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

Global Alliance for TB Drug Development

Status and phase: Completed; Phase 3

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

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

Study type: Interventional

Funder types: Other

Identifiers

NCT03086486

ZeNix (B-Pa-L) NC-007

Details and patient eligibility

About

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.

Full 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.

Enrollment: 181 patients

Sex: All

Ages: 14+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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181 participants in 4 patient groups

1200mg L x 26 weeks + Pa + B

Experimental group

Description:

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

Treatment:

Drug: Pretomanid

Drug: Placebo Linezolid

Drug: Bedaquiline

Drug: Linezolid

1200 mg L x 9 weeks + Pa + B

Experimental group

Description:

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

Treatment:

Drug: Pretomanid

Drug: Placebo Linezolid

Drug: Bedaquiline

Drug: Linezolid

600 mg L x 26 weeks + Pa + B

Experimental group

Description:

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

Treatment:

Drug: Pretomanid

Drug: Placebo Linezolid

Drug: Bedaquiline

Drug: Linezolid

600 mg L x 9 weeks + Pa + B

Experimental group

Description:

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

Treatment:

Drug: Pretomanid

Drug: Placebo Linezolid

Drug: Bedaquiline

Drug: Linezolid