Clinical trial NCT06192160: 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
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: TB Alliance
First posted: 2024-01-05
Enrollment: 315
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 experimental or SOC treatment (based on treatment arm assignment) followed by 18 weeks of SOC treatment with 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm.


Eligibility criteria: Inclusion Criteria:

1. Pulmonary TB (among individuals either without history of prior TB treatment or with history of TB treatment more than 5 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" are required.
2. 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.
3. 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
   * Confirmed 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
4. For individuals with HIV: CD4+ cell count ≥100 cells/mm3 based on testing performed within 30 days prior to study entry.
5. 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.
6. Individuals age ≥18 years.
7. The following laboratory values obtained within 7 days prior to study entry at any network-approved non-US 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 ≥9.5 g/dL for individuals assigned to female sex at birth and ≥10.0 g/dL for individuals assigned to male sex at birth
   * Platelet count ≥100,000/mm\^3
   * Negative for hepatitis B core antibody (HBcAb) total, hepatitis B surface antigen (HBsAg)
   * Negative for hepatitis C virus (HCV) antibody (or if HCV antibody positive, must have a negative HCV PCR)
8. For individuals assigned to female sex at birth and 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-US laboratory or clinic that operates in accordance with GCLP and participates in appropriate external quality assurance programs.

   Individuals assigned to female sex at birth, 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)
9. For individuals who are assigned male sex at birth 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.
10. For individuals assigned male sex at birth with pregnant partners, willingness to use condoms during vaginal intercourse while on study and for 90 days after experimental treatment discontinuation.
11. For individuals assigned male sex at birth, willingness to refrain from sperm donation while on study and for 90 days after experimental treatment discontinuation.
12. Documentation of Karnofsky performance score ≥60 obtained within 14 days prior to study entry.
13. Chest x-ray obtained within 14 days prior to study entry.
14. 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.
15. Ability and willingness of individual to provide informed consent.

Exclusion Criteria:

1. More than cumulative 7 days of treatment directed against active TB for the current TB episode in the 60 days preceding study entry.
2. Current extrapulmonary TB, in the opinion of the investigator.
3. QTcF interval \>450 ms within 7 days prior to study entry.
4. History of or ongoing heart failure.
5. Personal or family history of congenital QT prolongation.
6. History of known, untreated, ongoing hypothyroidism.
7. History of or ongoing bradyarrhythmia.
8. History of torsades de pointes.
9. Current Grade 2 or higher peripheral neuropathy.
10. 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.
11. Pregnant or breastfeeding or planning to become pregnant within the next 12 months.
12. Weight \<35 kg.
13. Unable to take oral medications.
14. Taking any of prohibited medications.
15. Known allergy/sensitivity or any hypersensitivity to components of investigational agents or their formulation.
16. 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.
17. Taking an investigational drug or vaccine within 30 or more days prior to study entry.

Primary outcomes:
measure: 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
timeFrame: Weeks 0, 1, 2, 3, 4 and 6
measure: Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment
timeFrame: 8 weeks
Secondary outcomes:
measure: 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.
timeFrame: 8 weeks
measure: Mean log10 TTP slope from longitudinal MGIT liquid culture measurements over the first 8 weeks of treatment.
timeFrame: Weeks 0, 1, 2, 3, 4, 6 and 8
measure: Cumulative proportion of participants with a new Grade 3 or higher AE by week 26 of treatment.
timeFrame: 26 weeks
measure: Cumulative proportion of participants with permanent discontinuation of study-provided anti-TB drugs due to any reason prior to Week 8 of treatment.
timeFrame: 8 weeks
measure: 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.
timeFrame: 8 weeks
measure: Cumulative proportion of participants with permanent discontinuation of at least one anti-TB drug due to any reason prior to week 26 of treatment.
timeFrame: 26 weeks
measure: A composite of stable culture conversion at week 6 of treatment and no new Grade 3 or higher AE through week 8.
timeFrame: 8 weeks
measure: Proportion of participants with durable cure by 52 weeks after treatment initiation.
timeFrame: 52 Weeks
Other outcomes:
Locations:
city: Gaborone
country: Botswana
facility: 12701, Gaborone CRS
city: Porto Alegre
country: Brazil
facility: 12201, Hospital Nossa Senhora da Conceicao CRS
city: Rio De Janeiro
country: Brazil
facility: 12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
city: Port-au-Prince
country: Haiti
facility: 30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
city: Port-au-Prince
country: Haiti
facility: 31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS
city: Pune
country: India
facility: 31441, Byramjee Jeejeebhoy Medical College (BJMC) CRS
city: Eldoret
country: Kenya
facility: 12601, Moi University Clinical Research Center (MUCRC) CRS
city: Kericho
country: Kenya
facility: 12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
city: Blantyre
country: Malawi
facility: 30301, Blantyre CRS
city: Lilongwe
country: Malawi
facility: 12001, Malawi CRS
city: Mexico City
country: Mexico
facility: 32078, Nutrición-Mexico CRS
city: Lima
country: Peru
facility: 11301, Barranco CRS
city: Cavite
country: Philippines
facility: 31981, De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC)
city: Cape Town
country: South Africa
facility: 31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS
city: Cape Town
country: South Africa
facility: 31792, University of Cape Town Lung Institute (UCTLI) CRS
city: Durban
country: South Africa
facility: 31422, CAPRISA eThekwini CRS
city: Durban
country: South Africa
facility: 11201, Durban International CRS
city: Johannesburg
country: South Africa
facility: 12301, Soweto ACTG CRS
city: Johannesburg
country: South Africa
facility: 11101, University of the Witwatersrand Helen Joseph (WITS HJH) CRS
city: Rustenburg
country: South Africa
facility: 31684, Rustenburg CRS
city: Chiang Mai
country: Thailand
facility: 31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
city: Chiang Rai
country: Thailand
facility: 5116 Chiangrai Prachanukroh Hospital NICHD CRS
city: Pathum Wan
country: Thailand
facility: 31802, Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
city: Kampala
country: Uganda
facility: 12401, Joint Clinical Research Centre (JCRC)/Kampala CRS
city: Hanoi
country: Vietnam
facility: 32483 National Lung Hospital CRS
city: Harare
country: Zimbabwe
facility: 30313, Milton Park CRS
Study officials:
affiliation: University of California
name: Radojka Savic, PharmD, PhD
role: STUDY_CHAIR
affiliation: Vanderbilt University Medical Center
name: Kelly Dooley, MD, PhD
role: STUDY_CHAIR
affiliation: University of California
name: Gustavo Velásquez, MD, MPH
role: STUDY_CHAIR
References: