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

Phase 1

Completed

• Conditions: Pediatric; Multidrug Resistant Tuberculosis
• Interventions: Drug: 10 mg Delamanid Pediatric Formulation; Drug: 50 mg Delamanid; Drug: 100 mg Delamanid; Drug: 25 mg Pediatric Formulation Delamanid; Drug: 5 mg Delamanid Pediatric Formulation; Drug: Optimized Background Regimen

• Registration Number: NCT01856634
• Lead Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

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

Study Timeline

• Study First Submitted: 2013-05-15
• Study First Submitted QC: 2013-05-15
• Study First Posted: 2013-05-17
• Study Start: 2013-06-14
• Primary Completion: 2017-12-10
• Study Completion: 2017-12-28
• Status Verified: 2018-01
• Last Update Submitted: 2018-01-27
• Last Update Posted: 2018-01-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 37

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group 4: Birth to 2 years of age	5 mg Delamanid Pediatric Formulation	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
Group 1: 12 to 17 years of age	Optimized Background Regimen	Group 1: 100 mg Delamanid BID for 10 days + OBR
Group 3: 3 to 5 years of age	Optimized Background Regimen	25 mg Pediatric Formulation Delamanid BID for 10 days + OBR
Group 4: Birth to 2 years of age	10 mg Delamanid Pediatric Formulation	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
Group 2: 6 to 11 years of age	50 mg Delamanid	50 mg Delamanid BID for 10 days + OBR
Group 2: 6 to 11 years of age	Optimized Background Regimen	50 mg Delamanid BID for 10 days + OBR
Group 1: 12 to 17 years of age	100 mg Delamanid	Group 1: 100 mg Delamanid BID for 10 days + OBR
Group 3: 3 to 5 years of age	25 mg Pediatric Formulation Delamanid	25 mg Pediatric Formulation Delamanid BID for 10 days + OBR
Group 4: Birth to 2 years of age	Optimized Background Regimen	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

Primary Outcome Measures

Name	Time	Method
Plasma Concentrations	Days 1, 2, 10, 11, 13 (Groups 1 and 2 only), 15, 18	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

Name	Time	Method
Adverse Events	40 Days	Number of reported adverse events
Safety Summary	40 Days	Summary statistics of subjects with clinically significant abnormal laboratory test results, vitals, ECGs
Palatability of the Pediatric Formulation	Days 1 and 10	Palatability of the pediatric formulation will be assessed using an age-appropriate visual hedonic scale and clinical assessment for Groups 3 and 4 only.

Trial Locations

Locations (2)

De La Salle Health Sciences Institute; 🇵🇭 Dasmariñas, Cavite, Philippines

Brooklyn Chest Hospital; 🇿🇦 Ysterplaat, Cape Town, South Africa