Clinical Trials Register

Summary
EudraCT Number:	2012-000447-27
Sponsor's Protocol Code Number:	USKH_VL1
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2012-04-23
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

Germany - BfArM

A.2

EudraCT number

2012-000447-27

A.3

Full title of the trial

Open Label Study for the Functional Characterization of Drug Metabolism and Transport in patients before routine visceral surgery

Offene Studie zur funktionellen Charakterisierung von Arzneimittelmetabolismus und –transport in Patienten vor abdominellen Routineeingriffen

A.3.1

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

Open Label Study for the Functional Characterization of Drug Metabolism and Transport in patients before routine visceral surgery

A.4.1

Sponsor's protocol code number

USKH_VL1

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	Universitätsklinikum Schleswig-Holstein, Campus Kiel
B.1.3.4	Country	Germany
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	BmBf
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Universitätsklinikum Schleswig-Holstein, Campus Kiel
B.5.2	Functional name of contact point	Klinik für Allgemeine Chirurgie
B.5.3	Address:
B.5.3.1	Street Address	Arnold-Heller-Str. 3, Haus 18
B.5.3.2	Town/ city	Kiel
B.5.3.3	Post code	24105
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4943150020401
B.5.5	Fax number	-4943150020404
B.5.6	E-mail	witigo.vonschoenfels@uksh.de

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	Codeintropfen-CT
D.2.1.1.2	Name of the Marketing Authorisation holder	CT Arzneimittel
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.3.1	Product name	Codeinphosphat-Hemihydrat
D.3.4	Pharmaceutical form	Oral drops
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	CODEINE PHOSPHATE HEMIHYDRATED
D.3.9.4	EV Substance Code	SUB30038
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	21,72
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-ratiopharm
D.2.1.1.2	Name of the Marketing Authorisation holder	ratiopharm
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.3.1	Product name	Midazolam
D.3.4	Pharmaceutical form	Oral drops, solution
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	MIDAZOLAM
D.3.9.1	CAS number	59467-70-8
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB08950MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	Yes
D.2.1.1.1	Trade name	Pravastatin
D.2.1.1.2	Name of the Marketing Authorisation holder	HEXAL
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.3.1	Product name	Pravastatin-Natrium
D.3.4	Pharmaceutical form	Capsule, hard
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.3.9.1	CAS number	81131-70-6
D.3.9.3	Other descriptive name	PRAVASTATIN SODIUM
D.3.9.4	EV Substance Code	SUB04011MIG
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: 4
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.2.1.2	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.3.1	Product name	Torasemid
D.3.4	Pharmaceutical form	Capsule, hard
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	TORASEMIDE
D.3.9.1	CAS number	56211-40-6
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB11195MIG
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	0,25
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.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

Pharmacokinetic trial in patients, with a good general condition before standard abdominal surgery

E.1.1.1

Medical condition in easily understood language

good general condition, absence of any decompensated condition. Inclusion of patients with compensated impaired liver or renal function

E.1.1.2

Therapeutic area

Not possible to specify

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 establish a cohort of patients before routine visceral surgery. This cohort should serve as a patient cohort for the related healthy volunteer study in Tübingen, Germany (IKP243; EudraCT: 2011-002291-16).
Functional pharmacokinetic phenotyping of major drug metabolism pathways (cytochrome P450 1A2, 2C9, 2D6, 3A4/5, and uridine glucuronosyl transferase 2B4/7) and drug transporter (OATP1B1) pathways.
Functional measurement of liver metabolic function

E.2.2

Secondary objectives of the trial

Noninvasive functional characterization of liver, heart, and kidneys using MRI
Detailed multi-scale modeling of individuals and personalized prediction of liver detoxification capacity based on biomarkers
Sampling of biological material (serum, plasma, peripheral blood cells)
Generation of hypotheses and identification and evaluation of (epi)genetic, genomic, transcriptomic, proteomic and metabolic biomarkers.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients before elective visceral surgery including patient with Child A/B liver cirrhosis and/or compensated renal impairment (grade 1-2) without severe edema, ascites etc..
2. Written informed consent obtained prior to study entry including informed consent for genetic research
3. Both genders (male and female)
4. Adults aged ≥18 to <85 years
5. BMI of subjects of both genders not less than 18 kg/m² and/or not greater than 75 kg/m².
6. Smokers and nonsmokers.
7. Willingness to meet the study instructions and to co-operate with the study personal
8. Female subjects will only be included if they have negative pregnancy test during screening and the willingness not to become pregnant during the entire study period by practicing reliable methods of contraception as specified in the respective protocol section.

E.4

Principal exclusion criteria

1. Participation in a clinical trial involving the administration of medicines during the last 30 days or use of any other investigational or non-registered drug or vaccine during the study period or within 30 days preceding the first dose of study drugs
2. Blood, plasma or thrombocyte donation during the last 30 days prior to application of the test drugs.
3. Pregnancy or lactation period
4. Bradycardia, prolonged PQ-time, AV-block.
5. Raynaud’s syndrome
6. Short bowel syndrome, previous bariatric surgery, chronic inflammatory bowel disease (Crohn disease, ulcerative colitis), malabsorption, celiac disease, previous operative intestinal anastomoses such as Y-Roux as they may interfere with the PK of the study drug
7. Patients with any decompensated medical condition, cardiac failure, edema, active infection, sepsis, open wounds, necrosis, uncontrolled psychiatric disorder or psychosis.
8. Inability to walk, dementia, parenteral nutrition or nutrition over enteral feeding tube.
9. Change of the concomitant standard medication of the patients within the last two weeks unless allowed for the specific drug as detailed in the “Concominant Medication” section 3.4.2.
10. Active alcohol and/or drug addiction and/or active abusive use of medicaments.
11. Transplanted patients.
12. History of severe hypersensitivity reactions and anaphylaxis.
13. History of intolerance or allergic reactions to or contraindication for any of the IMPs. If intolerance, allergic reactions to or contraindication against one of the IMPs is known, enrolment is possible but application of the concerned substance must not be allowed in the affected individual and all siblings (e.g. allergy to sulphonamide prohibits specifically the application of torasemide)
14. Contraindication against MRI, e.g. pacemakers, cochlea implants, aneurysm clips, claustrophobia, allergy against gadolinum-containing contrast agents. If allergic reactions against gadolinum-containing contrast agents is known, enrolment is possible but the affected patient is excluded from MRI.
15. Inability or unwillingness to provide informed consent and to abide by the requirements of the study

E.5 End points

E.5.1

Primary end point(s)

Blood levels and clearance (dose/AUC) of midazolam, torasemide, codeine, pravastatin
Endogenous CYP3A markers (urinary 6betaOH cortisol/cortisol ratio or plasma 4-OH cholesterol (CYP3A4/5))
Blood levels and clearance (dose/AUC) of caffeine, paraxanthine, 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 5-acetylamino-6-amino-3-methyluracil (AAMU)
PK variables are:
Area under plasma concentration versus time curve (AUC), oral clearance (CL/F), maximum plasma drug concentration (Cmax), terminal half-life (t½), time to reach Cmax (tmax) and oral volume of distribution (V/F)

E.5.1.1

Timepoint(s) of evaluation of this end point

While visit 2

E.5.2

Secondary end point(s)

Plasma metabolite profiles and PK parameters (1-OH-midazolam, OH-torasemide (M1), carboxy-torasemide (M5), morphine, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide, norcodeine, normorphine)
Urinary levels of 1-OH-midazolam, codeine-3-glucuronide, codeine-6-glucuronide, morphine-6-glucuronide, morphine-3-glucuronide, norcodeine, normorphine, pravastatin, AFMU, AAMU
Plasma and/or urinary metabolic ratios of parent compound versus the metabolites generated by the enzymes of interest (Table 5).
Following selected secondary endpoints will be calculated per phenotyping probe:
Pravastatin
-Elimination rate constant of pravastatin as an indicator of hepatic OATP1B1 activity
Codeine:
-Renal excretion (Ae) of morphine as an indicator of CYP2D6 activity
-Renal excretion (Ae) of codeine-glucuronides and morphine-glucuronides as indicators of UGT2B4 and -2B7 activity
-Renal excretion (Ae) of norcodeine and normorphine as indicators of CYP2C8 and CYP3A4 activities
Torasemide:
-Metabolite formation clearances for torasemide as indicators of hepatic CYP2C9 activity
13C-caffeine test:
-Urinary metabolite ratio of caffeine metabolites AAMU and AFMU as indicators of hepatic NAT2 activity
-1,7-Dimethylxanthine (paraxanthine) over caffeine plasma metabolic ratios at 2 hours as an indicator of hepatic CYP1A2 activity
Laborchemical parameters for liver and renal function
Liver MRI (facultative): Cross-sectional area (S), maximum velocity (Vmax), Mean velocity (Vmean), and flow rate (Q) of portal and proper hepatic artery; liver volume (LV)
Cardiac MRI (facultative): left / right ventricular end-diastolic volume (LVEDV, RVEDV), left / right ventricular end-systolic volume (LVESV, RVESV), left / right ventricular ejection fraction (LVEF, RVEF), left / right ventricular stroke volume (LVSV / RVSV)
Body composition MRI (facultative): visceral adipose tissue, subcutaneous adipose tissue, sagittal and transverse abdominal diameters
Spirometry (facultative): minute ventilation (VE), oxygen consumption (VO2), carbon dioxide production (VCO2), heart rate (HR), blood pressure (RR) and respiratory frequency (RF).

E.5.2.1

Timepoint(s) of evaluation of this end point

while visit 2

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

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

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

closure of clinical trial data base

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

E.8.9.2

In all countries concerned by the trial years

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

200

F.1.3

Elderly (>=65 years)

Yes

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

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)

standart treatment according to the surgery

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-07-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-09

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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