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

A Phase 3 Partially-blinded, Randomized Trial Assessing the Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary Infection of Either Extensively Drug-resistant Tuberculosis (XDR-TB), Pre-XDR-TB or Treatment Intolerant or Non-responsive Multi-drug Resistant Tuberculosis (MDR-TB)

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis; Tuberculosis, MDR; XDR-TB; Pre-XDR-TB
• Intervention / Treatment: Drug: Pretomanid; Drug: Linezolid; Drug: Bedaquiline; Drug: Placebo Linezolid

Detailed Description

A phase 3, multi-center, partially-blinded, randomized clinical trial in 4 parallel treatment groups. Bedaquiline and pretomanid treatment will not be blinded. Linezolid treatment dose and duration will be double-blinded.

Participants will have a screening period of up to 14 days and will be randomized to receive one of the 4 active treatment arms. Participants will be randomized to one of the 4 regimens in a 1:1:1:1 ratio, using an interactive voice and web response system (IXRS) which will utilize a randomization system using stratification with a random element to allocate participants evenly across the arms by HIV status and type of TB.

Each participant will receive 26 weeks of treatment. If participant's week 16 sputum sample is culture positive between the week 16 and week 26 treatment visits and their clinical condition suggests they may have an ongoing TB infection, Investigator may consider extending current treatment to 39 weeks. If the culture results between week 16 and week 26 are contaminated, missing or considered an isolated positive without clinical significance, available culture results should be used to make this decision. All decisions regarding treatment extension should be discussed with and approved by, in consultation with the Sponsor Medical Monitor before implementation. The treatment may also require modification due to toxicities. All dose modifications should be discussed with the Sponsor Medical Monitor prior to implementation, unless a pause or dose reduction is required urgently for safety concerns.

Participants will be followed for 78 weeks after end of treatment.

• Study Type: Interventional
• Enrollment (Actual): 181
• Phase: Phase 3

Contacts and Locations

Study Locations

• Georgia
  • Tbilisi, Georgia, 0101
    • National Center for Tuberculosis and Lung Diseases
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, 2025
    • Institute of Phthisiopneumology Chiril Draganiuc
• Russian Federation
  • Moscow, Russian Federation
    • National Medical Research Center of Phthisiopulmonology and Infectious Diseases
  • Moscow, Russian Federation, 107014
    • Moscow City Research and Practice Tuberculosis Treatment Centre
  • Moscow, Russian Federation, 107564
    • Central TB Research Institute of the Federal Agency of Scientific Organizations Moscow
  • Saint Petersburg, Russian Federation, 191036
    • FSBI "Saint-Petersburg Research Institute of Phthisiopulmonology"
  • Yekaterinburg, Russian Federation, 620039
    • Ural research Institute of Phthisiopulmonology
• South Africa
  • Durban, South Africa, 4015
    • King DinuZulu Hospital Complex
  • Johannesburg, South Africa, 2131
    • Clinical HIV Research Unit (CHRU) Sizwe Tropical Diseases Hospital
  • Eastern Cape
    • Port Elizabeth, Eastern Cape, South Africa
      • Empilweni TB Hospital
  • North - West
    • Klerksdorp, North - West, South Africa, 2574
      • Tshepong Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.

Exclusion criteria:

• 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)
  • Total bilirubin greater than 1.5 x ULN
  • Direct bilirubin greater than ULN
  • Serum creatinine level greater than 1.5 times upper limit of normal
  • Albumin <3.0 g/dl or < 30 g/L

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1200mg L x 26 weeks + Pa + B; 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; 200mg tablets; Other Names: PA-824; Pa; Drug: Linezolid; Scored 600mg tablets; Other Names: Zyvox; L; Lin; Drug: Bedaquiline; 100mg tablets; Other Names: B; Sirturo; TMC-207; Drug: Placebo Linezolid; Scored 600 mg tablets
Experimental: 1200 mg L x 9 weeks + Pa + B; 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; 200mg tablets; Other Names: PA-824; Pa; Drug: Linezolid; Scored 600mg tablets; Other Names: Zyvox; L; Lin; Drug: Bedaquiline; 100mg tablets; Other Names: B; Sirturo; TMC-207; Drug: Placebo Linezolid; Scored 600 mg tablets
Experimental: 600 mg L x 26 weeks + Pa + B; 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; 200mg tablets; Other Names: PA-824; Pa; Drug: Linezolid; Scored 600mg tablets; Other Names: Zyvox; L; Lin; Drug: Bedaquiline; 100mg tablets; Other Names: B; Sirturo; TMC-207; Drug: Placebo Linezolid; Scored 600 mg tablets
Experimental: 600 mg L x 9 weeks + Pa + B; 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; 200mg tablets; Other Names: PA-824; Pa; Drug: Linezolid; Scored 600mg tablets; Other Names: Zyvox; L; Lin; Drug: Bedaquiline; 100mg tablets; Other Names: B; Sirturo; TMC-207; Drug: Placebo Linezolid; Scored 600 mg tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 26 Weeks After the End of Treatment	Unfavourable status: Participants not classified as having achieved or maintained culture negative status when last seen; Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture; Participants who had a positive culture not followed by at least two negative cultures when last seen; Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide; Participants definitely or possibly dying from TB related cause during the follow-up phase; 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; Participants who have had surgery and the resected tissue is cultured and is positive for MTB; Participants lost to follow up or withdrawn from the study before the end of treatment	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) Through Follow up Until 78 Weeks After the End of Treatment.	Unfavourable status: Participants not classified as having achieved or maintained culture negative status when last seen; Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture; Participants who had a positive culture not followed by at least two negative cultures when last seen; Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide; Participants definitely or possibly dying from TB related cause during the follow-up phase; 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; Participants who have had surgery and the resected tissue is cultured and is positive for MTB; Participants lost to follow up or withdrawn from the study before the end of treatment	78 weeks
Time to Sputum Culture Conversion to Negative Status Through the Treatment Period	Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with tuberculosis can no longer produce tuberculosis cell cultures. Note: Culture conversion requires at least 2 consecutive culture negative/positive samples at least 7 days apart.; Participants who are documented at a visit as unable to produce sputum and who are clinically considered to be responding well to treatment will be considered to be culture negative at that visit.	26 weeks
Sputum Culture Conversion to Negative Status at End of Treatment for Those Positive at Baseline	Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with tuberculosis can no longer produce tuberculosis cell cultures.	End of Treatment, 26 weeks

Collaborators and Investigators

• Sponsor: Global Alliance for TB Drug Development
• Investigators: Principal Investigator: Francesca Conradie, Isango Lethemba TB Research Unit

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2017
• Primary Completion (Actual): February 15, 2021
• Study Completion (Actual): February 8, 2022

Study Registration Dates

• First Submitted: March 7, 2017
• First Submitted That Met QC Criteria: March 15, 2017
• First Posted (Actual): March 22, 2017

Study Record Updates

• Last Update Posted (Actual): June 29, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Tuberculosis; PA-824; TB Alliance; Linezolid; Pretomanid; Bedaquiline; Extensively Drug-Resistant Tuberculosis; Multi Drug-Resistant Tuberculosis; Drug-Resistant Tuberculosis; NC-007; pre-XDR-TB; Sirturo; Zyvox; ZeNix
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Antitubercular Agents; Linezolid; Bedaquiline
• Other Study ID Numbers: ZeNix (B-Pa-L) NC-007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No