Various Doses and Durations of Linezolid Plus Bedaquiline & Pretomanid in Participants With Drug Resistant Tuberculosis

NCT03086486 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: ZeNix (B-Pa-L) NC-007
• Study Type: interventional
• Target: 181
• Locations: 4 countries
• Sites: 11

Brief Summary

To evaluate the efficacy, safety and tolerability of various doses and durations of linezolid plus bedaquiline and pretomanid after 26 weeks of treatment in participants with either pulmonary XDR-TB, pre-XDR-TB, or treatment intolerant or non-responsive MDR-TB.

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis, MDR; Tuberculosis; Extensively Drug-Resistant Tuberculosis; Pre-XDR-TB; XDR-TB

Keywords

Tuberculosis; Multi Drug-Resistant Tuberculosis; Extensively Drug-Resistant Tuberculosis; Drug-Resistant Tuberculosis; Pretomanid; PA-824; Bedaquiline; Linezolid; NC-007; TB Alliance; pre-XDR-TB; Sirturo; Zyvox; ZeNix

Outcome Measures

Primary Outcomes (1)

• Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment

  Unfavourable status: 1. Participants not classified as having achieved or maintained culture negative status when last seen 2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture 3. Participants who had a positive culture not followed by at least two negative cultures when last seen 4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide 5. Participants definitely or possibly dying from TB related cause during the follow-up phase 6. Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy 7. Participants who have had surgery and the resected tissue is cultured and is positive for MTB 8. Participants lost to follow up or withdrawn from the study before the end of treatment

  26 weeks

Secondary Outcomes (3)

• Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 78 Weeks After the End of Treatment.

  78 weeks

• Time to Sputum Culture Conversion to Negative Status Through the Treatment Period

  26 weeks

• Sputum Culture Conversion to Negative Status at End of Treatment for Those Positive at Baseline

  End of Treatment, 26 weeks

Study Arms (4)

1200mg L x 26 weeks + Pa + B

EXPERIMENTAL

2 linezolid 600 mg active tablets once daily for 26 weeks plus 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

Drug: Pretomanid; Drug: Linezolid; Drug: Bedaquiline; Drug: Placebo Linezolid

1200 mg L x 9 weeks + Pa + B

EXPERIMENTAL

2 linezolid 600 mg active tablets once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

Drug: Pretomanid; Drug: Linezolid; Drug: Bedaquiline; Drug: Placebo Linezolid

600 mg L x 26 weeks + Pa + B

EXPERIMENTAL

1 linezolid 600 mg active tablet once daily for 26 weeks, 1 placebo linezolid 600 mg tablet once daily for 26 weeks, 1 placebo linezolid 300 mg half tablet once daily for 26 weeks plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

Drug: Pretomanid; Drug: Linezolid; Drug: Bedaquiline; Drug: Placebo Linezolid

600 mg L x 9 weeks + Pa + B

EXPERIMENTAL

1 linezolid 600 mg active tablets once daily for 8 weeks, 1 placebo linezolid 600 mg half tablet once daily for 9 weeks, 1 placebo linezolid 300 mg half tablet once daily for 9 weeks (for Weeks 1-9); 2 placebo linezolid 600 mg tablets once daily for 17 weeks, 1 placebo linezolid 300 mg half tablet once daily for 17 weeks (for Weeks 10-26) plus; bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks plus; pretomanid 200 mg once daily for 26 weeks

Drug: Pretomanid; Drug: Linezolid; Drug: Bedaquiline; Drug: Placebo Linezolid

Interventions

Pretomanid DRUG

200mg tablets

Also known as: PA-824, Pa

1200 mg L x 9 weeks + Pa + B; 1200mg L x 26 weeks + Pa + B; 600 mg L x 26 weeks + Pa + B; 600 mg L x 9 weeks + Pa + B

Linezolid DRUG

Scored 600mg tablets

Also known as: L, Lin, Zyvox

1200 mg L x 9 weeks + Pa + B; 1200mg L x 26 weeks + Pa + B; 600 mg L x 26 weeks + Pa + B; 600 mg L x 9 weeks + Pa + B

Bedaquiline DRUG

100mg tablets

Also known as: TMC-207, B, Sirturo

1200 mg L x 9 weeks + Pa + B; 1200mg L x 26 weeks + Pa + B; 600 mg L x 26 weeks + Pa + B; 600 mg L x 9 weeks + Pa + B

Placebo Linezolid DRUG

Scored 600 mg tablets

1200 mg L x 9 weeks + Pa + B; 1200mg L x 26 weeks + Pa + B; 600 mg L x 26 weeks + Pa + B; 600 mg L x 9 weeks + Pa + B

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, aged 14 years or older.
• One of the following with documentation of culture positive or molecular test within 3 months of screening:
• XDR-TB defined as resistance to rifamycins, a fluoroquinolone AND an injectable OR
• Pre-XDR-TB with defined as resistance to rifamycins, and to a fluoroquinolone OR an injectable OR
• MDR-TB with resistance to rifamycins, and either non-responsive or non-tolerant to current treatment.
• Of non-childbearing potential or willing to practice effective birth control methods.
• Complete informed consent form.

