Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis With(J-M-Pa-Z) (NC-001)

NCT01215851 | Completed Phase 2 Results

• 1 other identifier: NC-001-(J-M-Pa-Z)
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 2

Brief Summary

The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of TMC207 alone, TMC207 with pyrazinamide, TMC207 with PA-824, PA-824 with pyrazinamide and PA-824 with moxifloxacin and pyrazinamide, as determined by the rate of change of log CFU in 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; TMC207; pretomanid; Early Bactericidal Activity; Pulmonary Tuberculosis; PA-824; bedaquiline; pyrazinamide; moxifloxacin; ethambutol; rifafour

Outcome Measures

Primary Outcomes (1)

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-14).

  Log10 CFU rates of change were calculated for each individual patient from the slopes β1 and β2 of the bi-linear regression fitted to the data for each individual patient (log10CFU versus Day). Mean log10 CFU changes from baseline were compared. A higher slope value indicates a greater change in log10 CFU from baseline. Note that to facilitate interpretation the sign of these slopes are reversed for logCFU. A positive slope value therefore indicates a reduction in log10 CFU from baseline.

  14 consecutive days of treatment

Secondary Outcomes (4)

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-2).

  Day 0-2

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 2-14).

  Day 2-14

• Early Bactericidal Activity (EBA) Measured as the Mean Rate of Change of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 7-14).

  Day 7-14

• Rate of Change in Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14)

  14 Days

Study Arms (6)

TMC207

EXPERIMENTAL

TMC207 administered once daily as 100mg tablet for total daily dose of 700 mg on Day 1; 500mg on Day 2; 400mg on Days 3-14 plus pyrazinamide placebo administered once daily

Drug: TMC207

TMC207 and pyrazinamide

EXPERIMENTAL

TMC207 administered once daily as 100mg tablet for total daily dose of 700 mg on Day 1; 500mg on Day 2; 400mg on Days 3-14 plus pyrazinamide administered once daily in 500mg tablets dosed by weight as follows: \< or = 55kg received 2 tablets/day; \>55kg to 75kg received 3 tablets/day; \>75kg received 4 tablets/day

Drug: Pyrazinamide; Drug: TMC207

PA-824 and pyrazinamide

EXPERIMENTAL

PA-824 administered once daily as 200mg tablets and pyrazinamide administered once daily in 500mg tablets dosed by weight as follows: \< or = 55kg received 2 tablets/day; \>55kg to 75kg received 3 tablets/day; \>75kg received 4 tablets/day and moxifloxacin placebo (matched to moxifloxacin tablets) administered once daily

Drug: PA-824; Drug: Pyrazinamide

PA-824 and moxifloxacin and pyrazinamide

EXPERIMENTAL

PA-824 administered once daily as 200mg tablets and pyrazinamide administered once daily in 500mg tablets dosed by weight as follows: \< or = 55kg received 2 tablets/day; \>55kg to 75kg received 3 tablets/day; \>75kg received 4 tablets/day and moxifloxacin administered once daily as 400mg tablets

Drug: PA-824; Drug: Moxifloxacin

Rifafour e-275 mg

ACTIVE COMPARATOR

Rifafour e-275 administered once daily with each tablet containing 150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, and 275mg ethambutol and dose by weight as follows: 30kg-37kg received 2 tablets/day; 38kg-54kg received 3 tablets/days; 55kg-70kg received 4 tablets/day; \> or = 71kg received 5 tablets/day

Drug: Rifafour

TMC207 and PA-824

EXPERIMENTAL

TMC207 administered once daily as 100mg tablet for total daily dose of 700 mg on Day 1; 500mg on Day 2; 400mg on Days 3-14 plus PA-824 administered once daily as 200mg tablets

Drug: PA-824; Drug: TMC207

Interventions

PA-824 DRUG

200 mg tablet, once daily for 14 days

PA-824 and moxifloxacin and pyrazinamide; PA-824 and pyrazinamide; TMC207 and PA-824

Pyrazinamide DRUG

Dosed by Weight

PA-824 and pyrazinamide; TMC207 and pyrazinamide

TMC207 DRUG

TMC207 700 mg Day 1; 500mg Day 2; 400mg Days 3-14

TMC207; TMC207 and PA-824; TMC207 and pyrazinamide

Rifafour DRUG

Rifafour e-275

Rifafour e-275 mg

Moxifloxacin DRUG

moxifloxacin 400 mg

PA-824 and moxifloxacin and pyrazinamide

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 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).
• Females may participate if they are: 1) of non-childbearing potential (have had a bilateral oophorectomy and/or hysterectomy or have been postmenopausal for at least 12 consecutive months), 2) if they are using effective birth control methods and are willing to continue practicing birth control methods throughout treatment or 3) be non-heterosexually active, practice sexual abstinence or have a vasectomized partner (confirmed sterile). Therefore to be eligible for this study women of childbearing potential should either: 1) use a double barrier method to prevent pregnancy (i.e. use a condom with either diaphragm or cervical cap) or 2) use hormonal based contraceptives in combination with a barrier contraceptive, or 3) use an intrauterine device in combination with a barrier contraceptive. They must also be willing to continue these contraceptive measures until 6 months after the last dose of study medication or 6 months after 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 participants to prevent pregnancy).
• Male participants who are having heterosexual intercourse with females of child-bearing potential are required to use one of the following birth control methods during their participation in the trial and for 12 weeks after their last dose of study medication to prevent pregnancy:
• a double barrier method which can include a male condom, diaphragm, cervical cap, or female condom; or
• a barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner.
• The use of the above mentioned birth control method does not apply if the male participant has been vasectomised or has had a bilateral orchidectomy minimally one month prior to screening, or is not heterosexually active, or practice sexual abstinence or if the female sexual partner has had a bilateral oophorectomy and/or hysterectomy or has been postmenopausal for at least 12 consecutive months.

You may not qualify if:

• Medical History
• 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).
• 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, including a known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones or suspected hypersensitivity to any rifamycin antibiotics.
• Isoniazid-resistant and 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 \<300 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.

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (2)

Centre for Tuberculosis Research Innovation, UCT Lung Institute

Cape Town, 7700, South Africa

Location

Task Applied Science, Karl Bremer Hospital

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, Winter H, Becker P, Mendel CM, Spigelman MK. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet. 2012 Sep 15;380(9846):986-93. doi: 10.1016/S0140-6736(12)61080-0. Epub 2012 Jul 23.

  PMID: 22828481 RESULT

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis

Interventions

pretomanid; Pyrazinamide; bedaquiline; Moxifloxacin

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; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

With the small sample, individual results can influence overall results. Comparison between groups and studies is difficult. The ability to assign AEs to a particular compound is limited. The value of EBA studies for predicting relapse is uncertain.

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

  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: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2010
• First Posted: October 7, 2010
• Study Start: October 1, 2010
• Primary Completion: May 1, 2011
• Study Completion: August 1, 2011
• Last Updated: February 28, 2017
• Results First Posted: April 1, 2016

Record last verified: 2017-01

Locations

ZA (2)