Clinical trial NCT02256696: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Tuberculosis
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: University of Cape Town
First posted: 2014-10-06
Enrollment: 157
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 -

Primary outcomes:
measure: Time to Sputum Culture Conversion on Liquid Medium
timeFrame: 12 weeks
measure: Number of Participants With Grade 3 or Higher Adverse Events
timeFrame: 12 weeks
Secondary outcomes:
measure: Number of Participants With Permanent Discontinuation of Assigned Study Regimen
timeFrame: 12 weeks
measure: Time to Culture Conversion on Solid Medium
timeFrame: 12 weeks
measure: Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment
timeFrame: 8 weeks
measure: Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin
timeFrame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
measure: PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment
timeFrame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
measure: Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: University of Cape Town Lung Institute
Study officials:
affiliation: Johns Hopkins University
name: Kelly E Dooley, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.