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

Study Overview
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Brief Summary
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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
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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: To estimate the costs and compare the cost-effectiveness of the three strategies for delivering 3HP. To identify processes and contextual factors that influence patient acceptance and completion of 3HP under each delivery strategy. To identify clinic-level barriers to adoption and implementation of 3HP under each delivery strategy. To determine the proportion of patients for whom 3HP treatment is discontinued due to adverse events/intolerance. 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). 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).

Official Title
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Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention: the 3HP Options Implementation Trial

Conditions
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Tuberculosis, Latent Tuberculosis, HIV/AIDS

Intervention / Treatment
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* Other: Streamlined weekly DOT visits
* Other: Weekly DOT visit reminders
* Other: Cost reimbursement DOT
* Other: 99DOTS
* Other: Weekly SAT dosing reminders/check-ins
* Other: Cost reimbursement SAT


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Facilitated Directly Observed Therapy (DOT)<br>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. | Other: Streamlined weekly DOT visits<br>* Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects<br>Other: Weekly DOT visit reminders<br>* Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits<br>Other: Cost reimbursement DOT<br>* Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)<br>|
| Experimental: Facilitated Self-Administered Therapy (SAT)<br>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. | Other: 99DOTS<br>* 99DOTS-based digital adherence technology to monitor and promote adherence<br>Other: Weekly SAT dosing reminders/check-ins<br>* Weekly SMS or IVR phone call dosing reminder/check-in for side effects<br>Other: Cost reimbursement SAT<br>* Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)<br>|
| Experimental: Patient Choice between facilitated DOT and facilitated SAT<br>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. | Other: Streamlined weekly DOT visits<br>* Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects<br>Other: Weekly DOT visit reminders<br>* Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits<br>Other: Cost reimbursement DOT<br>* Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)<br>Other: 99DOTS<br>* 99DOTS-based digital adherence technology to monitor and promote adherence<br>Other: Weekly SAT dosing reminders/check-ins<br>* Weekly SMS or IVR phone call dosing reminder/check-in for side effects<br>Other: Cost reimbursement SAT<br>* Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Who Accepted and Completed 3HP | 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. | Within 16 weeks of treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Who Accepted 3HP Treatment | 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. | Within 16 weeks of treatment initiation | 
| Proportion of Participants Who Completed 3HP Treatment | 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. | Within 16 weeks of treatment initiation | 
| Proportion of People Who Discontinued 3HP Treatment Due to Adverse Events/Intolerance | Count of participants for whom treatment is discontinued due to adverse events or intolerance divided by the count of those who initiated 3HP. | Within 16 weeks of treatment initiation | 
| Cumulative Incidence of Tuberculosis (TB) | Cumulative 16-month incidence of active TB in each arm | 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 Incidence of TB | Cumulative 28-month incidence of active TB in each arm | 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 | 
| Cost Effectiveness (Patient Perspective) | The incremental patient cost per disability-adjusted life year (DALY) averted. | At the conclusion of the study period, estimated 3 years | 
| Cost Effectiveness (Health System Perspective) | The incremental health system cost per disability-adjusted life year (DALY) averted. | At the conclusion of the study period, estimated 3 years | 
| Cost Effectiveness (Overall Perspective) | Incremental cost of each delivery strategy per disability adjusted life year (DALY) averted. | At the conclusion of the study period, estimated 3 years | 
| Visit Cost Reimbursement - Overall | Proportion reimbursed overall | Through study completion, an average of 16 weeks | 
| Visit Cost Reimbursement | Proportion reimbursed on the same day as each 3HP clinic visit | On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks | 
| Time to Complete Clinic Visit - Mean Minutes | Mean number of minutes for each DOT/refill visit | On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks | 
| Time to Complete Clinic Visit - Median Minutes | Median number of minutes for each DOT/refill visit | On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks | 
| Short Messages Service (SMS) or Interactive Voice Response (IVR) Phone Call Reminders Delivered - Clinic Visits | Proportion of SMS or IVR phone call reminders delivered to participants for clinic visits | The day before each 3HP clinic visit throughout study completion, an average of 16 weeks | 
| Screening for Active TB | Proportion of participants screened for active TB during DOT or refill visits | On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks | 
| Screening for Side Effects | Proportion of participants screened for side effects during DOT or refill visits. | On the same day as each 3HP clinic visit throughout study completion, an average of 16 weeks | 
| Dosing Confirmation Via 99DOTS (SAT Only) | 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. | On the same day as each scheduled dose throughout study completion, an average of 16 weeks | 
| SMS or IVR Phone Call Reminders Delivered - Medication Dosing (SAT Only) | Proportion of SMS or IVR phone call reminders delivered to participants for medication dosing | The day before each scheduled dose throughout study completion, an average of 16 weeks | 
| SMS or IVR Phone Calls Delivered - Weekly check-in (SAT Only) | Proportion of weekly SMS or IVR phone call check-ins delivered to participants | On the same day as each scheduled dose throughout study completion, an average of 16 weeks | 
| SMS or IVR Phone Call Reminders Delivered - Missed Dose (SAT Only) | Proportion of SMS or IVR phone call reminders delivered to participants following missed doses | 24 hours after missed scheduled dose throughout study completion, an average of 16 weeks | 
| SMS or IVR Phone Call Missed Appointment Reminders Delivered | Proportion of SMS or IVR phone call reminders delivered to participants following missed appointments | 24 hours after missed scheduled appointment throughout study completion, an average of 16 weeks | 
| Follow up (Phone Calls or Home Visits) for Negative Response to Weekly SMS or IVR Phone Call check-in (SAT Only) | 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 | 24 hours after negative response throughout study completion, an average of 16 weeks | 
| Costs of Preventive Services | Mean total participant costs related to TB preventive care services | Through study completion, an average of 16 weeks | 
| Participant Satisfaction | Mean score on participant satisfaction questionnaire | Through study completion, an average of 16 weeks | 
| Barriers to 3HP Delivery From the Provider/Clinic Perspective | Thematic interpretation of provider- and clinic-level barriers to care from provider focus group discussions. | At the conclusion of the study period, estimated 3 years | 
| Barriers to 3HP Completion From the Patient Perspective | Thematic interpretation of barriers to 3HP completion from patient interviews | Through study completion, an average of 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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latent tuberculosis, tuberculosis, HIV/AIDS, implementation science, Uganda, 3HP, shared decision making, rifapentine