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

Prior treatment

• Previously completed treatment for TBD.
• 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
• Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to enrollment
• Diagnosis of porphyria at any time prior to study enrollment
• 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
• 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)

Other illness

• 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
• Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation

Other

• Unwilling or unable to provide informed consent
• Weight ≤ 3 kg
• A current diagnosis of confirmed or probable or possible pulmonary or extrapulmonary TB at time of enrollment or confirmed or unconfirmed TB for children.
• Current enrollment into another therapeutic clinical trial (See Section 5.8).
• Peripheral neuropathy ≥ Grade 2 (DAIDS)
• Corrected QTcF (Fridericia's formula) of \>460 msec
• Known bedaquiline resistance in Index Patient
• 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

• 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
• Ability and willingness of participant (and/or parent/guardian) to provide informed consent (and assent, as applicable)
• 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
• 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.
• Chest radiograph without evidence of active TBD, performed within 30 days prior to Enrollment
• 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
• 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).