NCT03959566

PanACEA Sutezolid Dose-finding and Combination Evaluation

A Phase IIB, Open-Label, Randomized Controlled Dose Ranging Multi-Center Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Exposure-Response Relationship of Different Doses of Sutezolid in Combination With Bedaquiline, Delamanid and Moxifloxacin in Adult Subjects With Newly Diagnosed, Uncomplicated, Smear-Positive, Drug-sensitive Pulmonary Tuberculosis

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 75 (actual)
• Sponsor: Michael Hoelscher · Academic / Other
• Sex: All
• Age: 18 Years – 65 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Pulmonary Tuberculosis
• Other Specified Pulmonary Tuberculosis

Interventions

Type	Name	Description
DRUG	Sutezolid	Sutezolid is not licensed yet. Current experience in humans up to Phase IIA. Dose according to randomization to dosing arms 2-5.
DRUG	Bedaquiline, Delamanid, Moxifloxacin	These three licensed drugs form the backbone of a new regimen to which sutezolid is added in arms 2-5.
DRUG	Midazolam oral solution	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

Timeline

• Start date: 2021-05-06
• Primary completion: 2022-09-30
• Completion: 2022-09-30
• First posted: 2019-05-22
• Last updated: 2023-05-01

Locations

4 sites across 2 countries: South Africa, Tanzania

Regulatory

• FDA-regulated drug study