Clinical Trials Register

Summary
EudraCT Number:	2013-005010-36
Sponsor's Protocol Code Number:	CR-TFB-2013/502
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:	2014-01-08
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
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

2013-005010-36

A.3

Full title of the trial

The effect of protracted saphenous nerve and obturator nerve blockade versus saphenous nerve blockade versus local infiltration analgesia in opioid consumption, pain, blockade duration of action and mobilization after total knee arthroplasty.

A.3.1

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

The effect of prolonged saphenous nerve and obturator nerve blockade compared with saphenous nerve blockade compared with infiltration of local anesthetic in the tissue around the knee joint, on consumption of morfine, pain, time of duration and mobilization after knee replacement.

A.3.2

Name or abbreviated title of the trial where available

Prolonged blockade after total knee arthroplasty

A.4.1

Sponsor's protocol code number

CR-TFB-2013/502

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	Thomas Fichtner Bendtsen
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	Hospital of Silkeborg
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	Hospital of Silkeborg
B.5.2	Functional name of contact point	Centre of elective surgery
B.5.3	Address:
B.5.3.1	Street Address	Falkevej 3
B.5.3.2	Town/ city	Silkleborg
B.5.3.3	Post code	8600
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004525883172
B.5.6	E-mail	charlotte.runge@aarhus.rm.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	Marcain-adrenalin
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca A/S
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	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Perineural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	bupivacaine
D.3.9.3	Other descriptive name	BUPIVACAINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00902MIG
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	46,25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ADRENALIN
D.3.9.3	Other descriptive name	adrenalin
D.3.9.4	EV Substance Code	SUB63123
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	46,25
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	Yes
D.2.1.1.1	Trade name	Catapresan
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
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	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Perineural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	clonidine
D.3.9.3	Other descriptive name	CLONIDINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB01362MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	37,5
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	Yes
D.2.1.1.1	Trade name	Dexagalen
D.2.1.1.2	Name of the Marketing Authorisation holder	GALENpharma GmbH
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	Concentrate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Perineural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	dexamethasone
D.3.9.3	Other descriptive name	DEXAMETHASONDIHYDROGENPHOSPHAT DISODIUM
D.3.9.4	EV Substance Code	SUB32979
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	4
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	Yes
D.2.1.1.1	Trade name	natriumklorid
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun Medical A/S
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Perineural use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	natriumchloride
D.3.9.3	Other descriptive name	SODIUM CHLORIDE SOLUTION 0.9%
D.3.9.4	EV Substance Code	SUB20079
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Perineural use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The medical condition to be examined in this study is the first postoperative period after total knee replacement with a view to pain management.

E.1.1.1

Medical condition in easily understood language

The medical condition to be examined in this study is the first time after total knee replacement with a view to pain management.

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10038286
E.1.2	Term	Regional nerve block
E.1.2	System Organ Class	100000004865

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 aim is to investigate the effect of combined saphenous nerve and obturator nerve blockade with a mixture of local analgesics; bupivacain, adrenalin, clonidine and dexamethasone (protacted mixture), compared with saphenous nerve blockade with protracted mixture, compared with local infiltration analgesia in the tissue around the knee joint on opioid consumption after total knee arthroplasty.

E.2.2

Secondary objectives of the trial

Secondary it is to investigate the effect of combined saphenous nerve and obturator nerve blockade with protracted mixture, compared with saphenous nerve blockade with protracted mixture, compared with local infiltration analgesia in the tissue around the knee joint on pain, duration and mobilization after total knee arthroplasty.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age> 50 years
• Patients set to cemented Total knee arthroplasty in spinal block
• Patients who have given written informed consent to participate in the study after having understood the contents of the protocol and limitations fully
• ASA 1-3

E.4

Principal exclusion criteria

• Patients who can not cooperate with the investigation
• Patients who do not understand or speak Danish
• Patients receiving immunosuppressive therapy
• Patients with a treatment-dependent diabetes mellitus
• Patients with known neuropathy in the lower limbs
• Allergy to those used in the study drugs
• Alcohol and / or drug abuse - the investigator's opinion
• Patients who can not tolerate NSAIDs
• Fixed several times daily consumption of strong opioids (morphine, ketogan,
Oxynorm, methadone, fentanyl)

E.5 End points

E.5.1

Primary end point(s)

• Consumption of opioid from 1 to 24 hours postoperatively, via patient-controlled analgesia-(PCA) pump. The patient is instructed to self-administer a dose when NRS (numeric rating scale) > 3 at rest.

E.5.1.1

Timepoint(s) of evaluation of this end point

Time 24 hours postoperatively.

E.5.2

Secondary end point(s)

• The total consumption of opioid from 1 to 48 hours postoperatively , at the PCA pump .
• Pain Score with NRS - with values from 0 to 10, with 0 being no pain and 10 being the worst pain imaginable, by passive flexion of the knee joint from 0-90 degrees time 1, 2 , 5, 7 , 24, 31 and 48 hours postoperatively .
• Pain Score at rest recorded time 1, 2 , 5, 7 , 24, 31 and 48 hours postoperatively . Where highest score since last score recorded.
• Patient - record time of initial postoperative opioid pain breakthrough ( NRS > 3 at rest)
• Nausea Score with NRS ( numeric rating scale ) - with values from 0 to 10, where 0 is no nausea and 10 being the worst nausea time 1, 2 , 5, 7 , 24, 31 and 48 hours postoperatively .
• Number of vomiting between 24 hours postoperatively .
• Consumption of Ondansetron between 24 hours postoperatively .
• Number of nights with patient-reported sleep disruptions during 48 hours postoperatively
• Duration of stay (length of stay , LOS ) in the observation unit (post anesthesia care unit , pacu). The end time for the LOS in PACU recorded at the time when the patient meets DASAIMs (Danish Society of Anaesthesiology and Intensive Therapy) printing criteria - regardless of Pacu 's logistics in general.
• Discharge time from the hospital.
• Patient - recorded consumption of opioids from the discharge date from hospital to ambulatory monitoring 2 weeks postoperatively .
• Quantitative satisfaction of pain 2 weeks postoperatively by indicating satisfaction score (0-10 ) , where the value 0 = complete dissatisfaction and 10 = complete satisfaction.
• Mobilization and Function:
• Isometric tests of muscle strength in the hip adductors by a handheld dynamometer before bringing nerve blokack (1-2 hours preoperatively) and again 30 minutes after the application of obturator nerve blockade. The patient performed 4-10 measurements with a 30 second break in between each measurement. The difference between the highest value for the test before and after blockade construction calculated.
• The first time the patient after the operation mobilized to walk with or without support in the form of a walker , crutches or caregivers.
• Timed Up and Go test ( TUG ) performed 1-2 hours preoperatively , 24 hours and 2 weeks postoperatively . In the test , the patient rise from a chair and walk round 3 metres and sit on the chair again . The time for completion of the test are recorded .
• Cumulated Ambulation Score ( CAS) to illustrate the basic level of mobilization (50 ) is carried out 1-2 hours pre-operatively, during the first postoperative mobilization, and time 24 hours postoperatively . The patient scores based on 3 gradations according to their ability to mobilize up and in bed, getting up from a chair and walk with or without aids in the form of high walker or crutches .
• Movement of the knee joint is tested 1-2 hours preoperatively , 24 hours and 2 weeks postoperatively . The patient ability to extend and flex in the knee joint are recorded. The tests are performed with a goniometer.

E.5.2.1

Timepoint(s) of evaluation of this end point

1-2 hours preoperatively evaluation:
- Cumulative Ambulation Score (CAS)
- Timed up and go test (TUG)
- Isometric tests of muscle strength in the hip adductor
Time 1., 2., 5., 7., 24., 31., 48. hours postoperatively evaluation:
- Pain score at rest and by passive flexion of the knee joint
- Nausea Score
Time 24 hours postoperatively evaluation:
- Number of vomiting
- Consumption of Ondansetron
- CAS
- TUG
- Movement of the knee joint
Time 48 hours postoperatively evaluation:
- Total consumption of opioid at the PCA pump
- Number of nights with patient-reported sleep disruptions
Time 2 weeks postoperatively evaluation:
- Patient-recorded consumption of opioids
- Quantitative satisfaction score of pain
- TUG
- Movement of the knee joint

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

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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)

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

Yes

E.8.2.2

Placebo

Yes

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

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.8.9.1

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

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:

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

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

2014-01-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-12

P. End of Trial
P.	End of Trial Status	Completed

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Orphan Designation Number:
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