Multistage designs for vaccine safety studies.

In a placebo-controlled vaccine safety trial, the primary interest is to demonstrate that the vaccine is sufficiently safe, rejecting the null hypothesis that the relative risk of an adverse event attributable to the vaccine is above a prespecified value, greater than one. We develop sequential as well as multistage designs for such trials where the interim analyses are conducted not after a given number of subjects but rather after a given number of events observed. We show that these designs achieve significant improvement over single-stage conditional test in terms of both the required number of events to be observed and the required number of subjects to be enrolled.

Estimation of the combined response to treatment in multicenter trials.

Analyses of multicenter trials consider the estimated treatment effect differences of the individual centers and combine them into an estimate of the overall treatment effect. There has been much debate in the literature concerning the best way to combine these treatment effect differences. We emphasize that first of all one should define the combined response to treatment (CRT), the object that has to be estimated from the results of a multicenter clinical trial. It is shown that the choice of CRT determines not only the best estimator, but also the allocation of patients among the centers that minimizes the mean squared error. A new estimator of the CRT is proposed that is based on a preliminary clustering of the centers and the use of a weighted average of the Type I estimators obtained from within each cluster. The clustering aims to minimize the bias of the combined estimator. We show via a simulation study that the simple clustering procedure provides a reasonably improved estimator. The clustering can be done on blinded data, as long as the numbers of patients on each treatment arm in each center are known. The methodology is illustrated by analyzing a multicountry, multicenter trial to compare an active treatment with placebo for the treatment of a psychiatric disorder.

Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study.

BACKGROUND: Hot flashes are the most frequently reported side effect of tamoxifen treatment. Although hormones are an effective treatment, their safety is questionable in women with breast cancer. It is therefore important to evaluate nonhormonal treatments for hot flashes. OBJECTIVE: To evaluate the effectiveness of oral clonidine for control of hot flashes associated with tamoxifen therapy in postmenopausal women with breast cancer. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: University of Rochester Cancer Center Community Clinical Oncology Program. PATIENTS: 194 postmenopausal women with breast cancer who were receiving adjuvant tamoxifen therapy. INTERVENTION: Oral clonidine hydrochloride, 0.1 mg/d, or placebo for 8 weeks. MEASUREMENTS: In a daily diary, patients recorded number, duration, and severity of hot flashes and overall quality-of-life score (on a 10-point scale) during a 1-week baseline period and during the 4th, 8th, and 12th weeks of the study. RESULTS: Patients in the placebo and treatment groups were similar in age, duration of tamoxifen use, reported frequency and duration of hot flashes at baseline, and dropout rates. One hundred forty-nine patients completed 12 weeks of follow-up. The mean decrease in hot flash frequency was greater in the clonidine group than in the placebo group after 4 weeks of treatment (37% compared with 20% [95% CI for difference, 7% to 27%]) and 8 weeks of treatment (38% compared with 24% [CI for difference, 3% to 27%]). Patients receiving clonidine were more likely than patients receiving placebo to report difficulty sleeping (41% compared with 21%; P = 0.02). A significant difference was seen in the mean change in quality-of-life scores (0.3 points in the clonidine group compared with -0.2 points in the placebo group; P = 0.02) at 8 weeks, although the median difference was 0 in both groups. CONCLUSION: Oral clonidine, 0.1 mg/d, is effective against tamoxifen-induced hot flashes in postmenopausal women with breast cancer.

Variables influencing penicillin treatment outcome in streptococcal tonsillopharyngitis.

OBJECTIVE: To examine whether penicillin treatment success for group A beta-hemolytic streptococcal tonsillopharyngitis is influenced by patient age, number of days ill prior to initiation of treatment, number of prior episodes, season, total dosage (milligrams per kilogram), and frequency of administration (2 vs 3 times daily). METHODS: Four hundred seventy-eight children, adolescents, and young adults aged 2 to 21 years with acute symptoms compatible with the clinical diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis and a positive streptococcus rapid antigen detection test result were enrolled (intent-to-treat group). Patients were randomly assigned to receive penicillin V potassium, 250 mg 3 times daily (n = 239) or 500 mg 2 times daily (n = 239). Randomization was independent of patient body weight and treatment was for 10 days with both regimens. Follow-up examinations occurred, and cultures were obtained at 14 to 21 days after the initiation of antibiotic therapy; those with group A beta-hemolytic streptococcus isolated from a throat culture and who returned for follow-up were assessed for outcome (n = 359). RESULTS: Using a logistic regression analysis with a stepwise variable selection, we found the major variables associated with penicillin treatment success to be the number of days ill prior to initiation of treatment (P = .001; odds ratio, 1.55 [95% confidence interval, 1.2-2.1]) and the age of the child when infected (P = .004; odds ratio, 1.14 [95% confidence interval, 1.05-1.25]). The number of prior episodes within the preceding year, the season, the total daily penicillin dose (range, 8-76 mg/kg), and 2 vs 3 times daily dosing did not significantly alter treatment outcome. CONCLUSION: Treatment after 2 days of illness and of adolescent patients increases penicillin treatment success for group A beta-hemolytic streptococcal tonsillopharyngitis.