An interventional study of DOT Adherence Monitoring in Tuberculosis, Alcohol Consumption and Treatment Adverse Effect, sponsored by Boston Medical Center. Completed at 1 site in South Africa. Open to participants aged 15 Years and older. Per ClinicalTrials.gov, last updated 2024-08-27.
Sponsored by Boston Medical Center · Not applicable, Interventional, and Supportive care
After HIV/AIDS, tuberculosis (TB) remains the second leading cause of death due to an infectious disease globally. Retrospective studies from many countries, including the United States and South Africa, have consistently reported that in addition to having a higher burden of TB disease, patients with problem alcohol use have worse TB treatment outcomes. This prospective study will attempt to clarify both behavioral and biologic causal mechanisms underlying the deleterious effects of problem alcohol use on TB treatment response.
A major knowledge gap is the degree to which poor treatment outcomes in alcohol-abusing patients are due to noncompliance alone. Problem alcohol use impacts on retention in care and adherence to daily TB treatment. Poor medication adherence and increased default from TB care have been documented for patients consuming alcohol regularly in several countries. Yet there has been no research to identify reasons (beyond adherence) for these poorer outcomes among patients with problem alcohol use. A key barrier to understanding the persistent biologic effect of alcohol on TB disease is inadequate data on adherence, including detailed data on daily adherence (or number of missed doses of medication). Research combining better approaches to alcohol ascertainment and adherence monitoring is needed to advance understanding of the pathways by which alcohol use and TB disease interact.
Aim 1: To (i) examine the associations between problem alcohol use and TB treatment outcomes, and (ii) demonstrate that these associations persist independent of adherence to TB treatment.
Aim 2: To evaluate the effect of problem alcohol use on the pharmacokinetics (PK)/pharmacodynamics (PD) of TB drugs.
Aim 3: We will use existing samples and data and continue to collect samples and data to (A) evaluate Mtb diversity in host, its dynamics overtime and in a specific set of drug resistance, drug tolerance, virulence and immune regulator genes, for evidence of directional and diversifying selection. We will (B) also evaluate how Mtb diversity and genes under selection associate with time-to culture conversion (three consecutive weeks of negative growth) and negative treatment outcomes, adherence, HIV, diabetes mellitus (DM), and substance use. We will (C) leverage MIC and sequence data from TRUST. We will combine these with a large public Mtb MIC and WGS dataset enriched for high-level antibiotic resistance generated by studies that include the NIAID funded Harvard TB Centers of Excellence for Translational Research (CETR). We will train an in silico MIC predictor and probe interactions between mutations and the Mtb lineage on a genome-wide scale. The current TRUST investigators, as well as Dr. Maha Farhat, Harvard Medical School will oversee this aim.
Aim 4: A) To compare rates of dysglycemia (both hyperglycemia and hypoglycemia) in people living with HIV (PLWH) and HIV-uninfected persons receiving TB treatment in order to assess changes in blood glucose levels from study enrollment by HIV status and how alcohol use mediates the relationship; and B) to assess the role stress, inflammation and alcohol consumption play in relation to blood sugar levels in PLWH and HIV-uninfected individuals and to assess epigenetic modifications at DNA sites known to be involved in TB risk and neutrophil, monocyte, T and B cell function.
Culture-positive, pulmonary TB patients will be recruited in Worcester, South Africa, and followed over an 18-month period. Patients will complete an interviewer-administered questionnaire on their alcohol use and other health-related behaviors, and their recent alcohol use will be confirmed using a biomarker (phosphatidylethanol). Chest radiographs, sputum smears and culture, and blood samples will be collected to compare the biology of treatment response in patients with and without problem alcohol use. During the 6-month treatment period, smart mobile-phone technology will be used to document daily drug adherence by trained community workers. Serial measures of alcohol intake and serial sputa isolates will be collected to assess treatment response and TB drug side effects will be recorded. In addition, intensive PK/PD studies of isoniazid, rifampin, ethambutol, and pyrazinamide will be performed in 200 HIV-seronegative patients. The full cohort will be followed for 12 months post-treatment to examine long-term TB outcomes, including relapse and death.
1,435 studies on the registry are indexed under Tuberculosis; 208 are open to participants now.
This study's enrollment of 303 is above the median of 150 across 963 interventional studies indexed under Tuberculosis.
Browse Tuberculosis studies →Boston Medical Center is the lead sponsor of 323 studies on the registry; 33 are open to participants now.
Of its 34 completed or terminated interventional studies of FDA-regulated products, 28 (82%) have results posted.
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Exclusion Criteria:
Daily adherence monitoring by study-employed directly observed therapy (DOT) worker on weekdays throughout the course of TB therapy
Behavioral: DOT Adherence Monitoring
Study participants will meet with a study-employed DOT worker daily during weekdays throughout the course of their TB treatment
Time to Culture Conversion
Time to sterilization/culture conversion during the first twelve weeks of treatment in patients with problem alcohol use compared to those without
Time frame: 12 weeks
Cmax
Peak concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol in patients with problem alcohol use compared to those without
Time frame: 4 weeks
Area Under Curve (AUC)
Individual patient steady state 24-hour area under curve (AUC) of isoniazid, rifampin, pyrazinamide, and ethambutol
Time frame: 4 weeks
Poor Treatment Outcome
Number and percent of participants that had favorable (defined as cured, treatment completed) and unfavorable (defined as treatmentfailure, death, relapse) TB outcomes. The 'other' category is defined as the treatment defaulted, was extended, participant moved or was transferred).
