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

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ClinicalTrials.gov Identifier: NCT03934931
Recruitment Status : Recruiting
First Posted : May 2, 2019
Last Update Posted : August 6, 2020
Sponsor:
Collaborators:
Makerere University
Johns Hopkins Bloomberg School of Public Health
University of Colorado, Denver
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Tuberculosis Latent Tuberculosis HIV/AIDS 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 Not Applicable

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 study enrollment. 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1656 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Options for Delivering Isoniazid-Rifapentine (3HP) for TB Prevention: the 3HP Options Implementation Trial
Actual Study Start Date : July 13, 2020
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Rifapentine

Arm Intervention/treatment
Experimental: Facilitated Directly Observed Therapy (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.
Other: Streamlined weekly DOT visits
Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects

Other: Weekly DOT visit reminders
Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits

Other: Cost reimbursement DOT
Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)

Experimental: Facilitated Self-Administered Therapy (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.
Other: 99DOTS
99DOTS-based digital adherence technology to monitor and promote adherence

Other: Weekly SAT dosing reminders/check-ins
Weekly SMS or IVR phone call dosing reminder/check-in for side effects

Other: 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)

Experimental: Patient Choice between facilitated DOT and facilitated 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.
Other: Streamlined weekly DOT visits
Streamlined, weekly DOT clinic visits to have health worker observe medication ingestion and screen for side effects

Other: Weekly DOT visit reminders
Weekly SMS or interactive voice response (IVR) phone call reminder for DOT clinic visits

Other: Cost reimbursement DOT
Reimbursement of costs associated with weekly clinic visits (15,000 Ush/visit in Weeks 2-12)

Other: 99DOTS
99DOTS-based digital adherence technology to monitor and promote adherence

Other: Weekly SAT dosing reminders/check-ins
Weekly SMS or IVR phone call dosing reminder/check-in for side effects

Other: 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)




Primary Outcome Measures :
  1. Acceptance and completion of 3HP [ Time Frame: Within 16 weeks of study enrollment ]
    The proportion of eligible participants who accept treatment and take at least 11 of 12 once weekly doses of RPT/INH within 16 weeks of study enrollment.


Secondary Outcome Measures :
  1. Treatment acceptance [ Time Frame: Within 16 weeks of study enrollment ]
    Proportion of eligible PLHIV offered 3HP who accept to initiate treatment (by age, gender, CD4 stratum, viral load suppression).

  2. Treatment completion [ Time Frame: Within 16 weeks of study enrollment ]
    Proportion of participants who take at least 11 of 12 doses within 16 weeks of enrollment of those who take at least one dose of 3HP.

  3. 3HP discontinuation due to adverse events/intolerance [ Time Frame: Within 16 weeks of study enrollment ]
    Proportion of participants who initiate 3HP for whom treatment is discontinued due to adverse events or intolerance.

  4. Cumulative incidence of TB [ Time Frame: 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

  5. Cost effectiveness (patient perspective) [ Time Frame: At the conclusion of the study period, estimated 3 years ]
    The incremental patient cost per DALY averted.

  6. Cost effectiveness (health system perspective) [ Time Frame: At the conclusion of the study period, estimated 3 years ]
    The incremental health system cost per disability-adjusted life year (DALY) averted.

  7. Cost effectiveness (overall perspective) [ Time Frame: At the conclusion of the study period, estimated 3 years ]
    Incremental cost of each delivery strategy per disability adjusted life year (DALY) averted.

  8. Visit Cost Reimbursement - overall [ Time Frame: Through study completion, an average of 16 weeks ]
    Proportion reimbursed overall

  9. Visit Cost Reimbursement [ Time Frame: 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

  10. Time to complete clinic visit - mean minutes [ Time Frame: 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

  11. Time to complete clinic visit - median minutes [ Time Frame: 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

  12. SMS or IVR phone call reminders delivered - clinic visits [ Time Frame: 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

  13. Screening for active TB [ Time Frame: 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

  14. Screening for side effects [ Time Frame: 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.

  15. Dosing confirmation via 99DOTS (SAT only) [ Time Frame: 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.

  16. SMS or IVR phone call reminders delivered - medication dosing (SAT only) [ Time Frame: 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

  17. SMS or IVR phone calls delivered - weekly check-in (SAT only) [ Time Frame: 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

  18. SMS or IVR phone call reminders delivered - missed dose (SAT only) [ Time Frame: 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

  19. SMS or IVR phone call missed appointment reminders delivered [ Time Frame: 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

  20. Follow up (phone calls or home visits) for negative response to weekly SMS or IVR phone call check-in (SAT only) [ Time Frame: 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

  21. Costs of preventive services [ Time Frame: Through study completion, an average of 16 weeks ]
    Mean total participant costs related to TB preventive care services

  22. Participant satisfaction [ Time Frame: Through study completion, an average of 16 weeks ]
    Mean score on participant satisfaction questionnaire

  23. Barriers to 3HP delivery from the provider/clinic perspective [ Time Frame: 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.

  24. Barriers to 3HP completion from the patient perspective [ Time Frame: Through study completion, an average of 16 weeks ]
    Thematic interpretation of barriers to 3HP completion from patient interviews



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03934931


Contacts
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Contact: Adithya Cattamanchi, MD +1-415-206-5489 adithya.cattamanchi@ucsf.edu

Locations
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Uganda
Mulago Immune Suppression Syndrome (ISS) Clinic Recruiting
Kampala, Uganda
Contact: Fred C Semitala, M.B.Ch.B    +256-755-553-004    semitala@gmail.com   
Principal Investigator: Fred C Semitala, M.B.Ch.B         
Sponsors and Collaborators
University of California, San Francisco
Makerere University
Johns Hopkins Bloomberg School of Public Health
University of Colorado, Denver
Investigators
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Principal Investigator: Adithya Cattamanchi, MD University of California, San Francisco
Principal Investigator: David W Dowdy, PhD Johns Hopkins Bloomberg School of Public Health
Publications:
TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, Ouassa T, Ouattara E, Anzian A, Ntakpé JB, Minga A, Kouame GM, Bouhoussou F, Emieme A, Kouamé A, Inwoley A, Toni TD, Ahiboh H, Kabran M, Rabe C, Sidibé B, Nzunetu G, Konan R, Gnokoro J, Gouesse P, Messou E, Dohoun L, Kamagate S, Yao A, Amon S, Kouame AB, Koua A, Kouamé E, Ndri Y, Ba-Gomis O, Daligou M, Ackoundzé S, Hawerlander D, Ani A, Dembélé F, Koné F, Guéhi C, Kanga C, Koule S, Séri J, Oyebi M, Mbakop N, Makaila O, Babatunde C, Babatounde N, Bleoué 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-Semdé C, Kouame A, Massumbuko JM, Chêne G, Dosso M, Domoua SK, N'Dri-Yoman T, Salamon R, Eholié 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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03934931    
Other Study ID Numbers: R01HL144406 ( U.S. NIH Grant/Contract )
First Posted: May 2, 2019    Key Record Dates
Last Update Posted: August 6, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Provided upon request
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by University of California, San Francisco:
latent tuberculosis
tuberculosis
HIV/AIDS
implementation science
Uganda
3HP
shared decision making
rifapentine
Additional relevant MeSH terms:
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Tuberculosis
Latent Tuberculosis
Acquired Immunodeficiency Syndrome
HIV Infections
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases