Linezolid Dosing Strategies in Drug-Resistant TB

NCT05007821 | Completed Phase 2 Results FDA Drug

• 1 other identifier: A5356
• Study Type: interventional
• Target: 138
• Locations: 7 countries
• Sites: 13

Brief Summary

The purpose of the study was to evaluate the efficacy (how well the medicines work) and tolerability (whether participants stop treatment because of side effects from a drug) of an anti-TB treatment regimen that compared two doses of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). This study also measured the level of LZD and BDQ in the participants' blood.

Conditions

Tuberculosis, Multidrug-Resistant; Tuberculosis; Tuberculosis, Pulmonary

Outcome Measures

Primary Outcomes (2)

• Time to 26 Weeks Stable Culture Conversion in Liquid Media

  Time of stable liquid culture conversion was the visit corresponding to the 1st of 2 consecutive MTB-neg cultures obtained at least 7 days apart without an intervening MTB-pos culture. Inability to produce sputum with or without induction was considered an MTB-neg culture. A participant was MTB-pos at a visit if at least 1 of the liquid cultures was MTB-pos. A participant was MTB-neg at a visit if both liquid cultures were MTB-neg or if 1 liquid culture was MTB-neg and the other was missing or indeterminate. If the 1st MTB-neg liquid culture was at week 26, then conversion was met. If a participant did not convert by week 26, they were censored at their last culture result. If a participant died (any cause except trauma), they were censored at week 26 (worst possible outcome). Within-arm Kaplan-Meier estimates of proportions at week 26 and the Cox proportional hazards regression model hazard ratio were calculated; between-arm differences were tested with the log rank test.

  Up to 26 weeks

• Proportion of Participants With Permanent Discontinuation of At Least One Anti-TB Drug Due To Adverse Events, Intolerance, Or Death

  Time of permanent discontinuation of at least one anti-TB drug due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with at least one anti-TB drug or study visits, or due to participant request was the corresponding date of discontinuation. If a participant did not permanently discontinue at least one anti-TB drug due to side effects that did not lead to a protocol-required discontinuation, due to participant non-compliance with at least one anti-TB drug or study visits, or due to participant request by week 26, they were censored at the date of permanent treatment discontinuation of all study drugs or, if still on study treatment, at week 26. Within-arm Kaplan-Meier estimates of proportions of participants with permanent discontinuation were calculated with 2-sided 95% confidence intervals using standard errors based on Greenwood's formula.

  Up to 26 weeks

Secondary Outcomes (27)

• Proportion of Participants Achieving Stable Liquid Culture Conversion

  At week 8

• Proportion of Participants Achieving Stable Liquid Culture Conversion

  At week 16

• Proportion of Participants Achieving Stable Liquid Culture Conversion

  At week 26

• Proportion of Participants Achieving Stable Liquid Culture Conversion

  At week 38

• Proportion of Participants With Permanent Discontinuation of LZD Due To Adverse Events, Intolerance, or Death

  Up to 26 weeks

Study Arms (2)

Arm A

EXPERIMENTAL

Everyone in the study took bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) once a day for the entire treatment period. Arm A participants took linezolid (LZD) once a day for the entire treatment period. * Weeks 1-26: LZD 600 mg once daily (QD) * Weeks 1-2: BDQ 200 mg QD + DLM 300 mg QD + CFZ 300 mg QD * Weeks 3-8: BDQ 200 mg QD + DLM 300 mg QD + CFZ 100 mg QD * Weeks 9-26: BDQ 100 mg QD + DLM 300 mg QD + CFZ 100 mg QD

Drug: Linezolid 600 mg; Drug: Bedaquiline 200 mg; Drug: Bedaquiline 100 mg; Drug: Delamanid 300 mg; Drug: Clofazimine 300 mg; Drug: Clofazimine 100 mg

