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Increasing the power of randomized trials comparing different treatment durations.

ABSTRACT: When the optimal treatment duration is uncertain, a randomized trial may allocate patients to receive active treatment for different durations. We use an example where patients receive treatment for 0, 24, or 52 weeks. In this trial, patients in the 24-weeks and 52-weeks arms receive the same treatment during the first 24 weeks. This overlap allows for more powerful analyses than conventional pair-wise comparisons of arms. When the outcome is the time-to-event, the power for the 0-weeks versus 24-weeks comparison can be increased by including patients in the 52-weeks arm as patients in the 24-weeks arm for the first 24 weeks and censoring at 24 weeks. Furthermore, differences observed between the 24-weeks and 52-weeks arms during the first 24 weeks can only reflect noise. Hence, the comparison of these two arms should be restricted to only patients who remain on the study at 24 weeks and include only the events after 24 weeks. Through simulation, we show that modified analyses accounting for these considerations increase study power substantially. Moreover, if patients were allocated equally to the arms, then events or discontinuations during the first 24 weeks will reduce the number of patients available for the 24-weeks versus 52-weeks comparison, and hence the power of this analysis will be lower than that for the 0-weeks versus 24-weeks comparison. We present a sample size calculation procedure for equalizing the power of these two analyses. Typically, this allocation requires much larger sample sizes in the 24-weeks and 52-weeks arms than in the 0-week arm.

SUBMITTER: Ouyang Y

PROVIDER: S-EPMC7322686 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Increasing the power of randomized trials comparing different treatment durations.

Ouyang Yongdong Y Qian Hong H Yatham Lakshmi N LN Wong Hubert H

Contemporary clinical trials communications 20200610

When the optimal treatment duration is uncertain, a randomized trial may allocate patients to receive active treatment for different durations. We use an example where patients receive treatment for 0, 24, or 52 weeks. In this trial, patients in the 24-weeks and 52-weeks arms receive the same treatment during the first 24 weeks. This overlap allows for more powerful analyses than conventional pair-wise comparisons of arms. When the outcome is the time-to-event, the power for the 0-weeks versus 2 ...[more]

PMID: 32617431

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Project description:Rationale: No evidence-based tools exist to enhance precision in the selection of patient-specific optimal treatment durations to study in tuberculosis clinical trials. Objectives: To develop risk stratification tools that assign patients with tuberculosis into risk groups of unfavorable outcome and inform selection of optimal treatment duration for each patient strata to study in clinical trials. Methods: Publicly available data from four phase 3 trials, each evaluating treatment duration shortening from 6 to 4 months, were used to develop parametric time-to-event models that describe unfavorable outcomes. Regimen, baseline, and on-treatment characteristics were evaluated as predictors of outcomes. Exact regression coefficients of predictors were used to assign risk groups and predict optimal treatment durations. Measurements and Main Results: The parametric model had an area under the receiver operating characteristic curve of 0.72. A six-item risk score (HIV status, smear grade, sex, cavitary disease status, body mass index, and Month 2 culture status) successfully grouped participants into low (1,060/3,791; 28%), moderate (1,740/3,791; 46%), and high (991/3,791; 26%) risk, requiring treatment durations of 4, 6, and greater than 6 months, respectively, to reach a target cure rate of 93% when receiving standard-dose rifamycin-containing regimens. With current one-duration-fits-all approaches, high-risk groups have a 3.7-fold (95% confidence interval, 2.7-5.1) and 2.4-fold (1.9-2.9) higher hazard risk of unfavorable outcomes compared with low- and moderate-risk groups, respectively. Four-month regimens were noninferior to the standard 6-month regimen in the low-risk group. Conclusions: Our model discrimination was modest but consistent with current models of unfavorable outcomes. Our results showed that stratified medicine approaches are feasible and may achieve high cure rates in all patients with tuberculosis. An interactive risk stratification tool is provided to facilitate decision-making in the regimen development pathway.

