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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: PA-824
* Drug: PA-824
* Drug: PA-824
* Drug: Rifafour e-275 mg
* Drug: PA-824


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PA-824 50 mg/qd<br> | Drug: PA-824<br>* 50mg<br>|
| Experimental: PA-824 100mg/qd<br> | Drug: PA-824<br>* 100mg<br>|
| Experimental: PA-824 150mg/qd<br> | Drug: PA-824<br>* 150 mg<br>|
| Experimental: PA-824 200mg/qd<br> | Drug: PA-824<br>* 200 mg<br>|
| Active Comparator: Rifafour e-275mg<br> | Drug: Rifafour e-275 mg<br>* 275 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). |  | 14 consecutive days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). |  | 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). |  | 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). |  | Fourteen consecutive days of treatment | 
| Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 0-2). |  | Two consecutive days of treatment | 
| Rate of Change in Increased Time to Sputum Culture Positivity (TTP)(Hours) in Liquid Culture Media (Days 2-14). |  | Days 2-14 of 14 consecutive days of treatment | 
| Pharmacokinetics- Maximum Observed Plasma Concentration (Cmax) (Day 1). |  | 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). |  | 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). |  | 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). |  | 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). |  | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pretomanid, Early Bactericidal Activity, EBA, Pulmonary Tuberculosis, PA-824