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Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV

Primary Purpose

Tuberculosis, HIV

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Bedaquiline
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis

Eligibility Criteria

0 Months - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Parent/legal guardian willing and able to provide written informed consent for study participation; in addition, when applicable per local Institutional Review Board (IRB)/Ethics Committee (EC) policies and procedures, participant is willing and able to provide written assent for study participation.
  • Age at enrollment:

    • Cohort 1: 6 years of age or older but younger than 18 years of age
    • Cohort 2: 2 years of age or older but younger than 6 years of age
    • Cohort 3: 0 months of age or older but younger than 2 years of age
  • Weight at enrollment:

    • Cohort 1: At least 15 kg
    • Cohort 2: At least 7 kg
    • Cohort 3: At least 3 kg
  • Documented HIV status as defined in the protocol for HIV-infected participants and HIV-uninfected participants.
  • Either confirmed or probable multi-drug resistant tuberculosis (MDR-TB): Confirmed intra-thoracic (pulmonary) MDR-TB, and/or any of the following forms of extrathoracic tuberculosis (TB):

    • Peripheral TB lymphadenitis
    • Pleural effusion or fibrotic pleural lesions
    • Stage 1 TB meningitis
    • Miliary and abdominal TB,
    • Other non-disseminated forms of TB disease
    • More information on this criterion can be found in the protocol.
  • Initiated on an optimized background MDR-TB regimen as per routine treatment decision, at least two weeks but not more than 12 weeks prior to enrollment, and tolerating the regimen well at enrollment.
  • If HIV-infected: Initiated an acceptable antiretroviral therapy (ART) regimen defined as zidovudine (ZDV) + lamivudine (3TC) + abacavir (ABC), nevirapine (NVP) + 2 nucleoside reverse transcriptase inhibitors (NRTIs), or an additional integrase class drug including raltegravir, dolutegravir, or another regimen approved in advance by the protocol team and study sponsor at least two weeks prior to enrollment.
  • If male and engaging in sexual activity that could lead to pregnancy of the female partner: Agrees to use a barrier method of contraception (i.e., male condom) throughout the first 28 weeks on study (i.e., until four weeks after discontinuation of bedaquiline [BDQ]).
  • If female and of reproductive potential, defined as having reached menarche and not having undergone a documented sterilization procedure (hysterectomy, bilateral oophorectomy, or salpingotomy): Negative pregnancy test at screening within 48 hours prior to enrollment.
  • If female, of reproductive potential (defined in the protocol), and engaging in sexual activity that could lead to pregnancy: Agrees to avoid pregnancy and to use at least two of the following contraception methods throughout the entire period of study participation: condoms, diaphragm or cervical cap, intrauterine contraceptive device (IUCD), hormonal-based contraception. It is required that the method would have had to be initiated at the time of study entry.
  • Among Cohort 3 participants, no documentation that estimated gestational age at birth was less than 37 weeks. Note: Infants born to HIV-infected women will be eligible for enrollment in Cohort 3 regardless of feeding mode and receipt of antiretroviral drugs (ARVs) for prevention of perinatal transmissions.

Exclusion Criteria:

  • A clinically significant active medical condition or concomitant severe (Grade 3 or higher) illness or rapidly deteriorating health condition (excluding TB), including immune deficiency (excluding HIV infection), which, in the opinion of the site investigator, would be worsened by participation in the study or would prevent appropriate participation in the trial, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the participant a poor candidate for a clinical trial.
  • Known or presumed severe extrapulmonary manifestations of TB, including Grades 2 and 3 TB meningitis, and osteo-articular TB.
  • Pregnant or lactating.
  • A significant cardiac arrhythmia that requires medication or a history of heart disease (heart failure, coronary artery disease) that increases the risk for Torsade de Pointes.
  • Mean QTcF interval of greater than 460 ms (mean value of QT interval, corrected using Fredericia correction, on electrocardiogram [ECG] performed in triplicate).
  • Clinically relevant ECG changes including but not limited to pathological Q-waves (defined as greater than 40 ms or depth greater than 0.4-0.5 mV); evidence of ventricular pre-excitation; evidence of complete or incomplete left bundle branch block or right bundle branch block; evidence of second or third degree heart block; intraventricular conduction delay with QRS duration greater than 120 ms; age-related bradycardia as defined by sinus rate less than lower limit as indicated in the protocol.
  • Known personal or family history of long QT syndrome.
  • Having a Grade 2 or higher for any of the following abnormalities at the time of screening or known within 30 days prior to enrollment according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events ("DAIDS AE Grading Table"), Corrected Version 2.1, dated July 2017:

    • Absolute neutrophil count
    • Creatinine
    • Aspartate aminotransferase (AST)
    • Alanine aminotransferase (ALT)
    • Total bilirubin, or 1.5 times upper limit of normal accompanied by Grade 2 or higher increase in liver function test (LFT)
    • Retesting and screening of the abnormalities listed above may be done as long as the screening period of 30 days is observed. The last/latest values will be used for purposes of final screening decisions.
  • Having participated in other clinical studies with investigational agents or devices, within eight weeks prior to enrollment.
  • Currently taking any of the disallowed medications specified in the protocol. If taking any disallowed medications, a "washout period" of three days or more prior to entry is required.

Sites / Locations

  • Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRSRecruiting
  • Byramjee Jeejeebhoy Medical College (BJMC) CRSRecruiting
  • Sizwe CRSRecruiting
  • PHRU Matlosana CRSRecruiting
  • Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRSRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bedaquiline (BDQ)

Arm Description

Participants will receive bedaquiline (BDQ) once a day for 2 weeks. For the next 22 weeks, participants will take BDQ 3 times a week on Monday, Wednesday, and Friday.

Outcomes

Primary Outcome Measures

Frequency of participant termination from treatment due to a drug-related adverse event
Frequency of participant termination from treatment due to a drug-related adverse event
Frequency of adverse events of ≥ Grade 3 severity
Frequency of adverse events of ≥ Grade 3 severity assessed by the Core Team to be at least possibly related to the study medication
Frequency of participants with absolute QTcF ≥ 500 msec
Frequency of unstable dysrhythmias requiring hospitalization and treatment
Incidence of death
Area Under the Curve (AUC0-24h or AUC0-168h)

Secondary Outcome Measures

Frequency of adverse events ≥ Grade 3 severity
Frequency of adverse events ≥ Grade 3 severity assessed by the Core Team to be at least possibly related to the study drug.
Frequency of participants with absolute QTcF greater than or equal to 500 msec
Frequency of unstable dysrhythmias requiring hospitalization and treatment
Incidence of death
Pharmacokinetic parameter maximal concentration
Pharmacokinetic parameter trough concentration (concentration at the end of an dosing interval)
Pharmacokinetic parameter time of maximal concentration
Pharmacokinetic parameter oral clearance
Pharmacokinetic parameter theoretical steady state AUC
Quantitative post-treatment bedaquiline concentrations
Post-treatment bedaquiline concentrations below limit of quantifications

Full Information

First Posted
September 14, 2016
Last Updated
September 25, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT02906007
Brief Title
Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV
Official Title
A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Bedaquiline (BDQ) Given in Combination With an Individualized Rifampin-Resistant Tuberculosis (RR-TB) Therapy in Infants, Children, and Adolescents With RR-TB Disease, Living With or Without HIV
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 21, 2017 (Actual)
Primary Completion Date
February 28, 2024 (Anticipated)
Study Completion Date
August 15, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
P1108 is a Phase I/II, open-label, single-arm, exposure-controlled dose finding study of BDQ in infants, children, and adolescents living with and without HIV, with clinically diagnosed or bacteriologically confirmed rifampin-resistant tuberculosis (RR-TB). The study is designed to evaluate the PK, safety, and tolerability of BDQ over 24 weeks.
Detailed Description
The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of bedaquiline (BDQ) in combination with an individualized RR-TB therapy in infants, children, and adolescents with RR-TB disease, living with or without HIV. This study will be conducted among infants, children, and adolescents less than 18 years of age treated for clinically diagnosed or bacteriologically confirmed intra-thoracic (pulmonary) RR-TB and/or selected forms of extrathoracic RR-TB. Participants will be assigned to cohorts based on age. Cohort 1 will include children six years of age or older but less than 18 years of age; Cohort 2 will include children two years of age or older but less than six years of age; and Cohort 3 will include children 0 months of age and older but less than two years of age. Cohort 1 will be divided into two weight bands, one for participants weighing 15 kg or more but less than 30 kg and one for participants weighing 30 kg or more. Cohort 2 will include participants weighing greater than 7 kg. Cohort 3 will include participants weighing at least 3 kg. Study visits will occur at enrollment (Day 0) and at Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 60, 72, and 96. Participants who exited the study before implementation of protocol Version 2.0 also had a study visit at Week 120. Participants in each cohort will take BDQ once a day for approximately two weeks. For the next 22 weeks, BDQ will be taken three times a week. Dosing for Cohorts 2 and 3 is based on data from Cohort 1. Study visits may include physical examinations, blood and urine collection, an electrocardiogram (ECG), medical history reviews, and other assessments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, HIV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
84 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Bedaquiline (BDQ)
Arm Type
Experimental
Arm Description
Participants will receive bedaquiline (BDQ) once a day for 2 weeks. For the next 22 weeks, participants will take BDQ 3 times a week on Monday, Wednesday, and Friday.
Intervention Type
Drug
Intervention Name(s)
Bedaquiline
Other Intervention Name(s)
BDQ
Intervention Description
100 mg oral tablets. In Cohorts 2 and 3 only under protocol Version 2.0, 20 mg oral dispersible tablet may alternatively be used. Doses will vary based on the participant's age and weight.
Primary Outcome Measure Information:
Title
Frequency of participant termination from treatment due to a drug-related adverse event
Description
Frequency of participant termination from treatment due to a drug-related adverse event
Time Frame
Measured through Week 24
Title
Frequency of adverse events of ≥ Grade 3 severity
Time Frame
Measured through Week 24
Title
Frequency of adverse events of ≥ Grade 3 severity assessed by the Core Team to be at least possibly related to the study medication
Time Frame
Measured through Week 24
Title
Frequency of participants with absolute QTcF ≥ 500 msec
Time Frame
Measured through Week 24
Title
Frequency of unstable dysrhythmias requiring hospitalization and treatment
Time Frame
Measured through Week 24
Title
Incidence of death
Time Frame
Measured through Week 24
Title
Area Under the Curve (AUC0-24h or AUC0-168h)
Time Frame
Week 1 or 2, Week 8, and Week 24
Secondary Outcome Measure Information:
Title
Frequency of adverse events ≥ Grade 3 severity
Time Frame
Measured through Week 96 or 72 weeks post BDQ discontinuation
Title
Frequency of adverse events ≥ Grade 3 severity assessed by the Core Team to be at least possibly related to the study drug.
Time Frame
Measured through Week 96 or 72 weeks post BDQ discontinuation
Title
Frequency of participants with absolute QTcF greater than or equal to 500 msec
Time Frame
Measured through Week 96 or 72 weeks post BDQ discontinuation
Title
Frequency of unstable dysrhythmias requiring hospitalization and treatment
Time Frame
Measured through Week 96 or 72 weeks post BDQ discontinuation
Title
Incidence of death
Time Frame
Measured through Week 96 or 72 weeks post BDQ discontinuation
Title
Pharmacokinetic parameter maximal concentration
Time Frame
Time frame: Week 1 or 2, Week 8, and Week 24
Title
Pharmacokinetic parameter trough concentration (concentration at the end of an dosing interval)
Time Frame
Week 1 or 2, Week 8, and Week 24
Title
Pharmacokinetic parameter time of maximal concentration
Time Frame
Week 1 or 2
Title
Pharmacokinetic parameter oral clearance
Time Frame
Week 24
Title
Pharmacokinetic parameter theoretical steady state AUC
Time Frame
Week 24
Title
Quantitative post-treatment bedaquiline concentrations
Time Frame
Weeks 32-96
Title
Post-treatment bedaquiline concentrations below limit of quantifications
Time Frame
Weeks 32-96

10. Eligibility

Sex
All
Minimum Age & Unit of Time
0 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Less than 18 years old. Parent/legal guardian willing and able to provide written informed consent for study participation; in addition, when applicable per local Institutional Review Board (IRB)/Ethics Committee (EC) policies and procedures, participant is willing and able to provide written assent for study participation. Age at enrollment: Cohort 1: 6 years of age or older but younger than 18 years of age Cohort 2: 2 years of age or older but younger than 6 years of age Cohort 3: 0 months of age or older but younger than 2 years of age Weight at enrollment: Cohort 1: At least 15 kg Cohort 2: Greater than 7 kg Cohort 3: At least 3 kg HIV status determined by testing requirements in the protocol. Either bacteriologically confirmed intrathoracic RR-TB or probable RR-TB and/or extrathoracic TB as listed below: Peripheral TB lymphadenitis Pleural effusion or fibrotic pleural lesions Stage 1 TBM or clinically stable Stage 2A TBM Osteoarticular TB, including spinal TB Other non-disseminated forms of TB disease More information on this criterion can be found in the protocol. Participant is on an RR-TB regimen as per local standard of care for at least seven days and not more than 12 weeks prior to entry, and tolerating the regimen well at entry, as determined by the site investigator based on available medical records. Note: Participants may have received up to seven doses of non-study BDQ during the seven days prior to study enrollment. The date and dose amount of non-study BDQ doses must be available in medical records For potential participants living with HIV: At least 14 days prior to entry, initiated an acceptable ART regimen defined as zidovudine/lamivudine/abacavir; NVP and two NRTIs; LPV/r and two NRTIs; an integrase class drug including dolutegravir or raltegravir with two NRTIs; or another regimen approved in advance by the Core Team. At entry, the participant has the following laboratory test results according to the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to the protocol for guidance on severity grading): Absolute neutrophil count (normal or grade 1) Creatinine (normal or grade 1) Aspartate Amino Transferase (AST) (normal or grade 1) Alanine Amino Transferase (ALT) (normal or grade 1) Total bilirubin (normal or grade 1) If male and engaging in sexual activity that could lead to pregnancy of the female partner: At entry, participant agrees to use a barrier method of contraception (i.e., male condom) throughout the first 28 weeks on study (i.e., until four weeks after discontinuation of bedaquiline [BDQ]). If female and of reproductive potential, defined as having reached menarche and not having undergone a documented sterilization procedure (hysterectomy, bilateral oophorectomy, or salpingotomy): Negative pregnancy test at screening within five days prior to entry. If female, of reproductive potential (defined in the protocol), and engaging in sexual activity that could lead to pregnancy: Agrees to avoid pregnancy and to use at least two of the following contraception methods throughout the entire period of study participation: condoms, diaphragm or cervical cap, intrauterine contraceptive device (IUCD), hormonal-based contraception. It is required that the method would have had to be initiated at the time of study entry. Among Cohort 3 participants, no documentation that estimated gestational age at birth was less than 37 weeks. Note: Infants born to HIV-infected women will be eligible for enrollment in Cohort 3 regardless of feeding mode and receipt of antiretroviral drugs (ARVs) for prevention of perinatal transmissions. Exclusion Criteria: A clinically significant active medical condition or concomitant severe (Grade 3 or higher) illness or rapidly deteriorating health condition (excluding TB), including immune deficiency (excluding HIV infection), which, in the opinion of the site investigator, would be worsened by participation in the study or would prevent appropriate participation in the trial, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the participant a poor candidate for a clinical trial. Known or presumed severe extrapulmonary manifestations of TB, including Stages 2B and 3 TBM as determined by the site investigator based on participant/parent/guardian report and/or available medical records. Pregnant or lactating. A significant cardiac arrhythmia that requires medication or a history of heart disease (heart failure, coronary artery disease) that increases the risk for Torsade de Pointes as determined by the site investigator based on participant/parent/guardian report and available medical records. Mean QTcF interval of greater than 460 ms (mean value of QT interval, corrected using Fredericia correction, on electrocardiogram [ECG] performed in triplicate). Clinically relevant ECG changes including but not limited to pathological Q-waves (defined as greater than 40 ms or depth greater than 0.4-0.5 mV); evidence of ventricular pre-excitation; evidence of complete or incomplete left bundle branch block or right bundle branch block; evidence of second or third degree heart block; intraventricular conduction delay with QRS duration greater than 120 ms; age-related bradycardia as defined by sinus rate less than lower limit as indicated in the protocol. Known personal or family history of long QT syndrome. Having participated in other clinical studies with investigational agents or devices, within eight weeks prior to enrollment. Currently taking any of the disallowed medications specified in the protocol. If taking any disallowed medications, a "washout period" of three days or more prior to entry is required.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anneke Hesseling, M.D., Ph.D.
Organizational Affiliation
Desmond Tutu TB Centre, Stellenbosch University
Official's Role
Study Chair
Facility Information:
Facility Name
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
City
Port-au-Prince
ZIP/Postal Code
HT-6110
Country
Haiti
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Samuel Pierre
Phone
509-29-426327
Email
spierre@gheskio.org
Facility Name
Byramjee Jeejeebhoy Medical College (BJMC) CRS
City
Pune
State/Province
Maharashtra
ZIP/Postal Code
411001
Country
India
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nishi Suryavanshi, Ph.D.
Phone
91-98-23248979
Email
nishi@jhumitpune.com
Facility Name
Sizwe CRS
City
Johannesburg
State/Province
Gauteng
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Linah Mutshinya
Phone
27-11-8823912
Email
lbaloyi@witshealth.co.za
Facility Name
PHRU Matlosana CRS
City
Klerksdorp
State/Province
North West Province
ZIP/Postal Code
2574
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tumelo Moloantoa, MD
Phone
27-18-4653751
Email
moloantoat@phru.co.za
Facility Name
Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS
City
Cape Town
State/Province
Western Cape Province
ZIP/Postal Code
7505
Country
South Africa
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeannine du Bois
Phone
27-219389772
Email
dubois@sun.ac.za

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV

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