Clinical Trials Register

Summary
EudraCT Number:	2020-002190-10
Sponsor's Protocol Code Number:	UCDCRC/20/03
National Competent Authority:	Ireland - HPRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-01-22
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

Ireland - HPRA

A.2

EudraCT number

2020-002190-10

A.3

Full title of the trial

Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG)

A.3.1

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

A Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic

A.3.2

Name or abbreviated title of the trial where available

RAPID COVID COAG

A.4.1

Sponsor's protocol code number

UCDCRC/20/03

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	University College Dublin
B.1.3.4	Country	Ireland
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	University College Dublin
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University College Dublin
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	UCD School of Medicine
B.5.3.2	Town/ city	Belfield
B.5.3.3	Post code	Dublin 4
B.5.3.4	Country	Ireland
B.5.4	Telephone number	+3531716 4593
B.5.6	E-mail	crc.monitoring@ucd.ie

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	Clexane (enoxaparin sodium)
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Ireland Limited T/A SANOFI
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Clexane (Enoxaparin sodium)
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ENOXAPARIN SODIUM
D.3.9.1	CAS number	9041-08-1
D.3.9.4	EV Substance Code	SUB11933MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	4000 to 15000
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	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

Coagulopathy of COVID-19 appears to afflict approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time (PT), suggestive of coagulation consumption

E.1.1.1

Medical condition in easily understood language

Excessive blood clotting as a result of a severe inflammatory response appears to afflict approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death.

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

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

Primary Objective:
To determine the effect of therapeutic anticoagulation, with LMWH (enoxaparin sodium), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days.

E.2.2

Secondary objectives of the trial

Determine effect of therapeutic anticoagulation (enoxaparin sodium) compared to standard care in hospitalized patients up to day 28, on:
1. All-cause death
2. Composite of ICU admission or all-cause death
3. Composite of mechanical ventilation or all-cause death
4. Major bleeding as defined by the ISTH-SSC recommendation
5. Red blood cell transfusion (>1 unit)
6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate
7. Renal replacement therapy defined as CRRT or IHD
8. Hospital-free days alive
9. ICU-free days alive
10. Ventilator-free days alive
11. Organ support-free days alive
12. Venous thromboembolism
13. Arterial thromboembolism
14. Heparin induced thrombocytopenia
15. Trajectories of COVID-19 disease-related biomarkers
Tertiary Objective

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

4.1. The inclusion criteria are:
1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification); positive test prior to hospital admission OR within first 5 days (ie 120 hours) after hospital admission
2) Admitted to hospital for COVID-19;
3) One D-dimer value above ULN (within 5 days (ie 120 hours) of hospital admission) AND EITHER:
a. D-Dimer ≥2 times ULN OR
b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air;
4) > 18 years of age;
5) Informed consent from the patient (or legally authorized substitute decision maker).

E.4

Principal exclusion criteria

1) pregnancy;
2) hemoglobin <80 g/L in the last 72 hours;
3) platelet count <50 x 109/L in the last 72 hours;
4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation);
6) patient already on intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration);
7) patient already on therapeutic anticoagulation at the time of screening (low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban);
8) patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely;
9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization;
10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder;
11) known history of heparin-induced thrombocytopenia;
12) known allergy to UFH or LMWH;
13) admitted to the intensive care unit at the time of screening
14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not an exclusion criterion);
15) Imminent death according to the judgement of the most responsible physician;
16) enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients.

E.5 End points

E.5.1

Primary end point(s)

The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 28

E.5.2

Secondary end point(s)

Secondary outcomes (secondary endpoints), evaluated up to day 28, include:
1) All-cause death;
2) Composite of ICU admission or all-cause death;
3) Composite of mechanical ventilation intubation or all-cause death;
4) Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation (21);
5) Red blood cell transfusion (>1 unit);
6) Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate;
7) Renal replacement therapy defined as continuous renal replacement therapy {CRRT} or intermittent hemodialysis {IHD};
8) Hospital-free days alive;
9) ICU-free days alive;
10) Ventilator-free days alive;
11) Organ support-free days alive (see Appendix 4 for definition);
12) Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate recognizing that access to diagnostic imaging may be limited in the midst of the COVID-19 pandemic, however confirmatory testing at a later date once exposure risk/personal protective utilization is not an issue is encouraged);
13) Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate recognizing that access to diagnostic imaging may be limited in the midst of the COVID-19 pandemic, however confirmatory testing at a later date once exposure risk/personal protective utilization is not an issue is encouraged);
14) Heparin induced thrombocytopenia;
15) Trajectories of COVID-19 disease-related biomarkers.

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to day 28 (including days 1, 3, 7, 14, 28)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer.

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

Completion of the global trial with St Michael's Hospital.

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

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Legally authorized substitute decision maker (applies to initial consent and ongoing consent, should the participant lose capacity during the trial). Capacity will be assessed by the circle of care.

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.4.2.2

In the whole clinical trial

462

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-02-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-08-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-14

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