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Evaluating the Pharmacokinetics, Safety, and Tolerability of Bedaquiline in HIV-Infected and HIV-Uninfected Infants, Children, and Adolescents With Multidrug-Resistant Tuberculosis

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ClinicalTrials.gov Identifier: NCT02906007
Recruitment Status : Recruiting
First Posted : September 19, 2016
Last Update Posted : August 23, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of an antituberculosis drug, bedaquiline (BDQ), when used to treat multidrug-resistant tuberculosis (MDR-TB) in HIV-infected and HIV-uninfected infants, children, and adolescents.

Condition or disease Intervention/treatment Phase
Tuberculosis HIV Infections Drug: Bedaquiline Phase 1 Phase 2

Detailed Description:

This purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of bedaquiline (BDQ) in combination with an optimized background multidrug-resistant tuberculosis (MDR-TB) treatment regimen in HIV-infected and HIV-uninfected infants, children, and adolescents.

The study will enroll HIV-infected and HIV-uninfected children 0 to 18 years of age treated for clinically diagnosed or confirmed intrathoracic (pulmonary) MDR-TB and certain types of extrathoracic MDR-TB. Participants will be assigned to cohorts based on age. Cohort 1 will include children 6 years of age or older but less than 18 years of age; Cohort 2 will include children 2 years of age or older but less than 6 years of age; and Cohort 3 will include children 0 months of age and older but less than 2 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.

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, 96, and 120. Participants in Cohort 1 will take BDQ once a day during the first 2 weeks. For the next 22 weeks, BDQ will be taken three times a week. Dosing for Cohorts 2 and 3 will be determined 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, Open-Label, Single Arm Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Bedaquiline (BDQ) in Combination With Optimized Individualized Multidrug-Resistant Tuberculosis (MDR-TB) Therapy in HIV-Infected and HIV-Uninfected Infants, Children and Adolescents With MDR-TB Disease
Actual Study Start Date : August 18, 2017
Estimated Primary Completion Date : March 31, 2020
Estimated Study Completion Date : January 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Bedaquiline (BDQ)
Participants will receive bedaquiline (BDQ) once a day for 2 weeks. For the next 22 weeks, participants will take BDQ 3 times a week.
Drug: Bedaquiline

100 mg oral tablets.

Doses will vary based on the participant's age and weight.

Other Name: BDQ




Primary Outcome Measures :
  1. Frequency of participant termination from treatment due to a drug-related adverse event [ Time Frame: Measured through Week 24 ]
  2. Frequency of adverse events of Grade 3 or Grade 4 severity [ Time Frame: Measured through Week 24 ]
  3. Frequency of adverse events of Grade 3 or Grade 4 severity judged by the protocol team to be at least possibly related to the study medication [ Time Frame: Measured through Week 24 ]
  4. Absolute QTc interval greater than or equal to 500 msec [ Time Frame: Measured through Week 24 ]
  5. Frequency of unstable dysrhythmias requiring hospitalization and treatment [ Time Frame: Measured through Week 24 ]
  6. Incidence of death [ Time Frame: Measured through Week 24 ]

Secondary Outcome Measures :
  1. Frequency of participant termination from treatment due to a drug-related adverse event [ Time Frame: Measured through Week 120 ]
  2. Frequency of adverse events greater than or equal to Grade 3 or Grade 4 severity [ Time Frame: Measured through Week 120 ]
  3. Frequency of adverse events greater than or equal to Grade 3 or Grade 4 severity judged by the protocol team to be at least possibly related to the study medication [ Time Frame: Measured through Week 120 ]
  4. Absolute QTc interval greater than or equal to 500 msec [ Time Frame: Measured through Week 120 ]
  5. Frequency of unstable dysrhythmias requiring hospitalization and treatment [ Time Frame: Measured through Week 120 ]
  6. Incidence of death [ Time Frame: Measured through Week 120 ]


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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT02906007


Locations
Haiti
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS Recruiting
Port-au-Prince, Haiti, HT-6110
Contact: Cynthia Riviere, M.D.    509-22222241    criviere@gheskio.org   
India
Byramjee Jeejeebhoy Medical College (BJMC) CRS Recruiting
Pune, Maharashtra, India, 411001
Contact: Nishi Suryavanshi, Ph.D.    91-98-23248979    nishi@jhumitpune.com   
South Africa
Sizwe CRS Recruiting
Johannesburg, Gauteng, South Africa
Contact: Katerina Selibas    27-11-8823912    kselibas@witshealth.co.za   
PHRU Matlosana CRS Recruiting
Klerksdorp, North West Province, South Africa, 2574
Contact: Katlego Motlhaoleng    27-18-4063359    motlhaolengk@phru.co.za   
Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS Recruiting
Cape Town, Western Cape Province, South Africa, 7505
Contact: Frieda A. Verheye-Dua    27-21-9389772    Frieda@sun.ac.za   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Anneke Hesseling, M.D., Ph.D. Desmond Tutu TB Centre, Stellenbosch University

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02906007     History of Changes
Other Study ID Numbers: P1108
11884 ( Registry Identifier: DAIDES-ES Registry Number )
IMPAACT P1108 ( Other Identifier: NIAID )
First Posted: September 19, 2016    Key Record Dates
Last Update Posted: August 23, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
HIV Infections
Tuberculosis
Tuberculosis, Multidrug-Resistant
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bedaquiline
Diarylquinolines
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents