Dataset Information

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

ABSTRACT: Background: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01). We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment. Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C. Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified.

Trial registration

NCT02821832.

SUBMITTER: Chen RY

PROVIDER: S-EPMC5841574 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

Chen Ray Y RY Via Laura E LE Dodd Lori E LE Walzl Gerhard G Malherbe Stephanus T ST Loxton André G AG Dawson Rodney R Wilkinson Robert J RJ Thienemann Friedrich F Tameris Michele M Hatherill Mark M Diacon Andreas H AH Liu Xin X Xing Jin J Jin Xiaowei X Ma Zhenya Z Pan Shouguo S Zhang Guolong G Gao Qian Q Jiang Qi Q Zhu Hong H Liang Lili L Duan Hongfei H Song Taeksun T Alland David D Tartakovsky Michael M Rosenthal Alex A Whalen Christopher C Duvenhage Michael M Cai Ying Y Goldfeder Lisa C LC Arora Kriti K Smith Bronwyn B Winter Jill J Barry Iii Clifton E CE

Gates open research 20171106

<b>Background</b>: By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1. ...[more]

PMID: 29528048

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Project description:Background and objectivesIn children with nephrotic syndrome, steroids are the cornerstone of therapy for relapse. The adequate duration and dosage of steroids, however, have not been an active area of research, especially in children with infrequently relapsing nephrotic syndrome. This study investigated the efficacy of an abbreviated regimen for treatment of a relapse in this population.Design, setting, participants, & measurementsIn a single-center, open-label, randomized controlled trial, we evaluated the efficacy of prednisolone as a "short regimen" (40 mg/m2 on alternate days for 2 weeks) compared with "standard regimen" (40 mg/m2 on alternate days for 4 weeks) for children aged 1-16 years who achieved remission of a relapse. The primary outcome was the proportion of children developing frequent relapses or steroid dependence at 12 months.ResultsA total of 117 patients were enrolled and randomized to short (55) or standard (62) regimen. Fourteen (24%) patients in standard regimen and 12 (23%) in short regimen developed frequent relapses or steroid dependence over a period of 1 year (risk difference, -1%; 95% confidence interval, -15 to 16; P=0.90). A large 95% confidence interval crossed the proposed noninferiority margin. In a time to event analysis, there was no significant difference in the proportion of children developing frequent relapses or steroid dependence and time to outcome between the two groups (hazard ratio, 1.01; 95% confidence interval, 0.83 to 1.23; P=0.98). Time to relapse, relapse rate, and steroid-related adverse events were similar in both groups. Cumulative steroid exposure was significantly lower in the short regimen (risk difference, -541 mg/m2; 95% confidence interval, -917 to -164 mg/m2; P<0.001).ConclusionsIn children with infrequently relapsing nephrotic syndrome, a short steroid treatment for relapse resulted in a similar proportion of patients developing frequent relapses or steroid dependence; however, noninferiority of a short regimen was not established.Clinical trial registry name and registration numberCTRI/2015/11/006345.

Project description:Six months of chemotherapy using current agents is standard of care for pulmonary, drug-sensitive tuberculosis (TB), even though some are believed to be cured more rapidly and others require longer therapy. Understanding what factors determine the length of treatment required for durable cure in individual patients would allow individualization of treatment durations, provide better clinical tools to determine the of appropriate duration of new regimens, as well as reduce the cost of large Phase III studies to determine the optimal combinations to use in TB control programs. We conducted a randomized clinical trial in South Africa and China that recruited 704 participants with newly diagnosed, drug-sensitive pulmonary tuberculosis and stratified them based on radiographic disease characteristics as assessed by FDG PET/CT scan readers. Participants with less extensive disease (N=273) were randomly assigned to complete therapy after four months or continue receiving treatment for six months. Amongst participants who received four months of therapy, 17 of 141 (12.1%) experienced unfavorable outcomes compared to only 2 of 132 (1.5%) who completed six months of treatment (treatment success 98.4% in B, 86.7% in C (difference -11.7%, 95% CI, -18.2%, -5.3%)). In the non-randomized arm that included participants with more extensive disease, only 8 of 248 (3.2%) experienced unfavorable outcomes. Total cavity volume and total lesion glycolysis at week 16 were significantly associated with risk of unfavorable outcome in the randomized participants. Based on PET/CT scans at TB recurrence, bacteriological relapses (confirmed by whole genome sequencing) predominantly occurred in the same active cavities originally present at baseline. Automated segmentation of the serial PET/CT scans was later performed, and machine-learning was used to classify participants according to their likelihood of relapse, allowing the development of predictive models with good performance based on CT, PET, microbiological and clinical characteristics. These results open the possibility for more efficient studies of future TB treatment regimens.

Project description:BackgroundThe prevalence of chronic sleep deprivation is increasing in modern societies with negative health consequences. Recently, an association between short sleep and obesity has been reported.PurposePrimary objectivesTo assess the feasibility of increasing sleep duration to a healthy length (approximately 7(1/2) h) and to determine the effect of sleep extension on body weight.Secondary objectivesTo examine the long-term effects of sleep extension on endocrine (leptin and ghrelin) and immune (cytokines) parameters, the prevalence of metabolic syndrome, body composition, psychomotor vigilance, mood, and quality of life.MethodsOne hundred-fifty obese participants who usually sleep less than 6(1/2) h, are being randomized at a 2:1 ratio to either an Intervention or to a Comparison Group. They are stratified by age (above and below 35) and the presence or absence of metabolic syndrome. During the first 12 months (Efficacy Phase) of the study, participants are evaluated at bi-monthly intervals: the Intervention Group is coached to increase sleep by at least 30-60 min/night, while the Comparison Group maintains baseline sleep duration. In the second (Effectiveness) phase, participants converge into the same group and are asked to increase (Comparison Group) or maintain (Intervention Group) sleep duration and are evaluated at 6-month intervals for an additional 3 years. Non-pharmacological and behavior-based interventions are being utilized to increase sleep duration. Endocrine, metabolic, and psychological effects are monitored. The sleep, energy expenditure, and caloric intake are assessed by activity monitors and food recall questionnaires. At yearly intervals, body composition, abdominal fat, and basal metabolic rate are measured by dual energy X-ray absorptiometry (DXA), computerized tomography (CT), and indirect calorimetry, respectively.ResultsAs of January 2010, 109 participants had been randomized, 64 to the Intervention Group and 45 to the Comparison Group (76% women, 62% minorities, average age: 40.8 years; BMI: 38.5 kg/m(2)). Average sleep duration at screening was less than 6 h/night, 40.3 h/week. A total of 28 Intervention and 22 Comparison participants had completed the Efficacy Phase.LimitationsThe study is not blinded and the sample size is relatively small.ConclusionsThis proof-of-concept study on a randomized sample will assess whether sleep extension is feasible and whether it influences BMI. Clinical Trials 2010; 7: 274-285. http://ctj.sagepub.com.

Project description:ImportanceElectronic directly observed therapy (DOT) is used increasingly as an alternative to in-person DOT for monitoring tuberculosis treatment. Evidence supporting its efficacy is limited.ObjectiveTo determine whether electronic DOT can attain a level of treatment observation as favorable as in-person DOT.Design, setting, and participantsThis was a 2-period crossover, noninferiority trial with initial randomization to electronic or in-person DOT at the time outpatient tuberculosis treatment began. The trial enrolled 216 participants with physician-suspected or bacteriologically confirmed tuberculosis from July 2017 to October 2019 in 4 clinics operated by the New York City Health Department. Data analysis was conducted between March 2020 and April 2021.InterventionsParticipants were asked to complete 20 medication doses using 1 DOT method, then switched methods for another 20 doses. With in-person therapy, participants chose clinic or community-based DOT; with electronic DOT, participants chose live video-conferencing or recorded videos.Main outcomes and measuresDifference between the percentage of medication doses participants were observed to completely ingest with in-person DOT and with electronic DOT. Noninferiority was demonstrated if the upper 95% confidence limit of the difference was 10% or less. We estimated the percentage of completed doses using a logistic mixed effects model, run in 4 modes: modified intention-to-treat, per-protocol, per-protocol with 85% or more of doses conforming to the randomization assignment, and empirical. Confidence intervals were estimated by bootstrapping (with 1000 replicates).ResultsThere were 173 participants in each crossover period (median age, 40 years [range, 16-86 years]; 140 [66%] men; 80 [37%] Asian and Pacific Islander, 43 [20%] Black, and 71 [33%] Hispanic individuals) evaluated with the model in the modified intention-to-treat analytic mode. The percentage of completed doses with in-person DOT was 87.2% (95% CI, 84.6%-89.9%) vs 89.8% (95% CI, 87.5%-92.1%) with electronic DOT. The percentage difference was -2.6% (95% CI, -4.8% to -0.3%), consistent with a conclusion of noninferiority. The 3 other analytic modes yielded equivalent conclusions, with percentage differences ranging from -4.9% to -1.9%.Conclusions and relevanceIn this trial, the percentage of completed doses under electronic DOT was noninferior to that under in-person DOT. This trial provides evidence supporting the efficacy of this digital adherence technology, and for the inclusion of electronic DOT in the standard of care.Trial registrationClinicalTrials.gov Identifier: NCT03266003.

Dataset Information

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

Trial registration

Publications

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial.

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