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Assessing PA-824 for Tuberculosis (the APT Trial)

Primary Purpose

Pulmonary Tuberculosis

Status

Completed

Phase

Phase 2

Locations

South Africa

Study Type

Interventional

Intervention

PA-824

Rifampin

Rifabutin

Pyrazinamide

Ethambutol

Isoniazid

About this trial

This is an interventional treatment trial for Pulmonary Tuberculosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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)
More than five days of treatment directed against active tuberculosis in the past 6 months -

Sites / Locations

University of Cape Town Lung Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Arm 1

Arm 2

Arm 3

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

Time to Sputum Culture Conversion on Liquid Medium

The time (days) it takes for the sputum to convert from positive to negative.

Number of Participants With Grade 3 or Higher Adverse Events

Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table

Secondary Outcome Measures

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

Time to Culture Conversion on Solid Medium

The time (days) it takes for the sputum to convert form positive to negative on solid medium

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.

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.

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.

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).

Full Information

NCT ID

NCT02256696

First Posted

September 25, 2014

Last Updated

June 26, 2023

Sponsor

Johns Hopkins University

Collaborators

University of Cape Town

1. Study Identification

Unique Protocol Identification Number

NCT02256696

Brief Title

Assessing PA-824 for Tuberculosis (the APT Trial)

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Completed

Study Start Date

April 29, 2015 (Actual)

Primary Completion Date

May 1, 2022 (Actual)

Study Completion Date

May 1, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Johns Hopkins University

Collaborators

University of Cape Town

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

157 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm 1

Arm Type

Experimental

Arm Description

Arm Title

Arm 2

Arm Type

Experimental

Arm Description

Arm Title

Arm 3

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

PA-824

Other Intervention Name(s)

Pretomanid

Intervention Description

200 mg QD

Intervention Type

Drug

Intervention Name(s)

Rifampin

Intervention Description

600 mg QD

Intervention Type

Drug

Intervention Name(s)

Rifabutin

Intervention Description

300 mg QD

Intervention Type

Drug

Intervention Name(s)

Pyrazinamide

Intervention Description

25mg/kg QD

Intervention Type

Drug

Intervention Name(s)

Ethambutol

Intervention Description

15mg/kg QD

Intervention Type

Drug

Intervention Name(s)

Isoniazid

Intervention Description

300 mg QD

Primary Outcome Measure Information:

Title

Time to Sputum Culture Conversion on Liquid Medium

Description

The time (days) it takes for the sputum to convert from positive to negative.

Time Frame

12 weeks

Title

Number of Participants With Grade 3 or Higher Adverse Events

Description

Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

Number of Participants With Permanent Discontinuation of Assigned Study Regimen

Description

If it is in the best interest of a participant to stop the study regimen for any reason

Time Frame

12 weeks

Title

Time to Culture Conversion on Solid Medium

Description

The time (days) it takes for the sputum to convert form positive to negative on solid medium

Time Frame

12 weeks

Title

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

Description

Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media.

Time Frame

8 weeks

Title

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

Description

AUC of PA-824 when given with either rifampicin or rifabutin to determine steady state Pharmacokinetics (PK) of PA-824.

Time Frame

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

Title

PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment

Description

The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin.

Time Frame

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

Title

Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks

Description

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kelly E Dooley, MD PhD

Organizational Affiliation

Johns Hopkins University

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Cape Town Lung Institute

City

Cape Town

Country

South Africa

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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.

Citations:

PubMed Identifier

33229425

Citation

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.

Results Reference

derived

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Assessing PA-824 for Tuberculosis (the APT Trial)

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