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

A semi-automatic technique to quantify complex tuberculous lung lesions on 18F-fluorodeoxyglucose positron emission tomography/computerised tomography images

“…The two manual readers are clinicians, with experience in the diagnosis and treatment of pulmonary tuberculosis. They are also clinical trial investigators and trained in PET-CT evaluation for a phase 3 clinical trial that aims to use PET-CT parameters to guide TB treatment duration [ 28 ]. Manual segmentation of FDG-avid PET lesions in PTB scans took roughly 30–90 min per scan.…”

Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response

“…In related publications, these quantitative metrics also correlate well with host biomarkers, namely gene expression signatures [46], and urinary concentration of the recently discovered metabolite, serylleucine core 1 O-glycosylated peptide [50]. The potential of quantitative FDG PET-CT variables to identify patients with a low risk of treatment failure was also analysed in combination with other patient variables and is currently being tested in the PredictTB trial [51].…”

Assessing Response to Therapy for Nontuberculous Mycobacterial Lung Disease: Quo Vadis?

“…Multiple enrollment sites will be required to provide the statistical power for comparing alternative therapeutic strategies, given the smaller number of NTM lung disease patients compared with tuberculosis on a global scale. Furthermore, clinical studies supported by the National Institutes of Health ( Sigal et al, 2017 ) and the Bill & Melinda Gates Foundation ( Chen et al, 2017 ) have demonstrated the feasibility of integrating biomarker assessment into clinical trial design.…”