Phase I Study of the Pharmacokinetics, Safety, and Acceptability of a Single Dose of Pretomanid Added to an Optimized Background Regimen in Children With Rifampicin-Resistant Tuberculosis
Overview
- Phase
- Phase 1
- Intervention
- Pretomanid
- Conditions
- Tuberculosis
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 72
- Locations
- 6
- Primary Endpoint
- AUC0-48
- Status
- Recruiting
- Last Updated
- last month
Overview
Brief Summary
The purpose of the study is to evaluate the pharmacokinetics (PK), safety, tolerability, and acceptability of a single dose of pretomanid, added to an optimized background tuberculosis treatment regimen (OBR), in children with rifampicin-resistant tuberculosis (RR-TB) with or without human immunodeficiency virus (HIV).
Detailed Description
This is a Phase I, multi-site, open-label, non-comparative study of the PK, safety, tolerability, and acceptability of a single-dose of pretomanid added to an OBR in infants, children, and adolescents with RR-TB. The term children is used within the protocol to indicate the total age range from infants through adolescents; enrollment will be limited to children assigned female sex at birth and enrollment of neonates will be deferred until safety and pharmacokinetic data are available in older groups, pending review by the CMC and SMC during the interim analysis. Refer to the study design and the study eligibility criteria and a description of the study recruitment, screening, and enrollment process. Participants are expected to be enrolled at study sites in Brazil, India, South Africa and Thailand. Up to 72 participants will be enrolled to achieve at least nine evaluable participants in each of four weight groups, for a total of at least 36 enrolled participants. Participants will receive a single dose of pretomanid on the day of study entry. No additional doses of pretomanid will be administered; participants will continue their OBR. Intensive PK sampling and safety monitoring will be performed on the day of study entry and over the course of the next 48 hours. Participants will then complete a final study visit approximately two weeks after study entry.
Investigators
Eligibility Criteria
Inclusion Criteria
- •If not of legal age or circumstance to provide independent informed consent as determined by site standard operating procedures (SOPs) and consistent with institutional review board/ethics committee (IRB/EC) policies and procedures: Parent/legal guardian is willing and able to provide written informed consent for potential participant's study participation; in addition, when applicable per IRB/EC policies and procedures, potential participant is willing and able to provide written assent for study participation.
- •If of legal age or circumstance to provide independent informed consent as determined by site SOPs and consistent with IRB/EC policies and procedures: Potential participant is willing and able to provide written informed consent for study participation.
- •Note: All sites must follow all applicable IRB/EC policies and procedures.
- •Assigned female sex at birth, as determined by the site investigator based on participant and parent/guardian report and available medical records
- •Age less than 18 years of age at entry
- •Note: Neonates (defined as children who are 28 days of age or younger \[≤28 days of age\]) may be allowed to enroll after CMC and SMC evaluation of safety and PK data at the interim analysis.
- •Weight greater than or equal to 4 kg at entry
- •Has confirmed or probable intrathoracic (pulmonary) RR-TB and/or any form of extrathoracic (extrapulmonary) RR-TB (other than stage 2 or 3 TB meningitis, which is exclusionary)
- •Confirmed intrathoracic (pulmonary) RR-TB, based on chest radiograph and/or symptoms consistent with TB, and/or any forms of extrathoracic TB, with all of the following, as determined by the site investigator based on medical records:
- •Microbiological confirmation of M. tuberculosis from any clinical specimen by either culture or molecular methods
Exclusion Criteria
- •Has tuberculosis meningitis Stage 2 or 3, as determined by the site investigator based on medical records
- •Receipt of any of the following, within 14 days prior to entry, as determined by the site investigator based on participant/parent/guardian report and available medical records
- •Rifamycins
- •Any prohibited medication (see protocol for listing)
- •For participants living with HIV: ritonavir-boosted protease inhibitors (e.g., ritonavir-boosted lopinavir, ritonavir-boosted darunavir), atazanavir, nevirapine etravirine, efavirenz, or cobicistat
- •Receipt of any investigational agent or device within 28 days prior to entry, as determined by the site investigator based on participant/parent/guardian report and available medical records
- •Note: Co-enrollment in COVID-19 vaccine studies and receipt of a COVID-19 vaccine under emergency use authorization (or local equivalent) is allowed, with prior approval from the CMC.
