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

Phase 2
Completed
Conditions
Tuberculosis, Pulmonary
Tuberculosis, Multidrug-Resistant
Tuberculosis, MDR
Tuberculosis
Drug-Resistant Tuberculosis
Interventions
Drug: Pretomanid
Drug: HRZE
Drug: Bedaquiline
Drug: HR
Drug: Moxifloxacin
Drug: Pyrazinamide
Registration Number
NCT03338621
Lead Sponsor
Global Alliance for TB Drug Development
Brief Summary

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)

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).

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
455
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
Read More
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
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
Drug Sensitive BPaMZPretomanidBedaquiline 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 Sensitive BPaMZBedaquilineBedaquiline 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 Sensitive Standard TreatmentHRZEisoniazid 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 Sensitive Standard TreatmentHRisoniazid 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 Resistant BPaMZPretomanidBedaquiline 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 Sensitive BPaMZMoxifloxacinBedaquiline 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 Sensitive BPaMZPyrazinamideBedaquiline 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 Resistant BPaMZMoxifloxacinBedaquiline 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 Resistant BPaMZBedaquilineBedaquiline 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 Resistant BPaMZPyrazinamideBedaquiline 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)
Primary Outcome Measures
NameTimeMethod
Number of Participants With Culture Negative Status by 8 WeeksDays 0-56 (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.

Secondary Outcome Measures
NameTimeMethod
Number of Participants With Bacteriologic Failure or Relapse or Clinical Failure (Unfavorables) at 52 Weeks From Start of Therapy (12 Months)52 weeks after start of therapy

Unfavorable status:

1. Participants not classified as having achieved or maintained culture negative status when last seen

2. Participants previously classified as having culture negative status who, following the end of treatment, have two positive cultures without an intervening negative culture

3. Participants who had a positive culture not followed by at least two negative cultures when last seen

4. Participants dying from any cause during treatment, except from violent or accidental cause, not including suicide

5. Participants definitely or possibly dying from TB related cause during the follow-up phase

6. 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

7. Participants lost to follow up or withdrawn from the study before end of treatment

Time to Culture Negative StatusDuring treatment (17 or 26 weeks)

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

Trial Locations

Locations (26)

University of Cape Town Lung Institute

🇿🇦

Cape Town, South Africa

Madibeng Centre for Research

🇿🇦

Brits, South Africa

CHRU, Empilweni TB Hospital

🇿🇦

Port Elizabeth, South Africa

Research Institute of Phthisiopulmonology of I. M. Sechenov First Moscow State Medical University

🇷🇺

Moscow, Russian Federation

Enhancing Care Foundation

🇿🇦

Durban, South Africa

Tropical Disease Foundation

🇵🇭

Manila, Philippines

CHRU, King Dinuzulu

🇿🇦

Durban, South Africa

CHRU, Helen Joseph Hospital

🇿🇦

Johannesburg, South Africa

PHRU, Tshepong Hospital

🇿🇦

Klerksdorp, South Africa

Ural Research Institute of Phthisiopulmonology

🇷🇺

Yekaterinburg, Russian Federation

Setshaba Research Centre

🇿🇦

Soshanguve, South Africa

Research Institute of the Phthisiopulmonology

🇷🇺

Sankt Petersburg, Russian Federation

Lung Center of Philippines

🇵🇭

Manila, Philippines

Case Western Reserve University

🇺🇬

Kampala, Uganda

Ifakara Health Institute

🇹🇿

Bagamoyo, Tanzania

NIMR-Mbeya

🇹🇿

Mbeya, Tanzania

Institut Perubatan Respiratori

🇲🇾

Kuala Lumpur, Malaysia

Kilimanjaro Clinical Research Institute

🇹🇿

Moshi, Tanzania

Evandro Chagas

🇧🇷

Rio de Janeiro, Brazil

FIOCRUZ

🇧🇷

Rio de Janeiro, Brazil

Central TB Research Institute of the Federal Agency of Scientific Organizations

🇷🇺

Moscow, Russian Federation

National Center for Tuberculosis and Lung Diseases

🇬🇪

Tbilisi, Georgia

Moscow City Research and Practice Tuberculosis Treatment Centre

🇷🇺

Moscow, Russian Federation

THINK

🇿🇦

Pietermaritzburg, KwaZulu Natal, South Africa

TASK

🇿🇦

Cape Town, South Africa

Mwanza Intervention Trials Unit

🇹🇿

Mwanza, Tanzania

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