Roy N. Tamura

Fluoxetine treatment for obsessive-compulsive disorder in children and adolescents : A placebo-controlled clinical trial

OBJECTIVE This study assesses the efficacy and tolerability of fluoxetine in the acute treatment of child and adolescent obsessive-compulsive disorder (OCD) during a 13-week, double-blind, placebo-controlled study. METHOD Eligible patients aged 7 to 17 (N = 103) were randomized at a ratio of 2:1 to receive either fluoxetine or placebo. Dosing was initiated at 10 mg daily for 2 weeks, then increased to 20 mg daily. After 4 weeks of treatment, and again after 7 weeks of treatment, non-responders could have their dosage increased by 20 mg daily, for a maximum possible dosage of 60 mg daily. Primary measure of efficacy was improvement in OCD symptoms as measured by the Childrens Yale-Brown Obsessive Compulsive Scale (CY-BOCS). All analyses were intent-to-treat. RESULTS Fluoxetine was associated with significantly greater improvement in OCD as assessed by the CY-BOCS (p = .026) and other measures than was placebo. Fluoxetine was well tolerated and had a rate of discontinuation for adverse events similar to that of placebo (p = 1.00). CONCLUSIONS Fluoxetine 20 to 60 mg daily was effective and well tolerated for treatment of OCD in this pediatric population.

A Case Study of an Adaptive Clinical Trial in the Treatment of Out-Patients with Depressive Disorder

Abstract Adaptive clinical trials have attracted the attention of statisticians because they allow for information accrued early in the trial to influence the allocation of treatment of later enrolled patients, thus allowing those patients an increased likelihood of receiving the better treatment. Few adaptive clinical trials have been reported in the literature; the purpose of this article is to describe the rationale, design, and analysis of a recently completed adaptive trial. Simulations to address sample size issues are presented. A Bayesian and a frequentist randomization analysis are discussed. The randomization analysis addresses the use of an adaptive allocation scheme, a delayed response, and a surrogate response. In this trial, the differences between the Bayesian and randomization inference were small. Some suggestions for future implementation of adaptive clinical trials and future research areas are provided.

Minimum Hellinger Distance Estimation for Multivariate Location and Covariance

Abstract The Hellinger distance between a nonparametric density estimator and a model family is minimized to produce estimates of location and covariance in multivariate data. With suitable restrictions on the density estimators and the model family, these minimum Hellinger distance estimators (MHDEs) are shown to be affine invariant, consistent, and asymptotically normal. The robustness of the MHDE as measured by the breakdown point compares favorably against the previously studied M-estimators. Monte Carlo results suggest that the MHDEs are an attractive robust alternative to the usual sample means and covariance matrix.

A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis.

Abstract Our objective was to determine if chronic treatment with the non-competitive AMPA antagonist talampanel is efficacious and safe in subjects with ALS. A double-blind, placebo-controlled, multicenter, randomized clinical trial of nine months treatment duration was conducted in 59 subjects with ALS, with 40 subjects receiving talampanel 50 mg p.o. t.i.d, and 19 subjects receiving placebo. Primary outcome measure was rate of decline in isometric arm strength (as measured by change in arm strength megaslope of the Tufts Quantitative Neuromuscular Exam (TQNE)). Other efficacy endpoints included rate of decline in respiratory function, isometric leg strength, bulbar function, fine motor function, the ALS Functional Rating Scale (ALSFRS), and survival. Secondary safety outcome measures were frequency of adverse events, neurological status, plasma concentration of talampanel, vital signs, routine laboratory tests, and electrocardiograms. Decline in muscle strength was 15% less in talampanel treated subjects, and decline in ALSFRS was 30% slower in talampanel treated subjects. Talampanel was safe in subjects with ALS. Mortality rates (8% talampanel, 5% placebo) and drug discontinuation rates (25% talampanel, 16% placebo) were similar in active treatment and placebo groups. Dizziness and somnolence occurred significantly more often in talampanel treated subjects. Although no efficacy measure reached statistical significance, there was a repeated trend toward slower decline in ALSFRS and isometric muscle strength in talampanel treated subjects. Talampanel was well tolerated in subjects with ALS. Although certain adverse events occurred more frequently in the active treatment group, the rate of subject drop-out after nine months did not exceed that seen in other trials. These findings provide strong support for a phase III trial to determine the efficacy of talampanel in subjects with ALS.

Functional Outcomes in the Treatment of Adults With ADHD

Objective: ADHD is associated with significant functional impairment in adults. The present study examined functional outcomes following 6-month double-blind treatment with either atomoxetine or placebo. Method: Patients were 410 adults (58.5% male) with DSM-IV—defined ADHD. They were randomly assigned to receive either atomoxetine 40 mg/day to 80 mg/day (n = 271) or placebo (n = 139). The primary functional outcome measure was the Endicott Work Productivity Scale (EWPS), and the secondary measure was the Adult ADHD Quality of Life (AAQoL). Patients were seen for four visits in 6 months. Results: At 6 months, both groups had nonsignificantly different improvements in EWPS total scores. Atomoxetine-treated patients showed significantly greater improvement than placebo-treated patients on the AAQoL after controlling for baseline severity of ADHD. Both treatment groups had low 6-month study completion rates. Conclusion: Following 6-month treatment with atomoxetine, adults with ADHD showed significantly greater improvement in functioning on disease-specific measures of quality of life than patients treated with placebo. (J. of Att. Dis. 2008; 11(6) 720-727)

