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A 6-Month Safety, Efficacy, and PK Trial of Delamanid in Pediatric Patients With Multidrug Resistant Tuberculosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01859923
Recruitment Status : Active, not recruiting
First Posted : May 22, 2013
Last Update Posted : January 29, 2019
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information
First Submitted Date  ICMJE May 15, 2013
First Posted Date  ICMJE May 22, 2013
Last Update Posted Date January 29, 2019
Actual Study Start Date  ICMJE July 20, 2013
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 12, 2016)
  • Safety and Tolerability Summary [ Time Frame: 365 Days ]
    Safety and tolerability will be assessed by the following variables: physical examination including visual testing and audiometry, vital signs, treatment-emergent adverse events (TEAEs), ECGs and clinical laboratory tests
  • Pharmacokinetics (PK) [ Time Frame: Days 1, 14, 56, 98, 154, 182, 189, 196, 203, 210, 238 ]
    Delamanid and metabolite plasma concentrations reported by age and dose group on Days 1, 14, 56, 98, 154, 182, 189, 196, 203, 210, 238.
Original Primary Outcome Measures  ICMJE
 (submitted: May 21, 2013)
  • Adverse Events [ Time Frame: 12 Months ]
    Number of Subjects reporting an Adverse Event
  • Safety Summary [ Time Frame: 12 months ]
    Summary Statistics of subjects with clinically significant abnormal laboratory test results, vitals, EGGs and Physical Examinations
  • Pharmacokinetics [ Time Frame: Day 1 ]
    Delamanid and plasma concentrations predose (0 hours) on Day 1
  • Pharmacokinetics [ Time Frame: Day 56 ]
    Delamanid and plasma concentrations predose (0 hours) on Day 56
  • Pharmacokinetics [ Time Frame: Day 154 ]
    Delamanid and plasma concentrations predose (0 hours) on Day 154
  • Pharmacokinetics [ Time Frame: Day 182 ]
    Delamanid and plasma concentrations predose (0 hours) on Day 182
  • Pharmacokinetics [ Time Frame: Day 210 ]
    Delamanid and plasma concentrations predose (0 hours) on Day 210 at the theoretical predose time when delamanid would have been administered
  • Pharmacokinetics [ Time Frame: Day 14 ]
    Delamanid and plasma concentrations predose (0 hours) at any time point on Day 14
  • Pharmacokinetics [ Time Frame: Day 98 ]
    Delamanid and plasma concentrations predose (0 hours) at any time point on Day 98
  • Pharmacokinetics [ Time Frame: Day 189 ]
    Delamanid and plasma concentrations predose (0 hours) at any time point on Day 189
  • Pharmacokinetics [ Time Frame: Day 196 ]
    Delamanid and plasma concentrations predose (0 hours) at any time point on Day 196
  • Pharmacokinetics [ Time Frame: Day 203 ]
    Delamanid and plasma concentrations predose (0 hours) at any time point on Day 203
  • Pharmacokinetics [ Time Frame: Day 238 ]
    Delamanid and plasma concentrations predose (0 hours) at any time point on Day 238
Change History Complete list of historical versions of study NCT01859923 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 12, 2016)
  • Pharmacokinetics/Pharmacodynamics (PK/PD) Relationship Analysis of Delamanid and DM-6705 and Change in Corrected QT Interval [ Time Frame: Days 1, 56, 154, 182, and 210 ]
    ECG and blood samples for PK/PD analysis for changes in QTc as a function of delamanid and DM-6705 plasma concentrations on Days 1, 56, 154, 182, and 210.
  • Efficacy of Delamanid [ Time Frame: 365 Days ]
    The efficacy of delamanid in treating pediatric MDR-TB patients will be evaluated by chest radiography (patients with pulmonary disease), change in body weight/height, and evaluation of TB symptoms. Sputum culture conversion (for culture-positive patients) will be assessed in patients who are able to produce sputum (or provide other biological specimens) for microbiological evaluation.
  • Palatability of the Pediatric Formulation (Groups 3 and 4 only) [ Time Frame: Days 1, 28, 56, 182 ]
    Palatability of the delamanid pediatric formulation will be assessed using an age-appropriate visual hedonic scale and clinical assessment for Groups 3 and 4 only on Days 1, 28, 56, 182.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2013)
  • Pharmacokinetics/pharmacodynamics [ Time Frame: 365 Days ]
    DM-6705 plasma concentrations and changes in QTc interval using the paired pharmacokinetic/pharmacodynamic assessments on Days 1, 56, 154, 182, and 210.
  • Resolution of TB Symptoms [ Time Frame: 365 Days ]
    Proportion of subjects with resolution of TB symptoms based on investigator evaluation.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A 6-Month Safety, Efficacy, and PK Trial of Delamanid in Pediatric Patients With Multidrug Resistant Tuberculosis
Official Title  ICMJE Phase 2, Open-label, Multiple-dose Trial to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Delamanid (OPC-67683) in Pediatric Multidrug-resistant Tuberculosis Patients on Therapy With an Optimized Background Regimen of Anti-tuberculosis Drugs Over a 6-Month Treatment Period
Brief Summary The purpose of this trial is to assess the safety, tolerability, pharmacokinetics, and efficacy of long-term (6-month) treatment with delamanid plus an optimized background regimen of other anti-tuberculosis drugs in pediatric patients who completed Trial 242-12-232.
Detailed Description This is a phase 2, open-label, multiple-dose, multicenter trial to assess the safety, tolerability, pharmacokinetics, and efficacy of delamanid plus an optimized background regimen in pediatric patients with MDR-TB over a 6-month treatment period. This long-term trial, an extension of Trial 242-12-232, will be conducted in patients who have completed Trial 232.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Multidrug Resistant Tuberculosis
  • Pediatric
Intervention  ICMJE
  • Drug: 100 mg Delamanid
    100 mg Delamanid BID for 6 months
    Other Name: OPC-67683
  • Drug: 50 mg Delamanid
    50 mg Delamanid BID for 6 months
    Other Name: OPC-67683
  • Drug: 25 mg Pediatric Formulation Delamanid
    25 mg Pediatric Formulation Delamanid BID for 6 months
    Other Name: DPF
  • Drug: 10 mg Delamanid Pediatric Formulation
    Patients > 10 kg will receive DPF 10 mg BID for 6 months
    Other Name: DPF
  • Drug: 5 mg Delamanid Pediatric Formulation

