Trial to Evaluate the Efficacy, Safety and Tolerability of BPaMZ in Drug-Sensitive (DS-TB) Adult Patients and Drug-Resistant (DR-TB) Adult Patients

An Open-Label, Partially Randomized Trial to Evaluate the Efficacy, Safety and Tolerability of a 4-month Treatment of Bedaquiline Plus Pretomanid Plus Moxifloxacin Plus Pyrazinamide (BPaMZ) Compared to a 6-month Treatment of HRZE/HR (Control) in Adult Participants With Drug-Sensitive Smear-Positive Pulmonary Tuberculosis (DS-TB) and a 6-month Treatment of BPaMZ in Adult Participants With Drug Resistant, Smear-Positive Pulmonary Tuberculosis (DR-TB)

To evaluate the efficacy, safety and tolerability at 8 weeks (2-months), 52 weeks (12-months), and 104 Weeks (24-months) post the start of the following treatment regimens in participants with: Drug Sensitive TB (DS-TB) patients given BPaMZ for 17 Weeks ( or 4 months) vs. Standard HRZE/HR treatment given for 26 weeks (or 6 months) and Drug Resistant TB (DR-TB) patients given BPaMZ for 26 Weeks (or 6 months)

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis, MDR; Drug-Resistant Tuberculosis
• Intervention / Treatment: Drug: Moxifloxacin; Drug: Pretomanid; Drug: Bedaquiline; Drug: Pyrazinamide; Drug: HRZE; Drug: HR

Detailed Description

Phase 2c multi-center, open-label, partially randomized clinical trial in DS-TB and DR-TB participants.

All participants in the below arms will have follow-up for a period of 104 weeks (24 months) from the start of therapy.

Participants with Drug Sensitive TB (DS-TB):

Participants with DS-TB will be randomized to one of two treatment arms. These participants will receive either BPaMZ daily for 17 weeks (4 months), or HRZE/HR combination tablets daily for 26 weeks (6 months). participants will be stratified for co-infection with human immunodeficiency virus (HIV) and cavitation.

Participants with Drug Resistant TB (DR-TB):

Participants with DR-TB will be assigned to receive BPaMZ daily for 26 weeks (6 months).

• Study Type: Interventional
• Enrollment (Actual): 455
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • Evandro Chagas
  • Rio de Janeiro, Brazil
    • FIOCRUZ
• Georgia
  • Tbilisi, Georgia, 0101
    • National Center for Tuberculosis and Lung Diseases
• Malaysia
  • Kuala Lumpur, Malaysia
    • Institut Perubatan Respiratori
• Philippines
  • Manila, Philippines, 1104
    • Lung Center of Philippines
  • Manila, Philippines, 1230
    • Tropical Disease Foundation
• Russian Federation
  • Moscow, Russian Federation, 107014
    • Moscow City Research and Practice Tuberculosis Treatment Centre
  • Moscow, Russian Federation, 107564
    • Central TB Research Institute of the Federal Agency of Scientific Organizations
  • Moscow, Russian Federation, 119991
    • Research Institute of Phthisiopulmonology of I. M. Sechenov First Moscow State Medical University
  • Sankt Petersburg, Russian Federation, 191036
    • Research Institute of the Phthisiopulmonology
  • Yekaterinburg, Russian Federation, 620039
    • Ural Research Institute of Phthisiopulmonology
• South Africa
  • Brits, South Africa, 0250
    • Madibeng Centre for Research
  • Cape Town, South Africa, 7530
    • TASK
  • Cape Town, South Africa, 7700
    • University of Cape Town Lung Institute
  • Durban, South Africa, 4001
    • Enhancing Care Foundation
  • Durban, South Africa, 4015
    • CHRU, King Dinuzulu
  • Johannesburg, South Africa, 2092
    • CHRU, Helen Joseph Hospital
  • Klerksdorp, South Africa, 2571
    • PHRU, Tshepong Hospital
  • Port Elizabeth, South Africa, 7070
    • CHRU, Empilweni TB Hospital
  • Soshanguve, South Africa, 0152
    • Setshaba Research Centre
  • KwaZulu Natal
    • Pietermaritzburg, KwaZulu Natal, South Africa, 3216
      • THINK
• Tanzania
  • Bagamoyo, Tanzania
    • Ifakara Health Institute
  • Mbeya, Tanzania
    • NIMR-Mbeya
  • Moshi, Tanzania
    • Kilimanjaro Clinical Research Institute
  • Mwanza, Tanzania
    • Mwanza Intervention Trials Unit
• Uganda
  • Kampala, Uganda, 2109
    • Case Western Reserve University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Sputum positive for tubercule bacilli (at least 1+ on the International Union Against Tuberculosis and Lung Disease [IUATLD]/WHO scale (Appendix 1) on smear microscopy) at the trial laboratory.
• Participants with one of the following pulmonary TB conditions:

DS-TB treatment arm participants should be:

• sensitive to rifampicin and isoniazid by rapid sputum based test AND
• either newly diagnosed for TB or have a history of being untreated for at least 3 years after cure from a previous episode of TB.

DR-TB treatment arm participants should be Resistant to rifampicin and/or isoniazid.

