Pulmonary Tuberculosis
Conditions
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.
Interventions
DRUGIsoniazid
300 mg QD
DRUGPA-824
200 mg QD
DRUGRifampin
600 mg QD
DRUGRifabutin
300 mg QD
DRUGPyrazinamide
25mg/kg QD
DRUGEthambutol
15mg/kg QD
Sponsors
University of Cape Town
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Sputum Culture Conversion on Liquid Medium | 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 | 12 weeks | Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | 8 weeks | Percentage of participants whose sputum converts from positive to negative at Week 8 time point, on solid and liquid media. |
| Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin | 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. |
| Number of Participants With Permanent Discontinuation of Assigned Study Regimen | 12 weeks | If it is in the best interest of a participant to stop the study regimen for any reason |
| Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks | 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). |
| PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment | 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. |
| Time to Culture Conversion on Solid Medium | 12 weeks | The time (days) it takes for the sputum to convert form positive to negative on solid medium |
Countries
South Africa
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 56 |
| 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 | 53 |
| 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 | 48 |
| Total | 157 |
Baseline characteristics
| Characteristic | Total | Arm 3 | Arm 2 | Arm 1 |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 157 Participants | 48 Participants | 53 Participants | 56 Participants |
| Age, Continuous | 31 years | 31 years | 30 years | 32 years |
| Race/Ethnicity, Customized Black | 102 Participants | 29 Participants | 35 Participants | 38 Participants |
| Race/Ethnicity, Customized Colored | 54 Participants | 18 Participants | 18 Participants | 18 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 39 Participants | 9 Participants | 17 Participants | 13 Participants |
| Sex: Female, Male Male | 118 Participants | 39 Participants | 36 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 53 | 0 / 48 |
| other Total, other adverse events | 3 / 56 | 3 / 53 | 2 / 48 |
| serious Total, serious adverse events | 3 / 56 | 4 / 53 | 0 / 48 |
Outcome results
Primary
Number of Participants With Grade 3 or Higher Adverse Events
Any Grade 3 event according to the Division of AIDS (DAIDS) toxicity table
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 | Number of Participants With Grade 3 or Higher Adverse Events | 3 Participants |
| Arm 2 | Number of Participants With Grade 3 or Higher Adverse Events | 6 Participants |
| Arm 3 | Number of Participants With Grade 3 or Higher Adverse Events | 2 Participants |
Primary
Time to Sputum Culture Conversion on Liquid Medium
The time (days) it takes for the sputum to convert from positive to negative.
Time frame: 12 weeks
Population: 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)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Time to Sputum Culture Conversion on Liquid Medium | Time to culture conversion (mITT) | 42 days |
| Arm 1 | Time to Sputum Culture Conversion on Liquid Medium | Time to culture conversion (per protocol) | 42 days |
| Arm 2 | Time to Sputum Culture Conversion on Liquid Medium | Time to culture conversion (mITT) | 28 days |
| Arm 2 | Time to Sputum Culture Conversion on Liquid Medium | Time to culture conversion (per protocol) | 28 days |
| Arm 3 | Time to Sputum Culture Conversion on Liquid Medium | Time to culture conversion (mITT) | 56 days |
| Arm 3 | Time to Sputum Culture Conversion on Liquid Medium | Time to culture conversion (per protocol) | 56 days |
Comparison: modified intention to treat (mITT) analysisp-value: 0.195% CI: [0.93, 2.12]Regression, Cox
Comparison: mITT analysisp-value: 0.00395% CI: [1.24, 2.87]Regression, Cox
Comparison: per protocolp-value: 0.0995% CI: [0.95, 2.15]Regression, Cox
Comparison: per protocolp-value: 0.00595% CI: [1.21, 2.89]Regression, Cox
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
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 | Number of Participants With Permanent Discontinuation of Assigned Study Regimen | 2 Participants |
| Arm 2 | Number of Participants With Permanent Discontinuation of Assigned Study Regimen | 7 Participants |
| Arm 3 | Number of Participants With Permanent Discontinuation of Assigned Study Regimen | 0 Participants |
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.
Time frame: 8 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 | Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Liquid media | 79 percentage of participants |
| Arm 1 | Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Solid media | 98 percentage of participants |
| Arm 2 | Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Liquid media | 89 percentage of participants |
| Arm 2 | Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Solid media | 100 percentage of participants |
| Arm 3 | Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Liquid media | 69 percentage of participants |
| Arm 3 | Percentage of Participants With Sputum Culture Conversion by 8 Weeks of Treatment | Solid media | 96 percentage of participants |
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.
Time frame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
Population: This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment | 2.03 mg/L | Standard Deviation 0.51 |
| Arm 2 | PK (Cmax) of PA-824 at 200 mg Once Daily With Rifampin or Rifabutin-containing Treatment | 2.69 mg/L | Standard Deviation 0.82 |
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).
Time frame: 12 weeks
Population: This outcome was measured among all participants receiving study drug (PA-824), as one group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Relationship Between PA-824 Exposure (AUC) and Rate of Change in Time to Positivity (TTP) Over 12 Weeks | 9.4 % increase/10 unit increase PA-824 AUC |
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.
Time frame: pre-dose and 1, 2, 5, 8, and 24 hours post-dose on Day 14
Population: This outcome was not assessed in Arm 3, because no participants received PA-824 in Arm 3.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin | 31.91 mg*h/L | Standard Deviation 9.87 |
| Arm 2 | Steady State Pharmacokinetics (PK) (AUC) of PA-824 When Given With Rifampin or Rifabutin | 59.05 mg*h/L | Standard Deviation 13.3 |
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
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm 1 | Time to Culture Conversion on Solid Medium | Time to conversion on solid culture (mITT) | 28 days |
| Arm 1 | Time to Culture Conversion on Solid Medium | Time to conversion on solid culture (per protocol) | 28 days |
| Arm 2 | Time to Culture Conversion on Solid Medium | Time to conversion on solid culture (mITT) | 21 days |
| Arm 2 | Time to Culture Conversion on Solid Medium | Time to conversion on solid culture (per protocol) | 21 days |
| Arm 3 | Time to Culture Conversion on Solid Medium | Time to conversion on solid culture (mITT) | 42 days |
| Arm 3 | Time to Culture Conversion on Solid Medium | Time to conversion on solid culture (per protocol) | 42 days |
Comparison: mITT analysisp-value: 0.0295% CI: [1.07, 2.44]Regression, Cox
Comparison: mITT analysisp-value: 0.00695% CI: [1.18, 2.75]Regression, Cox
Comparison: per protocol analysisp-value: 0.0395% CI: [1.05, 2.42]Regression, Cox
Comparison: per protocol analysisp-value: 0.00795% CI: [1.18, 2.85]Regression, Cox