A Phase 2 Trial to Evaluate the Efficacy and Safety of Linezolid in Tuberculosis Patients. (LIN-CL001)

NCT02279875 | Completed Phase 2 DMC

• 1 other identifier: LIN-CL001
• Study Type: interventional
• Target: 113
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to evaluate the mycobactericidal activity, safety, tolerability, and pharmacokinetics of 6 doses of linezolid: 300 mg once per day, 300 mg twice per day, 600 mg once per day, 600 mg twice per day and 1200 mg once per day administered orally for 14 consecutive days or 1200 mg administered three times per week for two weeks in adult subjects with newly diagnosed drug-sensitive, smear-positive pulmonary tuberculosis.

Conditions

Pulmonary Tuberculosis

Keywords

Tuberculosis; Drug-Sensitive Tuberculosis; Linezolid; HRZE (isoniazid, rifampicin, pyrazinamide, ethambutol); Pulmonary Tuberculosis; TB

Outcome Measures

Primary Outcomes (1)

• Bactericidal Activity (Time to Positivity) Days 0 - 14 [BA(TTP)]

  \[BA(TTP)\] will be determined by the rate of change in time to sputum culture positivity (TTP) over 14 days of treatment in the Mycobacterial Growth Indicator Tube system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time.

  Days -2, -1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

Secondary Outcomes (7)

• The Bactericidal Activity (Time to Positivity) Days 0 - 2 [BA(TTP)](0-2), and Bactericidal Activity (Time to Positivity) Days 7 - 14 [BA(TTP)](7-14)

  Day -2, -1, 1, 2, 7, 8, 9, 10, 11, 12, 13, 14

• The Bactericidal Activity Colony Forming Unit (BACFU)(0-14), BACFU(0-2) and BACFU(7-14)

  Day 1, 2, 3, 4, 5, 6, 7, 8, 8, 9, 10, 11, 12, 13, 14

• Incidence of Treatment Emergent Adverse Events (TEAEs) presented by severity (DMID Grade), relatedness, and seriousness, leading to early withdrawal and leading to death.

  Screening (-9 to -3, -2, -1), Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and Follow-Up (Day 21)

• Pharmacokinetic parameters for subjects (except in the HRZE treatment arm): Cmax, T1/2, AUC 0 - 12

  Day 12 (pre-dose, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose) for 1200 3X per week, Day 14 (pre-dose, 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose) for 600 mg QD (B), and Day 14 (pre-dose, 0.5, 1, 2, 4, 8, and 12 hours post-dose) for other arms

• Time over minimum inhibitory concentration (MIC) will be calculated for each subject in the linezolid arms individually and for each of the linezolid arms as a group, based on the MIC determined at baseline.

  Baseline (Day -2 to -1), Day 12 (1200 mg three times per week), Day 14 (all other experimental arms)

Study Arms (8)

Linezolid 300 mg once per day

EXPERIMENTAL

Half of a 600mg (scored) tablet

Drug: Linezolid

Linezolid 300 mg twice per day

EXPERIMENTAL

Half of a 600mg (scored) tablet

Drug: Linezolid

Linezolid 600 mg once per day (A)

EXPERIMENTAL

600mg (scored) tablet

Drug: Linezolid

Linezolid 600 mg once per day (B)

EXPERIMENTAL

600mg (scored) tablet

Drug: Linezolid

Linezolid 600 mg twice per day

EXPERIMENTAL

600mg (scored) tablet

Drug: Linezolid

Linezolid 1200 mg once per day

EXPERIMENTAL

Two 600mg (scored) tablets

Drug: Linezolid

Linezolid 1200 mg 3 times per week

EXPERIMENTAL

Linezolid 1200 mg administered as a single oral dose three times per week (1200 mg: Day 1, 3, 5, 8, 10, and 12)

Drug: Linezolid

HRZE once per day

ACTIVE COMPARATOR

Treatment will be administered orally once daily for 14 days per the Subject's weight as follows: 30-37 kg: 2 tablets; 38-54 kg: 3 tablets; 55-70 kg: 4 tablets; 71 kg and over: 5 tablets.

Drug: HRZE (isoniazid rifampicin,pyrazinamide,ethambutol)

Interventions

Linezolid DRUG

Linezolid 1200 mg 3 times per week; Linezolid 1200 mg once per day; Linezolid 300 mg once per day; Linezolid 300 mg twice per day; Linezolid 600 mg once per day (A); Linezolid 600 mg once per day (B); Linezolid 600 mg twice per day

HRZE (isoniazid rifampicin,pyrazinamide,ethambutol) DRUG

isoniazid (H) 75 mg plus rifampicin (R) 150 mg plus pyrazinamide (Z) 400 mg plus ethambutol (E) 275 mg

HRZE once per day

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures.
• Male or female, aged between 18 and 75 years inclusive.
• Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.
• Drug-sensitive pulmonary Tuberculosis (TB) determined by testing at the trial appointed laboratory: M.tb positive and rifampicin sensitive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale).
• either newly diagnosed OR
• untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND

You may not qualify if:

• A chest X-Ray which in the opinion of the Investigator is consistent with TB.
• Ability to produce an adequate volume of sputum as estimated from a screening Coached Spot Sputum Sample assessment (estimated 10 ml or more overnight production).
• Be of non-childbearing potential or using effective methods of birth control, as defined below:
• Non-childbearing potential:
• Subject - not heterosexually active or practices sexual abstinence; OR
• Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; OR
• Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening;
• Effective birth control methods:
• A double contraceptive method should be used as follows:
• Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); OR
• Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female Subject/partner; AND
• Are willing to continue practicing one of the above mentioned birth control methods throughout treatment and for 1 month (both male and female Subjects) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation.
• Subjects will be excluded from participation if they meet any of the following criteria.
• Medical Criteria
• Evidence of clinically significant (as judged by the Investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including malaria.

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (2)

TASK Clinical Research Centre

Bellville, Cape Town, 7530, South Africa

Location

University of Cape Town Lung Institute (Pty) Ltd

Mowbray, Cape Town, 7700, South Africa

Location

Related Publications (2)

• Simeon S, Garcia-Cremades M, Savic R, Solans BP. Pharmacokinetic-pharmacodynamic modeling of tuberculosis time to positivity and colony-forming unit to assess the response to dose-ranging linezolid. Antimicrob Agents Chemother. 2024 Aug 7;68(8):e0019024. doi: 10.1128/aac.00190-24. Epub 2024 Jul 17.

  PMID: 39016594 DERIVED

• Diacon AH, De Jager VR, Dawson R, Narunsky K, Vanker N, Burger DA, Everitt D, Pappas F, Nedelman J, Mendel CM. Fourteen-Day Bactericidal Activity, Safety, and Pharmacokinetics of Linezolid in Adults with Drug-Sensitive Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2020 Mar 24;64(4):e02012-19. doi: 10.1128/AAC.02012-19. Print 2020 Mar 24.

  PMID: 31988102 DERIVED

Related Links

• TB Alliance Website

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

Linezolid

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

Study Officials

• Christo van Niekerk

  Global Alliance for TB Drug Development

  STUDY DIRECTOR

• Adreas Diacon

  Task Clinical Research Centre

  PRINCIPAL INVESTIGATOR

• Rod Dawson

  University of Cape Town Lung Institute (Pty) Ltd

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: October 28, 2014
• First Posted: October 31, 2014
• Study Start: November 1, 2014
• Primary Completion: November 28, 2016
• Study Completion: July 1, 2017
• Last Updated: January 11, 2019

Record last verified: 2017-04

Locations

ZA (2)