PanACEA - STEP2C -01

Phase 2

Recruiting

• Conditions: Other Specified Pulmonary Tuberculosis; Pulmonary Tuberculosis
• Interventions: Drug: Rifampicin; Drug: BTZ-043; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Moxifloxacin

• Registration Number: NCT05807399
• Lead Sponsor: Michael Hoelscher

Brief Summary

This is a phase 2B/C, open label platform study that will compare the efficacy, safety of 3 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. 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.

Detailed Description

This open label, phase 2B/C , randomized, controlled platform trial, will evaluate experimental arms including an increased dose of rifampicin, on optimized dose of pyrazinamide, moxifloxacin and BTZ-043, in adults with newly diagnosed, drug sensitive, smear-positive pulmonary tuberculosis A total of up to 270 adult (≥ 18 years of age) participants will be enrolled. In case of a high number of dropouts or non-evaluable participants, it may be necessary to recruit more participants into the study. Also, if the stage 2 starts later than stage 1, it may be necessary to increase the number of control arm participants to achieve a 1:1 ratio of concomitantly recruited control and arm 4 participants until the recruitment for arm 4 is completed (see sample size considerations).

Study Timeline

• Study First Submitted: 2023-02-14
• Study First Submitted QC: 2023-03-28
• Study First Posted: 2023-04-11
• Study Start: 2023-04-14
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-16
• Last Update Posted: 2024-04-17
• Primary Completion: 2025-02-23
• Study Completion: 2025-02-23

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 270

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 MTB complex and rapid molecular tests result confirming susceptibility to RIF and 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 IUATLD/WHO scale).

7. The participant understands the interaction between the study drugs and certain foods and is willing to forgo the consumption of foods high in tyramine for the period of study medication, which will be necessary if randomized to arm 4.

8. 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:

   1. 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 seen prior to 76 weeks after randomization 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.
   2. 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. ii. Male participants: Two methods, including methods that the participant's female sexual partner(s) use. At least one must be a barrier method. Effective contraception must be ensured for at least 16 weeks after the last dose of experimental treatment.

Exclusion Criteria

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

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

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

4. The participant is pregnant or breast-feeding or planning to become pregnant in the study period.

5. The participant is infected with HIV with a CD4 count <220 cells/mm3. If >22 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 Antiretroviral Therapy 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

6. 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.

7. The participant 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. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required.
   2. Evidence of clinically significant extra-pulmonary TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement).
   3. Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator.
   4. Uncontrolled diabetes mellitus.
   5. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
   6. Uncontrolled arterial hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure of ≥95 mmHg on two occasions during screening).
   7. Long QT syndrome or family history of long QT syndrome or family history of sudden death of unknown or cardiac-related cause
   8. 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.

8. Any of the following laboratory findings at screening:

   1. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) >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 Cockroft and Gault formula [57] 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. ECG findings in the screening ECG: (one or more):

   1. QTcF 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 MTB within the last 3 months prior to screening.
    3. Unable or unwilling to abide by the requirements regarding restricted medication or have taken restricted medication. Restricted medication includes the following drug classes, with relevant timing of intake. Exceptions may be permissible after discussion with the sponsor medical expert. Anti-TB drugs other than study drugs Medication that increases the risk for serious cardiac arrhythmia (see 8.5.4). Drugs that affect monoamine oxidase or serotonin metabolism CYP 450 inhibitors or inducers.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 (Stage 1)	Rifampicin	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 1,600mg moxifloxacin 600mg; given once daily for 17 weeks (R2100HZM600)
Arm 1 (Stage 1)	Isoniazid	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 1,600mg moxifloxacin 600mg; given once daily for 17 weeks (R2100HZM600)
Arm 1 (Stage 1)	Pyrazinamide	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 1,600mg moxifloxacin 600mg; given once daily for 17 weeks (R2100HZM600)
Arm 1 (Stage 1)	Moxifloxacin	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 1,600mg moxifloxacin 600mg; given once daily for 17 weeks (R2100HZM600)
Arm 3	Rifampicin	Stage 1: control arm (2HRZE-4RH) Stage 2: continuation of control-arm from STAGE 1 (2HRZE-4RH)
Arm 2 (Stage 1)	Rifampicin	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 2,000mg/2,400mg, moxifloxacin 600mg; given once daily for 12 weeks (R2100HZoptM600)
Arm 2 (Stage 1)	Isoniazid	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 2,000mg/2,400mg, moxifloxacin 600mg; given once daily for 12 weeks (R2100HZoptM600)
Arm 2 (Stage 1)	Pyrazinamide	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 2,000mg/2,400mg, moxifloxacin 600mg; given once daily for 12 weeks (R2100HZoptM600)
Arm 2 (Stage 1)	Moxifloxacin	Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 2,000mg/2,400mg, moxifloxacin 600mg; given once daily for 12 weeks (R2100HZoptM600)
Arm 3	Isoniazid	Stage 1: control arm (2HRZE-4RH) Stage 2: continuation of control-arm from STAGE 1 (2HRZE-4RH)
Arm 3	Pyrazinamide	Stage 1: control arm (2HRZE-4RH) Stage 2: continuation of control-arm from STAGE 1 (2HRZE-4RH)
Arm 4 (Stage 2)	Rifampicin	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)
Arm 4 (Stage 2)	Isoniazid	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)
Arm 4 (Stage 2)	Pyrazinamide	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)
Arm 4 (Stage 2)	BTZ-043	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)

