A Trial of Stratified Patient-Centered Treatment Regimens for Active TB (SPECTRA-TB)

Official title

A Phase 2C Trial of Stratified Patient-Centered Treatment Regimens for Active TB

Overview

The A5414 study will evaluate whether treatment for drug-susceptible pulmonary tuberculosis (TB) can be tailored according to a participant's risk of an unfavorable outcome. Participants will be assigned to lower-risk or higher-risk groups using baseline characteristics and then randomized within each group to receive either standard TB treatment or an investigational rifapentine- and moxifloxacin-containing regimen. The study will evaluate whether shorter treatment durations may be used in lower-risk participants and whether the investigational regimen may improve outcomes in higher-risk participants. Safety and tolerability will also be evaluated.

Detailed description

SPECTRA-TB is a Phase 2C, randomized, open-label trial of stratified medicine principles in TB treatment to identify the optimal duration of the HP1500ZM regimen for participants in the lower-risk stratum and to demonstrate improved TB-related favorable outcomes of this regimen in the higher-risk stratum. The study risk stratification includes a higher-risk group (1 control arm and 1 experimental arm) and a lower-risk group (1 control and 5 experimental arms).

Eligible participants will be stratified as either lower- or higher-risk based on the risk stratification algorithm which is based on the following results obtained during the screening period: Xpert MTB/RIF Ultra CT value, extent of disease on chest X-ray, age, BMI, sex at birth, diabetes status, and HIV status using the SPECTRA-TB risk algorithm prior to randomization. Those classified into the lower-risk group (consisting of the low and moderate risk randomization strata to facilitate balancing of risk within each lower-risk treatment arm) will be randomized to SOC or one of five durations of the experimental regimens while those classified into the higher-risk group will be randomized to receive either SOC or a single fixed duration of the experimental regimen. The lower and higher-risk groups will have the following arms:

* Lower-risk: 10, 12, 14, 16, 18, and 26 weeks (5 experimental arms \[weeks 10-18\] and one 26-week SOC arm with 100 participants in each arm). * Higher-risk: Two arms with 26 weeks duration (one SOC arm with 100 participants and one experimental arm with 200 participants).

All participants will be followed for 72 weeks from randomization for outcomes of efficacy, safety, and tolerability. Participants will be monitored closely for Possible Poor Treatment Response (PPTR), TB treatment failure or TB recurrence, safety, tolerability, and loss to follow-up.

Interventions

• Drug Isoniazid
  Administered orally once daily
• Drug Rifampin
  Administered orally once daily
• Drug Pyrazinamide
  Administered orally once daily
• Drug Ethambutol
  Administered orally once daily
• Drug Rifapentine
  Administered orally once daily
• Drug Moxifloxacin
  Administered orally once daily

Primary outcome measures

• Lower-risk group: Proportion of participants with sustained cure at 52 weeks after randomization [Time frame: 52 weeks after randomization]
• Lower-risk group: Proportion of participants with at least 1 new Grade 3 to 5 adverse event through 28 weeks after randomization [Time frame: Baseline through 28 weeks after randomization]

Secondary outcome measures (6)

• Higher-risk group: Proportion of participants with sustained cure at 52 week after randomization [Time frame: 52 weeks after randomization]
• Higher-risk group: Proportion of participants with at least 1 new Grade 3 to 5 adverse event through 28 weeks after randomization [Time frame: Baseline through 28 weeks after randomization]
• Proportion of participants with sustained cure at 72 weeks after randomization [Time frame: 72 weeks after randomization]
• Cumulative proportion of stable liquid mycobacterial culture conversion by 26 weeks after randomization [Time frame: Baseline through 26 weeks after randomization]
• Mean liquid mycobacterial culture log10 days to positivity slope during the first 10 weeks after randomization [Time frame: During the first 10 weeks after randomization]
• Proportion of participants who prematurely discontinue study treatment [Time frame: Baseline through 26 weeks after randomization]

Eligibility criteria

Inclusion criteria

• Has pulmonary tuberculosis (TB) that is likely to respond to standard TB medicines (drug-susceptible TB), based on sputum testing done within 7 days before entering the study. The test must show Mycobacterium tuberculosis is present, with no rifamycin resistance detected and no known resistance to isoniazid or fluoroquinolones.
• Has a SPECTRA-TB risk score and risk group assigned during screening using the study-specific calculator.
• Has a Karnofsky performance score of 50 or higher within 30 days before entering the study.
• Has documented HIV-1 status (either with HIV or without HIV) based on acceptable testing.
• If living with HIV, has a CD4+ cell count of at least 50 cells/mm3 within 60 days before study entry.
• If living with HIV, is currently receiving or plans to start an efavirenz-based or dolutegravir-based antiretroviral therapy regimen by study week 8.
• Has laboratory test results within 7 days before study entry that meet all of the following:

