Bedaquiline Roll-out Evidence in Contacts and People Living With HIV to Prevent TB (BREACH-TB)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 2,530
- 试验地点
- 16
- 主要终点
- 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
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
盲法说明
An independent Endpoint Review Committee (ERC), masked to study arm, will adjudicate the incident TB endpoints (both primary and secondary) and, if there are any deaths, determine the cause of death as TB-related or not TB-related.
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •For Index Patient
- •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).
排除标准
- •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
研究组 & 干预措施
Bedaquiline
4 weeks of daily bedaquiline
干预措施: Bedaquiline (Drug)
Levofloxacin
6 months of daily levofloxacin
干预措施: Levofloxacin (Drug)
3HP
3 months of weekly isoniazid (H) and rifapentine (P)
干预措施: Isoniazid, rifapentine (Combination Product)
结局指标
主要结局
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
时间窗: 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
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
时间窗: 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
Treatment Completion - PLHIV & CCs of DS-TB (Stage 1): Proportion of participants completing assigned treatment within window prescribed in protocol
时间窗: 18 weeks
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
Treatment Completion - CCs of RR-TB (Stage 1): Proportion of participants completing assigned treatment within window prescribed in protocol
时间窗: 36 weeks
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
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
时间窗: Up to 72 weeks post-treatment initiation
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)
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
时间窗: Varies by treatment regimen (1 month, 3 months, or 6 months)
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.
次要结局
- 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(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(Up to 72 weeks)
- Stage 1: Proportion of participants who permanently discontinue the randomized study drug due to a treatment-related adverse event by 18 weeks(18 weeks)
- Stage 1: Proportion of participants who permanently discontinue the randomized study drug due to a treatment-related adverse event by 36 weeks(36 weeks)
- Stage 1: Proportion of participants completing assigned treatment within window prescribed in protocol(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 18 weeks(18 weeks)
- 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(36 weeks)
- Stage 1: Proportion of participants who experience a TBD event at up to 72 weeks of follow-up, by study arm(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(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(Varies by treatment regimen duration (1 month, 3 months, or 6 months))
- Stage 1: Proportion of participants completing assigned treatment within window prescribed in protocol(Dependent on treatment assignment (1 month, 3 months, or 6 months))