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

Pediatric Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01856634
• Other study ID #: 242-12-232
• Status: Completed
• Phase: Phase 1
• First received: May 15, 2013
• Last updated: January 27, 2018
• Start date: June 14, 2013
• Est. completion date: December 28, 2017

Study information

• Verified date: January 2018
• Source: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: December 28, 2017
• Est. primary completion date: December 10, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

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)

Related Conditions & MeSH terms

• Multidrug Resistant Tuberculosis
• Pediatric
• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

Drug:
• 100 mg Delamanid
100 mg Delamanid BID for 10 days
• 50 mg Delamanid
50 mg Delamanid BID for 10 days
• 25 mg Pediatric Formulation Delamanid
25 mg Pediatric Formulation Delamanid BID for 10 days
• 10 mg Delamanid Pediatric Formulation
Patients > 10 kg will receive DPF 10 mg BID for 10 days
• 5 mg Delamanid Pediatric Formulation
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
• 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

Locations

Country	Name	City	State
Philippines	De La Salle Health Sciences Institute	Dasmariñas	Cavite
South Africa	Brooklyn Chest Hospital	Ysterplaat	Cape Town

Sponsors (1)

Lead Sponsor	Collaborator
Otsuka Pharmaceutical Development & Commercialization, Inc.

Countries where clinical trial is conducted

Philippines,  South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Days 1, 2, 10, 11, 13 (Groups 1 and 2 only), 15, 18
Secondary	Adverse Events	Number of reported adverse events	40 Days
Secondary	Safety Summary	Summary statistics of subjects with clinically significant abnormal laboratory test results, vitals, ECGs	40 Days
Secondary	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.	Days 1 and 10