Clinical Trials Register

Summary
EudraCT Number:	2018-002546-36
Sponsor's Protocol Code Number:	2018-002546-36
National Competent Authority:	Lithuania - SMCA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-27
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

Lithuania - SMCA

A.2

EudraCT number

2018-002546-36

A.3

Full title of the trial

TENECTEPLASE IN CENTRAL RETINAL ARTERY OCCLUSION STUDY
(TenCRAOS):
A PROSPECTIVE, RANDOMIZED-CONTROLLED, DOUBLE-DUMMY, DOUBLE-BLIND PHASE 3 MULTI-CENTRE TRIAL OF TNK 0.25 MG/KG + PLACEBO VS. ASA + PLACEBO (2 ARMS WITH 1:1 BLOCK RANDOMIZATION)

A.3.1

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

TENECTEPLASE IN CENTRAL RETINAL ARTERY OCCLUSION STUDY
(TenCRAOS):
A RANDOMIZED CONTROLLED TRIAL OF ACUTE CLOTSOLVING MEDICATION IN CENTRAL RETINALY ARTERY OCCLUSION.

A.4.1

Sponsor's protocol code number

2018-002546-36

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	Oslo University Hospital
B.1.3.4	Country	Norway
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	Oslo University Hospital
B.4.2	Country	Norway
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Oslo University Hospital
B.5.2	Functional name of contact point	Anne Hege Aamodt
B.5.3	Address:
B.5.3.1	Street Address	Sognsveien 20
B.5.3.2	Town/ city	Oslo
B.5.3.3	Post code	0424
B.5.3.4	Country	Norway
B.5.4	Telephone number	47915 02 770

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	Tenecteplase Metalyse
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Metalyse
D.3.4	Pharmaceutical form	Powder and solution for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Comparator
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	acetylsalisylic acid
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda
D.2.1.2	Country which granted the Marketing Authorisation	Norway
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.3.11 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 solution for injection
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
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

Central retinal artery occlusion

E.1.1.1

Medical condition in easily understood language

Central retinal artery occlusion (CRAO) is an ophthalmologic emergency that, without prompt revascularization, bears high risk of permanent blindness.

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007971
E.1.2	Term	Central retinal artery occlusion
E.1.2	System Organ Class	100000004853

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effect of systemic tenecteplase within 4.5 hours onset of CRAO.

E.2.2

Secondary objectives of the trial

1. To assess the mean improvement in logMAR visual acuity from baseline to 6 weeks after treatment
2. To assess the effect of systemic tenecteplase within 3 hours onset of CRAO in a large multi-site trial involving leading clinical research centres across the Scandinavian countries.
3. To assess the mean deviation (dB) in central 30º visual field on threshold perimetry 6 weeks after treatment
4. To assess the proportion of patients with complications such as systemic bleeding
5. To assess the proportion of patients with symptomatic intracranial haemorrhage at 24 hours
6. To assess the mean score on National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) at 6 weeks (1)
7. To assess the case fatality at 24 hours and 6 weeks
To assess the safety of systemic tenecteplase within 4.5 hours onset of CRAO.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Non-arteritic central retinal artery occlusion with ≥ 1.0 logMAR visual acuitiy and symptoms lasting less than 4.5 hours.
2. Ability to administer the Investigator Medicinal Product (IMP) within 4.5 hours of symptom onset.
3. Age ≥18 years.
4. Informed written consent of the patient.
5. A woman of childbearing potential (WOCBP) must confirm that in her opinion, she cannot be pregnant, OR if there is a possibility that she is pregnant, a negative pregnancy test must be confirmed before any IMP is given.

E.4

Principal exclusion criteria

1. Branch retinal artery occlusion, cilioretinal artery supplying the macula, combined arterial-venous occlusion, proliferative diabetic retinopathy, or elevated intraocular pressure (> 30 mmHg).
2. Systemic diseases; severe general diseases, systemic arterial hypertension (blood pressure >185/110 mmHg), despite medical therapy, or clinical suspicion of acute systemic inflammation.
3. Presence of intracranial haemorrhage on brain MRI/CT.
4. Medical history: heart attack within the last 6 weeks, intracerebral bleeding or neurosurgical operation within the last 4 weeks, therapy with anticoagulation, allergic reaction to contrast agent, haemorrhagic diathesis, aneurysms, inflammatory vascular diseases (eg, giant cell arteritis, granulomatosis with polyangitis), endocarditis, or gastric ulcer.
5. No willingness and ability of the patient to participate in all follow-up examinations.
6. Pregnancy (if suspicion of pregnancy s-hCG or u-hCG must be negative).
7. Allergy or intolerance to any ingredients of IMP or placebo or gentamicin.
8. Other conditions / circumstances likely to lead to poor treatment adherence (eg, history of poor compliance, alcohol or drug dependency, no fixed abode).
9. Significant bleeding disorder either at present or within the past 6 months.
10. Effective oral anticoagulant treatment, eg, warfarin sodium (INR >1.3).
11. Effective anticoagulant treatment with heparin or low molecular weight heparin the last 48 hours.

