PanACEA Sutezolid Dose-finding and Combination Evaluation
Condition: Pulmonary Tuberculosis; Other Specified Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 2

Summary: 
      This study is an open-label, randomized, controlled, multi-center Phase IIB dose-finding
      trial to evaluate the safety, tolerability, pharmacokinetics and
      exposure-response-relationship of different doses of sutezolid (STZ) in combination with
      bedaquiline, delamanid and moxifloxacin in adults with newly diagnosed, uncomplicated, smear
      positive and drug sensitive pulmonary tuberculosis. Participants will be randomized to one of
      five arms containing bedaquiline, delamanid and moxifloxacin with different doses of STZ
      (0mg, 600mg once daily (OD), 1200mg OD, 600 mg twice daily (BD), 800 mg BD). Study treatment
      duration will be three months, followed by a follow-up period of 2 weeks.

      The primary objective is to identify the optimal dose of sutezolid to be used in subsequent
      studies that provides the best efficacy at acceptable safety of the drug by describing the
      safety, tolerability and exposure toxicity relationship of sutezolid (and its main
      metabolite) given over three months, in combination with standard-dose bedaquiline, delamanid
      and moxifloxacin, compared to standard-dose bedaquiline, delamanid and moxifloxacin alone.
    

Detailed description: 
      This open-label Phase IIB dose-finding, randomized, controlled study with a duration of three
      months of experimental therapy in adult patients with newly diagnosed, smear positive,
      uncomplicated, drug sensitive pulmonary tuberculosis (TB) will be carried out to evaluate the
      safety, efficacy, tolerability, pharmacokinetics and exposure/response-relationship of
      different doses of sutezolid in combination with bedaquiline, delamanid and moxifloxacin
      (BDM).

      Participants will be randomized to one of five arms containing bedaquiline, delamanid and
      moxifloxacin with different doses of STZ (0mg, 600mg OD, 1200mg OD, 600 mg BD, 800 mg BD).
      Study treatment duration will be three month, followed by a follow-up period of 2 weeks.

      A total of 75 male or female subjects, aged between 18 and 65 years with newly diagnosed,
      drug sensitive, uncomplicated, smear-positive, pulmonary TB will be included and randomized
      to one of five arms containing BDM with different doses of STZ:

        -  Arm 1 (U0): Bedaquiline, delamanid, moxifloxacin

        -  Arm 2 (U600): Bedaquiline, delamanid, moxifloxacin, sutezolid 600 mg OD

        -  Arm 3 (U1200): Bedaquiline, delamanid, moxifloxacin, sutezolid 1200 mg OD

        -  Arm 4 (U600BD): Bedaquiline, delamanid, moxifloxacin, sutezolid 600 mg BD

        -  Arm 5 (U800BD): Bedaquiline, delamanid, moxifloxacin, sutezolid 800 mg BD

      A sub-study will assess CYP P450 3A4 enzyme induction potential using the probe drug
      midazolam, given to participants in arm 5.

      Using PK data and data from primary efficacy and safety objectives, we will develop an
      exposure-response and a population PK-model for sutezolid and its main metabolite to support
      the main objective, selection of a dose for subsequent studies.
    

Intervention name(s): Sutezolid; Bedaquiline, Delamanid, Moxifloxacin; Midazolam oral solution
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Sutezolid is not licensed yet. Current experience in humans up to Phase IIA. Dose according to randomization to dosing arms 2-5.; These three licensed drugs form the backbone of a new regimen to which sutezolid is added in arms 2-5.; Midazolam will be administered as per probe drug use in a single dose of 2 mg at day -1 and day 14 to assess the potential of sutezolid for CYP 459 3A4 enzyme induction, as measured by its influence on the ratio of AUCs of the CYP 3A4 probe drug
Other intervention name(s): PNU-100480; BDM
Intervention MeSH terms: Moxifloxacin; Bedaquiline; Midazolam
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 75 participants will be randomized to one of five arms (15 participants per arm) to receive study medication containing bedaquiline, delamanid, and moxifloxacin with different doses of sutezolid, ranging from 0mg sutezolid up to 800mg sutezolid twice a day. Participants will be randomised and stratified by site and HIV status.
Participants will visit the study clinic on a weekly basis for sputum collection, safety monitoring and receipt of study medication.
After the completion of three months of experimental treatment participants in the experimental arms will be handed over to government TB programmes to complete their course of anti-TB treatment.
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Tuberculosis, Pulmonary; Sutezolid; Randomized Controlled Trial (RCT); PNU-100480; Tuberculosis; Antitubercular Agents; Gram-positive Bacterial Infections; Oxazolidinones; Dose-finding; Combination-evaluation; Safety; Tolerability; Pharmacokinetics (PK); Exposure-Response Relationship; Bedaquiline; Delamanid; Moxifloxacin; Drug-sensitive TB