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

• ClinicalTrials.gov Identifier: NCT00944021
• Recruitment Status: Completed
• First Posted: July 22, 2009
• Results First Posted: March 9, 2016
• Last Update Posted: September 20, 2019
• Sponsor: Global Alliance for TB Drug Development
• Information provided by (Responsible Party): Global Alliance for TB Drug Development

Tracking Information

• First Submitted Date: July 21, 2009
• First Posted Date: July 22, 2009
• Results First Submitted Date: February 19, 2014
• Results First Posted Date: March 9, 2016
• Last Update Posted Date: September 20, 2019
• Study Start Date: August 2009
• Actual Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 11, 2016): 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 ]
• Original Primary Outcome Measures (submitted: July 21, 2009): Extended early bactericidal activity (EBA) measured as the rate of change in log CFUs (Colony forming units) in sputum [ Time Frame: 14 days of consecutive treatment ]

Current Secondary Outcome Measures (submitted: February 11, 2016)

• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]
• 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 ]

Original Secondary Outcome Measures (submitted: July 21, 2009)

• Standard EBA day 0-2 defined by change of CFU in sputum [ Time Frame: Day 0-2 ]
• Change in time to sputum culture positivity (TTP) [ Time Frame: 14 days ]
• Pharmacokinetics-Pharmacodynamics [ Time Frame: 14 days ]
• Proportion of patients with serious adverse events (SAEs) and proportion of patients who discontinue due to an adverse event (AE) [ Time Frame: 14 days plus 6 month follow-up for SAEs ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Early Bactericidal Activity in Pulmonary Tuberculosis (CL-010)
• 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
• Brief Summary: 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.
• 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Tuberculosis

Intervention

• Drug: PA-824
  50mg
• Drug: PA-824
  100mg
• Drug: PA-824
  150 mg
• Drug: Rifafour e-275 mg
  275 mg
• Drug: PA-824
  200 mg

Study Arms

• Experimental: PA-824 50 mg/qd
  Intervention: Drug: PA-824
• Experimental: PA-824 100mg/qd
  Intervention: Drug: PA-824
• Experimental: PA-824 150mg/qd
  Intervention: Drug: PA-824
• Experimental: PA-824 200mg/qd
  Intervention: Drug: PA-824
• Active Comparator: Rifafour e-275mg
  Intervention: Drug: Rifafour e-275 mg

• Publications *: Diacon AH, Dawson R, du Bois J, Narunsky K, Venter A, Donald PR, van Niekerk C, Erondu N, Ginsberg AM, Becker P, Spigelman MK. Phase II dose-ranging trial of the early bactericidal activity of PA-824. Antimicrob Agents Chemother. 2012 Jun;56(6):3027-31. doi: 10.1128/AAC.06125-11. Epub 2012 Mar 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 17, 2010): 69
• Original Estimated Enrollment (submitted: July 21, 2009): 68
• Actual Study Completion Date: May 2010
• Actual Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)

Eligibility 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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 64 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT00944021
• Other Study ID Numbers: PA-824-CL-010
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Global Alliance for TB Drug Development
• Original Responsible Party: Prof. Andreas Diacon, Karl Bremer Hospital, Cape Town South Africa
• Current Study Sponsor: Global Alliance for TB Drug Development
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Andreas Diacon, MD; Karl Bremer Hospital
• Principal Investigator: Rodney Dawson, MD; University of Cape Town Lung Institute

• PRS Account: Global Alliance for TB Drug Development
• Verification Date: September 2019