PanACEA - STEP2C -01

NCT05807399 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: PanACEA - STEP2C -01
• Study Type: interventional
• Target: 390
• Locations: 6 countries
• Sites: 10

Brief Summary

This is a phase 2B/C, open label platform study that will compare the efficacy, safety of experimental regimens with a standard control regimen in participants with newly diagnosed, drug sensitive pulmonary tuberculosis. In stage 1, participants will be randomly allocated to the control or one of the 2 rifampicin-containing experimental regimens in the ratio 1:1:1. In stage 2, the experimental arm 4 containing BTZ-043 will be added. The allocation ratio will be changed to co-enrol the remaining participants in arms 1- 3 simultaneously with arm 4 in a ratio of 1:1:1:2. When arms 1-2 are fully enrolled and arm 4 is not, further participants will be randomized 1:1 to control and experimental arm 4. Not all countries will participate in stage 2. In stage 3, participants will be allocated in parallel to control arm treatment (now designated arm 7) or the experimental arms 5 and 6, favouring arm 5, 2:1:1 over arms 6 and control. This stage will start after completion of recruitment in the stages 1 and 2. Enrolment of participants into arm 5 will proceed following review of data from the ENABLE/UNITE-03 (NCT06748937), non-clinical safety data and after endorsement by the DSMB. Thus, arm 5 recruitment might start after arms 6 and 7, which may require an increase in the control arm sample size to ensure controls are recruited concomitantly.

Conditions

Pulmonary Tuberculosis; Other Specified Pulmonary Tuberculosis

Keywords

Tuberculosis, Pulmonary; Tuberculosis; Antitubercular Agents; Safety; Tolerability; Pharmacokinetics (PK); Moxifloxacin; BTZ-043; Rifampicin

Outcome Measures

Primary Outcomes (2)

• Time to stable culture conversion to negative in liquid media

  The primary efficacy endpoint of arms 1 and 2 will be time to stable culture conversion to negative in liquid media defined as the time from enrolment to the first of two negative weekly sputum cultures without an intervening positive culture in liquid media, in comparison to arm 3. The efficacy of BTZ-043 will be evaluated by measuring the change in mycobacterial load over time on treatment as quantified by time to positivity in BD MGIT 960® liquid culture described by non-linear mixed-effects methodology, in comparison to arm 3.

  Day 01- Week 26

• Change in Mycobacterial load (Stage 3)

  The efficacy of the arms 5 and 6 (Stage 3) will be evaluated by measuring the change in mycobacterial load over time on treatment as quantified by time to positivity in BD MGIT 960® liquid culture described by non-linear mixed-effects methodology, in comparison to arm 7 using the TTP0-8 or 12 weeks slope.

  Baseline until week 12 of treatment.

Secondary Outcomes (14)

• Relapse - free survival at 12 months after randomization

  Day 01-364

• Frequency of all adverse events (serious and non-serious)

  Day 01-182

• Frequency of adverse events of Grade 3 severity (severe) or higher

  Day 01-182

• Frequency of adverse events possibly, probably or definitely related to study drug

  Day 01-182

• Frequency of treatment discontinuations or interruptions related to adverse events/serious adverse event

  Day 01-182

Study Arms (7)

Arm 1 (Stage 1)

EXPERIMENTAL

Rifampicin 2100mg, isoniazid 300mg, pyrazinamide 1600mg moxifloxacin 600mg; given once daily for 17 weeks (R2100HZM600)

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Moxifloxacin

Arm 2 (Stage 1)

EXPERIMENTAL

Rifampicin 2100mg, isoniazid 300mg, pyrazinamide 2000mg/2400mg, moxifloxacin 600mg; given once daily for 12 weeks (R2100HZoptM600)

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Moxifloxacin

Arm 3

ACTIVE COMPARATOR

Stage 1: control arm (2HRZE-4RH) Stage 2: continuation of control-arm from STAGE 1 (2HRZE-4RH)

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol (E)

Arm 4 (Stage 2)

EXPERIMENTAL

Rifampicin, Isoniazid, and Pyrazinamide in weight-banded standard dosages with BTZ-043 1,000mg; given once daily for 17 weeks (RHZT), then rifampicin and isoniazid in weight-banded dosages; given once daily for 9 weeks (RH)

Drug: BTZ-043; Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide

Arm 5 (Stage 3)

EXPERIMENTAL

Alpibectir (GSK3729098) 45mg, ethionamide 500mg (A/Eto) with possibility of lower alpibectir and Eto doses based on emerging clinical data, from the ENABLE study \[ Clinical Trials gov NCT06748937\] and non-clinical data and endorsed by the GSK Global safety board, rifampicin, pyrazinamide and ethambutol at standard doses given once daily for 8 weeks, continued with RIF and INH at standard doses for 18 weeks.

