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

NCT03141060 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 200520721
• Study Type: interventional
• Target: 37
• Locations: 3 countries
• Sites: 5

Brief Summary

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.

Conditions

Tuberculosis; HIV Infections

Outcome Measures

Primary Outcomes (18)

• Percentage of Participants With Adverse Events of ≥ Grade 3 Severity

  At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1). 95% CIconfidence interval (CI) computed using exact Clopper-Pearson method.

  Measured from entry through Week 24

• Percentage of Participants With Adverse Events of ≥ Grade 3 Assessed by the Core Team to be at Least Possibly Related to the Study Drug

  At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1). 95% CI computed using exact Clopper-Pearson method.

  Measured from entry through Week 24

• Percentage of Participants Who Were Terminated From Study Treatment Due to a Drug-related Adverse Event

  At entry and follow-up, all lab results, signs and symptoms, and diagnoses were recorded. The core team reviewed and confirmed the sites assessment of event relatedness to study drug. An adverse event (AE) is any unfavorable and unintended sign, symptom, or diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution. Adverse events are graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4= potentially life-threatening, 5=death. AE grading was per Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table V2.1. 95% CI computed using exact Clopper-Pearson method.

  Measured from entry through Week 24

• Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec

  Evaluation of the Electrocardiogram (ECG) QTcF was performed per protocol. ECGs conducted at these visits were performed in triplicate (if possible). Consultation with the protocol cardiologist was available and encouraged for any abnormal or equivocal ECG findings and/or questions related to cardiac toxicities and assessment. Participants were counted if they had QTcF ≥ 500 msec at any study visit from entry to Week 24. 95% CI computed using exact Clopper-Pearson method.

  Entry, weeks 2, 8, 12, 16, 20, and 24

• Percentage of Participants Who Died Through Week 24

  Death due to all causes included. 95% CI computed using exact Clopper-Pearson method.

  Measured from entry through Week 24

• Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h) DLM

  PK parameter was determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model The starting population PK model was developed on data from Otsuka study 232 and 233 (1). NONMEM was used when developing the final model for the population in this study. * Developed a population PK model as part of the final PK analysis * Data used in the population PK analysis included the semi-intensive PK visit (week 0, 2 and 8) and sparse PK visits (week 4, 12, 16, 24 and 28).

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Geometric Mean of Area Under the Concentration Versus Time Curve (AUC0-24h) DM-6705

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model The starting population PK model was developed on data from Otsuka study 232 and 233 (1). NONMEM was used when developing the final model for the population in this study. * Developed a population PK model as part of the final PK analysis * Data used in the population PK analysis included the semi-intensive PK visit (week 0, 2 and 8) and sparse PK visits (week 4, 12, 16, 24 and 28).

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Geometric Mean of Area of Maximal Concentration (Cmax) DLM

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Geometric Mean of Area of Maximal Concentration (Cmax) DM-6705

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Time of Maximal Concentration (Tmax) DLM

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Time of Maximal Concentration (Tmax) DM-6705

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Oral Clearance (Cl/F) DLM

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Oral Clearance (Cl/F) DM-6705

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Volume of Distribution (Vd) DLM

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Volume of Distribution (Vd) DM-6705

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Mean Absorption Time (MAT) DLM

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Terminal Half-life (t1/2) DLM

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

• Median Terminal Half-life (t1/2) DM-6705

  PK parameter determined from plasma concentration-time profiles, dosing information and participant covariates using the final population PK model

  Approximately day 10 (Week 2) at pre-dose, and 2, 4, and hours post dose

Secondary Outcomes (18)

• Percentage of Participants With Adverse Events ≥ Grade 3 Severity

  Measured from entry through Week 72 post DLM

• Percentage of Participants With Adverse Events ≥ Grade 3 Severity Assessed by the Core Team to be at Least Possibly Related to the Study Drug