- •Note: Any co-enrollment must be approved as noted in protocol
- •Has any of the following as determined by the site investigator based on participant/ parent/guardian report and available medical records
- •Clinical evidence of acute hepatitis A, B, C, or chronic hepatitis B or C
Arms & Interventions
Group 4 (4-<12 kg)
8-\<12 kg (Dispersible pediatric Formulation) 6-\<8 kg (Dispersible pediatric Formulation) 4-\<6 kg (Dispersible pediatric Formulation)
Intervention: Pretomanid
Group 1 (≥ 31 kg)
≥40 kg (Adult Formulation) 31-\<40 kg (Dispersible Pediatric Formulation)
Intervention: Pretomanid
Group 1 (≥ 31 kg)
≥40 kg (Adult Formulation) 31-\<40 kg (Dispersible Pediatric Formulation)
Intervention: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB)
Group 2 (20-<31 kg)
20-\<31 kg (Dispersible pediatric Formulation)
Intervention: Pretomanid
Group 2 (20-<31 kg)
20-\<31 kg (Dispersible pediatric Formulation)
Intervention: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB)
Group 3 (12-<20 kg)
12-\<20 kg (Dispersible pediatric Formulation)
Intervention: Pretomanid
Group 3 (12-<20 kg)
12-\<20 kg (Dispersible pediatric Formulation)
Intervention: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB)
Group 4 (4-<12 kg)
8-\<12 kg (Dispersible pediatric Formulation) 6-\<8 kg (Dispersible pediatric Formulation) 4-\<6 kg (Dispersible pediatric Formulation)
Intervention: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB)
Outcomes
Primary Outcomes
AUC0-48
Time Frame: Through 48 hours
Area under the curve from time zero to 48 hours from start of dose to 48 hours post-dose. Measured from study entry to Day 2. Blood samples were drawn at 1, 3, 6, 9, 24 and 48 hours post dose
AUC0-tlast
Time Frame: Through 48 hours
Area under curve-Last measure concentration from start of dose to 48 hours post-dose. Measured from study entry to Day 2. Blood samples were drawn at 1, 3, 6, 9, 24 and 48 hours post dose
CL/F
Time Frame: Through 48 hours
apparent clearance from start of dose to 48 hours post-dose. Measured from study entry to Day 2. Blood samples were drawn at 1, 3, 6, 9, 24 and 48 hours post dose
AUC0-∞
Time Frame: Through 48 hours
Area under the curve from start of dose to infinity from start of dose to 48 hours post-dose. Measured from study entry to Day 2. Blood samples were drawn at 1, 3, 6, 9, 24 and 48 hours post dose
Tmax
Time Frame: Through 48 hours
Time of maximal concentration from start of dose to 48 hours post-dose. Measured from study entry to Day 2. Blood samples were drawn at 1, 3, 6, 9, 24 and 48 hours post dose
Cmax
Time Frame: Through 48 hours
Peak concentration from start of dose to 48 hours post-dose. Measured from study entry to Day 2. Blood samples were drawn at 1, 3, 6, 9, 24 and 48 hours post dose
Secondary Outcomes
- Number of participants with an adverse event(From time of single Pa dose at study entry to study week 2)
- Number of participants with a Grade 3 or higher adverse event(From time of single Pa dose at study entry to study week 2)
- Number of participants with a grade 2 or higher adverse event assessed as related to study drug(From time of single Pa dose at study entry to study week 2)
- Number of participants with a serious adverse event(From time of single Pa dose at study entry to study week 2)
- Aggregated data on parent/guardian and/or participant (and/or study staff) reported palatability and acceptability of study drug given as single dose at entry(At day 0)