Clinical Trials Register

Summary
EudraCT Number:	2009-013165-25
Sponsor's Protocol Code Number:	TAK-491_109
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2013-05-07
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

2009-013165-25

A.3

Full title of the trial

A Comparative Single-Dose Pharmacokinetic and Safety Study of TAK-491 Between
Infants, Children, and Adolescents with Hypertension and Healthy Adults

A.3.1

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

A research project to find out how safe and effective a single dose of TAK-491 research medicine is, after it has been taken by children aged 6 months – 16 years who have high blood pressure. Healthy adults will also be included in this research project to provide a comparison.

A.4.1

Sponsor's protocol code number

TAK-491_109

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01078376

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/39/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Takeda Global Research & Development Centre (Europe) Ltd.
B.1.3.4	Country	United Kingdom
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	Takeda Global Research & Development Centre (Europe)
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Takeda Global Research & Development Centre (Europe) Ltd.
B.5.2	Functional name of contact point	Clinical Study Manager
B.5.3	Address:
B.5.3.1	Street Address	61 Aldwych
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC2B 4AE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+440203 116 8000
B.5.5	Fax number	+440203 116 8199
B.5.6	E-mail	clinicaloperations@tgrd.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	azilsartan medoxomil
D.3.2	Product code	TAK-491
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	azilsartan medoxomil
D.3.9.1	CAS number	863031-24-7
D.3.9.2	Current sponsor code	TAK-491
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	40
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	azilsartan medoxomil
D.3.2	Product code	TAK-491
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	azilsartan medoxomil
D.3.9.1	CAS number	863031-24-7
D.3.9.2	Current sponsor code	TAK-491
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	20
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	azilsartan medoxomil
D.3.2	Product code	TAK-491
D.3.4	Pharmaceutical form	Granules for oral suspension
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	azilsartan medoxomil
D.3.9.1	CAS number	863031-24-7
D.3.9.2	Current sponsor code	TAK-491
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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

Hypertension

E.1.1.1

Medical condition in easily understood language

High blood pressure

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10020772
E.1.2	Term	Hypertension
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10015488
E.1.2	Term	Essential hypertension
E.1.2	System Organ Class	10047065 - Vascular disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objectives of this study are to determine the pharmacokinetic parameters, safety, and tolerability of a single dose of TAK-491 in pediatric subjects with hypertension, who are between the ages of 6 months to 16 years (including those up to their 17th birthday) and gendermatched healthy adult subjects aged 18 to 45 years, inclusive.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Main Criteria for Inclusion:
Pediatric subjects:
boys or girls must have a diagnosis of hypertension (SBP and / or DBP ≥ 95th percentile for gender / age / height), aged ≥6 months to <17 years, subjects 6 years of age and older must have the ability to swallow a tablet;
subjects qualifying for Cohorts 1 and 2 must weigh at least 20 kg and up to 100 kg; subjects qualifying for Cohort 3 must weigh at least 6.5kg;
subjects must have been at a constant weight, or expected weight gain for that particular age, for 30 days with no change to the dose of their diuretic drugs;
subjects in Cohort 3 may be a renal transplant patient if all other inclusion and none of the exclusion criteria are met, time post-transplant has been > 6 months prior to Check-in (Day-1) with stable graft function (and estimated GFR ≥30mL/min/1.73 m2) for at least 6 months, with no change to medications such as immunosuppressive therapy for at least 60 days prior to Check-in (Day-1), and no evidence of transplant renal artery stenosis or anemia.

Adult subjects for Cohort 1: must be healthy male or females;
aged 18 to 45 years, inclusive;
have diastolic blood pressure (DBP) between 60 and 90 mm Hg, and systolic blood pressure (SBP) between 100 and 140 mm Hg, inclusive at Screening or Check-in (Day-1);
have a minimum body weight of 50kg, with a body mass index of 18 to 32 kg/m2 (inclusive) at Screening.

E.4

Principal exclusion criteria

Main Criteria for Exclusion:
Pediatric subjects:
current treatment with more than 2 antihypertensive agents;
sitting trough clinical SBP/DBP exceeding the 99th percentile for age/gender/height by >15/>10 mm Hg;
the subject has renovascular disease affecting both kidneys or solitary kidney, including dialysis treatment, severe nephrotic syndrome not in remission;
for Cohorts 1 and 2 only a previous renal transplant.

