Linezolid Dosing Strategies in Drug-Resistant TB

April 2, 2024 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

A Phase II, Prospective, Randomized, Multicenter Trial to Evaluate the Efficacy and Safety/Tolerability of Two Linezolid Dosing Strategies in Combination With a Short Course Regimen for the Treatment of Drug-Resistant Pulmonary Tuberculosis

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

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

There is currently no "standard of care" or single standardized treatment regimen recommended for everyone with drug resistant-tuberculosis (DR- TB). Current DR-TB treatments may not be well tolerated and can often have side effects. There is a need to identify drugs with enough anti-TB activity (treatment against TB) and good safety profiles that can improve outcomes in the treatment of DR-TB.

The main purpose of this study is to evaluate the efficacy and tolerability of a new shorter course anti-TB treatment regimen that compares two dosing strategies of linezolid (LZD), combined with bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ). As a secondary aim, the study will also assess the safety (the level and type of side effects from a drug or treatment) of the combination of these drugs.

Everyone in the study will take these drugs once a day for the entire treatment period: BDQ, DLM, and CFZ. The difference between the two treatment groups in the study is in how participants will take the fourth drug: LZD. Participants in group A will take one dose of LZD once a day for the entire treatment period. Participants in group B will take a higher dose of LZD once a day for 4 weeks and then continue taking that higher dose of LZD just three times a week for the rest of the treatment period.

Study Type

Interventional

Enrollment (Estimated)

132

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Constance A. Benson, MD
  • Phone Number: 619-543-8080
  • Email: cbenson@ucsd.edu

Study Contact Backup

Study Locations

  • Botswana
    • South-East District
      • Gaborone, South-East District, Botswana
        • Recruiting
        • Gaborone CRS (Site ID: 12701)
        • Contact:
  • Brazil
      • Rio De Janeiro, Brazil, 21040-360
        • Recruiting
        • Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS (Site ID: 12101)
        • Contact:
    • Rio Grande Do Sul
      • Porto Alegre, Rio Grande Do Sul, Brazil, 91850-200
        • Not yet recruiting
        • Hospital Nossa Senhora da Conceicao CRS (Site ID: 12201)
        • Contact:
  • Haiti
      • Port-au-Prince, Haiti, HT-6110
        • Recruiting
        • GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (Site ID: 31730)
        • Contact:
      • Port-au-Prince, Haiti, HT-6110
        • Recruiting
        • Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS (Site ID: 30022)
        • Contact:
  • India
    • Maharashtra
      • Pune, Maharashtra, India, 411001
        • Not yet recruiting
        • Byramjee Jeejeebhoy Medical College (BJMC) CRS (Site ID: 31441)
        • Contact:
  • Kenya
    • Rift Valley
      • Eldoret, Rift Valley, Kenya, 30100
        • Not yet recruiting
        • Moi University Clinical Research Center (MUCRC) CRS (Site ID: 12601)
        • Contact:
  • Peru
      • Lima, Peru, 15063
        • Recruiting
        • Barranco CRS (Site ID: 11301)
        • Contact:
  • Philippines
      • Cavite, Philippines, 4114
        • Recruiting
        • De La Salle Health Science Institute Angelo King Medical Research Center (DLSHSI-AKMRC) (Site ID: 31981)
        • Contact:
  • South Africa
    • Gauteng
      • Johannesburg, Gauteng, South Africa, 2092
        • Recruiting
        • Wits Helen Joseph Hospital CRS (Wits HJH CRS) (Site ID: 11101)
        • Contact:
    • Kwa Zulu Natal
      • Durban, Kwa Zulu Natal, South Africa, 4052
        • Recruiting
        • Durban International CRS (Site ID: 11201)
        • Contact:
    • North West Province
      • Rustenburg, North West Province, South Africa, 0300
    • Western Cape Province
      • Cape Town, Western Cape Province, South Africa, 7700
        • Recruiting
        • University of Cape Town Lung Institute (UCTLI) CRS (Site ID: 31792)
        • Contact:
      • Cape Town, Western Cape Province, South Africa, 7705
        • Recruiting
        • South African Tuberculosis Vaccine Initiative (SATVI) CRS (Site ID: 31793)
        • Contact:
  • Thailand
      • Chiang Mai, Thailand, 50200
        • Recruiting
        • Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS (Site ID: 31784)
        • Contact:
    • Bangkok
      • Pathum Wan, Bangkok, Thailand, 10330
        • Recruiting
        • Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site ID: 31802)
        • Contact:
  • Zimbabwe
    • Harare
      • Milton Park, Harare, Zimbabwe
        • Not yet recruiting
        • Milton Park CRS (Site ID: 30313)
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Aged greater than or equal to 18 years at screening.
  2. 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.
  3. HIV-1 infection status documented as either absent or present.
  4. 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.
  5. 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.
  6. 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.
  7. For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to entry.

