A Phase 2 to Evaluate the Efficacy, Safety and Tolerability of Combinations of Bedaquiline, Moxifloxacin, PA-824 and Pyrazinamide in Adult Subjects With Drug-Sensitive or Multi Drug-Resistant Pulmonary Tuberculosis.

NCT02193776 | Completed Phase 2 Results DMC

• 1 other identifier: NC-005-(J-M-Pa-Z)
• Study Type: interventional
• Target: 240
• Locations: 3 countries
• Sites: 10

Brief Summary

The purpose of this study is to determine the mycobactericidal activity of combinations of bedaquiline (J), moxifloxacin (M), PA-824 (Pa) and pyrazinamide (Z) regimens during 8 weeks of treatment.

Conditions

Tuberculosis

Keywords

Tuberculosis; Multi Drug-Resistant Tuberculosis; Drug-Sensitive Tuberculosis; PA-824; Bedaquiline; Moxifloxacin; Pyrazinamide; Quinolone; Pretomanid; NC-005

Outcome Measures

Primary Outcomes (1)

• Rate of Change in Time to Sputum Culture Positivity (TTP) Over 8 Weeks in the Mycobacterial Growth Indicator Tube (MGIT) System

  The bactericidal activity (BA) was determined by the rate of change in TTP collected from overnight sputum samples over 8 weeks of treatment in the liquid culture media MGIT system, represented by the model-fitted log(TTP) results as calculated by the regression of the observed log(TTP) results over time. The bactericidal activity of log(TTP) over Day 0 to Day 56 (BATTP\[0-56\]) was presented and expressed as the daily percentage change in TTP from Day 0 to Day 56. The mean BATTP (0-56) was calculated from Bayesian non-linear mixed effects regression models fitted to log(TTP) collected from sputum samples (observed from Day 0 to Day 56).

  Day 0 to Day 56 (8 weeks)

Secondary Outcomes (1)

• Number of Participants With Treatment Emergent Adverse Events (TEAEs)

  First study drug administration (Day 1) up to and including the Day 70 follow-up visit (or up to and including 14 days after last study drug administration for participants not having the Day 70 follow-up visit) (70 days)

Study Arms (4)

DS-TB: J(loading dose/t.i.w.)PaZ

EXPERIMENTAL

Subjects with DS-TB. J(loading dose/t.i.w.)PaZ: Bedaquiline 400mg once daily Days 1-14, 200mg three times per week Days 15-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.

Drug: PA-824; Drug: bedaquiline; Drug: pyrazinamide

DS-TB: J(200mg)PaZ

EXPERIMENTAL

Subjects with DS-TB. J(200mg)PaZ: Bedaquiline 200mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.

Drug: PA-824; Drug: bedaquiline; Drug: pyrazinamide

MDR-TB: J(200mg)MPaZ

EXPERIMENTAL

Subjects with MDR-TB. J(200mg)MPaZ: Bedaquiline 200mg once daily Days 1-56; plus moxifloxacin 400mg once daily Days 1-56; plus PA-824 200mg once daily Days 1-56; plus pyrazinamide 1500mg once daily Days 1-56.

Drug: PA-824; Drug: bedaquiline; Drug: moxifloxacin; Drug: pyrazinamide

DS-TB: HRZE

ACTIVE COMPARATOR

Subjects with DS-TB. HRZE tablets (Isoniazid 75mg plus rifampicin 150mg plus pyrazinamide 400mg plus ethambutol 275mg combination tablets) dosed once daily Days 1-56 per the Subject's weight as follows: 30-37kg: 2 tablets; 38-54kg: 3 tablets; 55-70kg: 4 tablets; 71kg and over: 5 tablets.

