indicate their approval for informed consent to be obtained by study staff. Adaptive randomization will assign up to 3000 patients, preferentially to the currently ‘winning’ strategy, and all care will proceed according to usual practices. Based on a Bayesian stopping rule, the study has acceptable frequentist operating characteristics (Type I error 6%, power 86%) against a 12% reduction of median length of stay from 5 to 4.4 days. The adaptive stopping rule promotes implementation of a successful treatment strategy.

Limitations Despite clinical equipoise, individual healthcare providers may have strong treatment preferences that jeopardize the success and implementation of the trial design, leading to low rates of randomization. Unblinded treatment assignment may bias results. In addition, generalization of clinical results to other healthcare systems may be limited by differences in patient population. Generalizability of the POC-CT method depends on the level of informatics and statistics infrastructure available to a healthcare system.

Conclusions The methods proposed will demonstrate outcome-based evaluation of control of hyperglycemia in hospitalized veterans. By institutionalizing a process of statistically sound and efficient learning, and by integrating that learning with automatic implementation of best practice, the participating VA Healthcare Systems will accelerate improvements in the effectiveness of care.

Background The introduction of antipsychotic medication has been a major advance in the treatment of schizophrenia and allows millions of people to live outside of institutions. It is generally believed that long-acting intramuscular antipsychotic medication is the most effective approach to increasing medication adherence and thereby reduce relapse in high-risk patients with schizophrenia, but the data are scant.

Purpose To report the design of a study to assess the effect of long-acting injectable risperidone in unstable patients and under more realistic conditions than previously studied and to evaluate the effect of this medication on psychiatric inpatient hospitalization, schizophrenia symptoms, quality of life, medication adherence, side effects, and health care costs.

Methods The trial was an open randomized clinical comparative effectiveness trial in patients with schizophrenia or schizo-affective disorders in which parenteral risperidone was compared to an oral antipsychotic regimen selected by each control patient’s psychiatrist. Participants had unstable psychiatric disease defined by recent hospitalization or exhibition of unusual need for psychiatric services. The primary endpoint was hospitalization for psychiatric indications; the secondary endpoint was psychiatric symptoms.

Results Overall, 382 patients were randomized. Determination of a persons’ competency to understand the elements of informed consent was addressed. The use of a closed-circuit TV interview for psychosocial measures provided an economical, high quality, reliable means of collecting data. A unique method for insuring that usual care was optimal was incorporated in the follow-up of all subjects.

Limitations Patients with schizophrenia or schizo-affective disorders and with the common co-morbid illnesses seen in the VA are a challenging group of subjects to study in long-term trials. Some techniques unique in the VA and found useful may not be generalizable or applicable in other research or treatment settings.

Conclusions The trial tested a new antipsychotic medication early in its adoption in the Veterans Health Administration. The VA has a unique electronic medical record and database which can be used to identify the endpoint, that is, first hospitalization due to a psychiatric problem, with complete ascertainment. Several methodologic solutions addressed competency to understand elements of consent, the costs and reliability of collecting interview data gathering, and insuring usual care.

Background Matriculation from high school to college is typified by an increase in alcohol use and related harm for many students. Therefore, this transition period is an ideal time for preventive interventions to target alcohol use and related problems.

Purpose The purpose of this report is to describe the design and methods used in the Transitions Project, a randomized controlled trial of two interventions designed to prevent and reduce heavy episodic drinking and alcohol-related negative consequences among incoming college students.

Methods This study used a 2 × 2 factorial design to investigate the effects of a two-session brief motivational intervention delivered to students and a handbook-based parent intervention. Interventions were administered to students and parents. Follow-up assessment took place at 10- and 22-months post-baseline.

Results The Transitions Project successfully recruited and retained participants across a major transition period (i.e., entering college), administered and compared two distinct but complementary interventions, and collected and analyzed highly skewed data. The application of a factorial design and two-part latent growth curve modeling allowed us to examine main and interactive intervention effects in terms of both initiation and growth in heavy drinking and alcohol-related problems.

Limitations While we conducted successful tests of our primary and secondary study hypotheses over a lengthy follow-up period, our study design did not permit full interpretation of null findings. We suggest that researchers carefully consider assessment timing, tests of assessment reactivity, and ensure objective tests of intervention efficacy when conducting clinical trials of motivational interventions.

Conclusions The lessons we learned while conducting this trial have the potential to assist other researchers designing and conducting future preventive interventions targeting parents and college students. The data analytic procedures presented can also help guide trials that plan to analyze zero-inflated non-normal outcome data.

Background To promote results in the National Lung Screening Trial (NLST) that are generalizable across the entire US population, a subset of NLST sites developed dedicated strategies for minority recruitment.

Purpose To report the effects of targeted strategies on the accrual of underrepresented groups, to describe participant characteristics, and to estimate the costs of targeted enrollment.

Methods The 2002–2004 Tobacco Use Supplement was used to estimate eligible proportions of racial and ethnic categories. Strategic planning included meetings/conferences with key stakeholders and minority organizations. Potential institutions were selected based upon regional racial/ethnic diversity and proven success in recruitment of underrepresented groups. Seven institutions submitted targeted recruitment strategies with budgets. Accrual by racial/ethnic category was tracked for each institution. Cost estimates were based on itemized receipts for minority strategies relative to minority accrual.

Results Of 18,842 participants enrolled, 1576 (8.4%) were minority participants. The seven institutions with targeted recruitment strategies accounted for 1223 (77.6%) of all minority participants enrolled. While there was a significant increase in the rate of minority accrual pre-implementation to post-implementation for the institutions with targeted recruitment (9.3% vs. 15.2%, p < 0.0001), there was no significant difference for the institutions without (3.5% vs. 3.8%, p = 0.46). Minority enrollees at the seven institutions tended to have less than a high school education, be economically disadvantaged, and were more often uninsured. These socio-demographic differences persisted at the seven institutions even after adjusting for race and ethnicity. The success of different strategies varied by institution, and no one strategy was successful across all institutions. Costs for implementation were also highly variable, ranging from $146 to $749 per minority enrollee.

Limitations Data on minority recruitment processes were not consistently kept at the individual institutions. In addition, participant responses via newspaper advertisements and the efforts of minority staff hired by the institutions could not be coded on Case Report Forms.

Conclusions Strategic efforts were associated with significant increases in minority enrollment. The greatest successes require that a priori goals be established based on eligible racial/ethnic proportions; the historical performance of sites in minority accrual should factor into the selection of sites; recruitment planning must begin well in advance of trial launch; and there must be endorsement by prominent representatives of the racial groups of interest.