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

• Register: ClinicalTrials.gov
• Last refreshed on: 15 April 2024
• Main ID: NCT03141060
• Date of registration: 01/05/2017
• Prospective Registration: Yes
• Primary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Public title: 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
• Scientific 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 Children With MDR-TB With and Without HIV
• Date of first enrolment: January 30, 2018
• Target sample size: 48
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03141060
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

Botswana, India, South Africa, Tanzania

Contacts

• Name: Kathryn Lypen

• Name: Ethel Weld, MD
• Affiliation: Johns Hopkins University

• Name: Anthony Garcia-Prats, MD
• Affiliation: University of Stellenbosch

Key inclusion & exclusion 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,
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)

- 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), 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:

- Peripheral TB lymphadenitis

- Pleural effusion or fibrotic pleural lesions

- Stage 1 TB meningitis

- Miliary and abdominal TB,

- 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 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

- 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 maternal report and available medical record


Age minimum: N/A
Age maximum: 18 Years
Gender: All

Health Condition(s) or Problem(s) studied

HIV Infections

Tuberculosis

Intervention(s)

Drug: Optimized multidrug background regimen (OBR) for children with MDR-TB

Drug: Delamanid

Primary Outcome(s)

Frequency of permanent discontinuations of DLM due to a toxicity or AE [Time Frame: Measured through Week 24]

Frequency of Grade 3 or 4 adverse events (AEs) [Time Frame: Measured through Week 24]

Frequency of Grade 3 or 4 AEs judged by the Clinical Management Committee (CMC) to be related to DLM [Time Frame: Measured through Week 24]

Frequency of QTcF interval greater than or equal to 500 ms [Time Frame: Measured through Week 24]

Frequency of participant deaths [Time Frame: Measured through Week 24]

Secondary Outcome(s)

Frequency of Grade 2, 3 or 4 AEs [Time Frame: Measured through Week 72]

Frequency of permanent discontinuations of DLM due to a toxicity or AE [Time Frame: Measured through Week 72]

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

Frequency of Grade 3 or 4 AEs [Time Frame: Measured through Week 72]

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

Frequency of Grade 3 or 4 AEs judged by the CMC to be related to DLM [Time Frame: Measured through Week 72]

Frequency of participant deaths [Time Frame: Measured through Week 72]

Frequency of Grade 2, 3 or 4 AEs judged by the CMC to be related to DLM [Time Frame: Measured through Week 72]

Secondary ID(s)

20721

IMPAACT 2005

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Otsuka Pharmaceutical Development & Commercialization, Inc.