  8. 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)
  9. Appropriate laboratory values as determined by the study doctor obtained within 14 days prior to entry.
  10. Karnofsky performance score (an assessment tool for functional impairment) greater than or equal to 50 within 30 days prior to entry.
  11. Ability and willingness of candidate and/or legal guardian/representative to provide informed consent and meet requirements for the study.
  12. Chest X-ray obtained within 30 days prior to entry.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Inability to take oral medications.
  4. 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.
  5. 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.
  6. History of allergy or hypersensitivity to any of the study drugs or medications in the same class as the study drugs.
  7. 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.
  8. Receipt of any investigational drugs within 60 days prior to entry.
  9. 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).
  10. 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.
  11. Pregnancy or current breastfeeding, or intent to become pregnant and/or breastfeed while on study treatment.
  12. Current use of monoamine oxidase inhibitors (type of medication used to treat depression) or use within 30 days prior to entry.
  13. Current use of serotonergic agents including SSRI/SNRI antidepressants or prior use within 30 days prior to entry.
  14. Known history of optic neuropathy (damage to the optic nerve in your eye) of any grade as diagnosed by an ophthalmologist.
  15. 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.).
  16. Weight less than 35 kg (77 lbs).
  17. Currently taking other prohibited medications.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A

Everyone in the study will take bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) once a day for the entire treatment period. Arm A participants will take 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
One 600mg tablet taken orally once daily (QD) in the morning during weeks 1-26
Other Names:
  • LZD
Drug: Bedaquiline 200 mg
Two 100mg tablets taken orally once daily in the morning during weeks 1-8
Other Names:
  • BDQ
Drug: Bedaquiline 100 mg
One 100mg tablet taken orally once daily in the morning during weeks 9-26
Other Names:
  • BDQ
Drug: Delamanid 300 mg
Six 50mg tablets taken orally once daily in the morning during weeks 1-26
Other Names:
  • DLM
Drug: Clofazimine 300 mg
Three 100mg capsules taken orally once daily in the morning during weeks 1-2
Other Names:
  • CFZ
Drug: Clofazimine 100 mg
One 100mg capsule taken orally once daily in the morning during weeks 3-26
Other Names:
  • CFZ
Experimental: Arm B

Everyone in the study will take bedaquiline (BDQ), delamanid (DLM), and clofazimine (CFZ) once a day for the entire treatment period. Arm B participants will take a higher dose of linezolid (LZD) once a day for 4 weeks and then continue taking 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: Bedaquiline 200 mg
Two 100mg tablets taken orally once daily in the morning during weeks 1-8
Other Names:
  • BDQ
Drug: Bedaquiline 100 mg
One 100mg tablet taken orally once daily in the morning during weeks 9-26
Other Names:
  • BDQ
Drug: Delamanid 300 mg
Six 50mg tablets taken orally once daily in the morning during weeks 1-26
Other Names:
  • DLM
Drug: Clofazimine 300 mg
Three 100mg capsules taken orally once daily in the morning during weeks 1-2
Other Names:
  • CFZ
Drug: Clofazimine 100 mg
One 100mg capsule taken orally once daily in the morning during weeks 3-26
Other Names:
  • CFZ
Drug: Linezolid 1200 mg (QD)
Two 600mg tablets taken orally once daily (QD) in the morning during weeks 1-4
Other Names:
  • LZD
Drug: Linezolid 1200 mg (TIW)
Two 600mg tablets taken orally three times per week (TIW; Mon-Wed-Fri) in the morning during weeks 5-26
Other Names:
  • LZD

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Cumulative probability of sputum culture conversion
Time Frame: Up to 26 weeks
Up to 26 weeks
Cumulative probability of permanent discontinuation of at least one anti-TB drug due to adverse events, intolerance, or death
Time Frame: Up to 26 weeks
Up to 26 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cumulative probability of sputum culture conversion
Time Frame: At week 8
Probability of sputum culture conversion in liquid media
At week 8
Cumulative probability of sputum culture conversion
Time Frame: At week 16
At week 16
Cumulative probability of sputum culture conversion
Time Frame: At week 26
At week 26
Cumulative probability of sputum culture conversion
Time Frame: At week 38
At week 38
Cumulative probability of permanent discontinuation of LZD due to AEs, intolerance, or death; temporary discontinuation of LZD for any reason; and dose reduction of LZD
Time Frame: Up to 26 weeks
Up to 26 weeks
Cumulative probability of treatment-related adverse events
Time Frame: Up to 26 weeks
Up to 26 weeks
Cumulative probability of unfavorable TB treatment outcome
Time Frame: At week 26
At week 26
Cumulative probability of unfavorable TB treatment outcome
Time Frame: At week 38
At week 38
Cumulative probability of unfavorable TB treatment outcome
Time Frame: At week 72
At week 72
Delamanid minimum plasma concentration (Cmin)
Time Frame: At week 4
At week 4
Delamanid maximum plasma concentration (Cmax)
Time Frame: At week 4
At week 4
Delamanid time to reach maximum plasma concentration (Tmax)
Time Frame: At week 4
At week 4
Delamanid area under the concentration-time curve (AUC)
Time Frame: At week 4
At week 4
Delamanid apparent oral clearance (CL/F)
Time Frame: At week 4
At week 4
Linezolid minimum plasma concentration (Cmin)
Time Frame: At week 4
At week 4
Linezolid maximum plasma concentration (Cmax)
Time Frame: At week 4
At week 4
Linezolid time to reach maximum plasma concentration (Tmax)
Time Frame: At week 4
At week 4
Linezolid area under the concentration-time curve (AUC)
Time Frame: At week 4
At week 4
Linezolid apparent oral clearance (CL/F)
Time Frame: At week 4
At week 4
Proportion of doses taken during the treatment period
Time Frame: Up to 26 weeks
Up to 26 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2022

Primary Completion (Estimated)

December 27, 2024

Study Completion (Estimated)

November 14, 2025

Study Registration Dates

First Submitted

July 22, 2021

First Submitted That Met QC Criteria

August 9, 2021

First Posted (Actual)

August 16, 2021

Study Record Updates

Last Update Posted (Actual)

April 3, 2024

Last Update Submitted That Met QC Criteria

April 2, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • A5356

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie results in the publication, after deidentification.

IPD Sharing Time Frame

Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.

IPD Sharing Access Criteria

  • With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.
  • For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.
  • By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Tuberculosis

Clinical Trials on Linezolid 600 mg

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Tanzania

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe