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Evaluating the Pharmacokinetics, Safety, and Tolerability of Delamanid in Combination With Optimized Multidrug Background Regimen (OBR) for Multidrug-Resistant Tuberculosis (MDR-TB) in HIV-Infected and HIV-Uninfected Children With MDR-TB

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ClinicalTrials.gov Identifier: NCT03141060
Recruitment Status : Recruiting
First Posted : May 4, 2017
Last Update Posted : October 9, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This study will evaluate the pharmacokinetics, safety, and tolerability of the anti-tuberculosis (TB) drug delamanid (DLM) in combination with an optimized multidrug background regimen (OBR) for multidrug-resistant tuberculosis (MDR-TB) in HIV-infected and HIV-uninfected children with MDR-TB.

Condition or disease Intervention/treatment Phase
Tuberculosis HIV Infections Drug: Delamanid Drug: Optimized multidrug background regimen (OBR) for children with MDR-TB Phase 1 Phase 2

Detailed Description:

The purpose of this study is to evaluate the pharmacokinetics, safety, and tolerability of the anti-TB drug DLM in combination with OBR for MDR-TB in HIV-infected and HIV-uninfected children with MDR-TB.

Participants will be enrolled in one of four age cohorts: 12 to less than 18 years, 6 to less than 12 years, 3 to less than 6 years, or 0 to less than 3 years. All participants will receive DLM dosed according to their age group and weight for 24 weeks.

Study visits will occur at study entry; Weeks 2 and 4; every 4 weeks through Week 40; and at Weeks 48, 60, 72, and 96. Visits may include physical examinations; blood, urine, and sputum collection; chest x-rays; electrocardiograms (ECGs); hearing tests; adherence assessments; and acceptability questionnaires.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 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 Delamanid in Combination With Optimized Multidrug Background Regimen (OBR) for Multidrug-Resistant Tuberculosis (MDR-TB) in HIV-Infected and HIV-Uninfected Children With MDR-TB
Actual Study Start Date : January 30, 2018
Estimated Primary Completion Date : May 31, 2020
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1: Delamanid
Participants will receive delamanid (DLM) twice daily for 24 weeks. Participants will also receive non-study prescribed OBR for MDR-TB.
Drug: Delamanid
Administered orally; dosing will be based on participants' age and weight.
Other Name: DLM

Drug: Optimized multidrug background regimen (OBR) for children with 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 DLM for 24 weeks.




Primary Outcome Measures :
  1. Frequency of Grade 3 or 4 adverse events (AEs) [ Time Frame: Measured through Week 24 ]
    Based on labs, signs/symptoms, diagnoses

  2. Frequency of Grade 3 or 4 AEs judged by the CMC to be related to DLM [ Time Frame: Measured through Week 24 ]
    Based on labs, signs/symptoms, diagnoses

  3. Frequency of permanent discontinuations of DLM due to a toxicity or AE [ Time Frame: Measured through Week 24 ]
    Based on study drug discontinuation criteria outlined in the protocol

  4. Frequency of QTcF interval greater than or equal to 500 ms [ Time Frame: Measured through Week 24 ]
    Based on electrocardiogram (ECG)

  5. Frequency of participant deaths [ Time Frame: Measured through Week 24 ]
    Grade 5 event


Secondary Outcome Measures :
  1. Frequency of Grade 3 or 4 AEs [ Time Frame: Measured through Week 72 ]
    Based on labs, signs/symptoms, diagnoses

  2. Frequency of Grade 3 or 4 AEs judged by the CMC to be related to DLM [ Time Frame: Measured through Week 72 ]
    Based on labs, signs/symptoms, diagnoses

  3. Frequency of permanent discontinuations of DLM due to a toxicity or AE [ Time Frame: Measured through Week 72 ]
    Based on study drug discontinuation criteria outlined in the protocol

  4. Frequency of QTcF interval greater than or equal to 500 ms [ Time Frame: Measured through Week 72 ]
    Based on ECG

  5. Frequency of participant deaths [ Time Frame: Measured through Week 72 ]
    Grade 5 event

  6. Frequency of Grade 2, 3 or 4 AEs [ Time Frame: Measured through Week 72 ]
    Based on labs, signs/symptoms, diagnoses

  7. Frequency of Grade 2, 3 or 4 AEs judged by the CMC to be related to DLM [ Time Frame: Measured through Week 72 ]
    Based on labs, signs/symptoms, diagnoses

  8. Frequency of change in QTcF interval from baseline of greater than 60 ms [ Time Frame: Measured through Week 72 ]
    Based on ECG



Information from the National Library of Medicine

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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 (or legal guardian) is willing and able to provide written informed consent for child study participation. Additionally, for children whose assent is required per site institutional review board/ethics committee (IRB/EC) policies and procedures, child is willing and able to provide written assent for his or her study participation.
  • Age less than 18 years at enrollment
  • HIV-uninfected, or HIV-infected (see the protocol for more information on this criterion)
  • If HIV-infected: Initiated the standard of care antiretroviral therapy (ART) regimen at least two weeks prior to enrollment (note: regimens including efavirenz [EFV], nevirapine [NVP], a boosted protease inhibitor [PI], or integrase strand transfer inhibitor [INSTI] are allowed)
  • Confirmed or probable MDR-TB classified as follows:

    • Confirmed MDR-TB (or rifampicin mono-resistant TB [RMR-TB], pre-extensively drug-resistant [XDR] or XDR-TB):

      • Intra-thoracic (pulmonary) TB based on chest radiograph consistent with TB, with or without one of the following forms of extrathoracic TB:
      • 1) Peripheral TB lymphadenitis
      • 2) Pleural effusion or fibrotic pleural lesions
      • 3) Stage 1 TB meningitis
      • 4) Miliary and abdominal TB,
      • 5) Other non-disseminated forms of TB disease
      • AND
      • Microbiological confirmation of Mycobacterium tuberculosis from any clinical specimen by either culture or molecular methods (including Xpert MTB/RIF)
      • AND
      • Drug-resistance demonstrated by genotypic (molecular) or phenotypic methods, with any of the following resistance patterns:
      • MDR-TB (resistance to both rifampicin and isoniazid)
      • Rifampicin mono-resistant TB (RMR-TB) or where additional isoniazid (INH) resistance has not been confirmed (i.e., isolated Xpert MTB/RIF rifampicin resistance)
      • Pre-XDR-TB (MDR-TB plus resistance to either a fluoroquinolone or a second-line injectable agent)
      • XDR-TB (MDR-TB plus resistance to both a fluoroquinolone and a second-line injectable)
      • Note: RMR-TB, MDR-TB, pre-XDR-TB and XDR-TB are therefore collectively referred to as "MDR-TB" for the purposes of the protocol
    • Probable MDR-TB (or RMR, pre-XDR or XDR-TB)

      • A presumptive diagnosis of intrathoracic (pulmonary) TB based on well-documented clinical symptoms or signs of TB AND chest radiograph consistent with TB, with or without one of the following forms of extrathoracic 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
      • AND
      • One of the following:
      • Exposure to a confirmed MDR-TB source case* (RMR-TB, pre-XDR-TB, XDR-TB)
      • Documented failure to respond to a first-line regimen, and where adherence was well documented.
      • AND
      • The clinical decision has been made to treat for MDR-TB
      • * Confirmed MDR-TB source cases defined as a case with intrathoracic TB with or without extrathoracic TB, with microbiological confirmation of Mycobacterium tuberculosis from any clinical specimen by either culture or molecular methods (including Xpert MTB/RIF), and with drug-resistance demonstrated by genotypic (molecular) or phenotypic methods, with any of the resistance patterns described above.
  • Albumin level greater than 2.8 g/dL within 30 days prior to enrollment
  • Potassium greater than 3.4 and less than 5.6 mmol/L; magnesium greater than 0.59 mmol/L within 30 days prior to enrollment. Note: Electrolytes can be repleted and a recheck may be performed to meet eligibility criteria.
  • BMI Z-score greater than -3 for children greater than or equal to 5 years of age; weight for length/height Z-score greater than -3 for children less than 5 years of age (using latest World Health Organization scores), at screening
  • For Cohorts 1 and 2, weight greater than 15 kg at screening
  • Has initiated an appropriate optimized background regimen (OBR) MDR-TB treatment regimen as per routine treatment decision, at least two weeks but not more than eight weeks prior to enrollment, and in the opinion of the site investigator, is tolerating the regimen well at enrollment. Note: An appropriate OBR MDR-TB treatment regimen is defined as including components based on the sensitivities of the infecting isolate, if known, and past treatment history, if known. This regimen should also follow the OBR MBR-TB treatment guidelines as described in the protocol.
  • 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 DLM).
  • If female and of reproductive potential, defined as having reached menarche and not having undergone a documented sterilization procedure (hysterectomy, bilateral oophorectomy, or salpingectomy): Negative pregnancy test at screening within 14 days prior to enrollment.
  • If female, of reproductive potential (as defined in the protocol), and engaging in sexual activity that could lead to pregnancy: Agrees to avoid pregnancy and to use one of the following forms of birth control while receiving DLM and for one month after stopping DLM: condoms, diaphragm or cervical cap, intrauterine device (IUD), hormonal-based contraception. The selected method must be initiated prior to enrollment.

Exclusion Criteria:

  • Known allergy to any nitroimidazoles or nitroimidazole derivatives
  • Active use of prohibited medications listed in the protocol, within 3 days of enrollment
  • Participant has a history of any of the following, as determined by the site investigator or designee based on maternal report and available medical records:

    • 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
    • Significant gastrointestinal (GI), metabolic, neuropsychiatric, kidney or endocrine disease at screening that would, in the investigator's opinion, preclude safe participation in the trial and/or assessment of primary endpoints
    • Previous DLM or pretomanid exposure
  • Abnormal electrocardiogram (ECG) (including QTcF [mean value of QT interval, corrected using Fredericia correction, on ECG performed in triplicate] greater than or equal to 450 ms, atrioventricular block, or prolonged QRS greater than or equal to 120 ms) at screening
  • Karnofsky score less than 30% for participants greater than or equal to 16 years of age or Lansky play score less than 30% for participants less than 16 years of age, at screening
  • Alcohol intake that in the opinion of the study investigator could potentially interfere with study participation and/or introduce safety concerns with use of DLM
  • Lactating with plans to breastfeed, at enrollment
  • Tuberculous meningitis (TBM) Stage 2 or 3, or osteoarticular TB, at screening
  • Co-enrolled in any other trial involving pharmacologic regimens, at screening
  • If HIV-exposed and less than 2 years of age: Breastfeeding at enrollment

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): NCT03141060


Contacts
Contact: Kathryn Lypen 919.544.7040 ext 11684 klypen@fhi360.org

Locations
Botswana
Gaborone CRS Recruiting
Gaborone, South-East District, Botswana
Contact: Tebogo J. Kakhu    267-3931353    tkakhu@bhp.org.bw   
Molepolole CRS Recruiting
Gaborone, Botswana
Contact: Unoda A. Chakalisa, MBBCh    267-3910388    uchakalisa@bhp.org.bw   
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
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   
Tanzania
Kilimanjaro Christian Medical Centre (KCMC) Recruiting
Moshi, Tanzania
Contact: Cynthia A. Asiyo    255-753698484    cynthia.asiyo@duke.edu   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Kelly Dooley, MD, PhD Johns Hopkins University

Additional Information:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03141060     History of Changes
Other Study ID Numbers: IMPAACT 2005
20721 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: May 4, 2017    Key Record Dates
Last Update Posted: October 9, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: 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