Pulmonary TuberculosisPhase 2NCT02256696
Assessing PA-824 for Tuberculosis (the APT Trial)
A Phase 2 study testing PA-824, Rifampin and Rifabutin in people with Pulmonary Tuberculosis, run by Johns Hopkins University at 1 site in South Africa.
Trial 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) Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pulmonary Tuberculosis
- What is being tested?
- PA-824, Rifampin and Rifabutin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 157 participants
- Where
- 1 siteSouth Africa
- Study dates
- 29 Apr 2015to 1 May 2022
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 9Show fewer
- Ability to adhere with study follow-up
- 8 Agrees to adhere to contraceptive requirements
- -
Who cannot join
- 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
Show all 19Show fewer
- 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 -
Trial locations and contacts
1 site in 1 country.
About this study
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
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)
Read the 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.
- Conditions
- Pulmonary Tuberculosis
- Being tested
- PA-824, Rifampin, Rifabutin, Pyrazinamide, Ethambutol
- Medical subject headings
- Tuberculosis, Pulmonary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PA-824Drug
Also called Pretomanid
200 mg QD
RifampinDrug
600 mg QD
RifabutinDrug
300 mg QD
PyrazinamideDrug
25mg/kg QD
EthambutolDrug
15mg/kg QD
IsoniazidDrug
300 mg QD
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | 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 Receives: Drug: PA-824; Drug: Rifampin; Drug: Pyrazinamide; Drug: Isoniazid |
| Arm 2 | Experimental | 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 Receives: Drug: PA-824; Drug: Rifabutin; Drug: Pyrazinamide; Drug: Isoniazid |
| Arm 3 | Active comparator | 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 Receives: Drug: Rifampin; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Isoniazid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Sputum Culture Conversion on Liquid Medium
The time (days) it takes for the sputum to convert from positive to negative.
Measured: 12 weeks
Number of Participants With Grade 3 or Higher Adverse Events
Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table
Measured: 12 weeks
Secondary outcomes (6)
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
Measured: 12 weeks
Time to Culture Conversion on Solid Medium
The time (days) it takes for the sputum to convert form positive to negative on solid medium
Measured: 12 weeks
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.
Measured: 8 weeks
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.
Measured: 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
The Pharmacokinetic results (Cmax) of the study drug when given with a rifampin or a rifabutin.
Measured: 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
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).
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2014 (estimated)
- Study start29 Apr 2015
- Primary completion1 May 2022
- Study completion1 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Pulmonary TuberculosisStudies of the same condition, open and under way.
- More trials run by Johns Hopkins UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 157 participants (actual)
Sponsor and investigators
- Lead sponsor
- Johns Hopkins University
- Sponsor type
- University, hospital or other
- Collaborators
- University of Cape Town
- Responsible party
- Sponsor
- Investigators
- Kelly E Dooley, MD PhD, Principal investigator, Johns Hopkins University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02256696
- Sponsor's protocol ID
- NA_00093014
- Other IDs
- #FD-R-004794-01
- Status last verified
- May 2023
- First submitted
- 25 Sep 2014
- Last updated
- 18 Jul 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: This plan is in process, to be finalized prior to the end of recruitment.
Publications
Dooley KE, Hendricks B, Gupte N, Barnes G, Narunsky K, Whitelaw C, Smit T, Ignatius EH, Friedman A, Dorman SE, Dawson R; Assessing Pretomanid for Tuberculosis (APT) Study Team. Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results. Am J Respir Crit Care Med. 2023 Apr 1;207(7):929-935. doi: 10.1164/rccm.202208-1475OC.
PubMed 36455068Ignatius 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.
PubMed 33229425
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02256696
- Acronym / sponsor ID
- NA_00093014
- Conditions
- Pulmonary Tuberculosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 157 participants (actual)
- Lead sponsor
- Johns Hopkins UniversityUniversity, hospital or other
- Collaborators
- University of Cape Town
- Study start
- 29 Apr 2015 (actual)
- Primary completion
- 1 May 2022 (actual)
- Study completion
- 1 May 2022 (actual)
- First posted
- 6 Oct 2014 (estimated)
- Results
- Posted 18 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Drug: PA-824, Drug: Rifampin, Drug: Pyrazinamide, Drug: IsoniazidPA-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 |
| Arm 2 | Experimental | Drug: PA-824, Drug: Rifabutin, Drug: Pyrazinamide, Drug: IsoniazidPA-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 |
| Arm 3 | Active comparator | Drug: Rifampin, Drug: Pyrazinamide, Drug: Ethambutol, Drug: IsoniazidRifampin 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (19 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PA-824Also: Pretomanid200 mg QD | Drug | Arm 1, Arm 2 |
| Rifampin600 mg QD | Drug | Arm 1, Arm 3 |
| Rifabutin300 mg QD | Drug | Arm 2 |
| Pyrazinamide25mg/kg QD | Drug | Arm 1, Arm 2, Arm 3 |
| Ethambutol15mg/kg QD | Drug | Arm 3 |
| Isoniazid300 mg QD | Drug | Arm 1, Arm 2, Arm 3 |
Primary outcome
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.
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
6 secondary outcomes
Number of Participants With Permanent Discontinuation of Assigned Study Regimen
Time frame: 12 weeks
Time to Culture Conversion on Solid Medium
Time frame: 12 weeks
Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment
Time frame: 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
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
Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36455068Dooley KE, Hendricks B, Gupte N, Barnes G, Narunsky K, Whitelaw C, Smit T, Ignatius EH, Friedman A, Dorman SE, Dawson R; Assessing Pretomanid for Tuberculosis (APT) Study Team. Assessing Pretomanid for Tuberculosis (APT), a Randomized Phase 2 Trial of Pretomanid-Containing Regimens for Drug-Sensitive Tuberculosis: 12-Week Results. Am J Respir Crit Care Med. 2023 Apr 1;207(7):929-935. doi: 10.1164/rccm.202208-1475OC.
- Derived from this study: PubMed 33229425Ignatius 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.
- Individual participant dataSharing planned: Yes. This plan is in process, to be finalized prior to the end of recruitment.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kelly E Dooley, MD PhD principal investigator
Johns Hopkins University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing PA-824, Rifampin and Rifabutin in people with Pulmonary Tuberculosis, run by Johns Hopkins University at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Sputum Culture Conversion on Liquid Medium (time frame: 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02256696, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2023.