Evaluating the Pharmacokinetics, Safety, and Tolerability of Delamanid in Combination With Optimized Multidrug Background Regimen (OBR) for Multidrug-Resistant Tuberculosis (MDR-TB) in Children With MDR-TB With and Without HIV

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 Children With MDR-TB With and Without HIV

This Phase I/II study evaluated 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 children with MDR-TB with and without HIV.

The purpose of this study was to evaluate the pharmacokinetics, safety, and tolerability of the anti-TB drug DLM in combination with OBR for MDR-TB in children with MDR-TB with and without HIV.

Participants were 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 were to receive DLM doses according to their age group and weight for 24 weeks.

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

Inclusion Criteria:

- Parent (or legal guardian) 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 willing and able to provide written assent for his or her study participation.

• HIV status determined by testing requirements in the protocol (see the protocol for more information on this criterion)

• If living with HIV: 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, and/or any 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 (see also exclusion criterion below)

       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 (INH))

       • RMR-TB or where additional INH resistance has not been confirmed (i.e., isolated Xpert MTB/RIF rifampicin resistance)
       • Pre-XDR-TB (MDR-TB plus resistance to any fluoroquinolone)
       • XDR-TB (MDR-TB plus resistance to both a fluoroquinolone and at least one additional Group A drug, i.e., bedaquiline or linezolid) 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), with inclusion of intrathoracic and/or extrathoracic TB as listed below:

    *A presumptive diagnosis of intrathoracic (pulmonary) TB based on well-documented clinical symptoms or signs of TB AND chest radiograph consistent with TB, and/or any 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 (see also exclusion criterion below)

       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 or equal to 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. The latest result should be used for eligibility determination.

• 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

• Weight greater than or equal to 3 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 parent/guardian 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
  • Note: Participants can have received up to 17 days of DLM prior to enrollment

• 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. Note: The value from centralized ECG read should be used to determine study eligibility.

• 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 osteo-articular TB at screening

• Co-enrolled in any other trial involving pharmacologic regimens, at screening

• If exposed to HIV and less than 2 years of age: Breastfeeding at enrollment