Bedaquiline Roll-out Evidence in Contacts and People Living With HIV to Prevent TB (BREACH-TB)

Bedaquiline Roll-out Evidence in Contacts and People Living With HIV to Prevent TB (BREACH-TB)

A seamless, staged Phase II/III, open-label, multicenter, non-inferiority trial, to compare the efficacy and safety of 4 weeks of bedaquiline (BDQ) versus a a standard regimen for preventing regimen for preventing confirmed or probable tuberculosis disease (TBD) during 72 weeks of follow-up among people living with HIV (PLHIV) and high-risk Close Contacts (CC) of adults with Drug Susceptible (DS) or Rifampin Resistant (RR) TB.

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis, Latent
• Intervention / Treatment: Drug: Bedaquiline; Drug: Levofloxacin; Combination product: Isoniazid, rifapentine

Detailed Description

Treating adult, adolescent, child, and pregnant close contacts (CCs) of drug-sensitive tuberculosis (DS-TB) who are high-risk for developing tuberculosis disease (TBD) as well as adult and adolescent people living with HIV (PLHIV) in high-tuberculosis burden regions with bedaquiline (BDQ) will be noninferior in reducing the risk of developing TBD compared with a WHO-recommended rifamycin-containing short-course regimen for TB preventive therapy (TPT).

Treating adult, adolescent, child, and pregnant CCs of rifampin-resistant tuberculosis (RR-TB) who are high-risk for developing TBD with BDQ will be noninferior in reducing the risk of developing TBD compared with levofloxacin.

• Study Type: Interventional
• Enrollment (Estimated): 2530
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Bonnie S. King, MHS; Phone Number: 4106249189; Email: bking6@jh.edu
• Study Contact Backup: Name: Kate Boehner, RN, MSN; Phone Number: 2012592222; Email: kate.b@jhu.edu

Study Locations

• Peru
  • Lima, Peru
    • Not yet recruiting
    • HNSEB (Hospital Nacional Sergio E. Bernales)
    • Contact: Program Manager Director; Email: SESCRO@pih.org
  • Lima, Peru
    • Not yet recruiting
    • SES Policlinico
    • Contact: Program Manager Director; Email: SESCRO@pih.org
• Tanzania
  • Moshi, Tanzania
    • Recruiting
    • Kilimanjaro Clinical Research Institute
    • Contact: Director; Email: blaymt@gmail.com
• Uganda
  • Kampala, Uganda
    • Recruiting
    • Joint Clinical Research Centre
    • Contact: Deputy Director of Research; Email: pamuge@jcrc.org.ug
  • Kampala, Uganda
    • Not yet recruiting
    • Makerere Lung Institute
    • Contact: Co-Investigator; Email: jmukwaba@gmail.com
  • Kampala, Uganda
    • Recruiting
    • MU-JHU Care Ltd.
    • Contact: Site Leader; Email: cnakabiito@mujhu.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

For Index Patient

• Any age

• A diagnosis of bacteriologically proven pulmonary TB
• Initiated on treatment for pulmonary TB within the past 90 days
• Have at least one close contact that is likely to be eligible for the study

For PLHIV Indication

Individuals must meet all of the following inclusion criteria to participate in this study:

• On a dolutegravir-based or other approved integrase inhibitor antiretroviral therapy (ART) regimen that does not interact with bedaquiline or rifapentine.

  • If on a protease inhibitor-based ART regimen, a participant can be enrolled following a 5-day washout with switch to a dolutegravir-based regimen prior to enrollment. A 14-day washout is required for efavirenz-based ART regimen with switch to a dolutegravir-based regimen prior to enrollment
  • If a participant is not currently on ART or is ART-naïve, the participant must have started a dolutegravir-based ART regimen prior to Enrollment.
• PLHIV who meet criteria for a TBD close contact should be enrolled under the close contact indication

For Close Contact Indication (DS- or RR-TB Index Patient)

• Definition of Close Contact (either/or):

  o Lives or lived in the same dwelling unit or plot of land and shares or has shared the same housekeeping arrangements as the Index Patient for one or more nights ≤ 90 days prior to the Index Patient starting TB treatment

  o Has shared more than four hours of indoor airspace with the Index Patient during any one-week period ≤ 90 days prior to the Index Patient starting TB treatment. This may include indoor airspace within or outside the home.

• Close contacts must be in one of the following high-risk groups:

  • All children 0 to <5 years old at the time of Enrollment, regardless of LTBI or HIV status
  • Adults, adolescents, and children ≥5 years of age who are TBI test positive (either skin test positive* or IGRA-positive) and whose HIV status is negative, indeterminate, or unknown.
  • Adults, adolescents, and children ≥5 years of age who have a documented HIV infection regardless of TBI test status.

Universal Enrollment Inclusion Criteria for PLHIV and Close Contacts of DS- or RR-TB Index Patient

A. Ability and willingness of participant (and/or parent/guardian) to provide informed consent (and assent, as applicable)

B. Documentation of HIV Status

For participants >=18 months of age known to be PLHIV:

• Certified copy of HIV clinic card or
• Certified copy of HIV testing that includes date, assay used and result

For participants <18 months of age who have never tested, or previous HIV test result was indeterminate, unknown, or negative more than three months prior to screening and/or result is not available:

• HIV-1 testing should be performed per Section 5.4.5 (HIV-1 Testing) during the study screen period.

For participants <18 months known to be CLHIV:

• Certified copies of HIV DNA and/or RNA testing that includes date, assay used, and result

For participants <18 months who have never tested, or previous HIV test result was indeterminate, unknown, or negative more than three months prior to screening and/or result is not available:

• HIV-1 testing should be performed per Section 5.4.5 (HIV-1 Testing) during the study screen period

C. Documentation of ART

• All PLHIV (for PLHIV indication and CC that are PLHIV) must be on a dolutegravir-based or other approved integrase inhibitor ART regimen that does not interact with bedaquiline or rifapentine.
• If on a protease inhibitor-based ART regimen, a participant can be enrolled following a 5-day washout with switch to a dolutegravir-based regimen prior to enrollment. A 14-day washout is required for efavirenz-based ART regimen with switch to a dolutegravir-based regimen prior to enrollment.
• If a participant is not currently on ART or is ART-naïve, they must have started a dolutegravir-based ART regimen prior to Enrollment.

D. Chest radiograph without evidence of active TBD, performed within 30 days prior to Enrollment

E. The following laboratory values obtained within 30 days prior to Enrollment.

• Alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal
• Total bilirubin ≤ 2.5 times the upper limit of normal
• Alkaline phosphatase ≤ 3 times the upper limit of normal
• Creatinine clearance ≥ 29 ml/min
• Serum potassium at or above the lower limit of normal
• Serum magnesium at or above the lower limit of normal
• Serum calcium at or above the lower limit of normal
• Platelet count of ≥ 50,000 /mm3
• Absolute neutrophil count (ANC) ≥ 1,000/mm3

F. Pregnancy test (for study candidates of childbearing potential*)

• Negative serum or urine pregnancy test within 7 days prior to enrollment.

*NOTE: Participants of childbearing potential are defined as females who have reached menarche or who have not been post-menopausal for at least 24 consecutive months (i.e., who have had menses within the preceding 24 months) or have not undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, or bilateral tubal ligation).

EXCLUSION CRITERIA

Exclusion Criteria for Index Patient A. Unwilling or unable to provide informed consent B. No close contacts likely to be eligible for the study C. Study staff unable to obtain status of TB drug susceptibility or resistance D. Known bedaquiline resistance of M. tb isolate E. Known fluoroquinolone resistance of M. tb isolate (for Index Patients with RR-TB)

Exclusion Criteria for PLHIV and Close Contacts of DS- or RR-TB Index Patient

A. Unwilling or unable to provide informed consent

B. Weight ≤ 3 kg

C. A current diagnosis of confirmed or probable or possible pulmonary or extrapulmonary TB at time of enrollment or confirmed or unconfirmed TB for children.

D. Previously completed treatment for TBD.

E. Prior completion of TPT (including but not limited to 6 or 9H, 1HP, 3HP, 4R, 3HR, 6Lfx) *

*NOTE: Completion of TBD treatment or TPT based on the opinion of the site investigator that a sufficient course of TPT was taken to constitute treatment completion

F. Current enrollment into another therapeutic clinical trial (See Section 5.8).

G. Any of the following medical conditions:

• Severe renal impairment (DAIDS Grade 4) or end-stage renal disease requiring hemodialysis or peritoneal dialysis
• Severe hepatic impairment (Child-Pugh C)
• Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to enrollment
• Severe cardiac arrythmia requiring medication
• Peripheral neuropathy ≥ Grade 2 (DAIDS)
• Diagnosis of porphyria at any time prior to study enrollment
• Corrected QTcF (Fridericia's formula) of >460 msec
• Unable to take oral medication
• Active drug or alcohol use or dependence that, in the site investigator's opinion, would interfere with adherence to study treatment.
• Serious illness requiring systemic treatment including parenteral therapy (e.g., antibiotics) and/or hospitalization within 30 days prior to Enrollment
• Prior exposure to bedaquiline or clofazimine
• Receipt of more than 7 cumulative days of isoniazid, a rifamycin, or a fluoroquinolone in the 90 days prior to enrollment
• Known bedaquiline resistance in Index Patient
• Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation
• Currently taking another medication that is prohibited with study medicines which cannot be stopped (with or without replacement) or requires a washout period longer than 14 days (See Appendix 7)
• Known pregnancy or breastfeeding

