Assessing PA-824 for Tuberculosis (the APT Trial)

NCT ID: NCT02256696

Last Updated: 2023-07-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 157 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-29
• Study Completion Date: 2022-05-01

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)

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.

Conditions

Pulmonary Tuberculosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

PA-824

Intervention Type: DRUG

200 mg QD

Rifampin

Intervention Type: DRUG

600 mg QD

Pyrazinamide

Intervention Type: DRUG

25mg/kg QD

Isoniazid

Intervention Type: DRUG

300 mg QD

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

Group Type: EXPERIMENTAL

PA-824

Intervention Type: DRUG

200 mg QD

Rifabutin

Intervention Type: DRUG

300 mg QD

Pyrazinamide

Intervention Type: DRUG

25mg/kg QD

Isoniazid

Intervention Type: DRUG

300 mg QD

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

Group Type: ACTIVE_COMPARATOR

Rifampin

Intervention Type: DRUG

600 mg QD

Pyrazinamide

Intervention Type: DRUG

25mg/kg QD

Ethambutol

Intervention Type: DRUG

15mg/kg QD

Isoniazid

Intervention Type: DRUG

300 mg QD

Interventions

PA-824

200 mg QD

Intervention Type: DRUG

Rifampin

600 mg QD

Intervention Type: DRUG

Rifabutin

300 mg QD

Intervention Type: DRUG

Pyrazinamide

25mg/kg QD

Intervention Type: DRUG

Ethambutol

15mg/kg QD

Intervention Type: DRUG

Isoniazid

300 mg QD

Intervention Type: DRUG

Other Intervention Names

Pretomanid

Eligibility Criteria

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 -

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Cape Town

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kelly E Dooley, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

University of Cape Town Lung Institute

Cape Town, , South Africa

Countries

South Africa

References

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.

Reference Type: DERIVED

PMID: 36455068 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33229425 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

#FD-R-004794-01

Identifier Type: OTHER

Identifier Source: secondary_id

NA_00093014

Identifier Type: -

Identifier Source: org_study_id