Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis

Pulmonary Tuberculosis Clinical Trial

— RAD-TB  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06192160
• Other study ID #: A5409
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 15, 2024
• Est. completion date: April 14, 2026

Study information

• Verified date: January 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: Radojka Savic, PharmD, PhD
• Phone: 415-502-0640
• Email: rada.savic[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 315
• Est. completion date: April 14, 2026
• Est. primary completion date: June 10, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• Isoniazid
INH 300 mg will be administered as one tablet orally once daily.
• 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.
• Pyrazinamide
PZA will be administered as 500 mg tablets, based on weight, orally once daily.
• Ethambutol
EMB will be administered as 400 mg tablets, based on weight, orally once daily.
• 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.
• Pretomanid
Pa 200 mg will be administered as one 200 mg tablet orally once daily with a meal.
• Linezolid
LZD 600 mg will be administered as one 600 mg tablet orally once daily.
• TBI-223
TBI-223 2400 mg once daily will be administered as four 600 mg tablets orally once daily with a meal.
• Sutezolid
SZD 1600 mg once daily will be administered as four 400 mg tablets orally once daily with a meal.
• TBI-223
TBI-223 1200 mg once daily will be administered as two 600 mg tablets orally with a meal.
• Sutezolid
SZD 800 mg once daily will be administered as two 400 mg tablets orally once daily with a meal.

Locations

Country	Name	City	State
Botswana	12701, Gaborone CRS	Gaborone
Brazil	12201, Hospital Nossa Senhora da Conceicao CRS	Porto Alegre
Brazil	12101, Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS	Rio De Janeiro
Haiti	30022, Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS	Port-au-Prince
Haiti	31730, GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS	Port-au-Prince
India	31441, Byramjee Jeejeebhoy Medical College (BJMC) CRS	Pune
Kenya	12601, Moi University Clinical Research Center (MUCRC) CRS	Eldoret
Kenya	12501, Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS	Kericho
Malawi	30301, Blantyre CRS	Blantyre
Malawi	12001, Malawi CRS	Lilongwe
Mexico	32078, Nutrición-Mexico CRS	Mexico City
Peru	11301, Barranco CRS	Lima
Philippines	31981, De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC)	Cavite
South Africa	31792, University of Cape Town Lung Institute (UCTLI) CRS	Cape Town
South Africa	31793, South African Tuberculosis Vaccine Initiative (SATVI) CRS	Cape Town
South Africa	11201, Durban International CRS	Durban
South Africa	31422, CAPRISA eThekwini CRS	Durban
South Africa	11101, University of the Witwatersrand Helen Joseph (WITS HJH) CRS	Johannesburg
South Africa	12301, Soweto ACTG CRS	Johannesburg
South Africa	31684, Rustenburg CRS	Rustenburg
Thailand	31784, Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS	Chiang Mai
Thailand	31802, Thai Red Cross AIDS Research Centre (TRC-ARC) CRS	Pathum Wan
Uganda	12401, Joint Clinical Research Centre (JCRC)/Kampala CRS	Kampala
Zimbabwe	30313, Milton Park CRS	Harare

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	TB Alliance

Countries where clinical trial is conducted

Botswana,  Brazil,  Haiti,  India,  Kenya,  Malawi,  Mexico,  Peru,  Philippines,  South Africa,  Thailand,  Uganda,  Zimbabwe, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	for each experimental treatment arm compared to the SOC arm.	Weeks 0, 1, 2, 3, 4 and 6
Primary	Difference in the cumulative proportion of participants having at least one new Grade 3 or higher adverse event (AE) by week 8 of treatment	for each experimental treatment arm compared to the SOC arm.	8 weeks
Secondary	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.		8 weeks
Secondary	Mean log10 TTP slope from longitudinal MGIT liquid culture measurements over the first 8 weeks of treatment.		Weeks 0, 1, 2, 3, 4, 6 and 8
Secondary	Cumulative proportion of participants with a new Grade 3 or higher AE by week 26 of treatment.		26 weeks
Secondary	Cumulative proportion of participants with permanent discontinuation of study-provided anti-TB drugs due to any reason prior to Week 8 of treatment.		8 weeks
Secondary	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.		8 weeks
Secondary	Cumulative proportion of participants with permanent discontinuation of at least one anti-TB drug due to any reason prior to week 26 of treatment.		26 weeks
Secondary	A composite of stable culture conversion at week 6 of treatment and no new Grade 3 or higher AE through week 8.		8 weeks
Secondary	Proportion of participants with durable cure by 52 weeks after treatment initiation.		52 Weeks