Clinical Trials Register

Summary
EudraCT Number:	2012-004473-25
Sponsor's Protocol Code Number:	242-12-232
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2018-09-14
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

2012-004473-25

A.3

Full title of the trial

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 Antituberculosis Drugs

A.3.1

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

Phase 1, Open-label, Multiple-dose, and Age De-escalation Trial to Assess the how the drug is processed by the body to determine safety, and Tolerability of Delamanid (OPC 67683) in Pediatric patients with Multidrug-resistant Tuberculosis on Therapy With a Background
Regimen of Antituberculosis Drugs

A.4.1

Sponsor's protocol code number

242-12-232

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	Europa-Allee 52
B.5.3.2	Town/ city	Frankfurt am Main
B.5.3.3	Post code	60327
B.5.3.4	Country	Germany
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.3.2	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.3.9.4	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.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.3.2	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.3.9.4	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: 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.3.2	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.3.9.4	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.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 (MDRTB) 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 determine the pharmacokinetics (PK) of delamanid and its metabolites in combination with an OBR in pediatric MDR-TB patients

E.2.2

Secondary objectives of the trial

- To determine the safety and tolerability of delamanid in combination with an OBR in pediatric MDR-TB patients
- 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:
- 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 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:
 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 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 informed consent form (Groups 1 and 2 only)

E.5 End points

E.5.1

Primary end point(s)

Pharmacokinetic parameters of delamanid and its main metabolites

E.5.1.1

Timepoint(s) of evaluation of this end point

Plasma samples will be performed in Day 1 (first dose), Day 10 (last dose) and Day 17

For children with tuberculosis meningitis, CSF concentrations of delamanid will be determined after lumbar puntcure

E.5.2

Secondary end point(s)

Safety assessments including:
- Vision and neurologic assessments
- Standard 12-lead ECG, intensive ECG monitoring.
- Laboratory testing, including coagulation testing
- Monitoring of electrolytes especially from birth to 2 years of age

E.5.2.1

Timepoint(s) of evaluation of this end point

- Safety assessments on Days 1, 10 (Groups 1 and 2 only),
and 18

Follow-up Period: Day 19 to Day 40 (2 days)
- All patients who complete their last scheduled visit will be contacted by telephone 28 to 30 days after the last dose of delamanid to assess any new or ongoing adverse events.

- Patients who terminate from the trial prior to their last scheduled visit will be contacted by telephone or home visit 14 days (2 days) after the last dose of delamanid to assess for any new or ongoing adverse events.

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

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

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)

Yes

E.7.1.1

First administration to humans

Yes

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)

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

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

November 2017

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial days

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.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

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 old

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: Day 19 to Day 40 (+/-2 days)
On Day 40 (+/-2 days), patients who complete their last scheduled visit will be
contacted by phone 28 to 30 days after the last dose of
delamanid to assess new or ongoing adverse events.

Patients who terminate from the trial prior to their last
scheduled visit will be contacted by telephone or home visit
14 days (+/-2 days) after the last dose of delamanid to assess for
any new or ongoing adverse events.

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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