A Phase 4 interventional study of Isoniazid 300 Mg ORAL TABLET and Pyridoxine 25 Mg Oral Tablet in Tuberculosis, HIV/AIDS and Alcohol Abuse, sponsored by University of California, San Francisco. Completed at 1 site in Uganda. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-10-19.
Sponsored by University of California, San Francisco · Phase 4, Interventional, and Other
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.
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).
1,170 studies on the registry are indexed under Tuberculosis; 175 are open to participants now.
This study's enrollment of 302 is above the median of 150 across 820 interventional studies indexed under Tuberculosis.
Browse Tuberculosis studies →University of California, San Francisco is the lead sponsor of 2,169 studies on the registry; 372 are open to participants now.
Of its 267 completed or terminated interventional studies of FDA-regulated products, 202 (76%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 · Drug: Pyridoxine 25 Mg Oral Tablet
The study intervention will include a single arm given (1) 6H: 300 mg INH daily by mouth for 6 months.
Also known as: INH
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.
Also known as: Vitamin B6
Cumulative Incidence of Participants Experiencing a Grade 3/4 Hepatotoxicity
Safety will be assessed by the occurrence of a Grade 3/4 hepatotoxicity at any time during the assigned treatment period.
Time frame: Hepatotoxicity occurring during the six month course (180 pills) of isoniazid (INH), which may be taken over a maximum of 9 months.
Number of Participants Who Discontinued Treatment
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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: 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
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.
Time frame: Self-reported INH medication adherence via SRSI will be measured 3- and 6- months after starting INH
INH Concentration in Hair: (INH Pmol + Acetyl INH Pmol) Per mg of Hair
INH concentration in hair (pmol/mg) will be measured at 3- and 6- months during INH therapy.
Time frame: Measured at 3- and 6- months after INH initiation
Number of Participants With Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Elevations at Study Screening
Alanine transaminase (ALT) or aspartate transaminase (AST) elevations (\>2x the upper limit of normal) at study screening
Time frame: Study screening visit
Number of Participants With Latent Tuberculosis at Study Screening.
Latent tuberculosis assessed at screening via tuberculin skin testing (TST). A TST induration \>=5mm was considered positive for latent tuberculosis.
Time frame: Study screening visit
Participants were recruited from an HIV clinic from April 2017 through December 2019.
| Milestone | INH and Vitamin B6 |
|---|---|
| Started | 302 |
| Completed 3 month visit | 295 |
| Completed 6 month visit | 289 |
| Completed | 301 |
| Not completed | 1 |
| Withdrew: Protocol violation | 1 |
Safety will be assessed by the occurrence of a Grade 3/4 hepatotoxicity at any time during the assigned treatment period.
| percent | INH and Vitamin B6 |
|---|---|
| Cumulative Incidence of Participants Experiencing a Grade 3/4 Hepatotoxicity | 8.3 (5.4 to 12.0) |
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.
| Participants | INH and Vitamin B6 |
|---|---|
| Number of Participants Who Discontinued Treatment | 32 |
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.
| percentage of participants | INH and Vitamin B6 |
|---|---|
| at 3 months | 31.3 |
| at 6 months | 43.9 |
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.
| days | INH and Vitamin B6 |
|---|---|
| at 3 months | 30 (28 to 30) |
| at 6 months | 30 (27 to 30) |
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.
| Participants | INH and Vitamin B6 |
|---|---|
| At 3 months — Excellent | 160 |
| At 3 months — Very good | 79 |
| At 3 months — Good | 38 |
| At 3 months — Fair | 0 |
| At 3 months — Poor | 2 |
| At 3 months — Very poor | 0 |
| At 6 months — Excellent | 124 |
| At 6 months — Very good | 90 |
| At 6 months — Good | 41 |
| At 6 months — Fair | 4 |
| At 6 months — Poor | 0 |
| At 6 months — Very poor | 1 |
INH concentration in hair (pmol/mg) will be measured at 3- and 6- months during INH therapy.
| pmol/mg | INH and Vitamin B6 |
|---|---|
| at 3 months | 36.0 (18.7 to 63.3) |
| at 6 months | 37.8 (13.7 to 60.4) |
Alanine transaminase (ALT) or aspartate transaminase (AST) elevations (\>2x the upper limit of normal) at study screening
| Participants | Study Screening |
|---|---|
| Number of Participants With Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Elevations at Study Screening | 80 |
Latent tuberculosis assessed at screening via tuberculin skin testing (TST). A TST induration \>=5mm was considered positive for latent tuberculosis.
| Participants | Study Screening |
|---|---|
| Number of Participants With Latent Tuberculosis at Study Screening. | 308 |
Collected over Data were collected over the course of study participation, for a maximum of 42 months.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| INH and Vitamin B6 | 2/301 (0.7%) | 11/301 (3.7%) | 88/301 (29.2%) |
| Event | INH and Vitamin B6 |
|---|---|
| Elevated AST or ALTHepatobiliary disorders | 6/301 |
| AccidentInjury, poisoning and procedural complications | 2/301 |
| DeathGeneral disorders | 2/301 |
| SepticemiaInfections and infestations | 1/301 |
| Low hemoglobinBlood and lymphatic system disorders | 1/301 |
| High blood pressureCardiac disorders | 1/301 |
| HospitalizationGeneral disorders | 1/301 |
| Event | INH and Vitamin B6 |
|---|---|
| Grade 2: AST or ALT elevationHepatobiliary disorders | 62/301 |
| Grade 3: AST or ALT elevationHepatobiliary disorders | 18/301 |
| PPD hypersensitivityImmune system disorders | 3/301 |
| ParesthesiasNervous system disorders | 2/301 |
| Skin rashSkin and subcutaneous tissue disorders | 2/301 |
| DizzinessGeneral disorders | 2/301 |
| HypertensionCardiac disorders | 2/301 |
| FatigueGeneral disorders | 1/301 |
| Abdominal painGastrointestinal disorders | 1/301 |
| VomitingGeneral disorders | 1/301 |
1 of 302 persons originally enrolled in the study was found to be ineligible during their baseline interview. They were disenrolled immediately and are excluded from all analyses, leaving 301 participants for analysis.
| Age, Continuous(year) | INH and Vitamin B6 |
|---|---|
| Median | 40 (33 to 47) |
| Sex: Female, Male(Participants) | INH and Vitamin B6 |
|---|---|
| Female | 154 |
| Male | 147 |
| Race and Ethnicity Not Collected(Participants) | INH and Vitamin B6 |
|---|
| Region of Enrollment(participants) | INH and Vitamin B6 |
|---|---|
| Uganda | 301 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No — 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.
Ran from Apr 2017 to primary completion in Apr 2021, 47 months.
Results were first posted in Oct 2023, 2 years 6 months after primary completion.
Of 22 phase 4 interventional studies under Tuberculosis, half reached primary completion within 36 months of starting (the median), counting those still running; a quarter within 26 and three quarters within 47. This study's 47 months is above that.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Sep 2023. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Isoniazid · Pyridoxine
University of California, San Francisco →