Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention (3HP Options Implementation Trial)

University of California San Francisco (UCSF)

Status: Completed

Conditions: Tuberculosis; Latent Tuberculosis; HIV/AIDS

Treatments: Other: Cost reimbursement SAT; Other: Weekly DOT visit reminders; Other: Cost reimbursement DOT; Other: 99DOTS; Other: Weekly SAT dosing reminders/check-ins; Other: Streamlined weekly DOT visits

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT03934931

R01HL144406

Details and patient eligibility

About

The Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention (3HP Options Implementation Trial) study will be a three-arm, open-label, parallel, randomized trial. This hybrid effectiveness-implementation trial will be conducted among people living with HIV infection (PLHIV) enrolled in HIV/AIDS care at the Mulago Immune Suppression Syndrome (i.e., HIV/AIDS) clinic in Kampala, Uganda. The overall objective of this study is to identify a patient-centered delivery strategy that will facilitate acceptance and completion of a three-month (12-dose) regimen of weekly rifapentine (RPT) and isoniazid (INH) by PLHIV enrolled in routine HIV/AIDS care in a high HIV/TB burden country. The primary outcome will be acceptance and completion of 3HP. Additional objectives will be to evaluate the implementation and cost-effectiveness of each delivery strategy.

Full description

The overall objective of this study is to identify a patient-centered strategy that will facilitate 3HP uptake by PLHIV in the context of routine HIV/AIDS care in a high HIV/TB burden country. The investigators' central hypothesis is that offering PLHIV an informed choice between directly observed therapy (DOT) and self-administered therapy (SAT) delivery strategies that are optimized to overcome key barriers to treatment adherence will result in greater acceptance and completion of 3HP. To test this hypothesis, the investigators will conduct a pragmatic randomized trial of three optimized strategies for delivering 3HP. Eligible participants will be randomized to one of three arms to receive latent tuberculosis infection (LTBI) treatment with once weekly INH and RPT for 12 weeks given by either facilitated DOT, facilitated SAT, or an informed choice between facilitated DOT and facilitated SAT (with the assistance of a decision aid tool).

Primary Objective: To compare the uptake of 3HP under three delivery strategies: 1) Facilitated DOT; 2) Facilitated SAT; and 3) Informed patient choice (using a decision aid) between facilitated DOT and facilitated SAT. The primary outcome will be defined as the proportion of eligible participants who accept treatment and take at least 11 of 12 doses of RPT/INH within 16 weeks of treatment initiation. Study staff will assess medication dosing using clinic records for participants taking 3HP by DOT and using a combination of 99DOTS (Everwell Health Solutions, India) digital medication adherence technology records and pill counts at refill visits for participants taking 3HP by SAT.

Secondary Objectives:

1. To estimate the costs and compare the cost-effectiveness of the three strategies for delivering 3HP.
2. To identify processes and contextual factors that influence patient acceptance and completion of 3HP under each delivery strategy.
3. To identify clinic-level barriers to adoption and implementation of 3HP under each delivery strategy.
4. To determine the proportion of patients for whom 3HP treatment is discontinued due to adverse events/intolerance.
5. To determine the cumulative 16-month incidence of active TB in each arm, categorized as definite (positive sputum Xpert MTB/RIF or culture) or probable (TB medications started at the discretion of a clinician, with evidence of subsequent improvement).
6. To determine the cumulative 28-month incidence of active TB in each arm, categorized as definite (positive sputum Xpert MTB/RIF or culture) or probable (TB medications started at the discretion of a clinician, with evidence of subsequent improvement).

Enrollment: 1,656 patients

Sex: All

Ages: 18 to 100 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

• HIV-positive client engaged in care at the Mulago ISS clinic
• Weight ≥40kg
• Age 18 years or older
• Capacity to provide informed consent in English or Luganda

Exclusion criteria

• Suspicion of active TB based on positive World Health Organization (WHO) symptom screen AND elevated point-of-care (POC) C-reactive protein (CRP), or current or planned TB treatment
• Actively taking an antiretroviral medication contraindicated for use with rifapentine under contemporary WHO or Ugandan policy
• Contact of a TB patient with known resistance to isoniazid or rifamycins
• Women who are pregnant, breast feeding or intending to get pregnant in the next 120 days
• Prisoners
• Previously completed treatment for active TB or at least 6 months of isoniazid preventive therapy within past 2 years
• Not intending to remain within 25 km of the Mulago ISS clinic during the study period or to receive further care at the Mulago ISS clinic
• Lack of access to a mobile telephone or lack of willingness to receive SMS reminders
• Pre-existing documentation of clinical liver disease.
• History of sensitivity or intolerance to isoniazid or rifamycins
• Another household member already enrolled in the study (household members cannot be effectively randomized to different arms)
• Actively taking medication contraindicated for use with rifamycin (e.g., warfarin, phenytoin)

Mixed methods and health economic sub-studies will include a subset of participants enrolled in the trial, as well as clinic administrators and clinicians (clinical officer, doctor, nurse or pharmacist) involved in 3HP delivery at the Mulago ISS clinic.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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1,656 participants in 3 patient groups

Facilitated Directly Observed Therapy (DOT)

Experimental group

Description:

Facilitated DOT arm participants will attend the Mulago Immune Suppression Syndrome (ISS) clinic on a weekly basis to ingest 3HP medication under direct observation. DOT will be defined as a designated clinic staff member observing ingestion of each dose of 3HP. Additionally, participants randomized to facilitated DOT will receive: 1) DOT cards with instructions to present directly to the pharmacy for a pharmacy-only visit, without the need to wait in the general queue; 2) Automated short message service (SMS) or phone call reminders at no cost to participants the day before each appointment, 3) A fixed level of reimbursement (\~$5/visit) for each weekly visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment.

Treatment:

Other: Streamlined weekly DOT visits

Other: Cost reimbursement DOT

Other: Weekly DOT visit reminders

Facilitated Self-Administered Therapy (SAT)

Experimental group

Description:

Facilitated SAT participants will take their 1st dose of medication under direct observation and be given a 4-week 3HP supply to take weekly via self-administration. Participants will return to the Mulago ISS clinic after completing their 5th dose to review adherence data with the clinic pharmacy technician and receive 5 additional 3HP doses (doses 7-11). At the scheduled refill visit (dose 6) and end-of-treatment visit (dose 12) participants will ingest 3HP via direct observation. Participants will also receive: 1) Free automated SMS reminders or phone call reminders before each scheduled dose; 2) Weekly check-ins inquiring about side effects via two-way SMS with a follow-up phone call depending on participant response, 3) Fixed level of reimbursement (\~$5/visit) for the refill/end-of-treatment visit, conditional on either directly observed therapy or evidence of an adverse event that would preclude further treatment.

Treatment:

Other: Weekly SAT dosing reminders/check-ins

Other: 99DOTS

Other: Cost reimbursement SAT

Patient Choice between facilitated DOT and facilitated SAT

Experimental group

Description:

Participants randomized to the Patient Choice between facilitated DOT and facilitated SAT arm will be offered a choice between arms 1 and 2. A research nurse will review each section of the decision aid with participants, discuss values and preferences, and, after addressing any questions, ask participants to select facilitated DOT or facilitated SAT. Participants will have the option to switch between DOT and SAT at any time. The reason for switching and time spent under each strategy will be recorded.

Treatment:

Other: Streamlined weekly DOT visits

Other: Weekly SAT dosing reminders/check-ins

Other: 99DOTS

Other: Cost reimbursement DOT

Other: Weekly DOT visit reminders

Other: Cost reimbursement SAT