Various Doses and Durations of Linezolid Plus Bedaquiline & Pretomanid in Participants With Drug Resistant Tuberculosis
Condition: Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis, MDR; Tuberculosis; Extensively Drug-Resistant Tuberculosis; Pre-XDR-TB; XDR-TB
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis
Intervention: Pretomanid; Linezolid; Bedaquiline; Placebo Linezolid
Intervention description: 200mg tablets; Scored 600mg tablets; 100mg tablets; Scored 600 mg tablets
Intervention MeSH terms: Linezolid; Bedaquiline
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: 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.
Enrollment: 181.0
Sex: All
Minimum age: 14 Years
Healthy volunteers: No
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

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.
    

Eligibility criteria:

        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