Clinical trial NCT00944021: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Keywords: Early Bactericidal Activity
EBA
Pulmonary Tuberculosis
PA-824
pretomanid
Lead sponsor: Global Alliance for TB Drug Development
Sponsor class: OTHER
First posted: 2009-07-22
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: 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).
timeFrame: 14 consecutive days of treatment
Secondary outcomes:
measure: 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).
timeFrame: Two consecutive days of treatment
measure: 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).
timeFrame: Days 2-14 of 14 consecutive days of treatment
measure: Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-14).
timeFrame: Fourteen consecutive days of treatment
measure: Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2).
timeFrame: Two consecutive days of treatment
measure: Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14).
timeFrame: Days 2-14 of 14 consecutive days of treatment
measure: Pharmacokinetics- Maximum Observed Plasma Concentration (Cmax) (Day 1).
timeFrame: 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
measure: Pharmacokinetics- Area Under the Plasma Concentration Time Curve From Zero to Infinity (AUC 0 to Infinity) (Day 1).
timeFrame: 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
measure: Pharmacokinetics- Terminal Elimination Phase Half-life (t1/2) (Day 1).
timeFrame: 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
measure: Pharmacokinetics-Maximum Observed Plasma Concentration (Cmax) (Day 14).
timeFrame: 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
measure: Pharmacokinetics- Terminal Elimination Phase Half-life (t1/2) (Day 14).
timeFrame: 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
Other outcomes:
Locations:
Study officials:
affiliation: Karl Bremer Hospital
name: Andreas Diacon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cape Town Lung Institute
name: Rodney Dawson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.