Assessing PA-824 for Tuberculosis (the APT Trial)

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

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)

Study Overview

• Status: Completed
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: Drug: PA-824; Drug: Rifampin; Drug: Pyrazinamide; Drug: Isoniazid; Drug: Rifabutin; Drug: Ethambutol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 157
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, South Africa
    • University of Cape Town Lung Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. Age > 18 years
3. . Weight ≥ 40 kg and ≤ 80 kg
4. Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs)
5. . Signed informed consent
6. . 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.
7. Ability to adhere with study follow-up

8 Agrees to adhere to contraceptive requirements

-

Exclusion Criteria:

1. Pregnant or breast-feeding
2. Known intolerance or allergy to any of the study drugs
3. 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.
4. Current or planned therapy, during the intensive phase of TB therapy with cyclosporine or tacrolimus, which have unacceptable interactions with rifamycins.
5. Any medical or psychosocial condition, which, in the view of the study investigator, makes study participation inadvisable.
6. Pulmonary silicosis
7. Central nervous system TB
8. 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
9. History and/or presence (or evidence) of neuropathy or epilepsy.
10. 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.
11. 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)

12. 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)
13. More than five days of treatment directed against active tuberculosis in the past 6 months -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; 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; 200 mg QD; Other Names: Pretomanid; Drug: Rifampin; 600 mg QD; Drug: Pyrazinamide; 25mg/kg QD; Drug: Isoniazid; 300 mg QD
Experimental: Arm 2; 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; 200 mg QD; Other Names: Pretomanid; Drug: Pyrazinamide; 25mg/kg QD; Drug: Isoniazid; 300 mg QD; Drug: Rifabutin; 300 mg QD
Active Comparator: Arm 3; 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; 600 mg QD; Drug: Pyrazinamide; 25mg/kg QD; Drug: Isoniazid; 300 mg QD; Drug: Ethambutol; 15mg/kg QD

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: University of Cape Town
• Investigators: Principal Investigator: Kelly E Dooley, MD PhD, Johns Hopkins University

Publications and helpful links

General Publications

• Ignatius EH, Abdelwahab MT, Hendricks B, Gupte N, Narunsky K, Wiesner L, Barnes G, Dawson R, Dooley KE, Denti P. Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results from a Randomized Trial among Patients with Tuberculosis. Antimicrob Agents Chemother. 2021 Jan 20;65(2):e01196-20. doi: 10.1128/AAC.01196-20. Print 2021 Jan 20.

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2015
• Primary Completion (Actual): May 1, 2022
• Study Completion (Actual): May 1, 2022

Study Registration Dates

• First Submitted: September 25, 2014
• First Submitted That Met QC Criteria: October 1, 2014
• First Posted (Estimated): October 6, 2014

Study Record Updates

• Last Update Posted (Actual): July 18, 2023
• Last Update Submitted That Met QC Criteria: June 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Fatty Acid Synthesis Inhibitors; Rifampin; Rifabutin; Isoniazid; Pyrazinamide; Ethambutol
• Other Study ID Numbers: NA_00093014; #FD-R-004794-01 (Other Identifier: Office of Orphan Products Development (OOPD))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This plan is in process, to be finalized prior to the end of recruitment.
• IPD Sharing Time Frame: Within one year of reaching recruitment goals.
• IPD Sharing Access Criteria: This plan is in process, to be finalized prior to the end of recruitment.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No