Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With Clofazimine (C)-TMC207 (J)-PA-824 (Pa)-Pyrazinamide (Z)

NCT01691534 | Completed Phase 2 Results

• 1 other identifier: NC-003-(C-J-Pa-Z)
• Study Type: interventional
• Target: 105
• Locations: 1 country
• Sites: 2

Brief Summary

The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of TMC207 plus PA-824 plus Pyrazinamide plus Clofazimine, TMC207 plus PA-824 plus Pyrazinamide, TMC207 plus PA-824 plus Clofazimine alone, TMC207 plus Pyrazinamide plus Clofazimine, Pyrazinamide alone, Clofazimine alone, and standard first line TB treatment as per South African TB Guidelines (Rifafour e-275) as determined by the rate of change of log CFU per ml sputum over the time period Day 0-14 in participants with smear positive pulmonary tuberculosis (TB). A control group will receive standard treatment.

Conditions

Pulmonary Tuberculosis

Keywords

Tuberculosis; EBA; PA824; pretomanid; TMC207

Outcome Measures

Primary Outcomes (1)

• Early Bactericidal Activity (EBA) Measured as the Daily Rate of Change in log10 CFUs (Colony Forming Units) of M. Tuberculosis in Sputum on Solid Media (Days 0-14).

  14 consecutive days of treatment

Secondary Outcomes (5)

• EBA Measured as the Daily Rate of Change in log10 CFUs of M. Tuberculosis in Sputum on Solid Media (Days 0-2)

  Days 0-2

• EBA Measured as the Daily Rate of Change in log10 CFUs of M. Tuberculosis in Sputum on Solid Media (Days 7-14)

  Day 7-14

• EBA Expressed as the Daily Percentage Change in Time to Positive (TTP) Signal in Liquid Culture for M. Tuberculosis (Days 0-14)

  Days 0-14

• EBA Expressed as the Daily Percentage Change in TTP Signal in Liquid Culture for M. Tuberculosis (Day 0-2)

  Day 0-2

• EBA Expressed as the Daily Percentage Change in TTP Signal in Liquid Culture for M. Tuberculosis (Days 7-14)

  Days 7-14

Study Arms (7)

TMC207, PA-824, pyrazinamide and clofazimine (J-PA-Z-C)

EXPERIMENTAL

TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus PA-824 200mg Days 1-14 plus pyrazinamide 1500mg Days 1-14 plus clofazimine 300mg Days 1-3 and Clofazamine 100mg Days 4-14

Drug: TMC207 (J); Drug: PA-824 (PA); Drug: pyrazinamide (Z); Drug: clofazimine (C)

TMC207, PA-824 and pyrazinamide (J-PA-Z)

EXPERIMENTAL

TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus PA-824 200mg Days 1-14 plus pyrazinamide 1500mg Days 1-14

Drug: TMC207 (J); Drug: PA-824 (PA); Drug: pyrazinamide (Z)

TMC207, PA-824 and clofazimine (J-PA-C)

EXPERIMENTAL

TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus PA-824 200mg Days 1-14 plus clofazimine 300mg Days 1-3 and clofazimine 100mg Days 4-14

Drug: TMC207 (J); Drug: PA-824 (PA); Drug: clofazimine (C)

TMC207, pyrazinamide and clofazimine (J-Z-C)

EXPERIMENTAL

TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14 plus pyrazinamide 1500mg Days 1-14 plus clofazimine 300mg Days 1-3 and Clofazimine 100mg Days 4-14

Drug: TMC207 (J); Drug: pyrazinamide (Z); Drug: clofazimine (C)

pyrazinamide (Z)

EXPERIMENTAL

pyrazinamide 1500mg Days 1-14

Drug: pyrazinamide (Z)

clofazimine (C)

EXPERIMENTAL

Clofazimine 300mg Days 1-3 and Clofazimine 100mg Days 4-14

Drug: clofazimine (C)

Rifafour

ACTIVE COMPARATOR

Rifafour e-275 mg dosed by weight

Drug: Rifafour

Interventions

TMC207 (J) DRUG

TMC207 400 mg Day 1; 300mg Day 2; 200mg Days 3-14

TMC207, PA-824 and clofazimine (J-PA-C); TMC207, PA-824 and pyrazinamide (J-PA-Z); TMC207, PA-824, pyrazinamide and clofazimine (J-PA-Z-C); TMC207, pyrazinamide and clofazimine (J-Z-C)

