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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: January 2010

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.

Interventions

  • 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

Arms, Groups and Cohorts

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

Clinical Trial Outcome Measures

Primary 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

Secondary 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
  • 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

Participating in This Clinical Trial

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 300×10-6/L. – Receiving antiretroviral therapy (ART).

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 64 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Global Alliance for TB Drug Development
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Andreas Diacon, MD, Principal Investigator, Karl Bremer Hospital
    • Rodney Dawson, MD, Principal Investigator, University of Cape Town Lung Institute

Citations Reporting on Results

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.

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