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Pharmacokinetic and Safety Trial to Determine the Appropriate Dose for Pediatric Patients With Multidrug Resistant Tuberculosis

Primary Purpose

Multidrug Resistant Tuberculosis, Pediatric

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
100 mg Delamanid
50 mg Delamanid
25 mg Pediatric Formulation Delamanid
10 mg Delamanid Pediatric Formulation
5 mg Delamanid Pediatric Formulation
Optimized Background Regimen
Sponsored by
Otsuka Pharmaceutical Development & Commercialization, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multidrug Resistant Tuberculosis focused on measuring Tuberculosis, Tuberculosis, Multidrug-Resistant, Mycobacterium Infections, Actinomycetales Infections, Gram-Positive Infections, Bacterial Infections, Pediatric

Eligibility Criteria

undefined - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Confirmed diagnosis of MDR-TB OR

  • Presumptive diagnosis of MDR-TB including one of the following:

    • Clinical specimen suggestive of TB
    • Persistent cough lasting > 2 weeks
    • Fever, weight loss, and failure to thrive
    • Findings on recent chest radiograph (prior to Visit 1) consistent with TB AND
    • Household contact of a person with known MDR-TB or a person who died while appropriately taking drugs for sensitive TB OR
    • On first-line TB treatment but with no clinical improvement
  • Negative urine pregnancy test for female patients who have reached menarche
  • Written informed consent/assent

Exclusion Criteria:

  • Laboratory evidence of active hepatitis B or C
  • Children with body weight < 5.5 kg
  • For patients with HIV co-infection, CD4 cell count ≤ 1000/mm3 for children 1-5 years old, and ≤ 1500/mm3 for children less than 1 year old
  • History of allergy to metronidazole and any disease or condition in which metronidazole is required
  • Use of amiodarone within 12 months or use of other predefined antiarrhythmic medications within 30 days prior to first dose of delamanid
  • Serious concomitant conditions
  • Preexisting cardiac conditions
  • Abnormalities in Screening ECG (including AV block, BBB or hemi-block, QRS prolongation > 120 msec, or QTcF > 450 msec in both males and females)
  • Concomitant condition such as renal impairment characterized by serum creatinine levels >1.5 mg/dL, hepatic impairment (ALT or AST > 3x ULN), or hyperbilirubinemia characterized by total bilirubin > 2x ULN
  • Current diagnosis of severe malnutrition or kwashiorkor
  • Positive urine drug screen (Groups 1 and 2 only)
  • Rifampicin and/or moxifloxacin within 1 week prior to the first dose of delamanid and/or any prior or concurrent use of bedaquiline
  • Lansky Play Performance Score < 50 (not applicable for children < 1 year old) or Karnofsky Score < 50
  • Administered an IMP within 1 month prior to Visit 1
  • Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the information consent form (Groups 1 and 2 only)

Sites / Locations

  • De La Salle Health Sciences Institute
  • Brooklyn Chest Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Group 1: 12 to 17 years of age

Group 2: 6 to 11 years of age

Group 3: 3 to 5 years of age

Group 4: Birth to 2 years of age

Arm Description

Group 1: 100 mg Delamanid BID for 10 days + OBR

50 mg Delamanid BID for 10 days + OBR

25 mg Pediatric Formulation Delamanid BID for 10 days + OBR

Delamanid Pediatric Formulation (DPF) for 10 days + OBR. DPF dose based on patient's body weight during baseline visit: Patient's > 10 kg will receive DPF 10 mg BID + OBR Patient's > 8 kg and ≤ 10 kg will receive DPF 5 mg BID + OBR Patients ≤ 8 kg will receive DPF 5 mg QD + OBR

Outcomes

Primary Outcome Measures

Plasma Concentrations
Plasma concentrations (Cmax, tmax, AUC 0-24h, accumulation ratio, apparent terminal elimination half-life, apparent total clearance) of delamanid and its metabolites on Days 1, 2, 10, 11, 13 (Groups 1 and 2 only), 15, 18.

Secondary Outcome Measures

Adverse Events
Number of reported adverse events
Safety Summary
Summary statistics of subjects with clinically significant abnormal laboratory test results, vitals, ECGs
Palatability of the Pediatric Formulation
Palatability of the pediatric formulation will be assessed using an age-appropriate visual hedonic scale and clinical assessment for Groups 3 and 4 only.

