Evaluating Urine Isoniazid Testing to Detect Nonadherence to Tuberculosis Medications in India

NCT ID: NCT06526221

Last Updated: 2025-01-06

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 900 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-01
• Study Completion Date: 2028-09-30

Brief Summary

Tuberculosis (TB) is the leading infectious cause of death globally. India has the largest TB epidemic, accounting for one-quarter of cases and one-third of TB deaths worldwide. Nonadherence to medications is a central challenge in TB care leading to increased death, disease recurrence, and drug resistance. Despite its importance, detecting nonadherence in routine care is challenging, as current measurement approaches are inaccurate, not person-centered, or ineffective at improving outcomes. Early and accurate detection of nonadherence may serve as an entry point for differentiated care, in which people with TB at risk for poor outcomes can be given intensified interventions. Urine isoniazid testing is a validated, low-cost, point-of-care, and direct adherence measure that may be predictive of TB outcomes and therefore serve as an ideal triage test to enable differentiated care. However, to integrate urine testing into routine care, research is needed to: (1) understand how the test performs at scheduled clinic visits, (2) gain a rich understanding of root causes of nonadherence to better leverage urine test results, and (3) identify barriers and facilitators to implementation. In this study, the investigators propose conducting a 900 participant prospective cohort study with translational research involving clinical, behavioral, and implementation science to facilitate integration of urine isoniazid testing into India's national TB program. The investigators' central hypothesis is that urine testing can be integrated into routine care to facilitate early and accurate identification of people with TB who are likely to suffer poor outcomes, including death and TB recurrence. In Aim 1, the investigators will assess the accuracy of urine test results assessed at scheduled clinic visits in comparison to those assessed at unannounced home visits. In Aim 2, the investigators will assess the relationship between nonadherence detected by urine testing and subsequent unfavorable TB outcomes of death, loss to follow-up, treatment failure, and post-treatment TB recurrence.. This study proposal aims to develop an innovative but pragmatic strategy for early identification of TB medication nonadherence that is feasible in low- and middle-income countries with a high TB burden.

Detailed Description

Tuberculosis (TB) is the leading infectious cause of death globally. India has the largest TB epidemic, accounting for one-quarter of cases and one-third of global TB deaths. Nonadherence to TB medications is associated with increased death, TB recurrence, and drug resistance. Specifically, missing >10% of doses is associated with six times greater risk of poor TB outcomes.2 The association between nonadherence to TB medications and emergence of drug resistance is one of the most concerning from a public health perspective. For example, one study found that nonadherence to TB therapy was associated with independent elevated risk of acquiring drug resistance (adjusted odds ratio 19.7, 95%CI 1.7-234). Another study found that, among people being treated for multidrug-resistant (MDR) TB, each additional month in which a patient failed to take 80% of their prescribed medication doses was associated with elevated risk of developing extensively drug-resistant (XDR) TB (adjusted hazard ratio 1.2, 95% CI 1.01-1.4).

Despite its importance, detecting nonadherence in routine care is challenging, especially as TB programs in low- and middle-income countries (LMICs) have moved away from directly observed therapy. Our research shows indirect measures-e.g., cellphone-based technology, pill counts, and patient-reported measures-miss detecting >30% of people with TB who are nonadherent by urine isoniazid testing.

Urine isoniazid testing is a low-cost, validated, direct point-of-care adherence measure that is predictive of TB outcomes. In a 650-participant cohort study in India, one unannounced home visit was conducted for each participant during TB therapy to conduct urine testing. That study found: (1) nonadherence was common by urine testing, with 18% of participants having missed more than 1 dose, and (2) negative urine test results were associated with 3.9 increased odds of death and 3.8 increased odds of loss to follow-up from treatment.

While urine testing has benefits, further research is needed to evaluate its uses under TB programs setting First, urine testing may perform differently in clinic as compared to unannounced home visits, as people with TB may modify adherence behavior in anticipation of scheduled clinic visits. Research is needed to understand how well testing at clinic visits represents adherence and predicts TB outcomes. Second, research is needed to understand reasons for nonadherence (i.e., negative urine test results) to inform personalized interventions for differentiated care. Third, implementation science research is needed to evaluate the use of urine testing in routine care in a manner that could lead to sustained use and impact.

The investigators propose conducting translational research involving clinical, behavioural, and implementation science to evaluate the use of urine isoniazid testing in the TB program. The investigators' central hypothesis is that urine testing could be useful within the routine care to facilitate early and accurate identification of people with TB who are likely to suffer poor outcomes, including death and TB recurrence. If this hypothesis is correct, the urine assay could serve as a triage test for developing differentiated care strategies, in which people at risk for poor outcomes are identified early and given intensified care

The investigators have the following specific aims:

Aim 1. To assess the agreement between urine test results collected at prescheduled clinic in comparison to unannounced home visits.

Summary of this aim: The investigators will enroll a cohort of 900 people starting 6-month drug-susceptible TB therapy. For each participant, to enable comparison of clinic and home samples, the investigators will conduct 1 urine test at a scheduled clinic visit and 1 urine test at an unannounced home visit during each of the intensive (first 2 months), early continuation (second 2 months), and late continuation (last 2 months) treatment phases.

Aim 2. To assess the relationship between nonadherence by urine testing and subsequent TB outcomes.

Summary of this aim: The investigators will follow the Aim 1 cohort participants through the completion of TB treatment (which usually takes 6 months) and then for 12 months after treatment and assess the following unfavorable outcomes: death, treatment failure, loss to follow-up, and TB recurrence. The investigators will assess the association between nonadherence by urine testing (separately for clinic and home samples) and the composite of these unfavorable outcomes (primary outcome) and with each unfavorable outcome individually (secondary outcomes).

Conditions

Tuberculosis, Pulmonary; Medication Adherence

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: HEALTH_SERVICES_RESEARCH
• Blinding Strategy: NONE

Study Groups

Urine isoniazid testing (intervention arm)

This is the only study group/arm in this study. Participants in this study arm will receive urine isoniazid testing using the IsoScreen test in the TB clinic at monthly clinical and medication refill visits at month 1, 2, 3, 4, and 5 (5 times total). The will also undergo urine isoniazid testing using the IsoScreen test at home visits after months 1, 3, and 5 of treatment (3 times total).

Group Type: EXPERIMENTAL

Urine isoniazid testing (IsoScreen test)

Intervention Type: DIAGNOSTIC_TEST

Developed by Arkansas' Public Health Service in the 1970s, this test detects metabolites of isoniazid, a drug present in drug-susceptible TB regimens. IsoScreen (GFC Diagnostics, UK) is a commercial version of the Arkansas method with reagents enclosed in a plastic vial, into which 2mL of urine can be injected with a syringe. If the urine contains isoniazid, reagents turn purple/blue (suggesting a dose was taken in the last 24 hours or appropriate adherence) or green (suggesting a dose was taken 24-48 hours before or one missed dose). A yellow result (no color change) suggests medication has not been taken for \>48 hours (two or more missed doses).

Interventions

Urine isoniazid testing (IsoScreen test)

Developed by Arkansas' Public Health Service in the 1970s, this test detects metabolites of isoniazid, a drug present in drug-susceptible TB regimens. IsoScreen (GFC Diagnostics, UK) is a commercial version of the Arkansas method with reagents enclosed in a plastic vial, into which 2mL of urine can be injected with a syringe. If the urine contains isoniazid, reagents turn purple/blue (suggesting a dose was taken in the last 24 hours or appropriate adherence) or green (suggesting a dose was taken 24-48 hours before or one missed dose). A yellow result (no color change) suggests medication has not been taken for \>48 hours (two or more missed doses).

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

1. 18+ years of age,

2. presumed or confirmed drug-susceptible pulmonary TB (with or without a previous TB history), and

3. taking an isoniazid-containing TB regimen.

Exclusion Criteria

1. inability to provide informed consent, or

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tuberculosis Research Centre, India

OTHER_GOV

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: collaborator

Tufts University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Ramnath Subbaraman, MD

Role: CONTACT

ramnath.subbaraman@tufts.edu

6175044335

Karikalan Nagarajan, PhD

Role: CONTACT

karikalan.n@icmr.gov.in

+91-7299226582

Other Identifiers

STUDY00004944

Identifier Type: -

Identifier Source: org_study_id