    Patients > 8 kg or ≤ 10 kg will receive DPF 5 mg BID for 6 months

    Patients ≤ 8 kg will receive DPF 5 mg QD for 6 months

    Other Name: DPF
  • Drug: Optimized Background Regimen
    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
    Other Name: OBR
Study Arms  ICMJE
  • Experimental: Group 1: 12 to 17 years of age
    100 mg Delamanid BID for 6 months + OBR
    Interventions:
    • Drug: 100 mg Delamanid
    • Drug: Optimized Background Regimen
  • Experimental: Group 2: 6 to 11 years of age
    50 mg Delamanid BID for 6 months + OBR
    Interventions:
    • Drug: 50 mg Delamanid
    • Drug: Optimized Background Regimen
  • Experimental: Group 3: 3 to 5 years of age
    25 mg Pediatric Formulation Delamanid BID for 6 months + OBR
    Interventions:
    • Drug: 25 mg Pediatric Formulation Delamanid
    • Drug: Optimized Background Regimen
  • Experimental: Group 4: Birth to 2 years of age

    Delamanid Pediatric Formulation (DPF) for 6 months + OBR. DPF dose based on patient's body weight during baseline visit:

    • Patients > 10 kg will receive DPF 10 mg BID + OBR
    • Patients > 8 kg and ≤ 10 kg will receive DPF 5 mg BID + OBR
    • Patients ≤ 8 kg will receive DPF 5 mg QD + OBR

    Delamanid dose will be adjusted as needed for Group 4 patients based on the weight measurement at specified study visits (Visits 5, 7, 9, 11, and 12).

    Interventions:
    • Drug: 10 mg Delamanid Pediatric Formulation
    • Drug: 5 mg Delamanid Pediatric Formulation
    • Drug: Optimized Background Regimen
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 27, 2018)
37
Original Estimated Enrollment  ICMJE
 (submitted: May 21, 2013)
12
Estimated Study Completion Date  ICMJE February 2020
Estimated Primary Completion Date February 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Successfully completed Trial 242-12-232
  • Confirmed diagnosis of MDR-TB OR
  • Presumptive diagnosis of pulmonary or extrapulmonary MDR-TB including one of the following:

    • Clinical specimen suggestive of tuberculosis disease
    • 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 with a person with known MDR-TB or with 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:

  • Patients who have not completed Trial 242-12-232
  • 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 other than delamanid given as IMP in Trial 242-12-232
  • Pregnant, breast-feeding, or planning to conceive or father a child within the timeframe described in the informed consent form (Groups 1 and 2 only)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Philippines,   South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01859923
Other Study ID Numbers  ICMJE 242-12-233
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Otsuka Pharmaceutical Development & Commercialization, Inc.
Study Sponsor  ICMJE Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Melchor VG Frias, IV, MD De La Salle Health Sciences Institute
Principal Investigator: Anjanette Reyes-De Leon, MD Lung Center of the Philippines
Principal Investigator: Anthony Garcia-Prats, MD Brooklyn Chest Hospital
PRS Account Otsuka Pharmaceutical Development & Commercialization, Inc.
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP