Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis, Living With or Without HIV
- Conditions
- TuberculosisHIV
Recruitment & Eligibility
- Status
- Active, not recruiting
- Sex
- All
- Target Recruitment
- Not specified
Inclusion Criteria:<br><br> - Less than 18 years old.<br><br> - Parent/legal guardian willing and able to provide written informed consent for study<br> participation; in addition, when applicable per local Institutional Review Board<br> (IRB)/Ethics Committee (EC) policies and procedures, participant is willing and able<br> to provide written assent for study participation.<br><br> - Age at enrollment:<br><br> - Cohort 1: 6 years of age or older but younger than 18 years of age<br><br> - Cohort 2: 2 years of age or older but younger than 6 years of age<br><br> - Cohort 3: 0 months of age or older but younger than 2 years of age<br><br> - Weight at enrollment:<br><br> - Cohort 1: At least 15 kg<br><br> - Cohort 2: Greater than 7 kg<br><br> - Cohort 3: At least 3 kg<br><br> - HIV status determined by testing requirements in the protocol.<br><br> - Either bacteriologically confirmed intrathoracic RR-TB or probable RR-TB and/or<br> extrathoracic TB as listed below:<br><br> - Peripheral TB lymphadenitis<br><br> - Pleural effusion or fibrotic pleural lesions<br><br> - Stage 1 TBM or clinically stable Stage 2A TBM<br><br> - Osteoarticular TB, including spinal TB<br><br> - Other non-disseminated forms of TB disease<br><br> - More information on this criterion can be found in the protocol.<br><br> - Participant is on an RR-TB regimen as per local standard of care for at least seven<br> days and not more than 12 weeks prior to entry, and tolerating the regimen well at<br> entry, as determined by the site investigator based on available medical records.<br><br>Note: Participants may have received up to seven doses of non-study BDQ during the seven<br>days prior to study enrollment. The date and dose amount of non-study BDQ doses must be<br>available in medical records<br><br> - For potential participants living with HIV: At least 14 days prior to entry,<br> initiated an acceptable ART regimen defined as zidovudine/lamivudine/abacavir; NVP<br> and two NRTIs; LPV/r and two NRTIs; an integrase class drug including dolutegravir<br> or raltegravir with two NRTIs; or another regimen approved in advance by the Core<br> Team.<br><br> - At entry, the participant has the following laboratory test results according to the<br> DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to<br> the protocol for guidance on severity grading):<br><br> - Absolute neutrophil count (normal or grade 1)<br><br> - Creatinine (normal or grade 1)<br><br> - Aspartate Amino Transferase (AST) (normal or grade 1)<br><br> - Alanine Amino Transferase (ALT) (normal or grade 1)<br><br> - Total bilirubin (normal or grade 1)<br><br> - If male and engaging in sexual activity that could lead to pregnancy of the female<br> partner: At entry, participant agrees to use a barrier method of contraception<br> (i.e., male condom) throughout the first 28 weeks on study (i.e., until four weeks<br> after discontinuation of bedaquiline [BDQ]).<br><br> - If female and of reproductive potential, defined as having reached menarche and not<br> having undergone a documented sterilization procedure (hysterectomy, bilateral<br> oophorectomy, or salpingotomy): Negative pregnancy test at screening within five<br> days prior to entry.<br><br> - If female, of reproductive potential (defined in the protocol), and engaging in<br> sexual activity that could lead to pregnancy: Agrees to avoid pregnancy and to use<br> at least two of the following contraception methods throughout the entire period of<br> study participation: condoms, diaphragm or cervical cap, intrauterine contraceptive<br> device (IUCD), hormonal-based contraception. It is required that the method would<br> have had to be initiated at the time of study entry.<br><br> - Among Cohort 3 participants, no documentation that estimated gestational age at<br> birth was less than 37 weeks. Note: Infants born to HIV-infected women will be<br> eligible for enrollment in Cohort 3 regardless of feeding mode and receipt of<br> antiretroviral drugs (ARVs) for prevention of perinatal transmissions.<br><br>Exclusion Criteria:<br><br> - A clinically significant active medical condition or concomitant severe (Grade 3 or<br> higher) illness or rapidly deteriorating health condition (excluding TB), including<br> immune deficiency (excluding HIV infection), which, in the opinion of the site<br> investigator, would be worsened by participation in the study or would prevent<br> appropriate participation in the trial, or that would make implementation of the<br> protocol or interpretation of the study results difficult, or otherwise make the<br> participant a poor candidate for a clinical trial.<br><br> - Known or presumed severe extrapulmonary manifestations of TB, including Stages 2B<br> and 3 TBM as determined by the site investigator based on<br> participant/parent/guardian report and/or available medical records.<br><br> - Pregnant or lactating.<br><br> - A significant cardiac arrhythmia that requires medication or a history of heart<br> disease (heart failure, coronary artery disease) that increases the risk for Torsade<br> de Pointes as determined by the site investigator based on<br> participant/parent/guardian report and available medical records.<br><br> - Mean QTcF interval of greater than 460 ms (mean value of QT interval, corrected<br> using Fredericia correction, on electrocardiogram [ECG] performed in triplicate).<br><br> - Clinically relevant ECG changes including but not limited to pathological Q-waves<br> (defined as greater than 40 ms or depth greater than 0.4-0.5 mV); evidence of<br> ventricular pre-excitation; evidence of complete or incomplete left bundle branch<br> block or right bundle branch block; evidence of second or third degree heart block;<br> intraventricular conduction delay with QRS duration greater than 120 ms; age-related<br> bradycardia as defined by sinus rate less than lower limit as indicated in the<br> protocol.<br><br> - Known personal or family history of long QT syndrome.<br><br> - Having participated in other clinical studies with investigational agents or<br> devices, within eight weeks prior to enrollment.<br><br> - Currently taking any of the disallowed medications specified in the protocol. If<br> taking any disallowed medications, a washout period of three days or more prior to<br> entry is required.
Not provided
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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
Name Time Method 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