Candidate Clinical Correlate of Prognostic Outcome for TB Study

Overview

As part of the ongoing efforts within the Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) study, the Candidate Clinical Correlate as Prognostic Outcome for TB (C3PO) study serves as a supplement aimed at evaluating predictors and novel biomarkers of recurrent TB among TB survivors. Current tools for predicting TB recurrence risk are suboptimal, limiting the ability to assess new TB treatment regimens effectively. Identifying accurate sputum- or blood-based biomarkers for recurrence risk could significantly improve the efficiency and informativeness of Phase 2 and 3 clinical trials.

Detailed description

The Candidate Clinical Correlate as Prognostic Outcome for TB Study (C3PO) supplements the ongoing Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) study by identifying and accelerating novel TB diagnostics at various stages of development and across different use cases. There is an urgent need for treatments that can cure all forms of TB more quickly. However, the development of new, shorter, and more effective antibiotic regimens is hindered by the limitations of current methods used to assess treatment effectiveness in TB drug trials. The standard pharmacodynamic (PD) marker-sputum culture-does not predict clinical outcomes well, fails to detect residual Mycobacterium tuberculosis that causes relapse, and takes 6-8 weeks to provide results. New PD markers that more accurately predict clinical outcomes would help de-risk clinical trials and ensure that only the most effective new regimens move forward. C3PO aims to evaluate non-culture PD markers in predicting recurrent TB among patients who have completed the global standard HRZE regimen for drug-susceptible pulmonary TB under routine programmatic settings.

Interventions

• Diagnostic test RS ratio
  We will evaluate the non-culture, sputum-based assay RS ratio, which measures ongoing Mycobacterium tuberculosis activity by quantifying the abundance of precursor rRNA relative to mature rRNA (an indicator of active rRNA synthesis).
• Diagnostic test Blood-based host immune response assays
  We will evaluate blood-based assays measuring host immune response parameters for predicting mycobacterial activity.

Primary outcome measures

• Recurrent tuberculosis (TB) [Time frame: 1 year]
• Prognostic accuracy of novel biomarkers in predicting recurrent TB [Time frame: 1 year]

Eligibility criteria

Inclusion criteria

• . individuals age ≥ 12 years;
• . have completed treatment for drug-susceptible tuberculosis with the standard 6-month regimen of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE).

Exclusion criteria

• completed treatment for drug-susceptible tuberculosis >14 days prior to screening/enrollment;
• routinely taking any medication with anti-mycobacterial activity (including fluoroquinolones) for any reason not related to tuberculosis treatment within the last 14 days;
• unwilling to provide informed consent or return for study follow-up visits.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Uganda · 2 centers

• Kisenyi Health Center — Kampala
• Mulago Outpatient Department — Kampala

Vietnam · 1 center

• Hanoi Lung Hospital, Outpatient departments — Hanoi

Publications

• STREPTOMYCIN treatment of pulmonary tuberculosis. Br Med J. 1948 Oct 30;2(4582):769-82. No abstract available. PMID 18890300
• Sharma M, Nduba V, Njagi LN, Murithi W, Mwongera Z, Hawn TR, Patel SN, Horne DJ. TBscreen: A passive cough classifier for tuberculosis screening with a controlled dataset. Sci Adv. 2024 Jan 5;10(1):eadi0282. doi: 10.1126/sciadv.adi0282. Epub 2024 Jan 3. PMID 38170773
• Phillips PPJ, Mendel CM, Nunn AJ, McHugh TD, Crook AM, Hunt R, Bateson A, Gillespie SH. A comparison of liquid and solid culture for determining relapse and durable cure in phase III TB trials for new regimens. BMC Med. 2017 Nov 24;15(1):207. doi: 10.1186/s12916-017-0955-9. PMID 29169355
• Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, Kaminsky DA, McCarthy K, McCormack MC, Oropez CE, Rosenfeld M, Stanojevic S, Swanney MP, Thompson BR. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88. doi: 10.1164/rccm PMID 31613151
• Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012 Dec;40(6):1324-43. doi: 10.1183/09031936.00080312. Epub 2012 Jun 27. PMID 22743675
• Kurbatova EV, Phillips PPJ, Dorman SE, Sizemore EE, Bryant KE, Purfield AE, Ricaldi J, Brown NE, Johnson JL, Wallis CL, Akol JP, Ocheretina O, Van Hung N, Mayanja-Kizza H, Lourens M, Dawson R, Nhung NV, Pierre S, Musodza Y, Shenje J, Badal-Faesen S, Vilbrun SC, Waja Z, Peddareddy L, Scott NA, Yuan Y, Goldberg SV, Swindells S, Chaisson RE, Nahid P. A Standardized Approach for Collection of Objectiv PMID 36790881
• Horne DJ, Royce SE, Gooze L, Narita M, Hopewell PC, Nahid P, Steingart KR. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis. 2010 Jun;10(6):387-94. doi: 10.1016/S1473-3099(10)70071-2. PMID 20510279
• Imperial MZ, Phillips PPJ, Nahid P, Savic RM. Precision-Enhancing Risk Stratification Tools for Selecting Optimal Treatment Durations in Tuberculosis Clinical Trials. Am J Respir Crit Care Med. 2021 Nov 1;204(9):1086-1096. doi: 10.1164/rccm.202101-0117OC. PMID 34346856

Identifiers

NCT: NCT07018076 · U01AI152087-05S1 · U01AI152087-05S1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