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Assessing PA-824 for Tuberculosis (the APT Trial)

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ClinicalTrials.gov Identifier: NCT02256696
Recruitment Status : Recruiting
First Posted : October 6, 2014
Last Update Posted : March 12, 2019
Sponsor:
Collaborator:
University of Cape Town
Information provided by (Responsible Party):
Johns Hopkins University

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 183 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 : April 29, 2015
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

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 Name: 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 Name: 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




Primary Outcome Measures :
  1. Time to sputum culture conversion on liquid medium [ Time Frame: 12 weeks ]
    The time it takes for the sputum to convert from positive to negative

  2. Grade 3 or higher adverse events [ Time Frame: 12 weeks ]
    Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table


Secondary Outcome Measures :
  1. 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

  2. Time to culture conversion on solid medium [ Time Frame: 12 weeks ]
    The time it takes for the sputum to convert form positive to negative on solid medium

  3. Proportion of participants with sputum culture conversion by 8 and 12 weeks of treatment, on solid and liquid media [ Time Frame: 12 weeks ]
    Proportion of patients whose sputum converts from positive to negative at Week 8 and Week 12 timepoints

  4. Steady state Pharmacokinetics (PK) (AUC) of PA-824 when given with rifampin or rifabutin [ Time Frame: 12 weeks ]
    The Pharmacokinetics results of the study drug when given with a rifamycin

  5. PK (Cmax) of PA-824 at 200 mg once daily with rifampin or rifabutin-containing treatment [ Time Frame: 12 weeks ]
    The Pharmacokinetics results of the study drug when given with a rifamycin or a rifabutin

  6. 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 [ Time Frame: 12 weeks ]
    The time it takes for this relationship to effect negativity or rate of change in time to positivity (TTP)



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02256696


Contacts
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Contact: Kelly E Dooley, MD, PhD 443-955-3100 kdooley1@jhmi.edu
Contact: Grace Barnes, RN 410-614-3812 glbarnes@jhmi.edu

Locations
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South Africa
University of Cape Town Lung Institute Recruiting
Cape Town, South Africa
Contact: Rodney Dawson, MBChB    +27214066864    rodney.dawson@uct.ac.za   
Contact: Elizabeth Arangies    +27214066748    elizabeth.arangies@uct.ac.za   
Sponsors and Collaborators
Johns Hopkins University
University of Cape Town
Investigators
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Principal Investigator: Kelly E Dooley, MD PhD Johns Hopkins University

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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT02256696     History of Changes
Other Study ID Numbers: NA_00093014
#FD-R-004794-01 ( Other Identifier: Office of Orphan Products Development (OOPD) )
First Posted: October 6, 2014    Key Record Dates
Last Update Posted: March 12, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: This plan is in process, to be finalized prior to the end of recruitment.
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Rifampin
Rifabutin
Isoniazid
Pyrazinamide
Ethambutol
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents