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

Purpose

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	Intervention	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


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: No masking 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

Resource links provided by NLM:

MedlinePlus related topics: Tuberculosis

Genetic and Rare Diseases Information Center resources: Tuberculosis

U.S. FDA Resources

Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:

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
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:

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.
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.
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.


Estimated Enrollment:	36
Study Start Date:	August 2013
Estimated Study Completion Date:	February 2020
Estimated Primary Completion Date:	February 2020 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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

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.

Enrollment is complete for patients in Groups 1, 2, and 3.

Eligibility


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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01859923

Contacts


Contact: Leesa Gentry	301-728-3160	Leesa.Gentry@otsuka-us.com

Locations


Philippines
De La Salle Health Sciences Institute	Recruiting
Dasmariñas City, Cavite, Philippines
Principal Investigator: Melchor VG Frias, IV, MD
Sub-Investigator: Maria P Austria-Cantimbuhan, MD
Sub-Investigator: Hansel JE Ybanez, MD
Lung Center of the Philippines	Recruiting
Quezon City, Metro Manila, Philippines
Principal Investigator: Anjanette Reyes-De Leon, MD
Sub-Investigator: Jo-An Q Samoy-Tuy, MD
Sub-Investigator: Genalyne H Maroon-Berzabal, MD
Sub-Investigator: Racquel A Natividad, MD
South Africa
Brooklyn Chest Hospital	Recruiting
Ysterplaat, Cape Town, South Africa
Principal Investigator: Anthony Garcia-Prats, MD
Sub-Investigator: Anneke C Hesseling, MD
Sub-Investigator: Willem Burger, MD
Sub-Investigator: Marianne Willemse, MD
Sub-Investigator: Hendrik Schaaf, MD

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators


Study Director:	Jeffrey Hafkin, MD	Otsuka Pharmaceutical Development & Commercialization, Inc.

More Information


Responsible Party:	Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier:	NCT01859923 History of Changes
Other Study ID Numbers:	242-12-233
Study First Received:	May 15, 2013
Last Updated:	March 10, 2017

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:


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

ClinicalTrials.gov processed this record on July 17, 2017