Drug: Rifampicin; Drug: Pyrazinamide; Drug: Alpibectir (GSK3729098); Drug: Ethambutol (E); Drug: Ethionamide

Arm 6 (Stage 3)

EXPERIMENTAL

Pretomanid 200mg, ganfeborole (GSK3036656) 20mg, BTZ-043 1000mg and delpazolid (LCB01-0371) 1200mg; given once daily for 26 weeks

Drug: BTZ-043; Drug: Ganfeborole (GSK3036656); Drug: Delpazolid (LCB01-0371); Drug: Pretomanid (Pa)

Arm 7 (Stage 3)

ACTIVE COMPARATOR

Parallel control arm (2HRZE-4RH)

Drug: Rifampicin; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Ethambutol (E)

Interventions

BTZ-043 DRUG

BTZ-043 1000mg once daily in arms 4 and 6.

Arm 4 (Stage 2); Arm 6 (Stage 3)

Rifampicin DRUG

Rifampicin will be dosed in a fixed high-dose (2100 mg for arms 1 and 2) or a weight-banded regular dose (10 mg/kg) in arm 3, 5 and 7.

Arm 1 (Stage 1); Arm 2 (Stage 1); Arm 3; Arm 4 (Stage 2); Arm 5 (Stage 3); Arm 7 (Stage 3)

Isoniazid DRUG

Isoniazid will be dosed at fixed dose of 300mg in arms 1 and 2, and regular dose of 5 mg/kg in arm 3 and 7.

Arm 1 (Stage 1); Arm 2 (Stage 1); Arm 3; Arm 4 (Stage 2); Arm 7 (Stage 3)

Pyrazinamide DRUG

Pyrazinamide will be dosed in a fixed regular dose in arm 1 (1600 mg), a weight banded high dose in arm 2 (2000/2400 mg) or a weight-banded regular dose (25 mg/kg) in arm 3, 5 and 7.

Arm 1 (Stage 1); Arm 2 (Stage 1); Arm 3; Arm 4 (Stage 2); Arm 5 (Stage 3); Arm 7 (Stage 3)

Moxifloxacin DRUG

Moxifloxacin will be dosed at 600 mg orally once daily in arms 1-2.

Arm 1 (Stage 1); Arm 2 (Stage 1)

Alpibectir (GSK3729098) DRUG

Alpibectir 45 mg OD plus Ethionamide 500 mg OD combined with rifampicin pyrazinamide and ethambutol at standard weight-banded doses in arm 5.

Arm 5 (Stage 3)

Ganfeborole (GSK3036656) DRUG

Ganfeborole 20 mg OD in arm 6

Arm 6 (Stage 3)

Delpazolid (LCB01-0371) DRUG

Delpazolid 1200mg OD in arm 6

Arm 6 (Stage 3)

Pretomanid (Pa) DRUG

Pretomanid 20mg OD in arm 6.

Arm 6 (Stage 3)

Ethambutol (E) DRUG

Ethambutol 20mg/Kg OD in arm 3, 5 and 7

Arm 3; Arm 5 (Stage 3); Arm 7 (Stage 3)

Ethionamide DRUG

Ethionamide 500mg OD in arm 5.

Arm 5 (Stage 3)

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 MTB complex and rapid molecular tests result confirming susceptibility to RIF and INH such as GeneXpert and/or HAIN MTBDR plus. Participants who had a previous history of TB may be enrolled in this trial, if they:
• had a good treatment response in the opinion of the investigator; i.e. TB symptoms improved sufficiently or resolved suggesting a cure of the past episode; AND
• no persistent microbiological positivity is seen (in case microbiological results are available); AND - their treatment course was completed AND
• the last dose of treatment was more than 3 months ago.
• A chest X-ray (no older than 2 weeks) which shows abnormalities that, in the opinion of the Investigator, are consistent with TB.
• Sputum positive on microscopy from concentrated sputum for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale) AND/OR positive GeneXpert MTB/RIF Ultra® semi-quantitative result "medium" or "high" on at least one sputum sample.
• The participant understands the interaction between the study drugs and certain foods and is willing to forgo the consumption of those foods for the period of study medication.
• The participant is not of child-bearing potential or is willing to use effective methods of contraception when engaging in heterosexual intercourse, as defined below:
• 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 and confirmed by a FSH test.
• ii. Male participant/sexual partner of female participant: Vasectomised or has had a bilateral orchidectomy minimally three months prior to screening iii. Male participants having a pregnant female partner or a male sexual partner: At least one barrier method has to be used in this case.
• b. Effective contraception methods: i. Female participants: Two methods, including methods that the participant'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 experimental treatment. For stage 3, female participants of child-bearing potential must have used contraception if any sexual intercourse has occurred after last menses or within the last 3 weeks (whichever is later) before participation, and agree to use non-user dependent contraception: depo-provera injection\* or an intrauterine device additional to one barrier method.

