Clinical Trials Register

Summary
EudraCT Number:	2012-004620-38
Sponsor's Protocol Code Number:	242-12-233
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-01-14
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2012-004620-38

A.3

Full title of the trial

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 Antituberculosis Drugs over a 6-Month Treatment Period.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Phase 2, Open-label, Multiple-dose Trial to Assess how Delamanid (OPC 6768) is processed by the body to determine safety, tolerability, and efficacy of the drug in Pediatric patients with Multidrug-resistant Tuberculosis who are on a multi-drug antituberculosis standard of care regimen over a 6-Month Treatment Period .

A.4.1

Sponsor's protocol code number

242-12-233

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/281/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Otsuka Europe Development and Commercialisation Ltd (OEDC)
B.5.2	Functional name of contact point	Pharmacovigilance Region Europe
B.5.3	Address:
B.5.3.1	Street Address	Grüneburgweg 102
B.5.3.2	Town/ city	Frankfurt am Main
B.5.3.3	Post code	60323
B.5.3.4	Country	Germany
B.5.5	Fax number	1800438-6041
B.5.6	E-mail	Global_Intake@otsuka-us.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/524
D.3 Description of the IMP
D.3.1	Product name	Delamanid
D.3.2	Product code	OPC 67683
D.3.4	Pharmaceutical form	Dispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DELAMANID
D.3.9.1	CAS number	681492-22-8
D.3.9.2	Current sponsor code	OPC-67683
D.3.9.3	Other descriptive name	Delamanid
D.3.9.4	EV Substance Code	SUB33761
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/524
D.3 Description of the IMP
D.3.1	Product name	Delamanid
D.3.2	Product code	OPC 67683
D.3.4	Pharmaceutical form	Dispersible tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DELAMANID
D.3.9.1	CAS number	681492-22-8
D.3.9.2	Current sponsor code	OPC-67683
D.3.9.3	Other descriptive name	Delamanid
D.3.9.4	EV Substance Code	SUB33761
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/524
D.3 Description of the IMP
D.3.1	Product name	Delamanid
D.3.2	Product code	OPC-67683
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DELAMANID
D.3.9.1	CAS number	681492-22-8
D.3.9.2	Current sponsor code	OPC-67683
D.3.9.3	Other descriptive name	Delamanid
D.3.9.4	EV Substance Code	SUB33761
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pediatric patients with multidrug-resistant tuberculosis (MDR-TB) who are receiving an optimized background regimen (OBR) of antituberculosis drugs

E.1.1.1

Medical condition in easily understood language

Pediatric patients who received other treatments that did not work and
who are receiving treatment of Antituberculosis Drugs

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

• To evaluate the long-term safety and tolerability of delamanid and its metabolites in combination with an OBR during a 6-
month treatment period in pediatric patients with MDR-TB for the age-specific delamanid doses determined in Trial 232
• To report delamanid and metabolite plasma concentrations at each visit day by age groups and to conduct a population pharmacokinetics (POPPK) analysis of delamanid when delamanid is administered in combination with an OBR during a 6-month treatment period in pediatric patients with MDR TB.

E.2.2

Secondary objectives of the trial

• To evaluate the PK/PD relationship of delamanid and its
metabolite DM-6705 plasma concentrations and change in QTc
when delamanid is administered in combination with OBR
during a 6 month treatment period in pediatric patients with
MDR-TB
• To evaluate the efficacy of delamanid when administered in
combination with an OBR during a 6 month treatment period in
pediatric patients with MDR-TB
• To determine the palatability of the delamanid pediatric
formulation.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Key Inclusion Criteria:
 Successfully completed Trial 232
 Male or female
 Age birth to 17 years, inclusive
 Confirmed diagnosis of MDR-TB, ie, culture positive
for Mycobacterium tuberculosis (MTB) with isoniazid
and rifampicin resistance on drug-susceptibility testing,
or a positive rapid test demonstrating resistance to
rifampicin alone or to rifampicin and isoniazid
OR
Presumptive diagnosis of pulmonary or extrapulmonary
MDR-TB such that the treating physician has decided to
treat for MDR-TB the patient who has one of the
following:
 Clinical specimen (eg, cerebral spinal fluid, pleural
fluid, ascitic fluid, lymph node aspirate, or other tissue
specimen) suggestive of tuberculosis (TB) disease
 Persistent cough lasting > 2 weeks
 Fever, weight loss, and failure to thrive
 Findings on recent chest radiograph or other imaging
studies (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 drug-sensitive TB
OR
On first-line TB treatment but with no clinical
improvement
 Negative urine pregnancy test for female patients who
have reached menarche
 Study-specific written informed consent/assent
obtained from a parent(s) or guardian or legally
acceptable representative, as applicable for local laws
prior to the initiation of any protocol-required
procedures. In addition, for patients in Groups 1 and 2
and as required by local laws, the patient must provide
informed assent at screening and must be able to fully
understand that he or she can withdraw from the study
at any time.

E.4

Principal exclusion criteria

Key Exclusion Criteria:
 Patients who have not completed Trial 232
 Children with 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 prior to the first dose of investigational medicinal product (IMP) or use of other predefined antiarrhythmic medications within
30 days prior to the first dose of IMP
 Serious concomitant conditions (cardiovascular disorders, severe respiratory disease, severe diarrheal
disease, renal, hepatic, or neurological impairment)
 Preexisting cardiac conditions including but not limited to structural cardiac disease including suspected TB involvement of the heart on clinical or radiographic
grounds
 Abnormalities in screening electrocardiogram (ECG)
(including atrioventricular block, bundle branch block or hemi-block, QRS prolongation > 120 msec, or QT interval corrected using Fridericia’s method (QTcF)
> 450 msec in both males and females)
 A concomitant condition such as renal impairment characterized by serum creatinine levels > 1.5 mg/dL,
hepatic impairment (alanine aminotransferase or aspartate aminotransferase > 3 times the upper limit of normal [ULN]), or hyperbilirubinemia characterized by
total bilirubin > 2x ULN
 Concurrent diagnosis of severe malnutrition or kwashiorkor
 Positive urine drug screen (Groups 1 and 2 only)
 Use of rifampicin and/or moxifloxacin within 1 week
prior to the first dose of IMP 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 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)

E.5 End points

E.5.1

Primary end point(s)

- Safety and tolerability of delamanid and its metabolites.
- Pharmacokinetics: Descriptive statistics of delamanid and metabolite plasma concentrations and POPPK analysis for delamanid plasma concentrations.

E.5.1.1

Timepoint(s) of evaluation of this end point

Complete physical examination at each visit, and safety, PK, and efficacy evaluations on days 1 to 365.

E.5.2

Secondary end point(s)

- Pharmacokinetics/Pharmacodynamics: PK/PD analysis for changes in QTc as a function of delamanid and DM-6705 plasma concentrations
- Efficacy: Culture conversion, normal chest radiography results, resolution of TB symptoms

E.5.2.1

Timepoint(s) of evaluation of this end point

- PK blood draws: day 1, day 14, day 56, day 98, days 154-238
- Chest radiography: day -30 to -2, day 182, and day 365.
- Resolution of TB symptoms: at all visits (days 1 to 365).

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Palatability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

Yes

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

Philippines

South Africa

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects aged birth to 17 years.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Follow-up Period (Days 239 to 365) 6 Month Post Last Delamanid Dose: Physical examination, BMI, percentiles for age, vital signs, head circumference (Group 4 only), signs and symptoms of TB, chest radiograph, audiometry and visual assessments, safety labs, thyroid function tests (for patients taking ethionamide or para-aminosalicylic acid), OBR administration, and collection of AEs/IREs and concomitant medications.

G. Investigator Networks to be involved in the Trial

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	Philippines

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