PA-824 (PA) DRUG

PA-824 200mg Days 1-14

TMC207, PA-824 and clofazimine (J-PA-C); TMC207, PA-824 and pyrazinamide (J-PA-Z); TMC207, PA-824, pyrazinamide and clofazimine (J-PA-Z-C)

pyrazinamide (Z) DRUG

1500mg Days 1-14 Dosed by Weight

TMC207, PA-824 and pyrazinamide (J-PA-Z); TMC207, PA-824, pyrazinamide and clofazimine (J-PA-Z-C); TMC207, pyrazinamide and clofazimine (J-Z-C); pyrazinamide (Z)

clofazimine (C) DRUG

clofazimine 300mg Days 1-3 and clofazimine 100mg Days 4-14

TMC207, PA-824 and clofazimine (J-PA-C); TMC207, PA-824, pyrazinamide and clofazimine (J-PA-Z-C); TMC207, pyrazinamide and clofazimine (J-Z-C); clofazimine (C)

Rifafour DRUG

Rifafour e-275 mg dosed by weight

Rifafour

Eligibility Criteria

• Age: 18 Years - 65 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 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, sputum smear-positive pulmonary TB.
• \. A chest X-ray picture which in the opinion of the Investigator is compatible with TB.
• \. Sputum positive GeneXpert or TB Smear from TB clinic or site initial diagnosis
• \. Sputum positive on direct microscopy for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale).
• \. Ability to produce an adequate volume of sputum as estimated from a spot assessment (estimated 10 ml or more overnight production).
• \. Be of non-childbearing potential or using an effective method of birth control as defined as:
• Non-childbearing potential:
• Subject - Not heterosexually active or practice sexual abstinence or
• Female subject/sexual 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 month prior to screening
• Effective birth control methods:
• Double barrier method which can include a male condom, diaphragms, cervical cap, or female condom or

You may not qualify if:

• Evidence of clinically significant (as judged by the investigator), metabolic, gastrointestinal, cardiovascular, musculoskeletal, ophthalmological, pulmonary, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied) including malaria.
• Poor general condition where any delay in treatment cannot be tolerated per discretion of the Investigator.
• A history of previous TB.
• Clinically significant evidence of extrathoracic TB (miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis), as judged by the Investigator.
• History of allergy to the IMP or related substances.
• Isoniazid-resistant and/or Rifampicin-resistant bacteria detected with a sputum specimen collected within the pre-treatment period and tested at the study laboratory.
• Known or suspected, current or history of within the past 2 years, alcohol or drug abuse, that is, in the opinion of the Investigator, sufficient to compromise the safety or cooperation of the participant.
• HIV infected participants:
• having a CD4+ count \<200 cells/µL;
• or having received antiretroviral therapy medication within the last 90 days;
• or having received oral or intravenous antifungal medication within the last 90 days;
• or with an AIDS-defining opportunistic infection or malignancies (except pulmonary TB).
• Having participated in other clinical studies with investigational agents within 8 weeks prior to trial start.
• Significant cardiac arrhythmia requiring medication.
• Participants with the following at screening. For ECGs, central cardiology overread and the mean of triplicate reading must be used:

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (2)

Centre for Tuberculosis Research Innovation, UCT Lung Institute

Cape Town, South Africa

Location

Task Applied Science, Karl Bremer Hospita

Cape Town, South Africa

Location

Related Publications (1)

• Diacon AH, Dawson R, von Groote-Bidlingmaier F, Symons G, Venter A, Donald PR, van Niekerk C, Everitt D, Hutchings J, Burger DA, Schall R, Mendel CM. Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Am J Respir Crit Care Med. 2015 Apr 15;191(8):943-53. doi: 10.1164/rccm.201410-1801OC.

  PMID: 25622149 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

bedaquiline; pretomanid; Pyrazinamide; Clofazimine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenazines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Daniel E. Everitt, MD, Vice President and Senior Medical Officer
• Organization: Global Alliance for TB Drug Development

Dan.Everitt@tballiance.org

212-227-7540

Study Officials

• Andreas Diacon, MD

  Karl Bremer Hospital, Cape Town South Africa

  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: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2012
• First Posted: September 24, 2012
• Study Start: October 1, 2012
• Primary Completion: April 1, 2013
• Study Completion: May 1, 2013
• Last Updated: December 13, 2016
• Results First Posted: December 13, 2016

Record last verified: 2016-08

Locations

ZA (2)