Assessing PA-824 for Tuberculosis (the APT Trial)

Study Overview
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Brief Summary
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Assess the mycobactericidal activity of PA-824 (given at 200 mg daily) when added to first-line tuberculosis (TB) treatment (isoniazid, pyrazinamide, and a rifamycin antibiotic) over 12 weeks of treatment. Funding Source - FDA Office of Orphan Products Development (OOPD)

Detailed Description
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Phase IIB, 12-week, open-label, single-site, randomized clinical trial with three treatment groups. Patients with drug-sensitive TB will all receive once daily isoniazid and pyrazinamide for 8 weeks followed by 4 weeks of daily isoniazid. In addition, Arm 1 participants will receive PA-824 200 mg daily and rifampin 600 mg daily for 12 weeks. Arm 2 participants will receive PA-824 200 mg daily and rifabutin 300 mg daily for 12 weeks. Arm 3 participants (control group) will receive rifampin for 12 weeks and ethambutol for 8 weeks. Patients will be screened within 1 week of TB diagnosis, will receive 12 weeks of study treatment and will return for follow-up visits at 4, 12, and 36 weeks after study treatment completion. All patients will be referred to the local TB treatment program after completion of study treatment to finish their 24-week TB treatment course.

Official Title
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A Phase 2 Randomized, Open-Label Trial of PA-824-Containing Regimens Versus Standard Treatment for Drug-Sensitive Sputum Smear-Positive Pulmonary Tuberculosis

Conditions
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Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: PA-824
* Drug: Rifampin
* Drug: Rifabutin
* Drug: Pyrazinamide
* Drug: Ethambutol
* Drug: Isoniazid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Suspected pulmonary tuberculosis with acid-fast bacilli in a stained smear of expectorated sputum or Gene Xpert positive sputum sample. Patients having extra-pulmonary manifestations of tuberculosis, in addition to smear-positive pulmonary disease, are eligible for enrollment. Age > 18 years . Weight ≥ 40 kg and ≤ 80 kg Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs) . Signed informed consent . HIV negative, or positive with CD4 ≥350 cells/cu mm and not currently taking or planning to take combination antiretroviral therapy for HIV during the study. Ability to adhere with study follow-up 8 Agrees to adhere to contraceptive requirements - Exclusion Criteria: Pregnant or breast-feeding Known intolerance or allergy to any of the study drugs Concomitant disorders or conditions for which isoniazid, rifampin, rifabutin, pyrazinamide, or ethambutol is contraindicated. These include severe hepatic damage, acute liver disease of any cause, allergy to the drug, and acute uncontrolled gouty arthritis. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine or tacrolimus, which have unacceptable interactions with rifamycins. Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable. Pulmonary silicosis Central nervous system TB ECG at screening with corrected QT interval (QTc) (Fridericia correction) interval >450 ms or any clinically-significant, in the opinion of the investigator, ECG abnormality History and/or presence (or evidence) of neuropathy or epilepsy. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination with a value of 1.0 or higher on age-related eye disease scale 2 (AREDS2) Clinical Lens Opacity Classification and Grading System scale. Infection with an isolate known to be resistant to a first-line TB drug (for example, patients with Gene Xpert screening through the local TB program with results suggesting resistance to rifampin) Laboratory parameters done at, or 14 days prior to, screening (with results available for review by study personnel) demonstrating any of the following: Serum alanine aminotransferase (ALT) activity > 3 times the upper limit of normal Serum total bilirubin level > 2 times the upper limit of normal Serum creatinine greater than the upper limit of normal Hemoglobin level less than 7.0 g/dL Platelet count less than 100,000/mm3 Positive pregnancy test (women of childbearing potential) More than five days of treatment directed against active tuberculosis in the past 6 months -

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>PA-824 200 mg once daily (QD),Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks | Drug: PA-824<br>* 200 mg QD<br>* Other names: Pretomanid;Drug: Rifampin<br>* 600 mg QD<br>Drug: Pyrazinamide<br>* 25mg/kg QD<br>Drug: Isoniazid<br>* 300 mg QD<br>|
| Experimental: Arm 2<br>PA-824 200 mg once daily,Rifabutin 300 mg once daily , Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then PA-824 200 mg once daily, Rifabutin 300 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks | Drug: PA-824<br>* 200 mg QD<br>* Other names: Pretomanid;Drug: Rifabutin<br>* 300 mg QD<br>Drug: Pyrazinamide<br>* 25mg/kg QD<br>Drug: Isoniazid<br>* 300 mg QD<br>|
| Active Comparator: Arm 3<br>Rifampin 600 mg once daily, Ethambutol 15mg/kg once daily, Isoniazid 5 mg/kg once daily, Pyrazinamide 25 mg/kg once daily x 8 weeks, then Rifampin 600 mg once daily, Isoniazid 5 mg/kg once daily x 4 weeks | Drug: Rifampin<br>* 600 mg QD<br>Drug: Pyrazinamide<br>* 25mg/kg QD<br>Drug: Ethambutol<br>* 15mg/kg QD<br>Drug: Isoniazid<br>* 300 mg QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Sputum Culture Conversion on Liquid Medium | The time (days) it takes for the sputum to convert from positive to negative. | 12 weeks | 
| Number of Participants With Grade 3 or Higher Adverse Events | Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Permanent Discontinuation of Assigned Study Regimen | If it is in the best interest of a participant to stop the study regimen for any reason | 12 weeks | 
| Time to Culture Conversion on Solid Medium | The time (days) it takes for the sputum to convert form positive to negative on solid medium | 12 weeks | 
| Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media. | 8 weeks | 
| Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin | AUC of PA-824 when given with either rifampicin or rifabutin to determine steady state Pharmacokinetics (PK) of PA-824. | pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14 | 
| PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment | The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin. | pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14 | 
| Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks | Relationship between PA-824 exposure (AUC) and rate of change in TTP over 12 weeks, using non-linear mixed effects modeling. The data is reported as percentage increase in TTP per 10 unit increase in PA-824 AUC (% increase/10 unit increase PA-824 AUC). | 12 weeks |