Drug: isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet

Interventions

PA-824 DRUG

oral

DS-TB: J(200mg)PaZ; DS-TB: J(loading dose/t.i.w.)PaZ; MDR-TB: J(200mg)MPaZ

bedaquiline DRUG

oral

Also known as: TMC207, Sirturo

DS-TB: J(200mg)PaZ; DS-TB: J(loading dose/t.i.w.)PaZ; MDR-TB: J(200mg)MPaZ

moxifloxacin DRUG

oral

Also known as: BAY 12-8039, Avelox, Avalon, Avelon

MDR-TB: J(200mg)MPaZ

pyrazinamide DRUG

oral

DS-TB: J(200mg)PaZ; DS-TB: J(loading dose/t.i.w.)PaZ; MDR-TB: J(200mg)MPaZ

isoniazid, rifampicin, pyrazinamide and ethambutol combination tablet DRUG

oral

DS-TB: HRZE

Eligibility Criteria

• Age: 18 Years - 75 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. Male or female, aged between 18 and 75 years inclusive.
• Body weight (in light clothing and with no shoes) between 35 and 100 kg, inclusive.
• Tested at the trial appointed laboratory: M. Tb positive on molecular test (e.g. GeneXpert or Hain) and sputum smear-positive pulmonary TB on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale.
• For DS-TB treatment arms (defined as sensitive to rifampicin based on molecular sensitivity testing), Subjects should be:
• either newly diagnosed or untreated for at least 3 years after cure from a previous episode (Subject can give a history of cure and previous treatment); AND

You may not qualify if:

• For MDR-TB treatment arm (defined as resistant to rifampicin based on molecular sensitivity testing), Subjects should be:
• sensitive to moxifloxacin by molecular sensitivity testing; AND
• A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
• Ability to produce an adequate volume of sputum as estimated from a screening Coached Spot Sputum Sample assessment (estimated 10 ml or more overnight production).
• Be of non-childbearing potential or using effective methods of birth control, as defined below:
• Non-childbearing potential:
• Subject - not heterosexually active or practices sexual abstinence; or
• Female Subject/sexual partner - bilateral oophorectomy, bilateral tubal ligation and/or hysterectomy or has been postmenopausal with a history of no menses for at least 12 consecutive months; or
• Male Subject/sexual partner - vasectomised or has had a bilateral orchidectomy minimally three months prior to screening.
• Effective birth control methods:
• A double contraceptive method should be used as follows:
• Double barrier method which can include any 2 of the following: a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or
• Barrier method (one of the above) combined with hormone-based contraceptives or an intra-uterine device for the female Subject/partner; and are willing to continue practicing birth control methods throughout treatment and for 6 months (both male and female Subjects) after the last dose of study medication or discontinuation from study medication in case of premature discontinuation.
• (Note: Hormone-based contraception alone may not be reliable when taking IMP; therefore, hormone-based contraceptives alone cannot be used by female Subjects or female partners of male Subjects to prevent pregnancy).
• Medical Criteria

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (10)

The Aurum Institute: Tembisa Hospital

Tembisa, Gauteng, 1632, South Africa

Location

Klerksdorp Tshepong Hospital

Jouberton, Klerksdorp, 2570, South Africa

Location

TASK Applied Science

Cape Town, 7531, South Africa

Location

University of Cape Town Lung Institute (Pty) Ltd

Cape Town, 7937, South Africa

Location

THINK: Tuberculosis & HIV Investigative Network of KwaZulu-Natal

Durban, South Africa

Location

CHRU Themba Lethu Clinic

Johannesburg, South Africa

Location

University of Witwatersrand, Clinical HIV Research Unit (CHRU), Helen Joseph Hospital

Johannesburg, South Africa

Location

Ifakara Health Institute

Bagamoyo, Tanzania

Location

NIMR-Mbeya Medical Research Centre (MMRC)

Mbeya, Tanzania

Location

Uganda Case Western Reserve University Research Collaboration

Kampala, Uganda

Location

Related Publications (1)

• Tweed CD, Dawson R, Burger DA, Conradie A, Crook AM, Mendel CM, Conradie F, Diacon AH, Ntinginya NE, Everitt DE, Haraka F, Li M, van Niekerk CH, Okwera A, Rassool MS, Reither K, Sebe MA, Staples S, Variava E, Spigelman M. Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Lancet Respir Med. 2019 Dec;7(12):1048-1058. doi: 10.1016/S2213-2600(19)30366-2. Epub 2019 Nov 12.

  PMID: 31732485 DERIVED

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Multidrug-Resistant

Interventions

pretomanid; bedaquiline; Moxifloxacin; Pyrazinamide; Isoniazid; Rifampin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Almari Conradie, Director, Clinical Operations
• Organization: TB Alliance

almari.conradie@tballiance.org

+27 12 991 6328

Study Officials

• Rodney Dawson

  University of Cape Town Lung Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2014
• First Posted: July 18, 2014
• Study Start: October 23, 2014
• Primary Completion: February 8, 2016
• Study Completion: February 7, 2018
• Last Updated: July 26, 2019
• Results First Posted: July 26, 2019

Record last verified: 2019-05

Locations

ZA (7); UG (1); TA (2)