Full Information

First Posted
May 15, 2013
Last Updated
January 27, 2018
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01856634
Brief Title
Pharmacokinetic and Safety Trial to Determine the Appropriate Dose for Pediatric Patients With Multidrug Resistant Tuberculosis
Official Title
Phase 1, Open-label, Multiple-dose, and Age De-escalation Trial to Assess the Pharmacokinetics, Safety and Tolerability of Delamanid (OPC 67683) in Pediatric Multidrug-resistant Tuberculosis Patients on Therapy With an Optimized Background Regimen of Anti-tuberculosis Drugs
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
June 14, 2013 (Actual)
Primary Completion Date
December 10, 2017 (Actual)
Study Completion Date
December 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this trial is to determine the pediatric dose of delamanid that is equivalent to the adult dose already shown to be effective against multidrug-resistant tuberculosis.
Detailed Description
This trial will investigate the pharmacokinetics (PK) and safety of delamanid administered for 10 days to pediatric patients aged birth to 17 years who are also on therapy with an optimized background regimen. The purpose of the trial is to determine which dose in pediatric MDR-TB patients will result in delamanid plasma exposure similar to efficacious plasma exposure in adult MDR-TB patients. This is an age de-escalation trial in four groups: Group 1: 12 to 17 years (100 mg BID; n=6) Group 2: 6 to 11 years (50 mg BID; n=6) Group 3: 3 to 5 years (25 mg BID; n=12) Group 4: Birth to 2 years (Dose based on patient's body weight, n=12) Patients > 10 kg will receive 10 mg BID Patients > 8 kg and ≤ 10 kg will receive 5 mg BID Patient ≤ to 8 kg will receive 5 mg QD

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multidrug Resistant Tuberculosis, Pediatric
Keywords
Tuberculosis, Tuberculosis, Multidrug-Resistant, Mycobacterium Infections, Actinomycetales Infections, Gram-Positive Infections, Bacterial Infections, Pediatric

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
37 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1: 12 to 17 years of age
Arm Type
Experimental
Arm Description
Group 1: 100 mg Delamanid BID for 10 days + OBR
Arm Title
Group 2: 6 to 11 years of age
Arm Type
Experimental
Arm Description
50 mg Delamanid BID for 10 days + OBR
Arm Title
Group 3: 3 to 5 years of age
Arm Type
Experimental
Arm Description
25 mg Pediatric Formulation Delamanid BID for 10 days + OBR
Arm Title
Group 4: Birth to 2 years of age
Arm Type
Experimental
Arm Description
Delamanid Pediatric Formulation (DPF) for 10 days + OBR. DPF dose based on patient's body weight during baseline visit: Patient's > 10 kg will receive DPF 10 mg BID + OBR Patient's > 8 kg and ≤ 10 kg will receive DPF 5 mg BID + OBR Patients ≤ 8 kg will receive DPF 5 mg QD + OBR
Intervention Type
Drug
Intervention Name(s)
100 mg Delamanid
Other Intervention Name(s)
OPC-67683
Intervention Description
100 mg Delamanid BID for 10 days
Intervention Type
Drug
Intervention Name(s)
50 mg Delamanid
Other Intervention Name(s)
OPC-67683
Intervention Description
50 mg Delamanid BID for 10 days
Intervention Type
Drug
Intervention Name(s)
25 mg Pediatric Formulation Delamanid
Other Intervention Name(s)
DPF
Intervention Description
25 mg Pediatric Formulation Delamanid BID for 10 days
Intervention Type
Drug
Intervention Name(s)
10 mg Delamanid Pediatric Formulation
Other Intervention Name(s)
DPF
Intervention Description
Patients > 10 kg will receive DPF 10 mg BID for 10 days
Intervention Type
Drug
Intervention Name(s)
5 mg Delamanid Pediatric Formulation
Other Intervention Name(s)
DPF
Intervention Description
Patients > 8 kg and ≤ 10 kg will receive DPF 5 mg BID for 10 days Patients ≤ 8 kg will receive DPF 5 mg QD for 10 days
Intervention Type
Drug
Intervention Name(s)
Optimized Background Regimen
Other Intervention Name(s)
OBR
Intervention Description
Selection and administration of the treatment medications (i.e. OBRs) will be based on WHO's Guidelines for the programmatic management of drug-resistant TB, in conjunction with national TB program guidelines in each country
Primary Outcome Measure Information:
Title
Plasma Concentrations
Description
Plasma concentrations (Cmax, tmax, AUC 0-24h, accumulation ratio, apparent terminal elimination half-life, apparent total clearance) of delamanid and its metabolites on Days 1, 2, 10, 11, 13 (Groups 1 and 2 only), 15, 18.
Time Frame
Days 1, 2, 10, 11, 13 (Groups 1 and 2 only), 15, 18
Secondary Outcome Measure Information:
Title
Adverse Events
Description
Number of reported adverse events
Time Frame
40 Days
Title
Safety Summary
Description
Summary statistics of subjects with clinically significant abnormal laboratory test results, vitals, ECGs
Time Frame
40 Days
Title
Palatability of the Pediatric Formulation
Description
Palatability of the pediatric formulation will be assessed using an age-appropriate visual hedonic scale and clinical assessment for Groups 3 and 4 only.
Time Frame
Days 1 and 10