You may not qualify if:

• Karnofsky score \< 60 at screening.
• Body mass index (BMI) \< 17 kg/m2
• Participants who are expected to require a surgical procedure (for Pulmonary TB).
• Any risk factor for QT prolongation
• Pregnant or breast-feeding
• Any planned contraindicated medicines or received more than 2 weeks of bedaquiline, linezolid or delamanid prior to first dose of IMP.
• A peripheral neuropathy of Grade 3 or 4, according to DMID. Or, participants with a Grade 1 or 2 neuropathy which is likely to progress/worsen over the course of the study, in the opinion of the Investigator
• Any of the following lab toxicities/abnormalities:
• Viral load \>1000 copies/mL (Unless newly diagnosed HIV and not yet on ART who otherwise qualify for participation);
• CD4+ count \< 100 cells/µL (HIV positive participants);
• Serum potassium less than the lower limit of normal for the laboratory;
• Hemoglobin \< 9.0 g/dL or 90g/L;
• Platelets \<100,000/mm3 or \< 100 x 10\^9/L
• Absolute neutrophil count (ANC) \< 1500/ mm3 or \< 1.5 x 10\^9/L
• Aspartate aminotransferase (AST) and Alanini aminotransferase (ALT) Grade 3 or greater (\> 3.0 x ULN)

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (11)

National Center for Tuberculosis and Lung Diseases

Tbilisi, 0101, Georgia

Location

Institute of Phthisiopneumology Chiril Draganiuc

Chisinau, 2025, Moldova

Location

Moscow City Research and Practice Tuberculosis Treatment Centre

Moscow, 107014, Russia

Location

Central TB Research Institute of the Federal Agency of Scientific Organizations Moscow

Moscow, 107564, Russia

Location

National Medical Research Center of Phthisiopulmonology and Infectious Diseases

Moscow, Russia

Location

FSBI "Saint-Petersburg Research Institute of Phthisiopulmonology"

Saint Petersburg, 191036, Russia

Location

Ural Research Institute of Phthisiopulmonology

Yekaterinburg, 620039, Russia

Location

Empilweni TB Hospital

Port Elizabeth, Eastern Cape, South Africa

Location

Tshepong Hospital

Klerksdorp, North West, 2574, South Africa

Location

King DinuZulu Hospital Complex

Durban, 4015, South Africa

Location

Clinical HIV Research Unit (CHRU) Sizwe Tropical Diseases Hospital

Johannesburg, 2131, South Africa

Location

Related Publications (1)

• Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M; ZeNix Trial Team. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430.

  PMID: 36053506 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis; Extensively Drug-Resistant Tuberculosis

Interventions

pretomanid; Linezolid; bedaquiline

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

Limitations and Caveats

None reported.

Results Point of Contact

• Title: Morounfolu Olugbosi
• Organization: TB Alliance

morounfolu.olugbosi@tballiance.org

1 212 227 7540

Study Officials

• Francesca Conradie

  Isango Lethemba TB Research Unit

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Participants, trial investigators and staff, including laboratory staff, will be blinded to dose and scheduled duration of linezolid. Bedaquiline and pretomanid dosing will not be blinded. There will be three unblinded analyses which will contain results by linezolid treatment group in aggregate. The first analysis will be after all participants have completed 26 weeks of treatment and here sites, participants, and Sponsor staff will not be unblinded to individual linezolid treatment information. A limited number of statisticians will have access to individual linezolid treatment assignments. The blind for all individual participants will be broken for the primary endpoint analysis (the second unblinded analysis) once all clinical data and outcome parameters have been captured, no more data queries are pending, and the statistical analysis plan has been finalized. The third analysis will occur when all participants have completed 78 weeks of follow-up after end of treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2017
• First Posted: March 22, 2017
• Study Start: November 21, 2017
• Primary Completion: February 15, 2021
• Study Completion: February 8, 2022
• Last Updated: June 29, 2023
• Results First Posted: June 29, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

MO (1); RU (5); GE (1); ZA (4)