Clinical Trials Register

Summary
EudraCT Number:	2016-000896-26
Sponsor's Protocol Code Number:	ETLAS
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:	2016-03-10
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

2016-000896-26

A.3

Full title of the trial

Effect of Tadalafil on cerebral large arteries in stroke patients.

Effekten af Tadalafil på hjernens store arterier i patienter med apopleksi.

A.3.1

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

Tadalafil and stroke.

Tadalafil og slagtilfælde.

A.3.2

Name or abbreviated title of the trial where available

Tadalafil and apoplexia.

Tadalafil og apopleksi.

A.4.1

Sponsor's protocol code number

ETLAS

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	Herlev Gentofte 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	Herlev Gentofte 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	Herlev Gentofte Hospital
B.5.2	Functional name of contact point	Christina Rostrup Kruuse
B.5.3	Address:
B.5.3.1	Street Address	Herlev Ringvej 75
B.5.3.2	Town/ city	Herlev
B.5.3.3	Post code	2730
B.5.3.4	Country	Denmark
B.5.4	Telephone number	4538681233
B.5.6	E-mail	christina.rostrup.kruuse@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	Cialis
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly
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	Capsule
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	TADALAFIL
D.3.9.1	CAS number	171596-29-5
D.3.9.4	EV Substance Code	SUB12602MIG
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.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	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Stroke and small vessel disease.

Apopleksi og småkarssygdomme.

E.1.1.1

Medical condition in easily understood language

Stroke.

Slagtilfælde.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10070879
E.1.2	Term	Cerebral small vessel ischemic disease
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10076994
E.1.2	Term	Lacunar stroke
E.1.2	System Organ Class	10029205 - Nervous system 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 main objective is to investigate the effect of the phosphodiesterase-5-inhibitor (PDE-5-inhibitor) tadalafil on blood flow velocity in the brain's large arteries and cortical brain oxygenation in patients with former lacunar strokes caused by small vessel diseases.

Formålet med forsøget er at undersøge phosphodiesterase-5-hæmmeren (PDE-5-hæmmeren) tadalafils virkning på blodgennemstrømningen i hjernens store arterier samt kortikal iltmætning i hjernen hos patienter som tidligere har haft små blodpropper i hjernen forårsaget af småkarssygdomme.

E.2.2

Secondary objectives of the trial

Secundary objectives is to investigate if tadalafil improves the peripheral endothelial function measured as an improved blood vessel respons in the fingers after a short occlusion of blood suply to the arm measured with EndoPAT2000.
Besides that there will be a change in endothelial function markers in the blood after a single dosis of tadalafil and that these changes correspond to the measured peripheral or central blood vessel function.
Feasibility of applying tadalafil in stroke patients.

Sekundære formål er at undersøge om tadalafil forbedrer den perifere endothelfunktion målt som forbedret blodkarrespons i fingrene efter kortvarig afklemning af blodforsyningen til armen målt med EndoPAT2000.
Derudover at der sker en ændring af endothelfunktionsmarkører i blodet efter en enkelt dosis tadalafil og at disse ændringer svarer til den målte perifere eller centrale blodkarsfunktion.
Praktisk mulighed for at bruge tadalafil hos apopleksipatienter.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Radiological evidence of cerebral small vessel disease defined as: MRI evidence of lacunar infarct(s) (≤ 1.5 cm maximum diameter) and/or confluent deep white matter leukoaraiosis (≥ grade 2 on Fazekas scale).
2. Clinical evidence of cerebral small vessel disease defined as:
a) lacunar stroke syndrome with symptoms lasting >24 hours, occurring at least 5 months previously;
OR
b) transient ischaemic attack lasting < 24 hours with limb weakness, hemi-sensory loss or dysarthria at least 5 months previously AND with MR DWI performed acutely showing lacunar infarction, OR if MRI is not performed within 10 days of TIA, a lacunar infarction in an anatomically appropriate position is demonstrated on a subsequent MRI;
3. Age ≥ 50 years.
4. Imaging of the carotid arteries with Doppler ultrasound, CT angiography or MR angiography in the previous 12 months, demonstrating < 70% stenosis in both internal carotid arteries.

