PanACEA - STEP2C -01

Study Overview
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Brief Summary
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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 sutezolid will be added. Participants will be allocated to control or one of the three experimental regimens in the ratio 1:1:1:1. Towards the end of stage 2, when experimental arms 1 and 2 will be fully enrolled, participants will be randomized 1:1 to control and experimental arm 4. The objective is to evaluate the efficacy, safety, and tolerability of increased dose of rifampicin, an optimized dose of pyrazinamide, moxifloxacin, and sutezolid, in adult subjects with newly diagnosed, smear-positive pulmonary tuberculosis.

Detailed Description
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This open label, phase 2B/C , randomized, controlled platform trial, will evaluate experimental arms including an increased dose of rifampicin, an optimized dose of pyrazinamide, moxifloxacin and sutezolid, in adult subjects with newly diagnosed, smear-positive pulmonary tuberculosis A total of up to 360 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 will be necessary to increase the number of control arm participants to achieve a 1:1 ratio of concomitantly recruited control and arm 4 participants (see sample size considerations). 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. Arm 1: rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 1,600mg moxifloxacin 600mg; given once daily for 17 weeks (3R2100HZM600) Arm 2: rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 2,000mg/2,400mg, moxifloxacin 600mg; given once daily for 12 weeks (3R2100HZoptM600). Arm 3: control arm (2HRZE-4RH). In stage 2, the experimental arm 4 containing sutezolid will be added. Participants will be allocated to control or one of the three experimental regimens in the ratio 1:1:1:1. Arm 3: control-arm from (2HRZE-4RH), same as in stage 1 Arm 4: sutezolid 1200mg, delamanid 200 mg, bedaquiline 200/100mg, moxifloxacin 400mg; given once daily for 17 weeks (SDBM).

Official Title
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A Multiple Arm, Multiple Stage (MAMS), Phase 2B/C, Open Label, Randomized, Controlled Platform Trial to Evaluate Experimental Arms Including an Increased Dose of Rifampicin, an Optimized Dose of Pyrazinamide, Moxifloxacin and Sutezolid, in Adult Subjects With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis

Conditions
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Pulmonary Tuberculosis, Other Specified Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: Sutezolid
* Drug: Rifampicin
* Drug: Isoniazid
* Drug: Pyrazinamide
* Drug: Moxifloxacin
* Drug: Bedaquiline
* Drug: Delamanid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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 IUATLD/WHO scale). 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 (See Appendix, section 20.2, page 92). 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 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. 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: Circumstances that raise doubt about free, unconstrained consent to study participation (e.g., prisoner or mentally handicapped person) Poor general condition where delay in treatment cannot be tolerated or death within four months is likely. Poor social condition which would make it unlikely that the participant would be able to complete follow-up: 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 >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 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, 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: Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required. Evidence of clinically significant extra-pulmonary 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. Uncontrolled diabetes mellitus. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension Uncontrolled arterial hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure of ≥95 mmHg on two occasions during screening). Long QT syndrome or family history of long QT syndrome or family history of sudden death of unknown or cardiac-related cause 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. Any of the following laboratory findings at screening: Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) >3x the upper limit of normal (ULN), Serum alkaline phosphatase or y-glutamyl transferase > 2.5x the ULN, Serum total bilirubin level >1.5x the ULN Estimated creatinine clearance (eCrCl; using the Cockroft and Gault formula [57] lower than 30 ml/min) Serum albumin < 2.8 mg/dl Haemoglobin level <7.0 g/dl Platelet count <50,000/mm3 Serum potassium below the lower level of normal for the laboratory ECG findings in the screening ECG: (one or more): QTcF of >0.450 s Atrioventricular (AV) block with PR interval > 0.20 s, QRS complex > 120 milliseconds Any other changes in the ECG that are clinically relevant as per discretion of the investigator Restricted medication: Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation. Previous anti-TB treatment with drugs active against MTB within the last 3 months prior to screening. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study study 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 sutezolid will be added. Participants will be allocated to control or one of the three experimental regimens in the ratio 1:1:1:1. Towards the end of stage 2, when experimental arms 1 and 2 will be fully enrolled, participants will be randomized 1:1 to control and experimental arm 4
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Stage 1)<br>Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 1,600mg moxifloxacin 600mg; given once daily for 17 weeks (R2100HZM600) | Drug: Rifampicin<br>* 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.<br>Drug: Isoniazid<br>* Isoniazid will be dosed at fixed dose of 300mg in arms 1 and 2, and regular dose of 5 mg/kg in arm 3.<br>Drug: Pyrazinamide<br>* 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.<br>Drug: Moxifloxacin<br>* Moxifloxacin will be dosed at 600 mg orally once daily in arms 1-2, and 400 mg orally once daily in arm 4.<br>|
| Experimental: Arm 2 (Stage 1)<br>Rifampicin 2,100mg, isoniazid 300mg, pyrazinamide 2,000mg/2,400mg, moxifloxacin 600mg; given once daily for 12 weeks (R2100HZoptM600) | Drug: Rifampicin<br>* 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.<br>Drug: Isoniazid<br>* Isoniazid will be dosed at fixed dose of 300mg in arms 1 and 2, and regular dose of 5 mg/kg in arm 3.<br>Drug: Pyrazinamide<br>* 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.<br>Drug: Moxifloxacin<br>* Moxifloxacin will be dosed at 600 mg orally once daily in arms 1-2, and 400 mg orally once daily in arm 4.<br>|
| Active Comparator: Arm 3<br>Stage 1: control arm (2HRZE-4RH) Stage 2: continuation of control-arm from STAGE 1 (2HRZE-4RH) | Drug: Rifampicin<br>* 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.<br>Drug: Isoniazid<br>* Isoniazid will be dosed at fixed dose of 300mg in arms 1 and 2, and regular dose of 5 mg/kg in arm 3.<br>Drug: Pyrazinamide<br>* 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.<br>|
| Experimental: Arm 4 (Stage 2)<br>sutezolid 1200mg, delamanid 200 mg, bedaquiline 200/100mg, moxifloxacin 400mg; given once daily for 17 weeks (SDBM) | Drug: Sutezolid<br>* STZ belongs to the oxazolidinone class of antibiotics and is currently under development for the indication treatment of TB. Sutezolid is not licensed yet and will be dosed at 1200 mg once daily in arm 4<br>Drug: Moxifloxacin<br>* Moxifloxacin will be dosed at 600 mg orally once daily in arms 1-2, and 400 mg orally once daily in arm 4.<br>Drug: Bedaquiline<br>* Bedaquiline will be dosed as 200 mg orally once daily for the first 8 weeks, thereafter 100 mg once daily in arm 4.<br>Drug: Delamanid<br>* Delamanid will be dosed as 200 mg orally once daily in arm 4.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to stable culture conversion to negative in liquid media | The time on treatment required until a participant achieves the first of two successive visits with negative cultures To evaluate whether one or more of two experimental regimens based on optimized dose rifampicin, optimized dose of pyrazinamide, and moxifloxacin given for 12, respectively 17 weeks, are superior to standard treatment given for 26 weeks, as assessed by time to sputum culture conversion to negative in liquid media. | Day 01- Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse - free survival at 12 months after randomization | 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. | Day 01-364 | 
| Frequency of all adverse events (serious and non-serious) | To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations. | Day 01-182 | 
| Frequency of adverse events of Grade 3 severity (severe) or higher | 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. | Day 01-182 | 
| Frequency of adverse events possibly, probably or definitely related to study drug | To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations. | Day 01-182 | 
| Frequency of treatment discontinuations or interruptions related to adverse events/serious adverse event | To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations. | Day 01-182 | 
| Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF] | Proportion of participants with QTcF > 500ms in ECGs on treatment Proportion of participants who have a QTcF prolongation of grade 3 or higher | Day 01-182 | 
| Area under the plasma concentration curve from dosing to the end of the dosing interval (AUC 0-24) predicted from limited pharmacokinetic sampling. | The pharmacokinetics parameters will be assessed for rifampicin, pyrazinamide, moxifloxacin, and isoniazid (arms 1-3), and sutezolid, bedaquiline, and their major metabolites, delamanid and moxifloxacin (arm 4) in all participants with limited pharmacokinetic sampling being done on WK 02 (Day 14 ± 2 Days). | Day 14 | 
| The observed maximum concentration (Cmax) | The pharmacokinetics parameters will be assessed for rifampicin, pyrazinamide, moxifloxacin, and isoniazid (arms 1-3), and sutezolid, bedaquiline, and their major metabolites, delamanid and moxifloxacin (arm 4) in all participants with limited pharmacokinetic sampling being done on WK 02 (Day 14 ± 2 Days). | Day 14 | 
| Time to reach Cmax (Tmax) | The pharmacokinetics parameters will be assessed for rifampicin, pyrazinamide, moxifloxacin, and isoniazid (arms 1-3), and sutezolid, bedaquiline, and their major metabolites, delamanid and moxifloxacin (arm 4) in all participants with limited pharmacokinetic sampling being done on WK 02 (Day 14 ± 2 Days). | Day 14 | 
| Minimum observed plasma concentration 24 hours following the last dose (Cmin) | The pharmacokinetics parameters will be assessed for rifampicin, pyrazinamide, moxifloxacin, and isoniazid (arms 1-3), and sutezolid, bedaquiline, and their major metabolites, delamanid and moxifloxacin (arm 4) in all participants with limited pharmacokinetic sampling being done on WK 02 (Day 14 ± 2 Days). | Day 14. | 
| Dolutegravir concentration | In patients receiving dolutegravir, trough concentrations will be compared at screening and at week 2. These assessments will be performed contingent on laboratory capacity and funding, some may be omitted. | Day 01-15 | 
| Identification of M. tuberculosis complex and Rifampicin (RIF) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar) | 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. | Day 01-182 | 
| Identification of M. tuberculosis complex and Isoniazid (INH) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar) | 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. | Day 01-182 | 
| Minimum inhibitory concentrations (MIC) of study drugs the patient was receiving | Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed. | Day 01-182 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sutezolid, Rifampicin, Delamanid, Tuberculosis, Pulmonary, PNU-100480, Tuberculosis, Antitubercular Agents, Oxazolidinones, Dose-finding, Safety, Tolerability, Pharmacokinetics (PK), Bedaquiline, Moxifloxacin