Janet Wittes

THE EFFECT OF SPIRONOLACTONE ON MORBIDITY AND MORTALITY IN PATIENTS WITH SEVERE HEART FAILURE

BACKGROUND AND METHODS Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. RESULTS The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients. CONCLUSIONS Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

Blood Stage Malaria Vaccine Eliciting High Antigen-Specific Antibody Concentrations Confers No Protection to Young Children in Western Kenya

Objective The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccines safety, immunogenicity, and efficacy in African children. Methods A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12–47 months in general good health.Children were randomised in a 1∶1 fashion to receive either FMP1/AS02 (50 µg) or Rabipur® rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature ≥37.5°C with asexual parasitaemia of ≥50,000 parasites/µL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations. Results 374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-142 antibody concentrations increased from1.3 µg/mL to 27.3 µg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: −26% to +28%; p-value = 0.7). Conclusions FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-142 vaccine development should focus on other formulations and antigen constructs. Trial Registration Clinicaltrials.gov NCT00223990

Efficacy of Recombinant Circumsporozoite Protein Vaccine Regimens against Experimental Plasmodium falciparum Malaria

After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups. Of the 41 vaccinees and 23 control subjects who underwent sporozoite challenge, malaria developed in 7 of 10 who received 1 dose, in 7 of 14 who received 2 doses, in 3 of 6 who received 3 standard doses, in 3 of 7 who received 3 one-half doses, in 3 of 4 who received 3 one-fifth doses, and in 22 of 23 control subjects. Overall protective efficacy of RTS,S/SBAS2 was 41% (95% confidence interval, 22%-56%; P=.0006). This and previous studies have shown that 2 or 3 doses of RTS,S/SBAS2 protect against challenge with P. falciparum sporozoites.

Birth Order, Family Size and School Failure

The effect of birth order on educational outcome in the Netherlands is reported for two major social classes, manual and non‐manual. The rates of school failure (those who attended schools for the mentally retarded and who failed lower school) were studied in a population of some 200,000 young adult Dutch males born between 1944 and 1946 and whose families of origin had from one to six children. The data used were the records of the Dutch military pre‐induction examination.

The estimation of false negatives in medical screening.

In a medical screening program for early detection of disease, one or more screening modes are administered to an apparently healthy population. Knowledge of the true disease status for all screened individuals would allow estimation of the false negative and false positive rates for each mode of detection and for the program as a whole. This paper develops capture-recapture methods applicable to programs as a whole. This paper develops capture-recapture methods applicable to programs when follow-up of individuals negative on screening is not performed or is incomplete. The methods require at least two independent modes of detection. Data from a breast cancer screening program illustrate the procedure. The results of four screening examinations at approximately one-year intervals and the long-term follow-up of all screened individuals support the usefulness of these methods in the evaluation of a screening program.

Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop:

Background The clinical trials community has a never-ending search for dependable and reliable ways to improve clinical research. This exploration has led to considerable interest in adaptive clinical trial designs, which provide the flexibility to adjust trial characteristics on the basis of data reviewed at interim stages. Statisticians and clinical investigators have proposed or implemented a wide variety of adaptations in clinical trials, but specific approaches have met with differing levels of support. Within industry, investigators are actively exploring the benefits and pitfalls associated with adaptive designs (ADs). For example, a Drug Information Association (DIA) working group on ADs has engaged regulatory agencies in discussions. Many researchers working on publicly funded clinical trials, however, are not yet fully engaged in this discussion. We organized the Scientific Advances in Adaptive Clinical Trial Designs Workshop to begin a conversation about using ADs in publicly funded research. Held in November of 2009, the 1½-day workshop brought together representatives from the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the European Medicines Agency (EMA), the pharmaceutical industry, nonprofit foundations, the patient advocacy community, and academia. The workshop offered a forum for participants to address issues of ADs that arise at the planning, designing, and execution stages of clinical trials, and to hear the perspectives of influential members of the clinical trials community. The participants also set forth recommendations for guiding action to promote the appropriate use of ADs. These recommendations have since been presented, discussed, and vetted in a number of venues including the University of Pennsylvania Conference on Statistical Issues in Clinical Trials and the Society for Clinical Trials annual meeting. Purpose To provide a brief overview of ADs, describe the rationale behind conducting the workshop, and summarize the main recommendations that were produced as a result of this workshop. Conclusions There is a growing interest in the use of adaptive clinical trial designs. However, a number of logistical barriers need to be addressed in order to obtain the potential advantages of an AD. Currently, the pharmaceutical industry is well ahead of academic trialists with respect to addressing these barriers. Academic trialists will need to address important issues such as education, infrastructure, modifications to existing funding models, and the impact on Data and Safety Monitoring Boards (DSMB) in order to achieve the possible benefits of adaptive clinical trial designs.