Primary Outcome Measures

Name	Time	Method
Time to stable culture conversion to negative in liquid media	Day 01- Week 26	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.

Secondary Outcome Measures

Name	Time	Method
Time to reach Cmax (Tmax)	Day 14	For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
Minimum observed plasma concentration 24 hours following the last dose (Cmin)	Day 14.	For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
Relapse - free survival at 12 months after randomization	Day 01-364	To assess treatment efficacy based on proportion of patients with relapse free outcome at 12 months after randomization.; Sustained cure at 12 months (52 weeks) after randomization without a failure or relapse event is achieved when all the following criteria are met: * known to be alive at or after 48 weeks after randomization; * having Sustained Culture Negativity at 48 weeks after randomization; * not having met criteria for Failure or Relapse event (see below); * not in need of TB treatment and having had no substantial treatment modifications or additional treatment for TB outside of the pre-specified treatment strategies.
Frequency of all adverse events (serious and non-serious)	Day 01-182	To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations.
Frequency of adverse events of Grade 3 severity (severe) or higher	Day 01-182	Severity of AEs will be classified following the U.S. National Institutes of Health Common Terminology Criteria for Adverse Events 5.0 (CTCAE). The minimum grade is 1 (Mild) and the maximum grade is 5 (Death related to AE). Higher scores mean a worse outcome.
Frequency of adverse events possibly, probably or definitely related to study drug	Day 01-182	To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations.
Frequency of treatment discontinuations or interruptions related to adverse events/serious adverse event	Day 01-182	To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations.
Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF]	Day 01-182	* Proportion of participants with QTcF \> 500ms in ECGs on treatment; * Proportion of participants who have a QTcF prolongation of grade 3 or higher
Area under the plasma concentration curve from dosing to the end of the dosing interval (AUC 0-24) predicted from limited pharmacokinetic sampling.	Day 14	For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
The observed maximum concentration (Cmax)	Day 14	For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
DTG and TFD concentration	Day 01-15	concentrations will be compared at screening and at week 2. More time points may be determined if leftover samples are available. Timing of last DTG and TFD dose intake will be recorded.
Identification of M. tuberculosis complex and Rifampicin (RIF) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar)	Day 01-182	Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed. This test is qualitative, therefore the result will be: Detected, not detected or indeterminate.
Identification of M. tuberculosis complex and Isoniazid (INH) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar)	Day 01-182	Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed. This test is qualitative, therefore the result will be: Detected, not detected or indeterminate.
Minimum inhibitory concentrations (MIC) of study drugs the patient was receiving	Day 01-182	Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed.

Trial Locations

Locations (8)

Kamuzu College of Health Sciences (formerly College of Medicine); 🇲🇼 Blantyre, Malawi

Kilimanjaro Clinical Research Institute (KCRI); 🇹🇿 Moshi, Tanzania

Makerere University Lung Institute Limited; 🇺🇬 Kampala, Uganda

National Institute for Medical Research (NIMR-MMRC); 🇹🇿 Mbeya, Tanzania

Centre de Recherches Médicales de Lambaréné (CERMEL); 🇬🇦 Lambaréné, Gabon

TASK Applied Sciences Clinical Research Centre; 🇿🇦 Cape Town, South Africa

Instituto Nacional de Saúde (INS); 🇲🇿 Maputo, Mozambique

Ifakara Health Institute (IHI); 🇹🇿 Bagamoyo, Tanzania