Clinical trial NCT01859923: A 6-Month Safety, Efficacy, and Pharmacokinetic (PK) Trial of Delamanid in Pediatric Participants With Multidrug Resistant Tuberculosis (MDR-TB)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multidrug Resistant Tuberculosis
Keywords: Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetes Infections
Gram-Positive Infections
Bacterial Infections
Pediatric
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
First posted: 2013-05-22
Enrollment: 37
Sex: ALL
Minimum age (years): 0
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 (OBR) of other anti-tuberculosis drugs in pediatric participants who completed Study 242-12-232 (NCT01856634).

Detailed description: This study will assess the safety, tolerability, pharmacokinetics, and efficacy of delamanid plus an optimized background regimen in pediatric participants with MDR-TB over a 6-month treatment period. This long-term study, an extension of Study 242-12-232, will be conducted in participants who have completed Study 242-12-232.

Eligibility 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 participants who have reached menarche
* Written informed consent/assent

Exclusion Criteria:

* Participants who have not completed Trial 242-12-232
* Laboratory evidence of active hepatitis B or C
* Children with body weight \< 5.5 kg
* For participants with human-immunodeficiency virus (HIV) co-infection, cluster difference-4 (CD4) cell count ≤ 1000/mm\^3 for children 1-5 years old, and ≤ 1500/mm\^3 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
* Pre-existing cardiac conditions
* Abnormalities in Screening electrocardiogram (ECG) \[including atrio-ventricular (AV) block, blood brain barrier (BBB) or hemi-block, QRS prolongation \> 120 milliseconds (ms), or QT interval corrected by Fridericia's formula (QTcF) \> 450 ms in both males and females\]
* Concomitant condition such as renal impairment characterized by serum creatinine levels \> 1.5 mg/dL, hepatic impairment (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 3x upper limit of normal (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 investigational medicinal product (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)

Primary outcomes:
measure: Number of Participants With At Least One Treatment Emergent Adverse Event (TEAE)
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Number of Participants With Abnormal Physical Examination Values
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Number of Participants With Clinically Significant Abnormal Vital Sign Values
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Values
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Number of Participants With Clinically Significant Laboratory Test Abnormalities
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Population Pharmacokinetic (POPPK) Model Point Estimate for Central Clearance (L) and Inter-compartmental Clearance (Q) of Delamanid
timeFrame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
measure: POPPK Model Point Estimate for Central Volume of Distribution (Vc) and Peripheral Volume of Distribution (Vp) of Delamanid
timeFrame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
measure: POPPK Model Point Estimate for Absorption Rate Constant (Ka) of Delamanid
timeFrame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
measure: POPPK Model Point Estimate for Absorption Lag Time (ALAG1) of Delamanid
timeFrame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
Secondary outcomes:
measure: Baseline QT Interval (QTcB) Effect
timeFrame: Baseline (Day -1)
measure: PK/PD Relationship: POPPK Model Point Estimate for Slope of Linear Mixed Effects Model for Change in QTcB Interval Versus Delamanid Plasma Concentrations
timeFrame: Predose on Days 1, 56, 154, and 182, 210 and at any time point on Days 14, 98, 189, 196, 203, and 238
measure: Number of Participants With Treatment Outcome as Assessed by Principal Investigator
timeFrame: Month 24
measure: Number of Participants With Abnormal Chest X-ray
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Number of Participants With Investigator-Assessed Signs and Symptoms of Tuberculosis
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Sputum Culture Conversion (SCC)
timeFrame: From the first dose of study drug up to the end of the Post-treatment Follow-up Period (Up to Day 365)
measure: Number of Participants With Palatability Score as Assessed by the Investigator
timeFrame: Days 1, 28, 56 and 182
measure: Number of Participants With Palatability Score as Assessed by the Parent or Participant
timeFrame: Days 1, 28, 56 and 182
Other outcomes:
Locations:
city: Dasmariñas
country: Philippines
facility: De La Salle Health Sciences Institute
state: Cavite
city: Quezon City
country: Philippines
facility: Lung Center of the Philippines
state: Metro Manila
city: Ysterplaat
country: South Africa
facility: Brooklyn Chest Hospital
state: Cape Town
Study officials:
affiliation: De La Salle Health Sciences Institute
name: Melchor VG Frias, IV, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lung Center of the Philippines
name: Anjanette Reyes-De Leon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brooklyn Chest Hospital
name: Louvina van der Laan, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.