Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis

Official title

A Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis

Overview

A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, open-label, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB). A5409 hypothesizes that novel regimens for the treatment of pulmonary tuberculosis will result in superior early efficacy, as determined by longitudinal mycobacteria growth indicator tube (MGIT) liquid culture time to positivity (TTP) measurements over the first 6 weeks of treatment, and will have acceptable safety and tolerability over 8 weeks of treatment relative to standard of care \[(SOC) isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE)\]. The study will run for 52 weeks, inclusive of 26 weeks of TB treatment comprised of 8 weeks of study treatment (experimental or SOC, based on treatment arm assignment) followed by 18 weeks of SOC continuation phase treatment with 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm.

Interventions

• Drug Isoniazid
  INH 300 mg will be administered as one tablet orally once daily.
• Drug Rifampicin
  RIF 600 mg will be administered as two 300 mg capsules orally once daily on an empty stomach, 1 hour before or 2 hours after eating a meal.
• Drug Pyrazinamide
  PZA will be administered as 500 mg tablets, based on weight, orally once daily.
• Drug Ethambutol
  EMB will be administered as 400 mg tablets, based on weight, orally once daily.
• Drug Bedaquiline
  BDQ 400 mg will be administered as four 100 mg tablets orally once daily with a meal for the first 2 weeks followed by 200 mg (two 100 mg tablets) orally once daily with a meal for 6 weeks.
• Drug Pretomanid
  Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
• Drug Linezolid
  LZD 600 mg will be administered as one 600 mg tablet orally once daily.
• Drug TBI-223
  TBI-223 2400 mg once daily will be administered as four 600 mg tablets orally once daily with a meal.
• Drug Sutezolid
  SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
• Drug TBI-223
  TBI-223 1200 mg once daily will be administered as two 600 mg tablets orally with a meal.

Primary outcome measures

• Difference in mean log10 (Time to positivity (TTP)) slope from longitudinal mycobacteria growth indicator tube (MGIT) liquid culture measurements over the first 6 weeks of treatment [Time frame: Weeks 0, 1, 2, 3, 4 and 6]
• Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment [Time frame: 8 weeks]

Secondary outcome measures (8)

• Cumulative proportion of participants with stable sputum culture conversion by week 8 as measured by culture-negative status via MGIT liquid culture at two consecutive measurements. [Time frame: 8 weeks]
• Mean log10 TTP slope from longitudinal MGIT liquid culture measurements over the first 8 weeks of treatment. [Time frame: Weeks 0, 1, 2, 3, 4, 6 and 8]
• Cumulative proportion of participants with a new Grade 3 or higher AE by week 26 of treatment. [Time frame: 26 weeks]
• Cumulative proportion of participants with permanent discontinuation of study-provided anti-TB drugs due to any reason prior to Week 8 of treatment. [Time frame: 8 weeks]
• Cumulative proportion of participants with permanent discontinuation or temporary discontinuation for ≥3 days of at least one anti-TB drug due to any reason prior to week 8 of treatment. [Time frame: 8 weeks]
• Cumulative proportion of participants with permanent discontinuation of at least one anti-TB drug due to any reason prior to week 26 of treatment. [Time frame: 26 weeks]
• A composite of stable culture conversion at week 6 of treatment and no new Grade 3 or higher AE through week 8. [Time frame: 8 weeks]
• Proportion of participants with durable cure by 52 weeks after treatment initiation. [Time frame: 52 Weeks]

Eligibility criteria

Inclusion criteria

• Pulmonary TB (among individuals either without history of prior TB treatment or with history of TB treatment completed more than 2 years prior to study entry), identified within 7 days prior to study entry by at least one sputum specimen positive for Mtb by Xpert. Semiquantitative Mtb results of "medium" or "high" from Xpert MTB/RIF Ultra are required.
• Pulmonary TB with documented INH susceptibility (by Line Probe Assay (LPA) or Xpert MTB/XDR or other validated molecular test) and with documented RIF susceptibility (by LPA or Xpert MTB/RIF or Xpert MTB/RIF Ultra or other validated molecular test) within 7 days prior to study entry.
• Documentation of HIV-1 infection status, as below:

Presence or absence of HIV-1 infection, as documented by:

• Any licensed rapid HIV test or HIV-1 enzyme or chemiluminescence immunoassay (E/CIA) test kit, any time prior to study entry. AND for a positive result confirmation by one of the following:
• A second antibody test from different manufacturers or based on different principles and epitopes (combination antigen-antibody-based rapid tests may be used), or
• HIV-1 antigen, or
• Plasma HIV-1 RNA viral load, or
• A licensed Western blot
• For individuals with HIV: CD4+ cell count ≥100 cells/mm3 based on testing performed within 30 days prior to study entry.
• For individuals with HIV: Currently being treated with dolutegravir-based antiretroviral therapy (ART), or plan to initiate dolutegravir-based ART at or before study week 8.
• Individuals age ≥18 years.
• The following laboratory values obtained within 7 days prior to study entry at any network-approved non-U.S. laboratory that operates in accordance with Good Clinical Laboratory Practices (GCLP) and participates in appropriate external quality assurance programs:

• Serum or plasma alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN)
• Serum or plasma total bilirubin ≤2 times ULN
• Serum or plasma creatinine ≤2 times ULN
• Serum or plasma potassium ≥3.5 mEq/L
• Serum or plasma magnesium ≥1.0 mEq/L (≥0.500 mmol/L)
• Absolute neutrophil count (ANC) ≥1500/mm\^3
• Hemoglobin ≥9.0 g/dL
• Platelet count ≥100,000/mm\^3
• Negative for, hepatitis B surface antigen (HBsAg)
• Negative for hepatitis C virus (HCV) antibody (or if HCV antibody positive, must have a negative HCV PCR)
• For female study candidates who are of reproductive potential, negative pregnancy test (urine HCG or serum β-HCG) within 3 days (72 hours) prior to entry by any network-approved non-U.S. laboratory or clinic that operates in accordance with GCLP and participates in appropriate external quality assurance programs.

Females who are of reproductive potential and who participate in sexual activity that could lead to pregnancy must agree to use at least two of the following forms of birth control while receiving TB study medications and for 12 months after stopping study medications:

• Male or female condoms
• Diaphragm or cervical cap (with spermicide, if available)
• Intrauterine device (IUD) or intrauterine system (IUS)
• Hormone-based birth control (e.g., oral contraceptives, Depo-Provera, NuvaRing, implants)

Female study candidates who are of reproductive potential, but who abstain from sexual activity that could lead to pregnancy require no additional contraception.

Female study candidates who are not of reproductive potential are eligible without requiring the use of contraceptives. Self-reported history is acceptable documentation of menopause (i.e., at least 1 year amenorrheic), hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; these candidates are all considered not of reproductive potential.

• For male study candidates who engage in sexual activity that may lead to pregnancy in their partner must agree to either remain abstinent or use male contraceptives. They are also strongly advised to inform their non-pregnant sexual partners of reproductive potential to use effective contraceptives while the individual is on study and for 90 days after experimental treatment discontinuation.

For male study candidates who have undergone successful vasectomy with documented azoospermia or have documented azoospermia for any other reason, are eligible without requiring the use of contraceptives.

• For male study candidates with pregnant partners, willingness to use condoms during vaginal intercourse while on study and for 90 days after experimental treatment discontinuation.
• For male study candidates, willingness to refrain from sperm donation while on study and for 90 days after experimental treatment discontinuation.
• Documentation of Karnofsky performance score ≥60 obtained within 14 days prior to study entry.
• Chest x-ray obtained within 14 days prior to study entry.
• A verifiable address or residence readily accessible for visiting, and willingness to inform the study team of any change of address during study treatment and follow-up period.
• Ability and willingness of individual to provide informed consent.

Exclusion criteria

• More than cumulative 7 days of treatment directed against active TB for the current TB episode in the 60 days preceding study entry.
• Current extrapulmonary TB, in the opinion of the investigator.
• QTcF interval >450 ms within 7 days prior to study entry.
• History of or ongoing heart failure.
• Personal or family history of congenital QT prolongation.
• History of known, untreated, ongoing hypothyroidism.
• History of or ongoing bradyarrhythmia.
• History of torsades de pointes.
• Current Grade 2 or higher peripheral neuropathy.
• Other medical conditions (e.g., diabetes, liver or kidney disease, blood disorders, chronic diarrhea), in the opinion of the site investigator, in which the current clinical condition of the participant is likely to prejudice the response to, or assessment of, treatment.
• Pregnant or breastfeeding or planning to become pregnant within the next 12 months.
• Weight <35 kg.
• Unable to take oral medications.
• Taking any of prohibited medications.
• Known allergy/sensitivity or any hypersensitivity to components of investigational agents or their formulation.
• Active drug or alcohol use or dependence; or mental illness (e.g., major depression) that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Taking an investigational drug or vaccine within 30 or more days prior to study entry.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

South Africa · 7 centers

• 31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS — Cape Town
• 31792, University of Cape Town Lung Institute (UCTLI) CRS — Cape Town
• 31422, CAPRISA eThekwini CRS — Durban
• 11201, Durban International CRS — Durban
• 12301, Soweto ACTG CRS — Johannesburg
• 11101, University of the Witwatersrand Helen Joseph (WITS HJH) CRS — Johannesburg
• 31684, Rustenburg CRS — Rustenburg

Peru · 3 centers

• 11301, Barranco CRS — Lima
• 31985, Socios En Salud Sucursal Perú CRS — Lima
• 11302, San Miguel CRS San Miguel — Lima

Thailand · 3 centers

• 31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS — Chiang Mai
• 5116 Chiangrai Prachanukroh Hospital NICHD CRS — Chiang Rai
• 31802, Thai Red Cross AIDS Research Centre (TRC-ARC) CRS — Pathum Wan

Brazil · 2 centers

• 12201, Instituto de Pesquisas em AIDS do Rio Grande do Sul - IPARGS CRS — Porto Alegre
• 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS — Rio de Janeiro

Haiti · 2 centers

• 30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS — Port-au-Prince
• 31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) C — Port-au-Prince

Kenya · 2 centers

• 12601, Moi University Clinical Research Center (MUCRC) CRS — Eldoret
• 12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMR — Kericho

Malawi · 2 centers

• 30301, Blantyre CRS — Blantyre
• 12001, Malawi CRS — Lilongwe

Uganda · 2 centers

• 12401, Joint Clinical Research Centre (JCRC)/Kampala CRS — Kampala
• 30293 MU-JHU Research Collaboration (MUJHU CARE LTD) CRS — Kampala

Botswana · 1 center

• 12701, Gaborone CRS — Gaborone

India · 1 center

• 31441, Byramjee Jeejeebhoy Medical College (BJMC) CRS — Pune

Mexico · 1 center

• 32078, Nutrición-Mexico CRS — Mexico City

Philippines · 1 center

• 31981, TB HIV Innovations and Clinical Research Foundation Corp. — Cavite

Vietnam · 1 center

• 32483 National Lung Hospital CRS — Hanoi

Zimbabwe · 1 center

• 30313, Milton Park CRS — Harare

Publications

• Harrison LJ, Velasquez GE, Kempker RR, Imperial MZ, Nuermberger E, Dorman SE, Ignatius E, Granche J, Phillips PPJ, Furin J, Yang E, Foley C, Chiambah S, Rogers R, Van Grack A, Roa J, Shenje J, Nerette S, Kanyama C, Kyeyune RB, Mendoza-Ticona A, Murtaugh W, Foraida S, Goth M, Vernon A, Dooley KE, Savic RM. ACTG A5409 (RAD-TB): Study protocol for a phase 2 randomized, adaptive, dose-ranging, open-la PMID 40817073
• Harrison L, Velasquez GE, Kempker RR, Imperial MZ, Nuermberger E, Dorman SE, Ignatius E, Granche J, Phillips PP, Furin J, Yang E, Foley C, Chiambah S, Rogers R, Van Grack A, Roa J, Shenje J, Nerette S, Kanyama C, Kyeyune RB, Mendoza-Ticona A, Murtaugh W, Foraida S, Goth M, Vernon A, Dooley KE, Savic RM. ACTG A5409 (RAD-TB): Study Protocol for a Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Labe PMID 40195983

Identifiers

NCT: NCT06192160 · A5409 · DOH-27-032024-5399

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