  Measured from entry through Week 72 post DLM

• Percentage of Participants With Absolute Corrected QT Interval by Fridericia (QTcF) ≥ 500 Msec

  Screening, Entry, weeks 2, 8, 12, 16, 20, 24 and week 28

• Percentage of Participants Who Died Through Week 72 Post DLM

  Measured from entry through Week 72 post DLM

• Percentage of Participants With Adverse Events ≥ Grade 2 Severity

  Measured from entry through Week 72 post DLM

Study Arms (4)

Cohort 1 (>=12 to < 18 years)

EXPERIMENTAL

Participants received delamanid (DLM) twice daily for 24 weeks. Participants also received non-study prescribed OBR for MDR-TB.

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

Cohort 2 (>=6 to < 12 years)

EXPERIMENTAL

Participants received delamanid (DLM) twice daily for 24 weeks. Participants also received non-study prescribed OBR for MDR-TB.

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

Cohort 3 (>=3 to < 6 years)

EXPERIMENTAL

Participants received delamanid (DLM) twice daily for 24 weeks. Participants also received non-study prescribed OBR for MDR-TB.

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

Cohort 4 (>=0 to < 3 years)

EXPERIMENTAL

Participants received delamanid (DLM) twice daily for 24 weeks. Participants also received non-study prescribed OBR for MDR-TB.

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

Interventions

Delamanid DRUG

Administered orally; dosing based on participants' weight. ≥ 40 kg: 100 mg twice daily (adult formulation); 30 to \< 40 kg: 50 mg twice daily (adult formulation); 15 to \< 30 kg: 25 mg twice daily (pediatric formulation); \< 15 kg: 15 mg twice daily (pediatric formulation)

Also known as: DLM

Cohort 1 (>=12 to < 18 years); Cohort 2 (>=6 to < 12 years); Cohort 3 (>=3 to < 6 years); Cohort 4 (>=0 to < 3 years)

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

Non-study prescribed OBR varied according to local, national, and/or international guidelines for treatment of children with MDR-TB. Administered in addition to DLM for 24 weeks.

Cohort 1 (>=12 to < 18 years); Cohort 2 (>=6 to < 12 years); Cohort 3 (>=3 to < 6 years); Cohort 4 (>=0 to < 3 years)

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \- 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:
• Peripheral TB lymphadenitis
• Pleural effusion or fibrotic pleural lesions
• Stage 1 TB meningitis
• Miliary and abdominal TB
• 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))

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Otsuka Pharmaceutical Development & Commercialization, Inc.: collaborator

Study Sites (5)

Byramjee Jeejeebhoy Medical College (BJMC) CRS

Pune, Maharashtra, 411001, India

Location

Sizwe CRS

Johannesburg, Gauteng, South Africa

Location

PHRU Matlosana CRS

Klerksdorp, North West, 2574, South Africa

Location

Desmond Tutu TB Centre - Stellenbosch University (DTTC-SU) CRS

Cape Town, Western Cape, 7505, South Africa

Location

Kilimanjaro Christian Medical Centre (KCMC)

Moshi, Tanzania

Location

Related Links

• IMPAACT Network Studies
• The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study
• "Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010"

MeSH Terms

Conditions

Tuberculosis; HIV Infections

Interventions

OPC-67683

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DHL Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Anthony Garcia-Prats, MD

  University of Wisconsin, Madison

  STUDY CHAIR

• Ethel Weld, MD

  Johns Hopkins University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2017
• First Posted: May 4, 2017
• Study Start: February 18, 2019
• Primary Completion: April 22, 2025
• Study Completion: May 29, 2025
• Last Updated: June 25, 2026
• Results First Posted: June 25, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.
• Access Criteria: * With whom? \* Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network. * For what types of analyses? \* To achieve aims in the proposal approved by the IMPAACT Network. * By what mechanism will data be made available? * Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/studies/submit-research-proposal Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.

Locations

ZA (3); TA (1); IN (1)