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

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multidrug Resistant Tuberculosis; Pediatric	Drug: 100 mg Delamanid; Drug: 50 mg Delamanid; Drug: 25 mg Pediatric Formulation Delamanid; Drug: 10 mg Delamanid Pediatric Formulation; Drug: 5 mg Delamanid Pediatric Formulation; Drug: Optimized Background Regimen	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	37 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	July 20, 2013
Estimated Primary Completion Date :	February 2020
Estimated Study Completion Date :	February 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1: 12 to 17 years of age; 100 mg Delamanid BID for 6 months + OBR	Drug: 100 mg Delamanid; 100 mg Delamanid BID for 6 months; Other Name: OPC-67683; 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
Experimental: Group 2: 6 to 11 years of age; 50 mg Delamanid BID for 6 months + OBR	Drug: 50 mg Delamanid; 50 mg Delamanid BID for 6 months; Other Name: OPC-67683; 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
Experimental: Group 3: 3 to 5 years of age; 25 mg Pediatric Formulation Delamanid BID for 6 months + OBR	Drug: 25 mg Pediatric Formulation Delamanid; 25 mg Pediatric Formulation Delamanid BID 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
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).	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

Outcome Measures

Primary Outcome Measures :

1. 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
2. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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.

Eligibility Criteria

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Ages Eligible for Study:	up to 17 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)

Contacts and Locations

Locations

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Philippines
De La Salle Health Sciences Institute
Dasmariñas, Cavite, Philippines
Lung Center of the Philippines
Quezon City, Metro Manila, Philippines
South Africa
Brooklyn Chest Hospital
Ysterplaat, Cape Town, South Africa

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

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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

More Information

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Responsible Party:	Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:	NCT01859923 History of Changes
Other Study ID Numbers:	242-12-233
First Posted:	May 22, 2013
Last Update Posted:	January 29, 2019
Last Verified:	January 2019

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Tuberculosis; Tuberculosis, Multidrug-Resistant; Mycobacterium Infections; Actinomycetales Infections	Gram-Positive Infections; Bacterial Infections; Pediatric

Additional relevant MeSH terms:

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Tuberculosis; Tuberculosis, Multidrug-Resistant; Mycobacterium Infections	Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections