PanACEA Sutezolid Dose-finding and Combination Evaluation

NCT03959566 | Completed Phase 2 DMC FDA Drug

• 1 other identifier: PanACEA-SUDOCU-01
• Study Type: interventional
• Target: 75
• Locations: 2 countries
• Sites: 4

Brief 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.

Conditions

Pulmonary Tuberculosis; Other Specified Pulmonary Tuberculosis

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

Outcome Measures

Primary Outcomes (2)

• Primary Efficacy Endpoint: Change in sputum mycobacterial load over time

  Change in mycobacterial load over time on treatment as quantified by change in time to positivity in BD MGIT 960® liquid culture.

  Days 01 - 84

• Primary safety endpoint: proportion of patients experiencing adverse events as defined below

  * Proportion of adverse events of Grade 3 severity or higher * Proportion of adverse events possibly, probably or definitely related to study drugs * Proportion of treatment discontinuations or interruptions related to adverse events/serious adverse events * Specific ECG endpoints: * Frequency, severity and type of ECG alterations * Changes to PR, RR, QRS, QT, Fridericia-corrected QT \[QTcF\] * Proportion of participants with QTcF \> 500ms on treatment * Proportion of participants with a prolongation of QTcF \> 60ms relative to baseline measurement

  Days 01 - 98

Secondary Outcomes (19)

• Secondary Efficacy Endpoint 1: Time to stable culture conversion

  Days 01 - 98

• Secondary Efficacy Endpoint 2: Culture conversion in liquid media

  Days 01 - 98

• Secondary Efficacy Endpoint 3: Culture conversion on solid media

  Days 01 - 98

• Secondary Efficacy Endpoint 4: No conversion to negative culture

  Days 01 - 98

• Pharmacokinetics Endpoint Sutezolid 1: AUC 0-24

  Day 14

Study Arms (5)

Arm 1 (U0)

ACTIVE COMPARATOR

Participants receive the following medication for the duration of 12 weeks (with Bedaquiline, Delamanid and Moxifloxacin as per licensed dose): * 400 mg Bedaquiline orally once daily for the first 14 days, then 200 mg three times a week. * 200 mg Delamanid orally in two daily doses of 100 mg. * 400 mg Moxifloxacin orally once daily

Drug: Bedaquiline, Delamanid, Moxifloxacin

Arm 2 (U600)

EXPERIMENTAL

Participants receive the following medication for the duration of 12 weeks (with Bedaquiline, Delamanid and Moxifloxacin as per licensed dose): * 400 mg Bedaquiline orally once daily for the first 14 days, then 200 mg three times a week. * 200 mg Delamanid orally in two daily doses of 100 mg. * 400 mg Moxifloxacin orally once daily * 600 mg Sutezolid orally once daily

Drug: Sutezolid; Drug: Bedaquiline, Delamanid, Moxifloxacin

Arm 3 (U1200)

EXPERIMENTAL

Participants receive the following medication for the duration of 12 weeks (with Bedaquiline, Delamanid and Moxifloxacin as per licensed dose): * 400 mg Bedaquiline orally once daily for the first 14 days, then 200 mg three times a week. * 200 mg Delamanid orally in two daily doses of 100 mg. * 400 mg Moxifloxacin orally once daily * 1200 mg Sutezolid orally once daily

Drug: Sutezolid; Drug: Bedaquiline, Delamanid, Moxifloxacin

Arm 4 (U600BD)

EXPERIMENTAL

Participants receive the following medication for the duration of 12 weeks (with Bedaquiline, Delamanid and Moxifloxacin as per licensed dose): * 400 mg Bedaquiline orally once daily for the first 14 days, then 200 mg three times a week. * 200 mg Delamanid orally in two daily doses of 100 mg. * 400 mg Moxifloxacin orally once daily * 600 mg Sutezolid orally twice daily

Drug: Sutezolid; Drug: Bedaquiline, Delamanid, Moxifloxacin

Arm 5 (U800BD)

EXPERIMENTAL

Participants receive the following medication for the duration of 12 weeks (with Bedaquiline, Delamanid and Moxifloxacin as per licensed dose): * 400 mg Bedaquiline orally once daily for the first 14 days, then 200 mg three times a week. * 200 mg Delamanid orally in two daily doses of 100 mg. * 400 mg Moxifloxacin orally once daily * 800 mg Sutezolid orally twice daily * 2 mg Midazolam orally once per day on day-1 and day 14

Drug: Sutezolid; Drug: Bedaquiline, Delamanid, Moxifloxacin; Drug: Midazolam oral solution

Interventions

Sutezolid DRUG

Sutezolid is not licensed yet. Current experience in humans up to Phase IIA. Dose according to randomization to dosing arms 2-5.

Also known as: PNU-100480

Arm 2 (U600); Arm 3 (U1200); Arm 4 (U600BD); Arm 5 (U800BD)

Bedaquiline, Delamanid, Moxifloxacin DRUG

These three licensed drugs form the backbone of a new regimen to which sutezolid is added in arms 2-5.

Also known as: BDM

Arm 1 (U0); Arm 2 (U600); Arm 3 (U1200); Arm 4 (U600BD); Arm 5 (U800BD)

Midazolam oral solution DRUG

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

Arm 5 (U800BD)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures including HIV testing.
• Male or female, aged between 18 and 65 years, inclusive.
• Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
• Newly diagnosed, previously untreated, drug susceptible pulmonary TB: presence of MDR-TB complex and rapid molecular tests result confirming susceptibility to Rifampicin (RIF) and Isoniazid (INH) such as GeneXpert and/or HAIN MTBDR plus.
• A chest X-ray (no older than 2 weeks) which, in the opinion of the Investigator, is consistent with TB.
• Sputum positive on microscopy from concentrated sputum for acid-fast bacilli on at least one sputum sample (at least 1+ on the International Union Against Tuberculosis and Lung Disease (IUATLD) /WHO scale).
• The participant is willing to forgo consumption of foods high in tyramine for the period of taking study medication
• The participant is either unable to conceive/father children AND/OR his/her partner is unable to conceive/father children AND/OR they will be using effective methods of contraception, as defined below:
• a. Non-childbearing potential: i. Female participant/sexual partner of male participant - bilateral oophorectomy, and/or hysterectomy or bilateral tubal ligation more than 12 months ago and/or has been postmenopausal with a history of no menses for at least 12 consecutive months ii. Male participant/sexual partner of female participant - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening b. Effective contraception methods: i. Female participants: two methods, including methods that the patient's sexual partner(s) use. At least one must be a barrier method. Contraception must be practised for at least until 12 weeks after the last dose of STZ.
• (Note: hormone-based contraception alone may not be reliable when taking RIF during continuation Phase; therefore, hormone-based contraceptives alone cannot be used by female participants/female partners of male participants to prevent pregnancy).
• ii. Male participants must ensure effective contraception for at least 12 weeks after the last dose of STZ that includes at least one barrier method.

You may not qualify if:

• Circumstances that raise doubt about free, unconstrained consent to study participation (e.g. in a prisoner or mentally handicapped person)
• Poor general condition where delay in treatment cannot be tolerated or death within three months is likely.
• Poor social condition which would make it unlikely that the patient would be able to complete follow-up
• The patient is pregnant or breast-feeding.
• The patient is infected with HIV with a cluster of differentiation (CD) 4 count \<220 cells/mm3. If \>220 cells/mm3, patients will be included only if any of the following is applicable:
• The patient is antiretroviral (ARV) naïve and able to postpone commencing HIV treatment for 2 months after the trial has started and then restrict regimens to those containing dolutegravir (see section 12.6.2 on ARVs) or The patient is ARV experienced (has been on ARV´s a minimum of 5 months) and able to switch to a dolutegravir-based regimen.
• Nucleosidic reverse transcriptase inhibitors are permitted as concomitant medication.
• Protease inhibitors as part of antiretroviral treatment regimens: need to be stopped at least 3 days before the start of study treatment (WK00, d1) for a patient to be eligible.
• Efavirenz as part of antiretroviral treatment regimens: may not be taken during 14 days before the start of study treatment (WK00, d1) for a patient to be eligible.
• The patient has a known intolerance to any of the study drugs or concomitant disorders or conditions for which study drugs or standard TB treatment are contraindicated.
• The patient has a history of, or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:
• Conditions or history that predispose to epileptic seizures: personal or first-degree family history of epileptic seizures, stroke or transient ischemic attack, or history of severe traumatic head or brain injury, or meningitis/encephalitis, or others
• Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required
• Clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement)
• Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator

Sponsors & Collaborators

• Michael Hoelscher: lead
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• Sequella, Inc.: collaborator
• Radboud University Medical Center: collaborator
• University of California, San Francisco: collaborator
• German Federal Ministry of Education and Research: collaborator

Study Sites (4)

The Aurum Institute for Health Research

Johannesburg, 2193, South Africa

Location

Kilimanjaro Clinical Research Institute

Moshi, Arusha, Tanzania

Location

Ifakara Health Institute

Bagamoyo, P.O.Box 74, Tanzania

Location

National Institute for Medical Research (NIMR - MMRC)

Mbeya, P.O. Box 2410, Tanzania

Location

Related Publications (1)

• Heinrich N, Manyama C, Koele SE, Mpagama S, Mhimbira F, Sebe M, Wallis RS, Ntinginya N, Liyoyo A, Huglin B, Minja LT, Wagnerberger L, Stoycheva K, Zumba T, Norena I, Peter DD, Makkan H, Sloan DJ, Brake LT, Schildkraut J, Aarnoutse RE, McHugh TD, Wildner L, Boeree M, Aldana BH, Phillips PPJ, Hoelscher M, Svensson EM; PanACEA consortium. Sutezolid in combination with bedaquiline, delamanid, and moxifloxacin for pulmonary tuberculosis (PanACEA-SUDOCU-01): a prospective, open-label, randomised, phase 2b dose-finding trial. Lancet Infect Dis. 2025 Nov;25(11):1208-1218. doi: 10.1016/S1473-3099(25)00213-0. Epub 2025 Jul 8.

  PMID: 40645196 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis; Gram-Positive Bacterial Infections

Interventions

PNU-100480; bedaquiline; OPC-67683; Moxifloxacin; Midazolam

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzodiazepines; Benzazepines

Study Officials

• Michael Hoelscher, Prof.

  University Hospital, LMU Munich, Division of Infectious Diseases and Tropical Medicine

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Laboratory staff, analysing and evaluating the sputum and blood samples of the participants, will be blinded to the treatment arm.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: 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.

Study Record Dates

• First Submitted: March 11, 2019
• First Posted: May 22, 2019
• Study Start: May 6, 2021
• Primary Completion: September 30, 2022
• Study Completion: September 30, 2022
• Last Updated: May 1, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

TA (3); ZA (1)