All subjects:
history or clinical manifestations of significant disorders;
acute, clinically significant illness within 30 days prior to check-in (Day-1); hemodynamically significant left ventricular outflow obstruction due to aortic
valvular disease, cardiomyopathy, or uncorrected aortic coarctation;
diagnosis of malignant or accelerated hypertension;
severe hepatic impairment;
alanine aminotransferase, aspartate aminotransferase >2 times the upper limit of normal, or total bilirubin >1.5 times the upper limit of normal;
glycosylated hemoglobin >8.5%;
hyperkalemia;
creatinine clearance <30 mL/min/1.73 m2;
serum albumin <2.5 g/dL;
intake of potent CYP enzyme inducers or inhibitors or any other prespecified excluded medication, allergy to an angiotensin type II receptor blocker or any of the excipients;
pregnancy.

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints:
Primary plasma pharmacokinetic endpoints for TAK-536 and TAK-536 M-II are as follows: area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC[0-tlqc]), area under the plasma concentration-time curve from time 0 to infinity (AUC[0-inf]), maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination half-life (T1/2), and apparent oral clearance (CL/F) (TAK-536 only, assuming complete conversion from TAK-491 to TAK-536).

For Cohorts 1 and 2 urine pharmacokinetic endpoints for TAK-536 and TAK-536 M-II are as follows: total amount of drug excreted in urine from time 0 to 24 hours postdose (Ae[0-t]), fraction of unchanged drug excreted in urine from 0 to 24 hours postdose (Fe%), and renal clearance (CLr) from 0 to 24 hours postdose.

E.5.1.1

Timepoint(s) of evaluation of this end point

For Cohorts 1 and 2, one blood sample (2 mL for all pediatrics and 6 mL for adults in Cohort 1)
will be obtained at the following designated time points for pharmacokinetic analysis of the
plasma:
Day 1: predose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours postdose.
For Cohort 3, one blood sample (all samples 1 mL except the 0.25 and 1 hour which are 2 mL)
will be obtained at the following designated time points for pharmacokinetic analysis of the
plasma:
Day 1: predose and at 0.25, 1, 6, 12, and 24 hours postdose.
TAK-536 and TAK-536 M-II will be analyzed in all samples. TAK-491F will be analyzed in all
predose, 0.25 and 1 hour samples and the 0.5 hour samples of Cohorts 1 and 2.

E.5.2

Secondary end point(s)

For Cohorts 1 and 2 urine pharmacokinetic endpoints for TAK-536 and TAK-536 M-II are as follows: total amount of drug excreted in urine from time 0 to 24 hours postdose (Ae[0-t]),
fraction of unchanged drug excreted in urine from 0 to 24 hours postdose (Fe%), and renal clearance (CLr) from 0 to 24 hours postdose.

E.5.2.1

Timepoint(s) of evaluation of this end point

9.1.13.3 Collection of Urine for Pharmacokinetic Sampling
For Cohorts 1 and 2 only, urine samples will be obtained, when possible, at the following
designated time points from subjects for pharmacokinetic analysis of TAK-536 and TAK-536
M-II in urine:
Day 1: predose (a single collection between -12 to 0 hours), 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours postdose.

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetic

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

Yes

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

Yes

E.8.1.7.1

Other trial design description

Comparative

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

Yes

E.8.2.3.1

Comparator description

healthy adult subjects who are gender-matched to the pediatric subjects of Cohort 1

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

E.8.6.3

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

United States

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

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)

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)

Yes

F.1.2.1

Number of subjects for this age range:

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

Yes

F.3.2

Patients

Yes

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

Yes

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

Peadiatric Subjects.

See Protcocol sections 15 (ETHICAL ASPECTS OF THE STUDY) and 16 (ETHICAL CONSIDERATIONS FOR PEDIATRIC SUBJECTS) for details of consent/assent.

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)

A follow-up phone call to the subjects will be made on study Day 6 (±1 day) and study Day 15 (±1 day) for the assessment of AEs and concomitant medication.

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:	United States

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