1. Radiologiske beviser for cerebral småkarssygdom defineret som: MR-skanning visende lakunær infarkt(er) (≤ 1.5 cm maksimal diameter) og/eller konfluent dyb hvid substans leukaraiosis (≥ grad 2 på Fazekas skala).
2. Kliniske beviser for cerebral småkarssygdom kan være:
a. lakunær stroke syndrom med symptomer varende >24 timer, opstået for minimum 5 måneder siden;
eller:
b. transient iskæmisk attak (TIA) varende < 24 timer med ekstremitetsvaghed, hemi-sensorisk udfald eller dysartri for minimum 5 måneder siden OG med MR-DWI-skanning udført akut visende lakunær infarkt, ELLER hvis MR-skanning ikke er udført indenfor 10 dage efter TIA, er en lakunær infarkt påvist i en anatomisk korrekt position ved en efterfølgende MR-skanning.
3. Alder ≥ 50 år
4. Billeddiagnostik af karotis arterierne med Doppler ultralyd, CT angiografi eller MR angiografi i de foregående 12 måneder visende < 70 % stenose i begge a. carotis interna.

E.4

Principal exclusion criteria

1. Known diagnosis of dementia
2. Pregnancy or nursing women
3. Cortical infarction (>1.5 cm maximum diameter)
4. Systolic BP < 90 and/or diastolic BP < 50
5. eGFR < 30 ml/min/1,73 m2
6. Severe hepatic impairment
7. History of Lactose intolerance
8. Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, vardenafil
9. Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
10. Body weight > 130kg
11. Uncontrolled cardiac failure
12. Persistent or paroxysmal atrial fibrillation
13. History of ‘sick sinus syndrome’ or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block
14. Uncontrolled COPD
15. Stroke or TIA within the last 5 months.
16. MRI not tolerated or contra-indicated : MRI exclusion criteria -Participant has a cardiac pacemaker; recent surgery; vascular clips; metal implants or joint replacements that are not compatible with MRI; have had metal fragments in their eyes; has ever worked on a lathe; has shrapnel from a war injury; possibility of pregnancy
17. Known monogenic causes of stroke i.e. CADASIL
18. The patient does not wish to know important results from MRI
19. Unable to provide informed consent
20. Not possible to localise a. cerebri media bilaterally on inclusion day with Transcranial Doppler.

1. Diagnosticeret med kendt demens
2. Graviditet eller ammende
3. Kortikal infarkt (>1.5 cm i maksimal diameter)
4. Systolisk blodtryk <90 mmHg og/eller diastolisk blodtryk <50 mmHg
5. eGFR < 30 ml/min/1,73 m2
6. Svær leverinsufficiens
7. Laktoseintolerance
8. Samtidig behandling med PDE-5-hæmmere f.eks. sildenafil, tadalafil eller vardenafil.
9. Deltagere modtager nicorandil og nitrater f.eks. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
10. Vægt > 130 kg
11. Ukontrolleret hjertesvigt
12. Persisterende eller paroksystisk atrieflimren
13. Tidligere “syg sinus knude syndrom” eller andre supraventrikulære lednings-forstyrrelser så som sinoatrialt- eller atrioventrikulært blok
14. Ukontrolleret KOL
15. Apopleksi eller TIA indenfor de sidste 5 måneder
16. MR-skanning kan ikke udføres eller kontraindiceret: MR-skannings eksklusions kriterier: Deltagere har pacemaker; fornylig blevet opereret; vakulære clips; metal-implantat eller ledprotese som ikke er MR kompatibel; har haft metalfragmenter i deres øjne; har tidligere arbejdet med en drejebænk; har granatsplinter fra en krigsskade; mulighed for graviditet
17. Kendt monogen årsag til apopleksi f.eks. CADASIL
18. Patienten ønsker ikke oplysninger om resultaterne af betydende tilfældige fund på MR-skanning.
19. Ude af stand til at kunne give informeret samtykke
20. Ikke muligt at lokalisere a. cerebri media bilateralt ved forundesøgelse vha. Transkraniel Doppler.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is changes in the mean blood flow velocity in the middle cerebral artery (MCA) and changes in cortical brain oxygenation.

Primær endpoint er ændringer i den gennemsnitlige blodgennemstrømningshastigheden i a. cerebri media samt ændringer i iltmætning kortikalt i hjernen.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to three hours after intake of tadalafil.

Op til tre timer efter indtag af tadalafil.

E.5.2

Secondary end point(s)

Peripheral endothelial function measured with EndoPAT2000.
Endothelial function markers in blood.

Perifer endothelfunktion mål med EndoPAT2000.
Endothelfunktionsmarkører i blodet.

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to three hours after intake of tadalafil.

Op til tre timer efter indtag af tadalafil.

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

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)

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

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

Yes

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

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

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

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2016-03-10.

Yes

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

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

Ingen

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

2016-04-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-05-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-08-04

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