10. Eligibility

Sex
All
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Confirmed diagnosis of MDR-TB OR Presumptive diagnosis of MDR-TB including one of the following: Clinical specimen suggestive of TB Persistent cough lasting > 2 weeks Fever, weight loss, and failure to thrive Findings on recent chest radiograph (prior to Visit 1) consistent with TB AND Household contact of a person with known MDR-TB or a person who died while appropriately taking drugs for sensitive TB OR On first-line TB treatment but with no clinical improvement Negative urine pregnancy test for female patients who have reached menarche Written informed consent/assent Exclusion Criteria: Laboratory evidence of active hepatitis B or C Children with body weight < 5.5 kg For patients with HIV co-infection, CD4 cell count ≤ 1000/mm3 for children 1-5 years old, and ≤ 1500/mm3 for children less than 1 year old History of allergy to metronidazole and any disease or condition in which metronidazole is required Use of amiodarone within 12 months or use of other predefined antiarrhythmic medications within 30 days prior to first dose of delamanid Serious concomitant conditions Preexisting cardiac conditions Abnormalities in Screening ECG (including AV block, BBB or hemi-block, QRS prolongation > 120 msec, or QTcF > 450 msec in both males and females) Concomitant condition such as renal impairment characterized by serum creatinine levels >1.5 mg/dL, hepatic impairment (ALT or AST > 3x ULN), or hyperbilirubinemia characterized by total bilirubin > 2x ULN Current diagnosis of severe malnutrition or kwashiorkor Positive urine drug screen (Groups 1 and 2 only) Rifampicin and/or moxifloxacin within 1 week prior to the first dose of delamanid and/or any prior or concurrent use of bedaquiline Lansky Play Performance Score < 50 (not applicable for children < 1 year old) or Karnofsky Score < 50 Administered an IMP within 1 month prior to Visit 1 Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the information consent form (Groups 1 and 2 only)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Hafkin, MD
Organizational Affiliation
Otsuka Pharmaceutical Development & Commercialization, Inc.
Official's Role
Study Director
Facility Information:
Facility Name
De La Salle Health Sciences Institute
City
Dasmariñas
State/Province
Cavite
ZIP/Postal Code
4114
Country
Philippines
Facility Name
Brooklyn Chest Hospital
City
Ysterplaat
State/Province
Cape Town
Country
South Africa

12. IPD Sharing Statement

Citations:
PubMed Identifier
35404075
Citation
Garcia-Prats AJ, Frias M, van der Laan L, De Leon A, Gler MT, Schaaf HS, Hesseling AC, Malikaarjun S, Hafkin J. Delamanid Added to an Optimized Background Regimen in Children with Multidrug-Resistant Tuberculosis: Results of a Phase I/II Clinical Trial. Antimicrob Agents Chemother. 2022 May 17;66(5):e0214421. doi: 10.1128/aac.02144-21. Epub 2022 Apr 11.
Results Reference
derived

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Pharmacokinetic and Safety Trial to Determine the Appropriate Dose for Pediatric Patients With Multidrug Resistant Tuberculosis

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