PanACEA Sutezolid Dose-finding and Combination Evaluation

NCT ID: NCT03959566

Last Updated: 2023-05-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-06
• Study Completion Date: 2022-09-30

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Arm 1 (U0)

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

Group Type: ACTIVE_COMPARATOR

Bedaquiline, Delamanid, Moxifloxacin

Intervention Type: DRUG

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

Arm 2 (U600)

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

Group Type: EXPERIMENTAL

Sutezolid

Intervention Type: DRUG

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

Bedaquiline, Delamanid, Moxifloxacin

Intervention Type: DRUG

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

Arm 3 (U1200)

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

Group Type: EXPERIMENTAL

Sutezolid

Intervention Type: DRUG

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

Bedaquiline, Delamanid, Moxifloxacin

Intervention Type: DRUG

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

Arm 4 (U600BD)

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

Group Type: EXPERIMENTAL

Sutezolid

Intervention Type: DRUG

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

Bedaquiline, Delamanid, Moxifloxacin

Intervention Type: DRUG

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

Arm 5 (U800BD)

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

Group Type: EXPERIMENTAL

Sutezolid

Intervention Type: DRUG

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

Bedaquiline, Delamanid, Moxifloxacin

Intervention Type: DRUG

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

Midazolam oral solution

Intervention Type: 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

Interventions

Sutezolid

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

Intervention Type: DRUG

Bedaquiline, Delamanid, Moxifloxacin

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

PNU-100480; BDM

Eligibility Criteria

Inclusion Criteria

1. Provide written, informed consent prior to all trial-related procedures including HIV testing.

2. Male or female, aged between 18 and 65 years, inclusive.

3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

4. 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.

5. A chest X-ray (no older than 2 weeks) which, in the opinion of the Investigator, is consistent with TB.

6. 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).

7. The participant is willing to forgo consumption of foods high in tyramine for the period of taking study medication

8. 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.

Exclusion Criteria

1. Circumstances that raise doubt about free, unconstrained consent to study participation (e.g. in a prisoner or mentally handicapped person)

2. Poor general condition where delay in treatment cannot be tolerated or death within three months is likely.

3. Poor social condition which would make it unlikely that the patient would be able to complete follow-up

4. The patient is pregnant or breast-feeding.

5. 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.

6. 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.

7. 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:

1. 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

2. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required

3. Clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement)

4. Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator

5. Any diabetes mellitus

6. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension

7. Arterial hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg on two occasions during screening).

8. Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause

9. Alcohol or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the patient, that includes substances prohibited by the protocol or has led to significant organ damage at the discretion of the investigator.

8. Any of the following laboratory findings at screening:

1. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity >3x the upper limit of normal (ULN),

2. serum alkaline phosphatase or y-glutamyl transferase > 2.5x the ULN,

3. serum total bilirubin level >1.5x the ULN

4. estimated creatinine clearance (eCrCl; using the Cockcroft and Gault formula (52) lower than 30 ml/min

5. serum albumin < 2.8 mg/dl

6. haemoglobin level <7.0 g/dl

7. platelet count <50,000/mm3,

8. serum potassium below the lower level of normal for the laboratory

9. serum creatine phosphokinase > 5x ULN

10. blood glucose at screening of less than 70mg/dL (3.9mmol/L)

9. ECG findings in the screening ECG: (one or more):

1. Fridericia corrected QT (QTcF) interval of >0.450 s

2. Atrioventricular (AV) block with PR interval > 0.20 s,

3. QRS complex > 120 milliseconds

4. any other changes in the ECG that are clinically relevant as per discretion of the investigator

10. Restricted medication:

1. Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.

2. Previous anti-TB treatment with drugs active against Mycobacterium tuberculosis (MTB) within the last 3 months.

3. Unable or unwilling to abide by the requirements regarding restricted medication or have taken restricted medication. Restricted medication includes the following drug classes:

• anti-TB drugs
• medication that lowers the threshold for epileptic seizures
• medication that prolongs the QTcF interval
• drugs that affect monoamineoxidase or serotonin metabolism
• CYP 450 inhibitors or inducers

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European and Developing Countries Clinical Trials Partnership (EDCTP)

OTHER_GOV

Sponsor Role: collaborator

Sequella, Inc.

INDUSTRY

Sponsor Role: collaborator

Radboud University Medical Center

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

German Federal Ministry of Education and Research

OTHER_GOV

Sponsor Role: collaborator

Michael Hoelscher

OTHER

Sponsor Role: lead

Responsible Party

Michael Hoelscher

Prof. Dr.

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Michael Hoelscher, Prof.

Role: STUDY_DIRECTOR

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

Locations

The Aurum Institute for Health Research

Johannesburg, , South Africa

Kilimanjaro Clinical Research Institute

Moshi, Arusha, Tanzania

Ifakara Health Institute

Bagamoyo, , Tanzania

National Institute for Medical Research (NIMR - MMRC)

Mbeya, , Tanzania

Countries

South Africa; Tanzania

References

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 Jul 8:S1473-3099(25)00213-0. doi: 10.1016/S1473-3099(25)00213-0. Online ahead of print.

Reference Type: DERIVED

PMID: 40645196 (View on PubMed)

Other Identifiers

PanACEA-SUDOCU-01

Identifier Type: -

Identifier Source: org_study_id