Project description:BackgroundAvoidance of unnecessary antimicrobial administration is a key tenet of antimicrobial stewardship; knowing the optimal duration of therapy obviates over-treatment. However, little research has been performed to establish course lengths for common canine infections. In clinical practice, antimicrobial therapy is frequently prescribed in dogs presenting lower urinary tract signs (haematuria, pollakiuria and dysuria/stranguria). The proposed length of treatment in International Consensus guidelines has decreased with each iteration, but these recommendations remain arbitrary and largely extrapolated from experience in people.MethodsThe objective of this prospective, multi-centre study is to find the shortest course duration that is non-inferior to the standard duration of 7 days of amoxicillin/clavulanate in terms of clinical outcomes for female dogs with lower urinary tract signs consistent with a urinary tract infection. An electronic data capture platform will be used by participating veterinarians working in clinical practice in the United Kingdom. Eligible dogs must be female, aged between 6 months and 10 years and have lower urinary tract signs of up to seven days' duration. Enrolment will be offered in cases where the case clinician intends to prescribe antimicrobial therapy. Automatic pseudo-randomisation to treatment group will be based on the day of presentation (Monday-Friday); all antimicrobial courses will be completed on the Sunday after presentation generating different treatment durations. Follow-up data will be collected 1, 8 and 22-26 days after completion of the antimicrobial course to ensure effective safety netting, and to monitor short-term outcome and recurrence rates. Informed owner consent will be obtained in all cases. The study is approved by the Ethical Review Board of the University of Nottingham and has an Animal Test Certificate from the Veterinary Medicine's Directorate.DiscussionThis study has been designed to mirror current standards of clinical management; conclusions should therefore, be widely applicable and guide practising veterinarians in their antimicrobial decision-making process. A duration-response curve will be created allowing determination of the optimal treatment duration for the management of female dogs with lower urinary tract signs. It is hoped that these results will contribute valuable information to improve future antimicrobial stewardship as part of a wider one-health perspective.

Project description:Antibiotics seize an effect on bacterial composition and diversity and have been demonstrated to induce disruptions on gut microbiomes. This may have implications for human health and wellbeing, and an increasing number of studies suggest a link between the gut microbiome and several diseases. Hence, reducing antibiotic treatments may be beneficial for human health status. Further, antimicrobial resistance (AMR) is an increasing global problem that can be counteracted by limiting the usage of antibiotics. Longer antibiotic treatments have been demonstrated to increase the development of AMR. Therefore, shortening of antibiotic treatment durations, provided it is safe for patients, may be one measure to reduce AMR. In this study, the objective was to investigate effects of standard and reduced antibiotic treatment lengths on gut microbiomes using a murine model. Changes in the murine gut microbiome was assessed after using three different treatment durations of amoxicillin (3, 7 or 14 days) as well as a control group not receiving amoxicillin. Fecal samples were collected before and during the whole experiment, until three weeks past end of treatment. These were further subject for 16S rRNA Illumina MiSeq sequencing. Our results demonstrated significant changes in bacterial diversity, richness and evenness during amoxicillin treatment, followed by a reversion in terms of alpha-diversity and abundance of major phyla, after end of treatment. However, a longer restitution time was indicated for mice receiving amoxicillin for 14 days, and phylum Patescibacteria did not fully recover. In addition, an effect on the composition of Firmicutes was indicated to last for at least three weeks in mice treated with amoxicillin for 14 days. Despite an apparently reversion to a close to original state in overall bacterial diversity and richness, the results suggested more durable changes in lower taxonomical levels. We detected several families, genera and ASVs with significantly altered abundance three weeks after exposure to amoxicillin, as well as bacterial taxa that appeared significantly affected by amoxicillin treatment length. This may strengthen the argument for shorter antibiotic treatment regimens to both limit the emergence of antibiotic resistance and risk of gut microbiome disturbance.

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Increasing the power of randomized trials comparing different treatment durations.

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Increasing the power of randomized trials comparing different treatment durations.

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