Arm B

EXPERIMENTAL

Everyone in the study took bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) once a day for the entire treatment period. Arm B participants took a higher dose of linezolid (LZD) once a day for 4 weeks and then took that higher dose of LZD just three times a week for the rest of the treatment period. * Weeks 1-4: LZD 1200 mg once daily (QD) * Weeks 5-26: LZD 1200 mg three times per week (TIW) * Weeks 1-2: BDQ 200 mg QD + DLM 300 mg QD + CFZ 300 mg QD * Weeks 3-8: BDQ 200 mg QD + DLM 300 mg QD + CFZ 100 mg QD * Weeks 9-26: BDQ 100 mg QD + DLM 300 mg QD + CFZ 100 mg QD

Drug: Linezolid 1200 mg (QD); Drug: Linezolid 1200 mg (TIW); Drug: Bedaquiline 200 mg; Drug: Bedaquiline 100 mg; Drug: Delamanid 300 mg; Drug: Clofazimine 300 mg; Drug: Clofazimine 100 mg

Interventions

Linezolid 600 mg DRUG

One 600mg tablet taken orally once daily (QD) in the morning during weeks 1-26

Also known as: LZD

Arm A

Linezolid 1200 mg (QD) DRUG

Two 600mg tablets taken orally once daily (QD) in the morning during weeks 1-4

Also known as: LZD

Arm B

Linezolid 1200 mg (TIW) DRUG

Two 600mg tablets taken orally three times per week (TIW; Mon-Wed-Fri) in the morning during weeks 5-26

Also known as: LZD

Arm B

Bedaquiline 200 mg DRUG

Two 100mg tablets taken orally once daily in the morning during weeks 1-8

Also known as: BDQ

Arm A; Arm B

Delamanid 300 mg DRUG

Six 50mg tablets taken orally once daily in the morning during weeks 1-26

Also known as: DLM

Arm A; Arm B

Bedaquiline 100 mg DRUG

One 100mg tablet taken orally once daily in the morning during weeks 9-26

Also known as: BDQ

Arm A; Arm B

Clofazimine 300 mg DRUG

Three 100mg capsules taken orally once daily in the morning during weeks 1-2

Also known as: CFZ

Arm A; Arm B

Clofazimine 100 mg DRUG

One 100mg capsule taken orally once daily in the morning during weeks 3-26

Also known as: CFZ

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed pulmonary drug-resistant tuberculosis (DR-TB), with resistance to at least rifampicin or rifampin (which is a drug used in the therapy of tuberculosis) confirmed from a sputum specimen collected within 60 days prior to entry.
• HIV-1 infection status documented as either absent or present.
• For participants living with HIV, either currently on an antiretroviral therapy (ART) regimen or willing and able to start ART within 30 days after entry.
• Efavirenz or etravirine (drugs used to treat HIV) must be discontinued prior to a participant's starting anti-TB medications. For participants on efavirenz or etravirine, they must be willing and able to discontinue these at least 7 days prior to initiating study TB medications.
• For participants living with HIV, CD4+ cell (a type of white blood cell) count greater than or equal to 50 cells/mm3 obtained within 60 days prior to study entry.
• For females of reproductive potential, negative serum or urine pregnancy test.
• Females of reproductive potential who are participating in sexual activity that could lead to pregnancy must agree to use two of the following forms of birth control while receiving TB study medications and for 30 days 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)
• Appropriate laboratory values as determined by the study doctor obtained within 14 days prior to entry.
• Karnofsky performance score (an assessment tool for functional impairment) greater than or equal to 50 within 30 days prior to entry.
• Ability and willingness of candidate and/or legal guardian/representative to provide informed consent and meet requirements for the study.
• Chest X-ray obtained within 30 days prior to entry.

You may not qualify if:

