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

A Phase III, open-label, multicenter, non-inferiority trial, to compare the efficacy and safety of 4 weeks of bedaquiline (BDQ) versus a World Health Organization (WHO) -recommended regimen for preventing confirmed or probable tuberculosis disease (TBD) during 96 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.

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.

Eligibility Criteria:
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.

  o 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

  o 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 tuberculin skin test (TST) -positive (≥5 mm) or IGRA-positive) and whose HIV status is negative, indeterminate, or unknown (See Section 5.4 Laboratory Evaluations for testing time frame).
  * 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

* Certified copy of HIV clinic card or certified copy of HIV result that includes date, assay used and result to be included in the participant file.
* If adequate evidence of HIV status is not available, an HIV-1 antibody test sample must be collected during the study screen period. Note: Participant should also have an HIV-1 antibody test if never tested, or previous HIV test result was indeterminate, unknown, or negative more than one year prior to screening.

For potential participants, appropriate HIV-1 testing (and confirmatory testing as indicated by age) should be done following the standard of care in use at the site.

For participants \<18 months

* Initial and confirmatory HIV-1 DNA Polymerase Chain Reaction (PCR) and/or HIV-1 RNA viral load
* Certified copies of HIV DNA and/or RNA result that includes date, assay used, and result to be included in the participant file

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

D. 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
* 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

E. Pregnancy test (for study candidates of childbearing potential\*) a. PLHIV/DS-TB CC indication: i. PLHIV: negative serum or urine pregnancy test within 7 days prior to enrollment.

ii. DS-TB CC: participants without HIV who are pregnant with a singleton pregnancy in the second or third trimester (≥14 weeks gestational age) may be enrolled.

b. RR-TB CC indication: participants with or without HIV who are pregnant with a singleton pregnancy in the second or third trimester (≥14 weeks gestational age) may be enrolled.

c. Potentially eligible pregnant persons must have an ultrasound to confirm gestational age, singleton pregnancy, and no fetal anomalies.

\*Note: Participants of childbearing potential are defined as persons 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

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. DS- or RR-TB CC previously completed treatment for TBD Note: PLHIV that previously completed treated for TBD are not excluded on this basis, unless treatment regimen included bedaquiline E. Prior completion of TPT including but not limited to 6H (6 months of INH) or 9H (9 months of INH), 1HP (1 month of INH and rifapentine), 3HP (3 months of INH and rifapentine), 4R (4 months of rifampicin), 3HR (3 months of INH and rifampicin), Levofloxacin\*

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 TB clinical trial

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)
* Severe cardiac arrythmia requiring medication
* Peripheral neuropathy ≥ Grade 2 (DAIDS)
* Diagnosis of porphyria at any time prior to study enrollment
* Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to enrollment
* Corrected QTcF (Corrected QT interval 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
* Known bedaquiline or fluoroquinolone resistance in Index Patient
* Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation
* Severe tendinopathy related to fluoroquinolones
* 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