You may not qualify if:

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• Circumstances that raise doubt about free, unconstrained consent to study participation (e.g., person in detention or person with mental disability)
• Poor general condition where delay in treatment cannot be tolerated or death within four months is likely.
• Circumstances (in the opinion of the investigator) that raise doubt about ability to complete the follow-up during the study period.
• The participant is pregnant or breast-feeding or planning to become pregnant in the study period.
• The participant is infected with HIV with a CD4 count \<220 cells/mm3. If \>220 cells/mm3, participants will be included only if any of the following is applicable:
• The participant 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 mentioned in section on ARVs or
• The participant is ARV experienced (has been on ARV´s a minimum of 5 months), AND: ARV treatment is compliant to, or can be modified as described in the section on Antiretroviral Therapy
• The participant 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 participant has a history of, or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, hepato-biliary, renal, 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:
• a. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required b. Evidence of clinically significant extra-pulmonary TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement) c. Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator d. Uncontrolled diabetes mellitus or diabetes mellitus receiving/requiring treatment with metformin or sulfonylureas e. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension f. Uncontrolled arterial hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure of ≥95 mmHg on two occasions during screening. An attempt at antihypertensive treatment during the screening period is permitted).
• g. Long QT syndrome or family history of long QT syndrome or family history of sudden death of unknown or cardiac-related cause h. Alcohol, regular opiate, or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the participant, that includes substances prohibited by the protocol or has led to significant organ damage at the discretion of the investigator; AND/OR any abuse of methamphetamine.
• i. History of optic neuropathy j. Vitiligo
• Any of the following laboratory findings at screening:
• a. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) \>3x the upper limit of normal (ULN), b. Serum alkaline phosphatase or y-glutamyl transferase \> 2.5x the ULN, c. Serum total bilirubin level \>1.5x the ULN d. Estimated creatinine clearance -eCrCl (using the CKD-EPI 2021 creatinine formula):

Sponsors & Collaborators

• Michael Hoelscher: lead
• Radboud University Medical Center: collaborator
• University of California, San Francisco: collaborator
• University College, London: collaborator
• GlaxoSmithKline: collaborator
• LigaChem Biosciences, Inc.: collaborator

Study Sites (10)

Centre de Recherches Médicales de Lambaréné (CERMEL)

Lambaréné, Gabon

COMPLETED

Kamuzu College of Health Sciences (formerly College of Medicine)

Blantyre, Malawi

RECRUITING

Instituto Nacional de Saúde (INS)

Maputo, Mozambique

RECRUITING

Isango Lethemba TB Research Unit. Clinical HIV Research Unit (CHRU), Wits Health Consortium.

Port Elizabeth, Eastern Cape, 6003, South Africa

NOT YET RECRUITING

TASK Applied Sciences Clinical Research Centre

Cape Town, 7500, South Africa

RECRUITING

University of Cape Town Lung Institute

Cape Town, 7700, South Africa

NOT YET RECRUITING

National Institute for Medical Research (NIMR-MMRC)

Mbeya, Mbeya, Tanzania

RECRUITING

Ifakara Health Institute (IHI)

Bagamoyo, Tanzania

RECRUITING

Kilimanjaro Clinical Research Institute (KCRI)

Moshi, Tanzania

RECRUITING

Makerere University Lung Institute Limited

Kampala, Uganda

RECRUITING

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; Rifampin; Isoniazid; Pyrazinamide; Moxifloxacin; GSK656; delpazolid; pretomanid; Ethambutol; Ethionamide

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Heterocyclic Compounds, 1-Ring; Pyrazines; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Ethylenediamines; Diamines; Polyamines; Amines

Study Officials

• Michael Hoelscher, Prof Dr.

  LMU University Hospital

  STUDY DIRECTOR

Central Study Contacts

Norbert Heinrich, PD Dr.

CONTACT

+49894400; Norbert.Heinrich@med.uni-muenchen.de

Ivan Noreña, MSc. MD

CONTACT

+49894400; Ivan.Norena@med.uni-muenchen.de

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: This study will be open-label, participants and physicians will be aware of treatment allocation. To ensure unbiased assessment of efficacy endpoints, the personnel assessing participants' outcomes, like the microbiology laboratory staff, will remain blinded to treatment assignment throughout the whole study. Every effort will be made to maintain this blinding.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: The study will compare the efficacy, safety of 5 experimental regimens with a standard control regimen in participants with newly diagnosed, drug sensitive pulmonary tuberculosis. In stage 1, participants will be randomly allocated to the control or one of the 2 rifampicin-containing experimental regimens in the ratio 1:1:1. In stage 2, the experimental arm 4 containing BTZ-043 will be added. The allocation ratio will be changed to co-enrol the remaining participants in arms 1- 3 simultaneously with arm 4 with an allocation ratio of 1:1:1:2. When arms 1-2 are fully enrolled and arm 4 is not, further participants will be randomized 1:1 to control and experimental arm 4. Not all countries will participate in stage 2. In stage 3, participants will be allocated in parallel to control arm treatment (now designated arm 7) or the experimental arms 5 and 6, favouring arm 5, 2:1:1 over arms 6 and control. This stage will start after completion of recruitment in the stages 1 and 2.

Study Record Dates

• First Submitted: February 14, 2023
• First Posted: April 11, 2023
• Study Start: April 14, 2023
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): December 30, 2027
• Last Updated: October 7, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

GA (1); MA (1); UG (1); ZA (3); MO (1); TA (3)