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

Not Applicable

Active, not recruiting

• Conditions: Tuberculosis; Latent Tuberculosis; HIV/AIDS
• Interventions: Other: 99DOTS; Other: Streamlined weekly DOT visits; Other: Weekly SAT dosing reminders/check-ins; Other: Weekly DOT visit reminders; Other: Cost reimbursement DOT; Other: Cost reimbursement SAT

• Registration Number: NCT03934931
• Lead Sponsor: University of California, San Francisco

Brief Summary

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.

Detailed 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).

Study Timeline

• Study First Submitted: 2019-04-22
• Study First Submitted QC: 2019-04-29
• Study First Posted: 2019-05-02
• Study Start: 2020-07-13
• Primary Completion: 2022-09-29
• Results First Submitted: 2023-09-27
• Status Verified: 2023-11
• Results First Submitted QC: 2023-11-02
• Results First Posted: 2023-11-07
• Last Update Submitted: 2023-11-16
• Last Update Posted: 2023-11-18
• Study Completion: 2024-11-08

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 1656

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Facilitated Self-Administered Therapy (SAT)	99DOTS	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.
Facilitated Directly Observed Therapy (DOT)	Streamlined weekly DOT visits	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.
Facilitated Self-Administered Therapy (SAT)	Weekly SAT dosing reminders/check-ins	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.
Patient Choice between facilitated DOT and facilitated SAT	Weekly SAT dosing reminders/check-ins	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.
Facilitated Directly Observed Therapy (DOT)	Cost reimbursement DOT	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.
Patient Choice between facilitated DOT and facilitated SAT	Streamlined weekly DOT visits	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.
Facilitated Directly Observed Therapy (DOT)	Weekly DOT visit reminders	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.
Patient Choice between facilitated DOT and facilitated SAT	Weekly DOT visit reminders	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.
Patient Choice between facilitated DOT and facilitated SAT	Cost reimbursement DOT	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.
Facilitated Self-Administered Therapy (SAT)	Cost reimbursement SAT	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.
Patient Choice between facilitated DOT and facilitated SAT	99DOTS	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.
Patient Choice between facilitated DOT and facilitated SAT	Cost reimbursement SAT	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.

Primary Outcome Measures

Name	Time	Method
Proportion of Participants Who Accepted and Completed 3HP	Within 16 weeks of treatment initiation	The count of eligible participants who accept treatment and take at least 11 of 12 once weekly doses of rifapentine (RPT)/isoniazid (INH) within 16 weeks of treatment initiation divided by the count of those randomized.

Secondary Outcome Measures

Name	Time	Method
Cost Effectiveness (Patient Perspective)	At the conclusion of the study period, estimated 3 years	The incremental patient cost per disability-adjusted life year (DALY) averted.
Cost Effectiveness (Overall Perspective)	At the conclusion of the study period, estimated 3 years	Incremental cost of each delivery strategy per disability adjusted life year (DALY) averted.
Proportion of Participants Who Completed 3HP Treatment	Within 16 weeks of treatment initiation	Count of participants who take at least 11 of 12 doses within 16 weeks of treatment initiation divided by the count those who take at least one dose of 3HP.
Cumulative Incidence of Tuberculosis (TB)	from date of 3HP treatment completion (11/12 doses) or once reached 16 weeks (regardless of number of doses taken) until time of active TB diagnosis or treatment initiation, death, loss to follow-up or end of the 12-month post-treatment follow-up period	Cumulative 16-month incidence of active TB in each arm
Cumulative Incidence of TB	from date of 3HP treatment completion (11/12 doses) or once reached 16 weeks (regardless of number of doses taken) until time of active TB diagnosis or treatment initiation, death, loss to follow-up or end of the 24-month post-treatment follow-up period	Cumulative 28-month incidence of active TB in each arm
Visit Cost Reimbursement	On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks	Proportion reimbursed on the same day as each 3HP clinic visit
Time to Complete Clinic Visit - Median Minutes	On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks	Median number of minutes for each DOT/refill visit
Dosing Confirmation Via 99DOTS (SAT Only)	On the same day as each scheduled dose throughout study completion, an average of 16 weeks	Proportion of doses confirmed using digital adherence technology. Doses directly observed (i.e., during initial or refill visits) will not be included in the denominator.
Follow up (Phone Calls or Home Visits) for Negative Response to Weekly SMS or IVR Phone Call check-in (SAT Only)	24 hours after negative response throughout study completion, an average of 16 weeks	Proportion of participants who receive appropriate follow-up (phone call or home visit) for lack of response/negative response to weekly check-in SMS or IVR phone call
Costs of Preventive Services	Through study completion, an average of 16 weeks	Mean total participant costs related to TB preventive care services
Barriers to 3HP Delivery From the Provider/Clinic Perspective	At the conclusion of the study period, estimated 3 years	Thematic interpretation of provider- and clinic-level barriers to care from provider focus group discussions.
Proportion of People Who Discontinued 3HP Treatment Due to Adverse Events/Intolerance	Within 16 weeks of treatment initiation	Count of participants for whom treatment is discontinued due to adverse events or intolerance divided by the count of those who initiated 3HP.
Time to Complete Clinic Visit - Mean Minutes	On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks	Mean number of minutes for each DOT/refill visit
Barriers to 3HP Completion From the Patient Perspective	Through study completion, an average of 16 weeks	Thematic interpretation of barriers to 3HP completion from patient interviews
Proportion of Participants Who Accepted 3HP Treatment	Within 16 weeks of treatment initiation	The count of eligible people living with HIV (PLHIV) offered 3HP who accept to initiate treatment (by age, gender, CD4 stratum, viral load suppression) divided by the count of those randomized.
Cost Effectiveness (Health System Perspective)	At the conclusion of the study period, estimated 3 years	The incremental health system cost per disability-adjusted life year (DALY) averted.
Visit Cost Reimbursement - Overall	Through study completion, an average of 16 weeks	Proportion reimbursed overall
Short Messages Service (SMS) or Interactive Voice Response (IVR) Phone Call Reminders Delivered - Clinic Visits	The day before each 3HP clinic visit throughout study completion, an average of 16 weeks	Proportion of SMS or IVR phone call reminders delivered to participants for clinic visits
Screening for Active TB	On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks	Proportion of participants screened for active TB during DOT or refill visits
Screening for Side Effects	On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks	Proportion of participants screened for side effects during DOT or refill visits.
SMS or IVR Phone Call Reminders Delivered - Medication Dosing (SAT Only)	The day before each scheduled dose throughout study completion, an average of 16 weeks	Proportion of SMS or IVR phone call reminders delivered to participants for medication dosing
SMS or IVR Phone Calls Delivered - Weekly check-in (SAT Only)	On the same day as each scheduled dose throughout study completion, an average of 16 weeks	Proportion of weekly SMS or IVR phone call check-ins delivered to participants
SMS or IVR Phone Call Reminders Delivered - Missed Dose (SAT Only)	24 hours after missed scheduled dose throughout study completion, an average of 16 weeks	Proportion of SMS or IVR phone call reminders delivered to participants following missed doses
SMS or IVR Phone Call Missed Appointment Reminders Delivered	24 hours after missed scheduled appointment throughout study completion, an average of 16 weeks	Proportion of SMS or IVR phone call reminders delivered to participants following missed appointments
Participant Satisfaction	Through study completion, an average of 16 weeks	Mean score on participant satisfaction questionnaire

Trial Locations

Locations (1)

Mulago Immune Suppression Syndrome (ISS) Clinic; 🇺🇬 Kampala, Uganda