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Study of a Single Dose of Pretomanid Added to an Optimized Background Regimen in Children With Rifampicin-Resistant Tuberculosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05586230
Recruitment Status : Not yet recruiting
First Posted : October 19, 2022
Last Update Posted : March 22, 2023
Sponsor:
Collaborators:
Global Alliance for TB Drug Development
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Description
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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).

Condition or disease Intervention/treatment Phase
Tuberculosis Rifampicin Resistant Tuberculosis Drug: Pretomanid Drug: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB Phase 1

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. 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, Tanzania, 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : April 15, 2023
Estimated Primary Completion Date : June 1, 2025
Estimated Study Completion Date : June 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis
Drug Information available for: Pretomanid

Arms and Interventions
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Arm Intervention/treatment
Experimental: Group 1 (≥ 31 kg)

≥40 kg (Adult Formulation)

31-<40 kg (Dispersible Pediatric Formulation)

 Drug: Pretomanid
Administered orally based on participant's weight
Other Name: Pa

Drug: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB
Non-study prescribed OBR will vary according to local, national and/or international guidelines for treatment of children with MDR-TB. Administered in addition to single dose of Pa.
Experimental: Group 2 (20-<31 kg)
20-<31 kg (Dispersible pediatric Formulation)
 Drug: Pretomanid
Administered orally based on participant's weight
Other Name: Pa

Drug: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB
Non-study prescribed OBR will vary according to local, national and/or international guidelines for treatment of children with MDR-TB. Administered in addition to single dose of Pa.
Experimental: Group 3 (12-<20 kg)
12-<20 kg (Dispersible pediatric Formulation)
 Drug: Pretomanid
Administered orally based on participant's weight
Other Name: Pa

Drug: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB
Non-study prescribed OBR will vary according to local, national and/or international guidelines for treatment of children with MDR-TB. Administered in addition to single dose of Pa.
Experimental: Group 4 (4-<12 kg)

8-<12 kg (Dispersible pediatric Formulation)

6-<8 kg (Dispersible pediatric Formulation)

4-<6 kg (Dispersible pediatric Formulation)

 Drug: Pretomanid
Administered orally based on participant's weight
Other Name: Pa

Drug: Optimized background regimen (OBR) for multidrug-resistant TB (MDR-TB
Non-study prescribed OBR will vary according to local, national and/or international guidelines for treatment of children with MDR-TB. Administered in addition to single dose of Pa.


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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 Outcome Measures :
  1. Number of participants with an adverse event [ Time Frame: From time of single Pa dose at study entry to study week 2 ]
  2. Number of participants with a Grade 3 or higher adverse event assessed as related to study drug [ Time Frame: From time of single Pa dose at study entry to study week 2 ]
  3. Number of participants with a grade 2 or higher adverse event [ Time Frame: From time of single Pa dose at study entry to study week 2 ]
  4. Number of participants with a serious adverse event [ Time Frame: From time of single Pa dose at study entry to study week 2 ]
  5. 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 [ Time Frame: At day 0 ]
    Based on questionnaire responses


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  • 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
      • Rifampicin resistance demonstrated by genotypic (molecular) or phenotypic methods
      • Documented clinical decision to treat for RR-TB

Note: In the case of discrepant genotypic and phenotypic test results (i.e., rifampicin-susceptible by one method and rifampicin-resistant by another), this criterion will be considered to have been met if at least one rifampicin-resistant result is available and the participant is assessed as having RR-TB by the non-study care provider when study staff evaluate the participant for eligibility.

  • Probable intrathoracic (pulmonary) RR-TB, based on chest radiograph and/or symptoms consistent with TB, and/or any form of extrathoracic TB, with both of the following, as determined by the site investigator based on medical records:

    • Documented exposure to a source case with bacteriologically-confirmed intrathoracic rifampicin-resistant TB
    • Documented clinical decision to treat for RR-TB

Note: Full resistance profiles may be obtained after study entry.

  • Initiated an appropriate TB OBR treatment regimen as per routine treatment decision, at least two weeks prior to entry, as determined by the site investigator based on medical records, and is tolerating the regimen well at entry, in the opinion of the site investigator

Note: see exclusion criterion below for exclusionary TB medications

  • Has normal, grade 1, or grade 2 results for all of the following at screening (i.e., from specimens collected within 28 days prior to entry), based on grading per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table; refer to protocol for guidance on severity grading):

    • Creatinine
    • Platelets
    • Absolute neutrophil count
    • Hemoglobin
    • Estimated glomerular filtration rate (eGFR; bedside Schwartz formula)

Note: Laboratory tests may be repeated during the study screening period (i.e., within 28 days prior to entry), with the latest results used for eligibility determination.

