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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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Multidrug Resistant Tuberculosis, Pediatric

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: 12 to 17 years of age<br>Group 1: 100 mg Delamanid BID for 10 days + OBR | Drug: 100 mg Delamanid<br>* 100 mg Delamanid BID for 10 days<br>* Other names: OPC-67683;Drug: Optimized Background Regimen<br>* 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<br>* Other names: OBR;|
| Experimental: Group 2: 6 to 11 years of age<br>50 mg Delamanid BID for 10 days + OBR | Drug: 50 mg Delamanid<br>* 50 mg Delamanid BID for 10 days<br>* Other names: OPC-67683;Drug: Optimized Background Regimen<br>* 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<br>* Other names: OBR;|
| Experimental: Group 3: 3 to 5 years of age<br>25 mg Pediatric Formulation Delamanid BID for 10 days + OBR | Drug: 25 mg Pediatric Formulation Delamanid<br>* 25 mg Pediatric Formulation Delamanid BID for 10 days<br>* Other names: DPF;Drug: Optimized Background Regimen<br>* 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<br>* Other names: OBR;|
| Experimental: Group 4: Birth to 2 years of age<br>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 | Drug: 10 mg Delamanid Pediatric Formulation<br>* Patients > 10 kg will receive DPF 10 mg BID for 10 days<br>* Other names: DPF;Drug: 5 mg Delamanid Pediatric Formulation<br>* 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<br>* Other names: DPF;Drug: Optimized Background Regimen<br>* 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<br>* Other names: OBR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Number of reported adverse events | 40 Days | 
| Safety Summary | Summary statistics of subjects with clinically significant abnormal laboratory test results, vitals, ECGs | 40 Days | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, Tuberculosis, Multidrug-Resistant, Mycobacterium Infections, Actinomycetales Infections, Gram-Positive Infections, Bacterial Infections, Pediatric