Assessing PA-824 for Tuberculosis (the APT Trial)

NCT02256696 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: NA_00093014#FD-R-004794-01
• Study Type: interventional
• Target: 157
• Locations: 1 country
• Sites: 1

Brief Summary

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)

Conditions

Pulmonary Tuberculosis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Number of Participants With Permanent Discontinuation of Assigned Study Regimen

  12 weeks

• Time to Culture Conversion on Solid Medium

  12 weeks

• Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment

  8 weeks

• Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin

  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

  pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14

Study Arms (3)

Arm 1

EXPERIMENTAL

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; Drug: Rifampin; Drug: Pyrazinamide; Drug: Isoniazid

Arm 2

EXPERIMENTAL

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; Drug: Rifabutin; Drug: Pyrazinamide; Drug: Isoniazid

Arm 3

ACTIVE COMPARATOR

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; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Isoniazid

Interventions

PA-824 DRUG

200 mg QD

Also known as: Pretomanid

Arm 1; Arm 2

Rifampin DRUG

600 mg QD

Arm 1; Arm 3

Rifabutin DRUG

300 mg QD

Arm 2

Pyrazinamide DRUG

25mg/kg QD

Arm 1; Arm 2; Arm 3

Ethambutol DRUG

15mg/kg QD

Arm 3

Isoniazid DRUG

300 mg QD

Arm 1; Arm 2; Arm 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Agrees to adhere to contraceptive requirements

You may not qualify if:

• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• University of Cape Town: collaborator

Study Sites (1)

University of Cape Town Lung Institute

Cape Town, South Africa

Location

Related Publications (2)

• Dooley KE, Hendricks B, Gupte N, Barnes G, Narunsky K, Whitelaw C, Smit T, Ignatius EH, Friedman A, Dorman SE, Dawson R; Assessing Pretomanid for Tuberculosis (APT) Study Team. Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results. Am J Respir Crit Care Med. 2023 Apr 1;207(7):929-935. doi: 10.1164/rccm.202208-1475OC.

  PMID: 36455068 DERIVED

• 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.

  PMID: 33229425 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

pretomanid; Rifampin; Rifabutin; Pyrazinamide; Ethambutol; Isoniazid

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Ethylenediamines; Diamines; Polyamines; Amines; Organic Chemicals; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Pyridines

Results Point of Contact

• Title: Dr. Kelly Dooley
• Organization: Vanderbilt University

kelly.e.dooley@vumc.org

(615) 322-8972

Study Officials

• Kelly E Dooley, MD PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 25, 2014
• First Posted: October 6, 2014
• Study Start: April 29, 2015
• Primary Completion: May 1, 2022
• Study Completion: May 1, 2022
• Last Updated: July 18, 2023
• Results First Posted: July 18, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Time Frame: Within one year of reaching recruitment goals.
• Access Criteria: This plan is in process, to be finalized prior to the end of recruitment.

Locations

ZA (1)