  • Has normal or grade 1 results for all of the following at screening (i.e., from specimens collected within 28 days prior to entry), based on grading per the DAIDS AE Grading Table (refer to protocol for guidance on severity grading):

    • Alanine aminotransferase (ALT)
    • Lipase
    • Total bilirubin

Note: Laboratory tests may be repeated during the study screening period (i.e., within 28 days prior to entry), with the latest results used for eligibility determination.

  • Has a normal QT interval corrected by Fridericia's formula (QTcF) (mean interval value less than 450 milliseconds, on ECG performed in triplicate) at screening

Note: The mean QTcF value obtained from the centralized ECG reading must be used for eligibility determination.

  • Has a Karnofsky score greater than or equal to 50% for participants 16 years of age and older or Lansky play score greater than or equal to 50% for participants less than 16 years of age, at screening

  • Does not have severe acute malnutrition, defined below, and has no presence of nutritional edema, based on physical examination, at screening

    • Severe acute malnutrition is defined as any of the following:

      • For participants 5 years of age and younger: weight-for-height z-score less than -3, according to WHO growth standards
      • For participants 6 months to 5 years of age: mid-upper arm circumference (MUAC) less than 115 mm
      • For participants older than 5 years of age: BMI z-score less than -3, according to WHO growth standards

Note: Children who are stunted may be enrolled.

  • HIV status determined based on testing methods meeting the requirements specified in protocol
  • For participants living with HIV, has been taking a stable ARV regimen for at least two consecutive weeks at entry, as determined by the site investigator based on participant and parent/guardian report and available medical records

Note: Dose and formulation changes (e.g., for growth) within the two weeks prior to entry are permitted. See below for exclusionary ARVs.

  • For participants who have reached menarche or who are engaging in sexual activity (self-reported): not pregnant based on testing performed during the study screening period (i.e., within 28 days prior to entry)
  • For participants who are engaging in sexual activity (self-reported): agrees to use at least one effective, medically accepted birth control method while on study, based on participant and parent/guardian report at entry
  • Expected to be available for two weeks of study participation, based on participant and parent/guardian report at entry

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
    • Significant cardiac arrhythmia that requires medication or increases the risk for Torsade de Pointes
    • Known allergy or hypersensitivity to pretomanid or other nitroimidazole compounds
    • Known porphyria
  • Currently breastfeeding an infant at entry, as determined by the site investigator based on participant/parent/guardian report
  • Exposed to pretomanid through breast milk within seven days prior to entry (i.e., mother receiving pretomanid and breastfeeding a potential participant), as determined by the site investigator based on parent/guardian report
  • Has any documented or suspected clinically significant medical condition or any other condition that, in the opinion of the site investigator, would make participation in the study unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05586230


Contacts
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Contact: IMPAACT Clinicaltrials.gov Coordinator impaact.ctgov@fstrf.org
Contact: Katie McCarthy (919) 321-3326 kmccarthy@fhi360.org

Locations
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Brazil
Site 5071, Instituto de Puericultura e Pediatria Martagao Gesteira CRS
Rio De Janeiro, Brazil
Contact: Lorna Pestana    +55 21 968968383    lorena.pestana@gmail.com   
India
Site 31441, BJMC CRS
Pune, India
Contact: Mandar Paradkar    +91 9823457325    mparadk1@jh.edu   
South Africa
Site 31790, Desmond Tutu TB Centre (DTTC) CRS
Cape Town, South Africa
Contact: Mapule Mosidi    +27 21 510 1331    mmosidi@sun.ac.za   
Site 31929, Sizwe CRS
Johannesburg, South Africa
Contact: Linah Baloyi    +27 78 206 9092    lbaloyi@witshealth.co.za   
Site 31976, PHRU Matlosana CRS
Matlosana Klerksdorp, South Africa
Contact: Itumeleng Holele    +27 18 011 3822    holelei@phru.co.za   
Tanzania
Site 5118, Kilimanjaro Christian Medical Center (KCMC)
Moshi, Tanzania
Contact: Winfrida Shirima    +255693550264    winshirima2015@gmail.com   
Thailand
Site 5115, Siriraj Hospital, Mahidol University NICHD CRS
Bangkok Noi, Thailand
Contact: Puangphet Songsirithat    +66-2-866-0225;    puangphet.song@gmail.com   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Global Alliance for TB Drug Development
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
Investigators
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Study Chair: Ethel Weld Johns Hopkins University
More Information
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Additional Information:

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT05586230    
Other Study ID Numbers: IMPAACT 2034
38754 ( Other Identifier: DAIDS )
First Posted: October 19, 2022    Key Record Dates
Last Update Posted: March 22, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie results in the publication, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
Access Criteria:
  • With whom?
  • Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network.
  • For what types of analyses?
  • To achieve aims in the proposal approved by the IMPAACT Network.
  • By what mechanism will data be made available?
  • Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https:// www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
 Bacterial Infections
Bacterial Infections and Mycoses
Infections