Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) (ADEPTT)

September 21, 2023 updated by: University of California, San Francisco

URBAN ARCH (3/5) Uganda Cohort TB Preventive Therapy for HIV-infected Alcohol Users in Uganda: an Evaluation of Safety Tolerability and Adherence

The Alcohol Drinkers' Exposure to Preventive Therapy for TB (ADEPTT) will examine the safety and tolerability of, and adherence to, 6 months of daily INH (6H) in 300 TB and HIV-infected persons (200 drinkers and 100 non-drinkers) in Uganda. The first aim is to evaluate the safety and tolerability of 6H overall and by level of alcohol use. The second aim is to estimate adherence and compare adherence by level of alcohol use and at 3 and 6 months. Self-reported measures of alcohol use will be augmented by phosphatidylethanol (PEth), an established biomarker of alcohol use. Objective measures of adherence will include electronic pill bottle monitoring and a novel measure of INH exposure, INH concentration in hair. The study will actively monitor for hepatotoxicity using the U.S. standard of care for TB preventive therapy for heavy drinkers and discontinue if any Grade 3/4 toxicities are detected. The investigators will use the safety, tolerability, and adherence results, together with the known efficacy and mortality benefit of TB preventive therapy in HIV-infected persons in SSA, and an established decision analytic model of TB preventive therapy to conduct the third aim: to determine whether the benefits of TB preventive therapy outweigh the toxicity risks for HIV-infected drinkers in resource limited settings. The study will additionally follow the cohort every 6 months after completing INH to monitor drinking and the development of active TB.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Tuberculosis (TB) is the leading cause of mortality in persons with HIV worldwide, accounting for 20-33% of HIV-related deaths, and is a high-priority area of research in HIV/AIDS by the NIH. TB preventive therapy decreases both all-cause mortality and active TB in persons with HIV by 30-50% above and beyond the benefits of antiretroviral therapy (ART) alone. Based on these findings, the World Health Organization (WHO) recommends isoniazid (INH) preventive therapy (IPT) for all persons with HIV in resource constrained settings. However, the WHO warns against the use of IPT in persons with "regular and heavy alcohol use." This exclusion stems from concern for increased hepatotoxicity in heavy drinkers in settings where liver enzymes are not routinely monitored. Heavy drinking in persons with HIV is very common, approximately 25%, in sub-Saharan Africa (SSA). Heavy drinking increases the risk for active TB at least threefold; thus, HIV-infected alcohol users should be prioritized for TB prevention. However, no studies have systematically assessed the safety of TB preventive therapy in heavy drinkers with or without HIV infection. It is critical to examine the safety and tolerability of TB preventive therapy for HIV-infected drinkers, given the high rates of HIV, TB infection, and alcohol comorbidities worldwide. While the risk of toxicity exists, the risk of TB disease could outweigh the toxicity harms. Thus, it is also crucial to determine whether the mortality benefits outweigh the toxicity risks for this significant portion of the HIV-infected population.

In addition, TB preventive therapy is only effective if taken consistently for the full course. Alcohol use is an established risk factor for decreased ART pill taking and active TB treatment discontinuation. Whether HIV-infected drinkers on ART can be adherent to TB preventive therapy is not known. Therefore it is essential to determine the level of adherence to TB preventive therapy by HIV-infected drinkers on ART, thus this study aims to examine adherence to TB preventative therapy as well.

This is a study to examine 6 months of daily INH (6H) among N=300 persons co-infected with HIV and TB. The aims of the study are:

Aim 1: To examine the safety and tolerability of 6H in HIV/TB co-infected drinkers, measured by hepatotoxicity and treatment discontinuation rates. The main aim is to estimate safety and tolerability overall among drinkers (primary) and by level of drinking (secondary).

Aim 2: To determine the level of TB preventive therapy adherence overall among drinkers and by level of drinking, and at 3 and 6 months. The main goal of this aim is to estimate adherence overall among drinkers (primary). Secondarily the investigators will estimate adherence by level of drinking (heavy, current but not heavy drinkers, and non-drinkers) and compare adherence across drinking levels. The investigators hypothesize that adherence will be highest among the non-drinkers.

Aim 3: To determine whether the benefits of providing TB preventive therapy to HIV-infected drinkers in resource-limited settings outweigh the risks compared to no treatment. The investigators hypothesize that providing TB preventive therapy will result in longer life expectancy and quality-adjusted life expectancy than not providing TB preventive therapy (current standard of care).

Study Type

Interventional

Enrollment (Actual)

302

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Uganda
      • Mbarara, Uganda
        • Mbarara University of Science and Technology/Mbarara Regional Referral Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age > 18 years old
  2. Patient of the MRRH ISS Clinic
  3. HIV-infected
  4. Consume alcohol (self-reported consumption in the prior 3 months) (2/3) OR prior year non-drinker (1/3)
  5. Live within 2 hours of travel time to the ISS Clinic
  6. Fluent in either Runyankole or English
  7. No ALT/AST elevations (< = 2X ULN) confirmed by testing
  8. On ART for at least 6 months
  9. No history of active TB, TB treatment, or TB preventive therapy
  10. No probable current active TB as determined by symptom screening and followed by chest X-ray and Xpert MTB/RIF (if symptomatic)
  11. Positive TST results confirmed by testing

Exclusion Criteria:

  1. Plans to move out of the catchment area within 6 months
  2. Probable TB via symptom screen and subsequent assessments
  3. History or current or past active TB, TB treatment, or TB preventive therapy
  4. ALT or AST >2x ULN
  5. Pregnant women

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Isoniazid & pyridoxine
Isoniazid 300 mg oral tablet: 300 mg daily by mouth for 6 months. Pyridoxine 25 mg oral tablet: 25mg daily by mouth for 6 months.
Drug: Isoniazid 300 Mg ORAL TABLET
The study intervention will include a single arm given (1) 6H: 300 mg INH daily by mouth for 6 months.
Other Names:
  • INH
Drug: Pyridoxine 25 Mg Oral Tablet
All participants will also receive 25 mg pyridoxine (vitamin B-6) daily by mouth for 6 months for the treatment duration to reduce the risk of INH-induced peripheral neuropathy.
Other Names:
  • Vitamin B6

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative Incidence of Participants Experiencing a Grade 3/4 Hepatotoxicity
Time Frame: Hepatotoxicity occurring during the six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.
Safety will be assessed by the occurrence of a Grade 3/4 hepatotoxicity at any time during the assigned treatment period.
Hepatotoxicity occurring during the six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Who Discontinued Treatment
Time Frame: Six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.
Lack of tolerability will be defined as any isoniazid (INH) treatment discontinuation prior to completion of the prescribed course (6 months of INH taken over a maximum period of 9 months) due to side effects or alanine transaminase (ALT)/aspartate transaminase (AST) elevations.
Six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.
Percentage of Participants With Suboptimal INH Medication Adherence
Time Frame: Adherence will be measured over the 6 months on INH or until INH discontinuation (whichever is shorter)
Suboptimal INH adherence was defined as <90% of days with at least 1 electronic medication management (EMM) pill cap opening in the previous 90 days, at 3- and 6-months.
Adherence will be measured over the 6 months on INH or until INH discontinuation (whichever is shorter)
Self-reported INH Medication Adherence: Number of Days Taking INH in the Past 30 Days
Time Frame: Self-reported INH medication adherence via VAS will be measured 3- and 6- months after starting INH
Participants were asked "In the past 30 days, how many days in total have you not taken your pill?" and were presented with a visual analog scale (VAS) to indicate the percentage of INH taken in the past 30 days. We converted the VAS percentage into number of days out of 30 to match the first question. Our final self-report measure was the minimum number of the 2 self-reported measurements.
Self-reported INH medication adherence via VAS will be measured 3- and 6- months after starting INH
Self-reported INH Medication Adherence by the Self Rating Single Item (SRSI) Scale
Time Frame: Self-reported INH medication adherence via SRSI will be measured 3- and 6- months after starting INH
The Self Rating Single Item (SRSI) adherence scale asks participants to rate their ability to take their medications as prescribed over the past 30 days. Participants reporting INH use in the prior 30 days at the 3- or 6-month interview are included here, and reported their INH adherence in the prior 30 days as excellent, very good, good, fair, poor, or very poor.
Self-reported INH medication adherence via SRSI will be measured 3- and 6- months after starting INH

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
INH Concentration in Hair: (INH Pmol + Acetyl INH Pmol) Per mg of Hair
Time Frame: Measured at 3- and 6- months after INH initiation
INH concentration in hair (pmol/mg) will be measured at 3- and 6- months during INH therapy.
Measured at 3- and 6- months after INH initiation
Number of Participants With Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Elevations at Study Screening
Time Frame: Study screening visit
Alanine transaminase (ALT) or aspartate transaminase (AST) elevations (>2x the upper limit of normal) at study screening
Study screening visit
Number of Participants With Latent Tuberculosis at Study Screening.
Time Frame: Study screening visit
Latent tuberculosis assessed at screening via tuberculin skin testing (TST). A TST induration >=5mm was considered positive for latent tuberculosis.
Study screening visit

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

Boston University
Boston Medical Center
Mbarara University of Science and Technology

Investigators

  • Principal Investigator: Judith A Hahn, PhD, MA, University of California, San Francisco

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 7, 2017

Primary Completion (Actual)

April 1, 2021

Study Completion (Actual)

April 1, 2021

Study Registration Dates

First Submitted

September 15, 2017

First Submitted That Met QC Criteria

September 29, 2017

First Posted (Actual)

October 5, 2017

Study Record Updates

Last Update Posted (Actual)

October 19, 2023

Last Update Submitted That Met QC Criteria

September 21, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2U01AA020776-06 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

The investigators will make de-identified data available to investigators with relevant and well-articulated research plans, after the main study analyses have been conducted. No personal identifiers will be shared, and nor identifiers that could be linked back to the original study ID. In addition, some journals require de-identified data to be posted for public access.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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