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

Tuberculosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03934931
• Other study ID #: R01HL144406
• Secondary ID: R01HL144406
• Status: Active, not recruiting
• Phase: N/A
• Start date: July 13, 2020
• Est. completion date: November 8, 2024

Study information

• Verified date: November 2023
• Source: University of California, San Francisco
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1656
• Est. completion date: November 8, 2024
• Est. primary completion date: September 29, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• HIV/AIDS
• Latent Tuberculosis
• Tuberculosis

Intervention

Other:
• Streamlined weekly DOT visits
Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects
• Weekly DOT visit reminders
Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits
• Cost reimbursement DOT
Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)
• 99DOTS
99DOTS-based digital adherence technology to monitor and promote adherence
• Weekly SAT dosing reminders/check-ins
Weekly SMS or IVR phone call dosing reminder/check-in for side effects
• Cost reimbursement SAT
Reimbursement of costs associated with streamlined refill and end-of treatment clinic visits (15,000 Ush/visit in Weeks 6 and 12)

Locations

Country	Name	City	State
Uganda	Mulago Immune Suppression Syndrome (ISS) Clinic	Kampala

Sponsors (5)

Lead Sponsor	Collaborator
University of California, San Francisco	Johns Hopkins Bloomberg School of Public Health, Makerere University, National Heart, Lung, and Blood Institute (NHLBI), University of Colorado, Denver

Country where clinical trial is conducted

Uganda, 

References & Publications (28)

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TEMPRANO ANRS 12136 Study Group; Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, Ouassa T, Ouattara E, Anzian A, Ntakpe JB, Minga A, Kouame GM, Bouhoussou F, Emieme A, Kouame A, Inwoley A, Toni TD, Ahiboh H, Kabran M, Rabe C, Sidibe B, Nzunetu G, Konan R, Gnokoro J, Gouesse P, Messou E, Dohoun L, Kamagate S, Yao A, Amon S, Kouame AB, Koua A, Kouame E, Ndri Y, Ba-Gomis O, Daligou M, Ackoundze S, Hawerlander D, Ani A, Dembele F, Kone F, Guehi C, Kanga C, Koule S, Seri J, Oyebi M, Mbakop N, Makaila O, Babatunde C, Babatounde N, Bleoue G, Tchoutedjem M, Kouadio AC, Sena G, Yededji SY, Assi R, Bakayoko A, Mahassadi A, Attia A, Oussou A, Mobio M, Bamba D, Koman M, Horo A, Deschamps N, Chenal H, Sassan-Morokro M, Konate S, Aka K, Aoussi E, Journot V, Nchot C, Karcher S, Chaix ML, Rouzioux C, Sow PS, Perronne C, Girard PM, Menan H, Bissagnene E, Kadio A, Ettiegne-Traore V, Moh-Semde C, Kouame A, Massumbuko JM, Chene G, Dosso M, Domoua SK, N'Dri-Yoman T, Salamon R, Eholie SP, Anglaret X. A Trial of Early Antiretrovirals and Isoniazid Preventive Therapy in Africa. N Engl J Med. 2015 Aug 27;373(9):808-22. doi: 10.1056/NEJMoa1507198. Epub 2015 Jul 20. — View Citation

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* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Visit Cost Reimbursement - Overall	Proportion reimbursed overall	Through study completion, an average of 16 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Costs of Preventive Services	Mean total participant costs related to TB preventive care services	Through study completion, an average of 16 weeks
Secondary	Participant Satisfaction	Mean score on participant satisfaction questionnaire	Through study completion, an average of 16 weeks
Secondary	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
Secondary	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