Specific Exclusion Criteria for Close Contacts of RR-TB Index Patient

• Known fluoroquinolone resistance in Index Patient
• Severe tendinopathy related to fluoroquinolones

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bedaquiline; 4 weeks of daily bedaquiline	Drug: Bedaquiline; CCs (Close Contacts) of DS-TB Index Patients and PLHIV at high risk of developing TBD; Children 0 to <5 years old who are HIV negative, regardless of latent tuberculosis infection (LTBI) result by TST (tuberculin skin test) or IGRA (interferon-gamma release assay); Adults, pregnant people, adolescents, and children ≥5 years old who are HIV negative and LTBI positive (by IGRA); Adults and adolescents ≥15 years of age who are living with HIV regardless of LTBI status, regardless of whether the participant is a CC CCs of RR-TB Index Patients at high risk of developing TBD; Children 0 to <5 years old, regardless of HIV status or LTBI result (by TST or IGRA); Adults, adolescents, and children ≥5 years old who are HIV negative and LTBI positive (by IGRA); Adults, pregnant people, adolescents, and children ≥5 years old who are living with HIV regardless of LTBI status Bedaquiline based on weight and/or age at Enrollment daily for four weeks (28 doses); Other Names: Sirturo
Active Comparator: Levofloxacin; 6 months of daily levofloxacin	Drug: Levofloxacin; CCs of RR-TB Index Patients at high risk of developing TBD; Children 0 to <5 years old, regardless of HIV status or LTBI result (by TST or IGRA); Adults, adolescents, and children ≥5 years old who are HIV status negative and LTBI positive (by IGRA); Adults, pregnant people, adolescents, and children ≥5 years old who are living with HIV regardless of LTBI status Levofloxacin (LFX) based on weight at Enrollment daily for 6 months (182 doses); Other Names: Levaquin
Active Comparator: 3HP; 3 months of weekly isoniazid (H) and rifapentine (P)	Combination product: Isoniazid, rifapentine; CCs of DS-TB Index Patients and PLHIV at high risk of developing TBD; Children 0 to <5 years old who are HIV status negative, regardless of latent tuberculosis infection (LTBI) result (WHO-recommended skin test or interferon-gamma release assay [IGRA]); Adults, adolescents, and children ≥5 years old who are HIV status negative and LTBI positive (by IGRA); Adults and adolescents ≥15 years of age who are living with HIV regardless of LTBI status, regardless of whether they are a CC 3HP: 3 months of weekly isoniazid (H) and rifapentine (P) (12 doses); Other Names: 3HP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety DS-TB CCs and PLHIV (Stage 1): Proportion of participants who permanently discontinue the randomized study drug due to a treatment-related adverse event by 18 weeks	Estimate of the safety of 1BDQ and 3HP among adult, adolescent, and child CCs of DS-TB Index Patients at high risk of developing TBD, as well as adult and adolescent PLHIV in high TB-burden settings	18 weeks
Safety for RR-TB CCs (Stage 1): Proportion of participants who permanently discontinue the randomized study drug due to a treatment-related adverse event by 36 weeks	Estimate of the safety of 1BDQ and 6 months of levofloxacin (6L) among adult, adolescent, and child CCs of RR-TB Index Patients at high risk of developing TBD	36 weeks
Treatment Completion - PLHIV & CCs of DS-TB (Stage 1): Proportion of participants completing assigned treatment within window prescribed in protocol	Estimate on-time treatment completion of 1BDQ & 3HP in adult, adolescent, & child CCs of DS-TB Index Patients at high risk of developing TBD, & adult and adolescent PLHIV in high TB-burden countries	18 weeks
Treatment Completion - CCs of RR-TB (Stage 1): Proportion of participants completing assigned treatment within window prescribed in protocol	Estimate on-time treatment completion of 1BDQ and 6 months of levofloxacin (6L) among adult, adolescent, and child CCs of RR-TB Index Patients at high risk of developing TBD	36 weeks
Primary Efficacy Endpoint (Stage 2): Number of enrolled participants (PLHIV, contacts of DS-TB or RR-TB) diagnosed with bacteriologically confirmed or probable / (if adult), and confirmed or unconfirmed (if child) TB disease	Number (per person-years) of participants diagnosed with confirmed or probable (if adult) and unconfirmed or confirmed (if child) TB disease, compared between the comparator arm and investigational (BDQ) arm and expressed as the averted events ratio (AER)	Up to 72 weeks post-treatment initiation
Primary Safety Endpoint (Stage 2): Cumulative number of enrolled participants (PLHIV, contacts of DS-TB or RR-TB) who permanently discontinue the assigned study regimen due to an adverse drug reaction	Proportion of individuals who permanently discontinue assigned study regimen due to a treatment-related adverse event, compared between the comparator arm and investigational (BDQ) arm.	Varies by treatment regimen (1 month, 3 months, or 6 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Proportion of participants who permanently discontinue the randomized study drug due to a treatment-related adverse event by 18 weeks	To compare the safety of 1BDQ to 3HP among adult, adolescent, and child CCs of DS-TB Index Patients at high risk of developing TBD as well as adult and adolescent PLHIV in high TB-burden settings	18 weeks
Stage 1: Proportion of participants who permanently discontinue the randomized study drug due to a treatment-related adverse event by 36 weeks	To compare the safety of 1BDQ to 6 months of levofloxacin (6L) among adult, adolescent, and child CCs of RR-TB Index Patients at high risk of developing TBD	36 weeks
Stage 1: Proportion of participants completing assigned treatment within window prescribed in protocol	To compare on-time treatment completion of 1BDQ to 6 months of levofloxacin (6L) among adult, adolescent, and child CCs of RR-TB Index Patients at high risk of developing TBD	Dependent on treatment assignment (1 month, 3 months, or 6 months)
Stage 1: Proportion of individuals who experience a grade 3 or higher AE, compared between the comparator arm and investigational (1BDQ) arm at 18 weeks	To compare the safety of 1BDQ to 3HP among adult, adolescent, and child CCs of DS-TB Index Patients at high risk of developing TBD, as well as adult and adolescent PLHIV in high TB-burden settings	18 weeks
Stage 1: Proportion of participants completing assigned treatment within window prescribed in protocol	To compare on-time treatment completion of 1BDQ to 3HP among adult, adolescent, and child CCs of DS-TB Index Patients at high risk of developing TBD as well as adult and adolescent PLHIV in high TB-burden settings	Dependent upon treatment assignment (1 month, 3 months, or 6 months)
Stage 1: Proportion of individuals who experience a grade 3 or higher AE, compared between the comparator arm and investigational (1BDQ) arm at 36 weeks	To compare the safety of 1BDQ to 6 months of levofloxacin (6L) among adult, adolescent, and child CCs of RR-TB Index Patients at high risk of developing TBD	36 weeks
Stage 1: Proportion of participants who experience a TBD event at up to 72 weeks of follow-up, by study arm	To estimate the number of incident TBD events in each study arm, at up to 72 weeks of follow-up	Up to 72 weeks
Secondary Efficacy Endpoint (Stage 2): # of enrolled participants (PLHIV, contacts of DS-TB, RR-TB) who reach a composite outcome of bacteriologically confirmed, probable, or possible (if adult) and confirmed or unconfirmed (if child) TBD or death	Number, per person-years, of participants diagnosed with bacteriologically confirmed, probable, or possible (if adult) and confirmed or unconfirmed (if child) TB disease or death from any cause (except for violent or accidental death), compared between the comparator arm and investigational (BDQ) arm and expressed as the AER.	72 weeks post-treatment initiation
Secondary Safety Endpoint (Stage 2): Cumulative number of enrolled participants (PLHIV, contacts of DS-TB or RR-TB) who experience a grade 3 or higher AE	Proportion of individuals who experience a grade 3 or higher AE, compared between the comparator arm and investigational (BDQ) arm	Varies by treatment regimen duration (1 month, 3 months, or 6 months)
Secondary Endpoint of Treatment Completion (Stage 2): Proportion of participants who have taken at least 90% of the doses within the specified timeframe of the assigned regimen	The absolute difference in proportions of the number of participants who have taken at least 90% of their doses within the specified timeframe of their assigned regimen, and the corresponding 95% confidence interval	Varies by treatment regimen duration (1 month, 3 months, or 6 months)
Stage 1: Proportion of participants who experience a composite outcome at up to 72 weeks of follow-up, by study arm	To estimate the number of composite outcomes of confirmed, probable or possible (if adult), or confirmed or unconfirmed (if child) TBD & all-cause mortality due to any cause, except violent or accidental death in each study arm, up to 72 weeks	Up to 72 weeks

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: Elizabeth Glaser Pediatric AIDS Foundation; US Department of State
• Investigators: Study Chair: Eric Nuermberger, MD, Johns Hopkins School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: August 21, 2024
• First Submitted That Met QC Criteria: August 21, 2024
• First Posted (Actual): August 23, 2024

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Bedaquiline
• Additional Relevant MeSH Terms: Latent Infection; Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Latent Tuberculosis; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Ofloxacin; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Levofloxacin; Isoniazid; rifapentine; bedaquiline
• Other Study ID Numbers: IRB00443418; 7200AA22CA00005 (Other Grant/Funding Number: USAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified data that can be legally released.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• 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.: No