Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (CL-010)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier:
NCT00944021
First received: July 21, 2009
Last updated: February 11, 2016
Last verified: February 2014
  Purpose
The trial will evaluate the extended bactericidal activity of 14 consecutive days of oral administration of PA-824 at 50, 100, 150 and 200 mg per day in adult patients with newly diagnosed, uncomplicated, smear positive tuberculosis (TB). A control group will receive standard TB treatment.

Condition Intervention Phase
Pulmonary Tuberculosis
Drug: PA-824
Drug: Rifafour e-275 mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II Dose Ranging Trial to Evaluate the Extended Early Bactericidal Activity, Safety, Tolerability, and Pharmacokinetics of PA-824 in Adult Participants With Newly Diagnosed, Uncomplicated, Smear-Positive, Pulmonary Tuberculosis

Resource links provided by NLM:


Further study details as provided by Global Alliance for TB Drug Development:

Primary Outcome Measures:
  • Early Bactericidal Activity (EBA) Measured as the Mean Rate of Reduction of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-14). [ Time Frame: 14 consecutive days of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Early Bactericidal Activity (EBA) Measured as the Mean Rate of Reduction of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 0-2). [ Time Frame: Two consecutive days of treatment ] [ Designated as safety issue: No ]
  • Early Bactericidal Activity (EBA) Measured as the Mean Rate of Reduction of log10 Colony Forming Units (CFU) of M. Tuberculosis Per ml Sputum on Solid Medium Over Time (Days 2-14). [ Time Frame: Days 2-14 of 14 consecutive days of treatment ] [ Designated as safety issue: No ]
  • Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14). [ Time Frame: Fourteen consecutive days of treatment ] [ Designated as safety issue: No ]
  • Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2). [ Time Frame: Two consecutive days of treatment ] [ Designated as safety issue: No ]
  • Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14). [ Time Frame: Days 2-14 of 14 consecutive days of treatment ] [ Designated as safety issue: No ]
  • Pharmacokinetics- Maximum Observed Plasma Concentration (Cmax) (Day 1). [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, and 24 hours post-dose on Day 1 of treatment ] [ Designated as safety issue: No ]
  • Pharmacokinetics- Area Under the Plasma Concentration Time Curve From Zero to Infinity (AUC 0 to Infinity) (Day 1). [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, and 24 hours post-dose on Day 1 of treatment ] [ Designated as safety issue: No ]
  • Pharmacokinetics- Terminal Elimination Phase Half-life (t1/2) (Day 1). [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, and 24 hours post-dose on Day 1 of treatment ] [ Designated as safety issue: No ]
  • Pharmacokinetics-Maximum Observed Plasma Concentration (Cmax) (Day 14). [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12,16, 24, and 30 hours post-dose on Day 14 of 14 consecutive days of treatment ] [ Designated as safety issue: No ]
  • Pharmacokinetics- Terminal Elimination Phase Half-life (t1/2) (Day 14). [ Time Frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24 and 30 hours post-dose on Day 14 of 14 consecutive days of treatment ] [ Designated as safety issue: No ]

Enrollment: 69
Study Start Date: August 2009
Study Completion Date: May 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PA-824 50 mg/qd Drug: PA-824
50mg
Experimental: PA-824 100mg/qd Drug: PA-824
100mg
Experimental: PA-824 150mg/qd Drug: PA-824
150 mg
Experimental: PA-824 200mg/qd Drug: PA-824
200 mg
Active Comparator: Rifafour e-275mg Drug: Rifafour e-275 mg
275 mg

Detailed Description:
The planned sample size of 15 participants per treatment group is in keeping with other Phase II trials of this type and accounts for the possibility of up to 3 drop-outs per arm, which based on previous studies of this type conducted at these sites, represents a conservative estimate of the expected drop-out rate.
  Eligibility

Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Informed Consent
  • Body weight between 40 and 90 kg, inclusive.
  • Newly diagnosed, previously untreated, uncomplicated, sputum smear-positive, pulmonary TB.
  • A chest X-ray compatible with TB.
  • Sputum positive
  • Adequate volume of sputum
  • Female participants of childbearing potential negative serum pregnancy and agree to use birth control
  • Male participants must agree to use contraception throughout participation in the trial and for 12 weeks after last dose.

Exclusion Criteria:

  • Poor general condition
  • Rifampicin-resistant and/or Isoniazid-resistant
  • MTB Treatment received within the 3 months prior
  • Allergy to the IMP or related substances
  • Evidence of extrathoracic TB
  • A history of previous TB
  • Evidence of serious lung conditions other than TB or uncontrolled obstructive bronchial disease
  • History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination
  • Any evidence of renal impairment
  • For males, any evidence or history of abnormality in the reproductive system
  • History and/or presence (or evidence) of neuropathy or epilepsy.
  • Clinically relevant changes in the ECG
  • A history of or current clinically relevant cardiovascular disorder
  • Concomitant use of any drug known to prolong QTc interval
  • Diabetics using insulin
  • Evidence of clinically significant metabolic, gastrointestinal, neurological, psychiatric or endocrine diseases, malignancy, or other abnormalities (other than the indication being studied).
  • Any diseases or conditions in which the use of the standard TB drugs or any of their components is contra-indicated, including but not limited to allergy to any TB drug, their component or to the IMP.
  • Any disease or conditions in which any of the medicinal products listed in the section pertaining to prohibited medication is used.
  • alcohol or drug abuse
  • Administration of an IMP prior to Visit 1, within 5 half-lives for that IMP if known. If the half-life of the IMP is unknown within 1 month.
  • Pregnant, breast-feeding, or planning to conceive or father a child within twelve weeks of cessation of treatment for males and within one week of cessation of treatment for females.
  • Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes
  • Any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine) within 30 days prior to dosing.
  • glucocorticoids within one year prior to dosing.
  • HIV infection with helper/inducer T lymphocyte (CD4 cell) count of less than or equal to 300x10-6/L.
  • Receiving antiretroviral therapy (ART).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00944021

Sponsors and Collaborators
Global Alliance for TB Drug Development
Investigators
Principal Investigator: Andreas Diacon, MD Karl Bremer Hospital
Principal Investigator: Rodney Dawson, MD University of Cape Town Lung Institute
  More Information

Additional Information:
Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT00944021     History of Changes
Other Study ID Numbers: PA-824-CL-010 
Study First Received: July 21, 2009
Results First Received: February 19, 2014
Last Updated: February 11, 2016
Health Authority: United States: Food and Drug Administration
South Africa: Medicines Control Council

Keywords provided by Global Alliance for TB Drug Development:
Early Bactericidal Activity
EBA
Pulmonary Tuberculosis
PA-824
pretomanid

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections

ClinicalTrials.gov processed this record on August 25, 2016