Assessing PA-824 for Tuberculosis (the APT Trial)

June 26, 2023 updated by: Johns Hopkins University

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
157

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Time to Sputum Culture Conversion on Liquid Medium
Time Frame: 12 weeks
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
Time Frame: 12 weeks
Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table
12 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of Participants With Permanent Discontinuation of Assigned Study Regimen
Time Frame: 12 weeks
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
Time Frame: 12 weeks
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
Time Frame: 8 weeks
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
Time Frame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
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
Time Frame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
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
Time Frame: 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

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Johns Hopkins University

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
University of Cape Town

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Kelly E Dooley, MD PhD, Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 29, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
May 1, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
May 1, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 25, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 1, 2014

First Posted (Estimated)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
October 6, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 18, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 26, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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