Combination chemotherapy in metastatic malignant melanoma. A randomized study of three DTIC-containing combinations

The activity of three DTIC‐containing combinations was compared in a prospective randomized study. Of 101 patients randomized to receive one of the three regimens, 95 received adequate trials. Response rates were as follows: DTIC+cyclophosphamide 7/29 (24%); DTIC+vinblastine 6/34 (18%); DTIC+procarbazine 4/32 (13%). None of these response rates is significantly superior to any of the others. When the activity of the combination is analyzed by sex, DTIC+cyclophosphamide appears more active in females than the other regimens, but the difference is not statistically significant. Response to treatment is associated with significant prolongation of life; the median survival among responders was 11 months, while those who progressed lived a median of 4 months from the start of therapy. Toxicity of all regimens appeared to be about the same; therapy with DTIC+procarbazine was associated with significantly more nausea and vomiting. This study has failed to demonstrate clearly that any of three combinations is superior to any of the others.

Some practical problems in implementing randomization

Background While often theoretically simple, implementing randomization to treatment in a masked, but confirmable, fashion can prove difficult in practice. Purpose At least three categories of problems occur in randomization: (1) bad judgment in the choice of method, (2) design and programming errors in implementing the method, and (3) human error during the conduct of the trial. This article focuses on these latter two types of errors, dealing operationally with what can go wrong after trial designers have selected the allocation method. Results We offer several case studies and corresponding recommendations for lessening the frequency of problems in allocating treatment or for mitigating the consequences of errors. Recommendations include: (1) reviewing the randomization schedule before starting a trial, (2) being especially cautious of systems that use on-demand random number generators, (3) drafting unambiguous randomization specifications, (4) performing thorough testing before entering a randomization system into production, (5) maintaining a dataset that captures the values investigators used to randomize participants, thereby allowing the process of treatment allocation to be reproduced and verified, (6) resisting the urge to correct errors that occur in individual treatment assignments, (7) preventing inadvertent unmasking to treatment assignments in kit allocations, and (8) checking a sample of study drug kits to allow detection of errors in drug packaging and labeling. Limitations Although we performed a literature search of documented randomization errors, the examples that we provide and the resultant recommendations are based largely on our own experience in industry-sponsored clinical trials. We do not know how representative our experience is or how common errors of the type we have seen occur. Conclusions Our experience underscores the importance of verifying the integrity of the treatment allocation process before and during a trial. Clinical Trials 2010; 7: 235—245. http://ctj.sagepub.com

Correlates, Surrogates, and Vaccines

Knowledge concerning vaccine-induced immune responses related to vaccine-induced protection from disease is often extraordinarily helpful throughout vaccine development. Immune responses in early preclinical experiments may guide decisions concerning choice of antigen, broadness of coverage, and delivery systems. In preclinical development, despite the often uncertain relationships between animal and human responses, immunogenicity in animals can guide early process development, provide some confidence in the rapidly expanding investment decisions required, and serve as a component of vaccine release for clinical studies. In humans, safety assessments and immune responses, the only outcomes the extensive clinical development program provides before phase 2 and phase 3 efficacy trials, are generally essential to go/no-go decisions for such trials. For manufacturing, immune responses provide evidence of a likely satisfactory transition between early process development and final scale-up, and they help demonstrate the consistency of the final manufacturing process through testing of consecutive lots in humans. They serve as end points for end-expiry stability studies, in which safety determines the highest dose acceptable for release and immunogenicity generally determines when the vaccine’s potency has declined to an unacceptable level. During and after licensure, immune responses allow generalization to popula

Blinded subjective rankings as a method of assessing treatment effect : A large sample example from the Systolic Hypertension in the Elderly Program (SHEP)

Because many randomized clinical trials study more than one important outcome variable, evaluation of efficacy is often difficult and not completely satisfactory. This paper considers the use of a procedure for endpoint determination described by Follmann et al., that allows raters to integrate subjectively all relevant information about an individuals clinical course into a single univariate assessment. To explore the methods feasibility, we tested the procedure with data from a completed clinical trial, the Systolic Hypertension in the Elderly Program (SHEP). We provided raters blinded to treatment assignment with cards that schematically represent the clinical trajectories of SHEP study participants. The raters independently ranked these trajectories. The method combined ranks across raters to determine a single rank for each study participant; we used a rank procedure to test treatment effect. The major findings were: (i) the raters showed a high level of concordance of rankings; (ii) tests of treatment effect were highly statistically significant; (iii) three statistical methods were effective for implementing the ranking in the large study size case. These methods were use of: (a) scoring rules; (b) incomplete block designs, and (c) categorical ranking.