12. Any history of central nervous system damage (ie, neoplasm, aneurysm, intracranial or spinal surgery).
13. Known hemorrhagic diathesis.
14. Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with acute myocardial infarction).
15. Recent non-compressible vessel puncture within 2 weeks.
16. Recent trauma to the head or cranium.
17. Prolonged cardiopulmonary resuscitation (>2 minutes) within the past 2 weeks.
18. Acute pericarditis and/or subacute bacterial endocarditis.
19. Acute pancreatitis.
20. Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis.
21. Active peptic ulceration.
22. Arterial aneurysm and known arterial/venous malformation.
23. Neoplasm with increased bleeding risk.
24. Any known history of hemorrhagic stroke or stroke of unknown origin.
25. Known history of ischemic stroke or transient ischemic attack in the preceding 3 months.
26. Dementia.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint:
Proportion of patients with ≤ 0.7 logMAR visual acuity in the affected eye at 30 (±5) days after treatment, representing an improvement in visual acuity of at least 0.3 logMAR (intention-to-treat (ITT) analysis).

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days

E.5.2

Secondary end point(s)

Secondary endpoints:
1. Proportion of patients with ≤ 0.5 logMAR visual acuity in the affected eye at 30 (±5) and 90 (±15) days.
2. Mean improvement in logMAR visual acuity in the affected eye from baseline to 30 (±5) and 90 (±15 ) days.
3. Proportion of patients with visual recovery (logMAR ≤ 0.7) and (logMAR ≤ 0.5) in the affected eye 30 (±5) and 90 (±15) days in patients who were treated with tenecteplace within 3 hours of onset.
4. Number of test points seen (of 100) on monocular Esterman perimetry at 30 (±5) days.
5. Acute ischemic lesions on follow-up on diffusion-weighted (DWI) MRI or on brain CT at baseline and 24hrs.
6. National Institutes of Health Stroke Scale score (NIHSS) at 24hrs and discharge.
7. Modified Rankin Scale score (mRS) at discharge, 30 (±5) and 90 days (±15) days.
8. Mean score on National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) at 30 (±5) days (1).
9. Mean score on EQ-5D at 30 (±5) days.
10. Presence of ocular neovascularisation at 90 (±15) days.
Safety endpoints:
11. All-cause and stroke-related death at discharge, 30 (±5) and 90 (±15) days.
12. Proportion of patients with any intracranial haemorrhage at 24 hrs.
13. Proportion of patients with symptomatic intracranial haemorrhage until discharge.
14. Proportion of patients with complications such as systemic bleeding at 24 hrs, discharge and 30 (±5) days.
15. Other serious adverse events.
16. Occurrence of adverse events.

Exploratory endpoints:
17. Retrobulbar spot sign detection using Duplex/Doppler ultrasound at baseline, point-of-care ultrasound (POCUS).
18. Retrobulbar spot sign and central retinal artery recanalisation using Duplex/Doppler ultrasound at 24h and discharge.
19. Macular optical coherence tomography (OCT) volume scan and OCT angiography (OCTA) at 30 days.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 hours
Discharge
30 days
90 days

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

Yes

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)

Yes

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

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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 2020-11-27.

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.4.2

For a multinational trial

F.4.2.1

In the EEA

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Oslo University Hospital
G.4.3.4	Network Country	Norway
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Aarhus University Hospital
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Karolinska University Hospital
G.4.3.4	Network Country	Sweden
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	University Hospital Antwerp
G.4.3.4	Network Country	Belgium
G.4 Investigator Network to be involved in the Trial: 5
G.4.1	Name of Organisation	Mater Misericordiae University Hospital
G.4.3.4	Network Country	Ireland
G.4 Investigator Network to be involved in the Trial: 6
G.4.1	Name of Organisation	Turku University Hospital
G.4.3.4	Network Country	Finland
G.4 Investigator Network to be involved in the Trial: 7
G.4.1	Name of Organisation	Vilnius University Hospital
G.4.3.4	Network Country	Lithuania
G.4 Investigator Network to be involved in the Trial: 8
G.4.1	Name of Organisation	Centro Hospitalar Universitário de São João
G.4.3.4	Network Country	Portugal

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-03-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-10

P. End of Trial
P.	End of Trial Status	Ongoing

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