Pulmonary Tuberculosis
Conditions
Keywords
pulmonary tuberculosis, treatment
Brief summary
This Phase 2, multicenter, open-label clinical trial evaluated the antimicrobial activity and safety of rifapentine-containing regimens during the intensive phase of pulmonary tuberculosis treatment. Participants were randomized to receive either a standard rifampin-based regimen (RHZE) or a rifapentine-substituted regimen (PHZE). An extension study evaluated higher daily doses of rifapentine (10, 15, and 20 mg/kg). The primary endpoint was sputum culture conversion at 8 weeks. Secondary outcomes included time to culture conversion, safety, and treatment discontinuation.
Detailed description
This Phase 2, prospective, multicenter, open-label clinical trial evaluated the antimicrobial activity and safety of rifapentine-containing regimens during the intensive phase of pulmonary tuberculosis treatment. In the main study, adult participants with suspected pulmonary tuberculosis were randomized to receive either a standard intensive-phase regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE), or an experimental regimen in which rifapentine (10 mg/kg) was substituted for rifampin (PHZE). Treatment was administered five days per week under direct observation for 8 weeks. The study extension evaluated higher daily doses of rifapentine (10 mg/kg, 15 mg/kg, and 20 mg/kg) in combination with isoniazid, pyrazinamide, and ethambutol, compared to the standard rifampin-based regimen. In the extension, treatment was administered seven days per week. The primary efficacy endpoint was the proportion of participants with negative sputum cultures at completion of the intensive phase. Secondary endpoints included time to culture conversion, safety and tolerability, and rates of treatment discontinuation. Following completion of the intensive phase, participants received standard continuation-phase tuberculosis treatment per guidelines.
Interventions
DRUGrifapentine
tablet, 10 mg/kg, daily, 8 weeks
DRUGrifapentine 10 mg/kg
tablet, 10 mg/kg, daily, 8 weeks
DRUGrifapentine 15 mg/kg
tablet, 15 mg/kg, daily, 8 weeks
DRUGrifapentine 20 mg/kg
20 mg/kg, daily, 8 weeks
Sponsors
Centers for Disease Control and Prevention
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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 or induced sputum. 2. Willingness to have HIV testing performed, if HIV serostatus is not known or if the last documented negative HIV test was more than 3 months prior to enrollment. 3. 5 (five) or fewer days of multidrug therapy for tuberculosis disease in the 6 months preceding initiation of study drugs. 4. 7 (seven) or fewer days of fluoroquinolone therapy in the 30 days preceding initiation of study drugs. 5. Age \>= 18 years 6. Karnofsky score of at least 60 (requires occasional assistance but is able to care for most of his/her needs; see Appendix B) 7. Signed informed consent 8. Women of child-bearing potential must agree to practice an adequate (barrier) method of birth control or to abstain from heterosexual intercourse during study therapy. 9. Laboratory parameters done within 14 days prior to, enrollment: * Serum or plasma alanine aminotransferase (ALT) activity ≤ 3 times the upper limit of normal * Serum or plasma total bilirubin level ≤ 2.5 times the upper limit of normal * Serum or plasma creatinine level ≤ 2 times the upper limit of normal * Complete blood count with hemoglobin level of at least 7.0 g/dL * Complete blood count with platelet count of at least 100,000/mm3 * Negative pregnancy test (women of childbearing potential)
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 (INH), rifamycins, pyrazinamide (PZA), or ethambutol (EMB) are contraindicated. These include severe hepatic damage, acute liver disease of any cause, and acute uncontrolled gouty arthritis. 4. Current or planned therapy, during the intensive phase of TB therapy, with combination antiretroviral therapy for HIV, or with cyclosporine or tacrolimus. Cyclosporine and tacrolimus have unacceptable interactions with rifamycins. 5. Pulmonary silicosis 6. Central nervous system TB 7. Weight \< 40 kg or \> 85 kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Negative Sputum Culture at 8 Weeks | 8 weeks. | Proportion of participants with negative Mycobacterium tuberculosis sputum cultures at completion of the 8-week intensive phase of treatment. |
| Participants Who Discontinued Treatment During Intensive Phase | 8 weeks | Number of participants who permanently discontinued assigned study treatment for any reason during the first 8 weeks. |
Countries
Brazil, Canada, South Africa, Spain, Uganda, United States
Contacts
PRINCIPAL_INVESTIGATORSusan Dorman, MD
Johns Hopkins University
STUDY_CHAIRNeil Schluger, MD
Columbia University
STUDY_CHAIRJason Stout, MD
Duke University
Participant flow
Pre-assignment details
The Results section reports data from the TBTC Study 29 Extension dose-ranging phase only. Participants included in Participant Flow are those randomized to one of four treatment groups (rifampin, rifapentine 10 mg/kg, rifapentine 15 mg/kg, or rifapentine 20 mg/kg). The Protocol Enrollment value reflects enrollment information for the broader study record and therefore differs from the number of participants included in these reported results.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 31 years |
| HIV status HIV negative | 70 Participants |
| HIV status HIV positive | 26 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex/Gender, Customized Female | 104 participants |
| Sex/Gender, Customized Male | 230 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 85 | 0 / 85 | 0 / 81 | 0 / 81 |
| other Total, other adverse events | 0 / 85 | 0 / 85 | 0 / 81 | 0 / 81 |
| serious Total, serious adverse events | 0 / 85 | 0 / 85 | 0 / 81 | 0 / 81 |
Outcome results
None listed