Treatment-Associated Suicidal Ideation and Adverse Effects in an Open, Multicenter Trial of Fluoxetine for Major Depressive Episodes

Background: Some reports suggest that a subset of depressed patients may experience suicidality – that is increase or emergence of suicidal ideation (SI) or behavior – after initiation of an antidepressant. The time course and clinical correlates of this phenomenon have not been characterized in detail. Method: We conducted a secondary analysis of a multicenter, prospective, open, 12-week trial of fluoxetine 20 mg in outpatients with nonpsychotic major depressive episodes. Adverse effects and other clinical features associated with the emergence of suicidality, defined using item 3 of the Hamilton Depression Rating Scale, were examined using Cox regression models. Results: Among 414 subjects without SI at baseline, 59 (14.3%) reported SI on at least 1 postbaseline visit. In a Cox regression, emergence of activation and worsening of depression severity were independently associated with emergence of SI, along with female gender, younger age and having thoughts that life was not worth living prior to treatment. Treatment response and remission were significantly less likely among subjects who developed SI. Conclusions: New SI was relatively common in this trial of fluoxetine and associated with the emergence of activation and overall symptomatic worsening. Whether prophylaxis against or aggressive treatment of adverse events can decrease emergence of SI merits further study.

Mirtazapine, yohimbine or olanzapine augmentation therapy for serotonin reuptake-associated female sexual dysfunction: a randomized, placebo controlled trial

BACKGROUND Many agents have been proposed as potential treatments for SSRI-associated sexual dysfunction, but few placebo-controlled trials have been reported. METHOD After a 1-month baseline evaluation, pre-menopausal women with moderate to severe sexual dysfunction associated with the institution of fluoxetine therapy were randomized to augmentation therapy with placebo (N=39), mirtazapine (N=36), yohimbine (N=35) or olanzapine (N=38) for a 6-week period. Outcomes were measured using a daily diary, a biweekly self-report assessment, and a computer assisted structured interview. RESULTS At baseline, orgasm was most severely impaired. After 6 weeks, there was statistically significant improvement on most measures for the overall group of patients, however there were few differences between treatment groups. Isolated treatment differences were observed for the patient self-report of overall sexual function (olanzapine superior to placebo) and the structured interview sexual satisfaction item (mirtazapine inferior to placebo). CONCLUSION No drug assessed was consistently associated with differences from placebo. The results of the study do not support uncontrolled reports of efficacy for these agents in premenopausal women.

Comparison of the Immunogenicity of Recombinant and Pituitary Human Growth Hormone in Rhesus Monkeys

The relative concentrations of antibodies produced in monkeys against three forms of human growth hormone (hGH) were determined using an antigen-specific avidin/biotin ELISA assay. Monkeys were treated in two separate 90-day studies with recombinant methionyl-hGH (met-hGH) and pituitary-derived hGH (pit-hGH) (Study 1) and recombinant natural sequence hGH (Study 2). The lowest dose was equal to the expected therapeutic dose of 0.1 IU/kg. Sixty-nine percent of monkeys treated with pit-hGH and 81% of those treated with met-hGH developed detectable anti-hGH responses. The magnitudes of the responses exhibited wide animal to animal variability, were not markedly related to dose or sex, and were lower than levels obtained in monkeys immunized with hGH in Freunds adjuvant. In contrast, the incidence of antibody responses in monkeys treated with natural sequence hGH was lower (23% in one experiment and 5% in a replicate experiment) and took longer to develop. Antibody concentrations were lower, on average, than in those animals treated with met- or pit-hGH. These results are in accord with those observed clinically, thus supporting the use of the monkey model to predict the relative immunogenicity of some proteins in humans.

A Stabilized Moment Estimator for the Beta-Binomial Distribution

The beta-binomial distribution has been proposed as a model for the incorporation of historical control data in the analysis of rodent carcinogenesis bioassays. Low spontaneous tumor incidences along with the small number and sizes of historical control groups combine to make the moment and maximum likelihood estimates of the beta-binomial parameters deficient. We therefore propose a stabilized moment estimator for one of the parameters. The stabilized moment estimator is similar to the ridge regression estimator and introduces a shrinkage parameter. Computer simulations were run to examine the behavior of the stabilized moment estimator. The effect of the stabilized moment estimator on the score test for dose-related trend is considered both on simulated data and on an example from the literature.

An examination of the efficiency of the sequential parallel design in psychiatric clinical trials.

Background Psychiatric clinical trials have a high failure rate, even among agents which are known to be effective. Because of this high failure rate, a novel clinical trial design has been proposed which incorporates a second phase in which non-responders to placebo are randomly reassigned to drug or placebo. Purpose The purpose of this research is to examine the efficiency of this new design compared to the conventional two arm clinical trial. We consider both binary and continuous endpoints. Methods The limiting distribution of a class of weighted average test statistics is obtained for the binary case which allows analytic calculation of the power for a given set of parameters. For the continuous case, we examine the efficiency of seemingly unrelated regression and a weighted average statistic via simulation. Results The novel design reduces the sample size 20—25% compared to the standard design under a wide range of parameters. Limitations There are no actual trials with the novel design therefore assumptions of the effect size across two periods for actual psychiatric agents is unknown. Conclusions The new design reduces sample size which in turn should reduce the cost of clinical trials. Further refinements of the design are possible including alternative test statistics and incorporation of additional data from placebo responders. Clinical Trials 2007; 4: 309—317. http://ctj.sagepub.com