Assessing PA-824 for Tuberculosis (the APT Trial)

Sponsor

Johns Hopkins University (Other)

Overall Status

Completed

CT.gov ID

NCT02256696

Collaborator

University of Cape Town (Other)

157

Enrollment

Location

Arms

84.1

Actual Duration (Months)

1.9

Patients Per Site Per Month

Study Details

Study Description

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 OOPD

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Tuberculosis	Drug: PA-824 Drug: Rifampin Drug: Rifabutin Drug: Pyrazinamide Drug: Ethambutol Drug: Isoniazid	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

157 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Apr 29, 2015

Actual Primary Completion Date :

May 1, 2022

Actual Study Completion Date :

May 1, 2022

Arms and Interventions

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: Rifabutin 300 mg QD Drug: Pyrazinamide 25mg/kg QD Drug: Isoniazid 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: Ethambutol 15mg/kg QD Drug: Isoniazid 300 mg QD

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: Rifabutin

300 mg QD

Drug: Pyrazinamide

25mg/kg QD

Drug: Isoniazid

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: Ethambutol

15mg/kg QD

Drug: Isoniazid

300 mg QD

Outcome Measures

Primary Outcome Measures

Time to sputum culture conversion on liquid medium [12 weeks]
The time it takes for the sputum to convert from positive to negative
Grade 3 or higher adverse events [12 weeks]
Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table

Secondary Outcome Measures

Permanent discontinuation of assigned study regimen [12 weeks]
If it is in the best interest of a participant to stop the study regimen for any reason
Time to culture conversion on solid medium [12 weeks]
The time it takes for the sputum to convert form positive to negative on solid medium
Proportion of participants with sputum culture conversion by 8 and 12 weeks of treatment, on solid and liquid media [12 weeks]
Proportion of patients whose sputum converts from positive to negative at Week 8 and Week 12 timepoints
Steady state Pharmacokinetics (PK) (AUC) of PA-824 when given with rifampin or rifabutin [12 weeks]
The Pharmacokinetics results of the study drug when given with a rifamycin
PK (Cmax) of PA-824 at 200 mg once daily with rifampin or rifabutin-containing treatment [12 weeks]
The Pharmacokinetics results of the study drug when given with a rifamycin or a rifabutin
PK/pharmacodynamics (PD) relationship between PA-824 exposures (AUC) and outcomes(time to culture negativity or rate of change in TTP over 12 weeks) using non-linear mixed effects modeling [12 weeks]
The time it takes for this relationship to effect negativity or rate of change in time to positivity (TTP)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)