• Documentation of clinically significant (as judged by the study doctor) active infections (including HIV-related opportunistic infections) other than TB and HIV requiring treatment within 30 days prior to entry.
• Evidence of clinically significant (as judged by the study doctor) metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric, endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) that would interfere with study medications or procedures.
• Inability to take oral medications.
• Suspected or documented TB involving the central nervous system, clinically significant renal TB or TB pericarditis, or current extrapulmonary TB involving other organ systems that might interfere with study medications or procedures, as judged by the study doctor.
• Prior treatment with one or more of the study drugs at any time in the past for an episode of DR-TB that is not the qualifying episode or treatment for more than 7 cumulative days with one or more of the study drugs within 30 days prior to entry for the qualifying episode of DR-TB.
• History of allergy or hypersensitivity to any of the study drugs or medications in the same class as the study drugs.
• Known or suspected current alcohol and/or drug abuse that is, in the opinion of the study doctor, sufficient to compromise the safety and/or cooperation of the participant.
• Receipt of any investigational drugs within 60 days prior to entry.
• Known history of prolonged QT syndrome (heart rhythm condition that can potentially cause fast, chaotic heartbeats) or current prolonged QT interval on screening electrocardiogram (a medical test that detects cardiac (heart) abnormalities).
• Known history of clinically significant cardiac arrhythmia (a condition in which the heart beats with an irregular or abnormal rhythm) requiring medication or clinically significant electrocardiogram (ECG) abnormality, in the opinion of the study doctor, within 60 days prior to entry.
• Pregnancy or current breastfeeding, or intent to become pregnant and/or breastfeed while on study treatment.
• Current use of monoamine oxidase inhibitors (type of medication used to treat depression) or use within 30 days prior to entry.
• Current use of serotonergic agents including SSRI/SNRI antidepressants or prior use within 30 days prior to entry.
• Known history of optic neuropathy (damage to the optic nerve in your eye) of any grade as diagnosed by an ophthalmologist.
• Current peripheral neuropathy (when nerves are damaged or destroyed and can't send messages from the brain and spinal cord to the muscles, skin and other parts of the body) with severe paresthesias ("pins and needles") and/or mild weakness or worse (Grade ≥2.).

Sponsors & Collaborators

• Pfizer: collaborator
• Otsuka Pharmaceutical Development & Commercialization, Inc.: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (13)

Gaborone CRS (Site ID: 12701)

Gaborone, South-East District, Botswana

Location

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site ID: 12101)

Rio de Janeiro, 21040-360, Brazil

Location

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (Site ID: 31730)

Port-au-Prince, HT-6110, Haiti

Location

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS (Site ID: 30022)

Port-au-Prince, HT-6110, Haiti

Location

Barranco CRS (Site ID: 11301)

Lima, 15063, Peru

Location

De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC) (Site ID: 31981)

Cavite, 4114, Philippines

Location

Wits Helen Joseph Hospital CRS (Wits HJH CRS) (Site ID: 11101)

Johannesburg, Gauteng, 2092, South Africa

Location

Durban International CRS (Site ID: 11201)

Durban, KwaZulu-Natal, 4052, South Africa

Location

Rustenburg CRS (Site ID: 31684)

Rustenburg, North West, 0300, South Africa

Location

University of Cape Town Lung Institute (UCTLI) CRS (Site ID: 31792)

Cape Town, Western Cape, 7700, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI) CRS (Site ID: 31793)

Cape Town, Western Cape, 7705, South Africa

Location

Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site ID: 31802)

Pathum Wan, Bangkok, 10330, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site ID: 31784)

Chiang Mai, 50200, Thailand

Location

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Tuberculosis; Tuberculosis, Pulmonary

Interventions

Linezolid; bedaquiline; OPC-67683; Clofazimine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenazines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Constance A. Benson

  The University of California, San Diego

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: A5356 is a phase II, prospective, randomized, two-arm, open-label, multicenter clinical trial to evaluate the anti-tuberculosis (TB) activity, safety, and tolerability of an injectable-free short course regimen for treatment of multidrug-/rifampicin-resistant (MDR-/RR-), pre-extensively drug-resistant (pre-XDR-), and extensively drug-resistant (XDR-) TB comparing two dosing strategies of linezolid (LZD) combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ).

Study Record Dates

• First Submitted: July 22, 2021
• First Posted: August 16, 2021
• Study Start: September 27, 2022
• Primary Completion: March 14, 2025
• Study Completion: January 13, 2026
• Last Updated: May 1, 2026
• Results First Posted: May 1, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the ACTG (Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections) by NIH.
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG (Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections). * For what types of analyses? To achieve aims in the proposal approved by the ACTG. * By what mechanism will data be made available? Researchers may submit a request for access to data using the ACTG "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data.

Locations

ZA (5); PE (1); BO (1); BR (1); PH (1); TH (2); HA (2)