• alanine aminotransferase (ALT) no more than 3 times the upper limit of normal
• total bilirubin no more than 2.5 times the upper limit of normal
• creatinine no more than 2 times the upper limit of normal
• potassium between 3.5 and 5.5 mEq/L
• absolute neutrophil count at least 1000/mm3
• hemoglobin at least 7.0 g/dL
• platelet count at least 100,000/mm3
• If able to become pregnant, has a negative blood or urine pregnancy test within 7 days before study entry.
• If able to become pregnant and sexually active in a way that could lead to pregnancy, agrees not to try to become pregnant and agrees to use at least 1 reliable non-hormonal birth control method during study treatment and for 30 days after stopping study drugs. Acceptable methods include:

• condoms
• intrauterine device (IUD) or intrauterine system (IUS)
• cervical cap with spermicide
• diaphragm with spermicide
• If not able to become pregnant, has a history or documentation of menopause, hysterectomy, bilateral removal of the ovaries, or bilateral tubal ligation.
• Has a verifiable address or place of residence and is willing to tell the study team about any change of address during treatment and follow-up.
• Is willing and able to give informed consent, or assent with permission from a parent or legal guardian if required.

Exclusion criteria

• TB bacteria are known to be resistant to 1 or more of the following medicines: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones.
• Received more than 5 days of treatment for active TB within the 24 weeks before study entry.
• Received more than 5 days of treatment within the 30 days before study entry with certain TB medicines or related antibiotics, including isoniazid, rifampin, rifapentine, ethambutol, moxifloxacin, pyrazinamide, aminoglycosides, fluoroquinolones, linezolid, bedaquiline, pretomanid, and other specified anti-TB drugs.
• Has suspected or confirmed TB involving the brain or central nervous system, bones, joints, heart lining (pericardium), or miliary TB.
• Has a past history of suspected or confirmed drug-resistant TB of any type.
• Is currently pregnant or breastfeeding.
• Cannot take medicines by mouth.
• Has an HIV/AIDS-related opportunistic infection at study entry.
• Has acute or chronic hepatitis B, unless the hepatitis B infection has cleared.
• Has acute or chronic hepatitis C, unless the hepatitis C infection has cleared or has been successfully treated.
• Has alcohol-related liver disease.
• Has liver cirrhosis.
• Has a history of aortic aneurysm or aortic dissection.
• Has a known history of long QT syndrome, a first-degree relative with long QT syndrome, or a screening ECG showing QTcF greater than 470 ms that does not correct with treatment of contributing factors.
• Is taking other medicines that can prolong the QT interval and cannot safely switch to an alternative medicine.
• Has a known history of acute intermittent porphyria.
• Weighs less than 30 kg.
• Is currently using, or is expected to need within 24 weeks after enrollment, 1 or more medicines that are not allowed during the study.
• Has a known allergy, sensitivity, or hypersensitivity to any of the study drugs or their ingredients.
• Has active drug or alcohol use, dependence, mental illness, or another serious infection that, in the opinion of the site investigator, could make it hard to follow the study requirements.
• Is currently taking part in another interventional clinical trial.

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

Peru · 4 centers

• Centro de Investigaciones Tecnológicas, Biomédicas y Medioambientales CRS (CITBM) - Unidad — Callao
• Barranco CRS (Site #: 11301) — Lima
• San Miguel CRS (Site # 11302) — Lima
• Socios en Salud Sucursal Peru CRS (Site # 31985) — Lima

Thailand · 4 centers

• Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site #: 31802) — Pathum Wan
• Siriraj Hospital, Mahidol University NICHD CRS (Site # 5115) — Bangkok
• Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site #: 31784) — Chiang Mai
• Chiangrai Prachanukroh Hospital NICHD CRS (Site # 5116) — Chiang Rai

Botswana · 2 centers

• Gaborone CRS (Site #: 12701) — Gaborone
• Molepolole CRS (Site # 12702) — Gaborone

Brazil · 2 centers

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

Haiti · 2 centers

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

India · 2 centers

• Byramjee Jeejeebhoy Government Medical College (BJGMC) CRS (Site #: 31441) — Pune
• YRG CARE CRS (Site # 32075) — Chennai

Kenya · 2 centers

• Moi University Clinical Research Center (MUCRC) CRS (Site #: 12601) — Eldoret
• Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) — Kericho

Malawi · 2 centers

• Malawi CRS (Site #: 12001) — Lilongwe
• Blantyre CRS (Site #: 30301) — Blantyre

Uganda · 2 centers

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

Argentina · 1 center

• Fundacion Huesped CRS (Site # 31957) — Buenos Aires

Australia · 1 center

• Vietnam-University of Sydney CRS (Site # 32495) — Sydney

Mexico · 1 center

• Nutrición-Mexico CRS (Site #: 32078) — Mexico City

Philippines · 1 center

• TB HIV Innovations and Clinical Research Foundation Corp. (Site #: 31981) — Dasmariñas

Tanzania · 1 center

• Kilimanjaro Christian Medical Centre (KCMC) (Site # 5118) — Moshi

Vietnam · 1 center

• National Lung Hospital (Site #: 32483) — Hanoi

Zimbabwe · 1 center

• Milton Park CRS (Site #: 30313) — Harare

Identifiers

NCT: NCT07595042 · A5414 · 38987

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