Clinical Trials Register

Summary
EudraCT Number:	2014-004554-34
Sponsor's Protocol Code Number:	2014-004554-34
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-09-16
Trial 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
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2014-004554-34

A.3

Full title of the trial

An open label, explorative pharmacokinetic trial, to investigate the Cytochrome (CYP) CYP3A4, - 2E1 and – 1A2 clearance in Obese – versus Non Obese Children by use of well-tested probes (midazolam, chlorzoxazone, caffeine)

A.3.1

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

Drug metabolism related to obesity

A.4.1

Sponsor's protocol code number

2014-004554-34

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bispebjerg Hospital
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Klinisk Farmakologisk Afdeling Bispebjerg Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Klinisk Farmakologisk Afdeling, Bispebjerg Hospital
B.5.2	Functional name of contact point	Helle Holst
B.5.3	Address:
B.5.3.1	Street Address	Bispebjerg Bakke 23, opgang 51
B.5.3.2	Town/ city	Copenhagen NV
B.5.3.3	Post code	2400
B.5.3.4	Country	Denmark
B.5.6	E-mail	helle.holst.01@regionh.dk

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	Yes
D.2.1.1.1	Trade name	Klorzoxazon "DAK"
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.3.4	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	CHLORZOXAZONE
D.3.9.1	CAS number	95-25-0
D.3.9.4	EV Substance Code	SUB06215MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	250 to 500
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	Yes
D.2.1.1.1	Trade name	Midazolam
D.2.1.1.2	Name of the Marketing Authorisation holder	Hameln
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MIDAZOLAM
D.3.9.1	CAS number	59467-70-8
D.3.9.4	EV Substance Code	SUB08950MIG
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	0,001
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

E.1.1.1

Medical condition in easily understood language

We want to investigate, whether the activity of some of the most important drug metabolizing enzymes, is altered in obese children versus non-obese children.

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10029885
E.1.2	Term	Obesity, unspecified
E.1.2	System Organ Class	100000004861

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Research hypotheses:
• CYP2E1- clearance is higher in obese children versus non-obese children
• CYP3A4- clearance is lower in obese children versus non-obese children
• CYP1A2- clearance is altered in obese children versus non-obese children
Primary objectives:
We want to investigate, whether the activity of some of the most important drug metabolizing enzymes, is altered in obese children versus non-obese children.
Primary endpoints:
These are the combined primary endpoints: Clearance of CYP2E1-, CYP1A2- and CYP3A4 substrates, defined by using well-tested probes (midazolam, chlorzoxazone and caffein).
CYP2E1-, CYP1A2- and CYP3A4 clearance will be determined by following methods:
• Chlorzoxazone multi-sample method (CYP2E1 activity)
• Caffeine urinary metabolic ratio method (CYP1A2 activity)
• Midazolam microdosing method (CYP3A4 activity)

Cmax, Tmax , AUC, T1/2, and Vd will be defined blood samples collected at specific times and from urine collected for 24 hours.

E.2.2

Secondary objectives of the trial

Secondary objective
From and exploratory objective, we want to investigate whether an altered enzyme activity of CYP3A4, CYP2E1 and CYP1A2, is accociated with metabolic syndrome.
Secondary endpoints:
- Lipid profile
- Inflammatory markers
- Steatosis

Markers of metabolic syndrome and steatosis:
-Lipid profile: LDL, HDL, total cholesterol, triglyceride
-Markers of insulin-resistance: Hba1C, Blood Glucose, Insuline
-Inflammatory markers: TNFalfa, interleukin 6, leptin, adiponectin and CRP
-Liver test: ASAT, ALAT, alkaline phosphatase, bilirubin, albumine and liver MR scanning (to verify steatosis)
-24-hour blood pressure

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Obese children (BMI ≥ 99 % percentile)
• Healthy non-obese children (BMI≤ 90 % percentile)
• Age 11-18 years
• Both genders (block stratified)
• Postmenarche (females)
• Written informed consent from both parents (age<18)
Females included will be post menarche (Tanner stage 4) in order to avoid bias, as maturation of CYP1A2 activity mirrors pubertal growth, which peaks early in females.

E.4

Principal exclusion criteria

• Acute or chronic Liver diseases
• Other chronic diseases, except from allergic rhinitis, rash etc.
• Intake of drugs known to induce of inhibit CYP2E1-, CYP3A4 and/or CYP1A2, including paracetamol, ciprofloxacin, azithromycin, ketoconazol, estradiol etc.
• Citrus fruit
• Alcohol intake within minimum 72 hours
• Caffeine (Coca Cola©, coffee and tea) intake 48 h prior to administration of the caffeine-probe
• Smoking 96 hours prior to administration of the caffeine-probe, screening test will be performed (nicotine metabolite: cotinine)
• Kidney disease and dialysis
• Pregnancy (test will be performed)
• Known hypersensitivity to chlorzoxazone, midazolam or caffeine
• vigorous exercise 24 hours before administration

E.5 End points

E.5.1

Primary end point(s)

These are the combined primary endpoints: Clearance of CYP2E1-, CYP1A2- and CYP3A4 substrates, defined by using well-tested probes (midazolam, chlorzoxazone and caffein).
CYP2E1-, CYP1A2- and CYP3A4 will be determined by following methods:
•Chlorzoxazone clearance (CYP2E1 activity)
•Caffeine urinary metabolic ratio method (CYP1A2 activity)
•Midazolam microdosing methodErythromycin breath test (CYP3A4 activity)

E.5.1.1

Timepoint(s) of evaluation of this end point

All of the three probes will be given as single doses (t=0) to all included trial subjects (Chlorzoxazone and Caffeine orally and midazolam intravenousmethyl-erythromycin i.v.). Blood samples will be taken at specific times: After administration of chlorzoxazone: (t=10, 20, 30, 40, 50, 60, 90, 120 min and hourly for the next 4 hours) After administration of midazolam: Group 1 (25 obese and 25 non.obese trial participants): t=0, 2, 10, 20, 45, 90, 150, 210, 270, 360, 420, 480, 540 min. Group 2(25 obese and 25 non-obese trial participants): t=0, 5, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540 min.
Urine will be collected completely for 24 hours post-dose.

E.5.2

Secondary end point(s)

For Chlorzoxazone and midazolam: Cmax (maximum plasma concentration), Tmax (time to maximum plasma concentration), AUC (areal under the drug concentration /time curve), T1/2 (elimination half time) and Vd (volume of distribution) will be defined from blood samples taken at specific times.

Lipid profile (LDL, HDL, total cholesterol, triglyceride), markers of insulin- resistance (Hba1C, Blood Glucose, insuline) ,inflammatory markers (TNFα, interleukin 6, leptin, adiponectin and CRP), liver tests (ASAT, ALAT, alkaline phosphatase, bilirubin, albumin), and creatinine .

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline blood samples, and after administration of chlorzoxazone: (t=10, 20, 30, 40, 50, 60, 90, 120 min and hourly for the next 4 hours) After administration of midazolam: Group 1 (25 obese and 25 non.obese trial participants): t=0, 2, 10, 20, 45, 90, 150, 210, 270, 360, 420, 480, 540 min. Group 2(25 obese and 25 non-obese trial participants): t=0, 5, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540 min.
Urine will be collected completely for 24 hours post-dose.

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

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

An open exploratory pharmacokinetic trial

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

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

obese versus non-obese children

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned 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)

F.1.1.5

Children (2-11years)

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

Yes

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-10-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-05-31

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