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| ID | Type | Description | Link |
|---|---|---|---|
| #FD-R-004794-01 | Other Identifier | Office of Orphan Products Development (OOPD) |
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| Name | Class |
|---|---|
| University of Cape Town | OTHER |
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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)
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| 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 |
|
| 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| PA-824 | Drug | 200 mg QD |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Sputum Culture Conversion on Liquid Medium | 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 | Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 12 weeks |
| Time to Culture Conversion on Solid Medium |
Not provided
Inclusion Criteria:
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:
More than five days of treatment directed against active tuberculosis in the past 6 months -
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| Name | Affiliation | Role |
|---|---|---|
| Kelly E Dooley, MD PhD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Cape Town Lung Institute | Cape Town | South Africa |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36455068 | Derived | 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. | |
| 33229425 |
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This plan is in process, to be finalized prior to the end of recruitment.
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Within one year of reaching recruitment goals.
This plan is in process, to be finalized prior to the end of recruitment.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 PA-824: 200 mg QD Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD |
| FG001 | 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 PA-824: 200 mg QD Rifabutin: 300 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD |
| FG002 | 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 Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Ethambutol: 15mg/kg QD Isoniazid: 300 mg QD |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 PA-824: 200 mg QD Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Sputum Culture Conversion on Liquid Medium | The time (days) it takes for the sputum to convert from positive to negative. | Adult (> 18 years) drug sensitive pulmonary TB patients with weight 40 - 80 kg, HIV Negative or Positive with CD4 > 350, not on antiretroviral therapy (ART) | Posted | Median | Inter-Quartile Range | days | 12 weeks |
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 PA-824: 200 mg QD Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumothorax | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Low hemoglobin | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kelly Dooley | Vanderbilt University | (615) 322-8972 | kelly.e.dooley@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 7, 2018 | May 1, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | May 28, 2020 | Apr 25, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D014397 | Tuberculosis, Pulmonary |
| ID | Term |
|---|---|
| D014376 | Tuberculosis |
| D009164 | Mycobacterium Infections |
| D000193 | Actinomycetales Infections |
| D016908 | Gram-Positive Bacterial Infections |
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| ID | Term |
|---|---|
| C410767 | pretomanid |
| D012293 | Rifampin |
| D017828 | Rifabutin |
| D011718 | Pyrazinamide |
| D004977 | Ethambutol |
| D007538 | Isoniazid |
| ID | Term |
|---|---|
| D012294 | Rifamycins |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Rifampin | Drug | 600 mg QD |
|
| Rifabutin | Drug | 300 mg QD |
|
| Pyrazinamide | Drug | 25mg/kg QD |
|
| Ethambutol | Drug | 15mg/kg QD |
|
| Isoniazid | Drug | 300 mg QD |
|
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 | 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 | 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 | 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 | 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 |
| Derived |
| 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. |
| 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 PA-824: 200 mg QD Rifabutin: 300 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD |
| BG002 | 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 Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Ethambutol: 15mg/kg QD Isoniazid: 300 mg QD |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Age, Categorical | Count of Participants | Participants |
|
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 PA-824: 200 mg QD Rifabutin: 300 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD |
| OG002 | 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 Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Ethambutol: 15mg/kg QD Isoniazid: 300 mg QD |
|
|
|
| Primary | Number of Participants With Grade 3 or Higher Adverse Events | Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table | Posted | Count of Participants | Participants | 12 weeks |
|
|
|
| Secondary | 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 | Posted | Count of Participants | Participants | 12 weeks |
|
|
|
| Secondary | Time to Culture Conversion on Solid Medium | The time (days) it takes for the sputum to convert form positive to negative on solid medium | Posted | Median | Inter-Quartile Range | days | 12 weeks |
|
|
|
|
| Secondary | 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. | Posted | Number | percentage of participants | 8 weeks |
|
|
|
| Secondary | 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. | This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3. | Posted | Mean | Standard Deviation | mg*h/L | pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14 |
|
|
|
| Secondary | 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. | This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3. | Posted | Mean | Standard Deviation | mg/L | pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14 |
|
|
|
| Secondary | 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). | This outcome was measured among all participants receiving study drug (PA-824), as one group. | Posted | Number | 95% Confidence Interval | % increase/10 unit increase PA-824 AUC | 12 weeks |
|
|
|
| 0 |
| 56 |
| 3 |
| 56 |
| 3 |
| 56 |
| EG001 | 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 PA-824: 200 mg QD Rifabutin: 300 mg QD Pyrazinamide: 25mg/kg QD Isoniazid: 300 mg QD | 0 | 53 | 4 | 53 | 3 | 53 |
| EG002 | 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 Rifampin: 600 mg QD Pyrazinamide: 25mg/kg QD Ethambutol: 15mg/kg QD Isoniazid: 300 mg QD | 0 | 48 | 0 | 48 | 2 | 48 |
| Pleuritic chest pain | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Deep vein thrombosis | Vascular disorders | Non-systematic Assessment |
|
| Hemoptysis | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Increased liver enzymes | Hepatobiliary disorders | Systematic Assessment |
|
| Drug induced liver injury | Hepatobiliary disorders | Systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
|
| Increased blood pressure | Cardiac disorders | Systematic Assessment |
|
Not provided
Not provided
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D047029 | Lactams, Macrocyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D005029 | Ethylenediamines |
| D003959 | Diamines |
| D011073 | Polyamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D006834 | Hydrazines |
| D007539 | Isonicotinic Acids |
| D000147 | Acids, Heterocyclic |
| D011725 | Pyridines |
|
| Regression, Cox |
adjusted for age and sex at birth |
| 0.006 |
| Hazard Ratio (HR) |
| 1.80 |
| 2-Sided |
| 95 |
| 1.18 |
| 2.75 |
| Superiority |
| per protocol analysis | Regression, Cox | adjusted for age and sex at birth | 0.03 | Hazard Ratio (HR) | 1.60 | 2-Sided | 95 | 1.05 | 2.42 | Superiority |
| per protocol analysis | Regression, Cox | adjusted for age and sex at birth | 0.007 | Hazard Ratio (HR) | 1.84 | 2-Sided | 95 | 1.18 | 2.85 | Superiority |
| Title | Measurements |
|---|---|
|