Time frame: 18 months
Side Effects to TB Drugs
Nember and percentage of patients who develop side effects to the TB drugs in patients with problem alcohol use compared to those without
Time frame: 6 months
| Milestone | TRUST Cohort |
|---|---|
| Started | 303 |
| Completed | 282 |
| Not completed | 21 |
| Withdrew: Withdrawal by subject | 11 |
| Withdrew: Moved/transferred out | 5 |
| Withdrew: Lost to follow-up | 2 |
| Withdrew: Death | 1 |
| Withdrew: Changed treatment regimen, no longer on first line drugs. | 1 |
| Withdrew: Treatment extended due to bacterial meningitis. | 1 |
| Milestone | TRUST Cohort |
|---|---|
| Started | 282 |
| Completed | 271 |
| Not completed | 11 |
| Withdrew: Withdrawal by subject | 4 |
| Withdrew: Treatment failure | 1 |
| Withdrew: Moved/transferred out | 1 |
| Withdrew: Lost to follow-up | 4 |
| Withdrew: Death | 1 |
| Milestone | TRUST Cohort |
|---|---|
| Started | 271 |
| Completed | 205 |
| Not completed | 66 |
| Withdrew: Withdrawal by subject | 1 |
| Withdrew: Treatment failure | 7 |
| Withdrew: Relapse/recurrence of tb | 8 |
| Withdrew: Moved/transferred out | 6 |
| Withdrew: Lost to follow-up | 24 |
| Withdrew: Death | 4 |
| Withdrew: Diagnosed with multi-drug resistant tuberculosis. | 1 |
| Withdrew: Treatment stopped due to liver injury. | 1 |
| Withdrew: Still in study. | 14 |
Time to sterilization/culture conversion during the first twelve weeks of treatment in patients with problem alcohol use compared to those without
| weeks | TRUST Cohort |
|---|---|
| Low Alcohol Use | 5.6 ± 2.5 |
| Moderate Alcohol Use | 5.4 ± 2.5 |
| High Alcohol Use | 5.5 ± 2.6 |
Peak concentrations (Cmax) of isoniazid, rifampin, pyrazinamide, and ethambutol in patients with problem alcohol use compared to those without
| mg/L | TRUST Cohort |
|---|---|
| Rifampicin | 5.29 (3.53 to 6.88) |
| Isoniazid | 1.63 (1.25 to 2.23) |
| Pyrazinamide | 28.5 (26.2 to 32.8) |
| Ethambutol | 1.98 (1.75 to 2.20) |
Individual patient steady state 24-hour area under curve (AUC) of isoniazid, rifampin, pyrazinamide, and ethambutol
| mg x h/L | TRUST Cohort |
|---|---|
| Rifampin | 22.2 (15.5 to 31.2) |
| Isoniazid | 6.32 (4.53 to 13.1) |
| Pyrazinamide | 259 (236 to 292) |
| Ethambutol | 13.2 (11.7 to 15.1) |
Number and percent of participants that had favorable (defined as cured, treatment completed) and unfavorable (defined as treatmentfailure, death, relapse) TB outcomes. The 'other' category is defined as the treatment defaulted, was extended, participant moved or was transferred).
| Participants | TRUST Cohort |
|---|---|
| Favorable | 246 |
| Unfavorable | 24 |
| Other | 19 |
| Missing | 11 |
Nember and percentage of patients who develop side effects to the TB drugs in patients with problem alcohol use compared to those without
| Participants | TRUST Cohort |
|---|---|
| Side effects | 154 |
| No side effects | 146 |
Collected over 18 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| TRUST Cohort | 8/303 (2.6%) | 10/303 (3.3%) | 0/303 (0%) |
| Event | TRUST Cohort |
|---|---|
| Participant deathGeneral disorders | 8/303 |
| Participant coughing up blood during transportGeneral disorders | 1/303 |
| Ineligible participant enrolledInvestigations | 1/303 |
| Age, Continuous(years) | TRUST Cohort |
|---|---|
| Median | 37 (27 to 48) |
| Sex: Female, Male(Participants) | TRUST Cohort |
|---|---|
| Female | 121 |
| Male | 182 |
| Race/Ethnicity, Customized(Participants) | TRUST Cohort |
|---|---|
| Coloured/Mixed Ancestry | 284 |
| Black African | 16 |
| Indian/Asian | 1 |
| Other | 2 |
| Region of Enrollment(participants) | TRUST Cohort |
|---|---|
| South Africa | 303 |
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Plan to share: No
Ran from May 2017 to primary completion in Jun 2022, 61 months.
Results were first posted in Aug 2023, 1 year 1 month after primary completion.
Of 191 non-industry interventional studies with no phase under Tuberculosis, half reached primary completion within 25 months of starting (the median), counting those still running; a quarter within 15 and three quarters within 43. This study's 61 months is above that.
Counting every sponsor, half of 193 studies reached it within 25 months; a quarter within 15 and three quarters within 43.
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This study is completed, as verified in Aug 2024. You cannot join it, but the record below documents what was studied.
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