• Of non-childbearing potential or willing to practice effective methods of birth control
• Body weight (in light clothing and no shoes) ≥ 30 kg.
• Completed informed consent form

Exclusion Criteria:

• Karnofsky score <60%
• Any risk factor for QT prolongation
• Any planned contraindicated medicines
• Resistant to fluoroquinolones (rapid, sputum-based molecular screening tests).

Any of the following lab toxicities/abnormalities:

• CD4+ count < 100 cells/µL (HIV infected participants)
• platelets <75,000/mm³
• creatinine >1.5 times upper limit of normal (ULN)
• eGFR ≤ 60 mL/min
• haemoglobin <8.0 g/dL
• serum potassium less than the lower limit of normal for the laboratory.
• GGT: greater than 3 x ULN
• AST: ≥3.0 x ULN to be excluded;
• ALT: ≥3.0 x ULN to be excluded
• ALP: ≥3.0 x ULN to be excluded
• Total bilirubin: >1.5 x ULN to be excluded;
• Direct bilirubin: greater than 1x ULN to be excluded

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Drug Sensitive BPaMZ; Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 9 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 17 weeks (Total treatment duration 4 months	Drug: Moxifloxacin; 400 mg tablets; Other Names: M; Drug: Pretomanid; 200 mg tablets; Other Names: PA-824; Pa; Drug: Bedaquiline; 100 mg tablets; Other Names: B; TMC207; Drug: Pyrazinamide; 500 mg tablets; Other Names: Z
Active Comparator: Drug Sensitive Standard Treatment; isoniazid 75 mg + rifampicin 150 mg + pyrazinamide 400 mg + ethambutol 275 mg (HRZE) combination tablets for 8 weeks AND isoniazid 75 mg + rifampicin 150 mg (HR) combination tablets for Weeks 9 to 26	Drug: HRZE; isoniazid 75 mg plus rifampicin 150 mg plus pyrazinamide 400 mg plus ethambutol 275 mg combination tablets; Other Names: isoniazid; rifampicin; ethambutol; Drug: HR; isoniazid 75 mg plus rifampicin 150 mg combination tablets; Other Names: isoniazid; rifampicin
Experimental: Drug Resistant BPaMZ; Bedaquiline 200 mg daily for 8 weeks then 100 mg daily for 18 weeks, together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg daily for 26 weeks (Total treatment duration 6 months)	Drug: Moxifloxacin; 400 mg tablets; Other Names: M; Drug: Pretomanid; 200 mg tablets; Other Names: PA-824; Pa; Drug: Bedaquiline; 100 mg tablets; Other Names: B; TMC207; Drug: Pyrazinamide; 500 mg tablets; Other Names: Z

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Culture Negative Status by 8 Weeks	Culture negative status is achieved when a participant produces at least two negative culture results at different visits (at least 7 days apart) without an intervening positive culture result for M.tb.	Days 0-56 (8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months)	Unfavorable status: Participants not classified as having achieved or maintained culture negative status when last seen; Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture; Participants who had a positive culture not followed by at least two negative cultures when last seen; Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide; Participants definitely or possibly dying from TB related cause during the follow-up phase; Participants requiring an extension of their treatment beyond that permitted by the protocol a restart or a change of treatment for any reason except reinfection or pregnancy; Participants lost to follow up or withdrawn from the study before end of treatment	52 weeks after start of therapy
Time to Culture Negative Status	Culture conversion is a diagnostic criteria indicating the point at which samples taken from a patient infected with a tuberculosis can no longer produce tuberculosis cell cultures, that point is considered culture negativity	During treatment (17 or 26 weeks)

Collaborators and Investigators

• Sponsor: Global Alliance for TB Drug Development
• Investigators: Study Chair: Morounfolu Olugbosi, MD MSc, Global Alliance for TB Drug Development

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2018
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): June 10, 2022

Study Registration Dates

• First Submitted: November 3, 2017
• First Submitted That Met QC Criteria: November 8, 2017
• First Posted (Actual): November 9, 2017

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: TMC207; TB; tuberculosis; PA-824; pretomanid; TB Alliance; moxifloxacin; bedaquiline; drug-sensitive tuberculosis; DR-TB; drug-resistant tuberculosis; pyrazinamide; HRZE; NC-008; DS-TB
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Hypersensitivity; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Moxifloxacin; Rifampin; Bedaquiline; Isoniazid; Pyrazinamide; Ethambutol
• Other Study ID Numbers: SimpliciTB (B-Pa-M-Z) NC-008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD from the trial will be submitted to Critical Path Institute which will make fully anonymized data available through the Tuberculosis Platform for Aggregation of Clinical TB Studies (TB-PACTS) database. Data sets for Drug susceptibility data, Demographic data, MTB diagnostic testing results, Concomitant medications information, Adverse event information, Treatment adherence information, Co-morbidities, Treatment outcomes, HIV co-infection information, CD4 counts, TB disease symptoms from all collected IPD will be made available.
• IPD Sharing Time Frame: Data is expected to become available in mid-2024.
• IPD Sharing Access Criteria: Researchers must agree to the Terms and Conditions for Use of the TB-PACTS data platform and submit an online application form to request access to the data platform.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No