Clinical Trials Register

Summary
EudraCT Number:	2020-000374-21
Sponsor's Protocol Code Number:	19-515
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-03-12
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

Germany - PEI

A.2

EudraCT number

2020-000374-21

A.3

Full title of the trial

PROSPECTIVE, OPEN-LABEL STUDY OF ANDEXANET ALFA IN PATIENTS RECEIVING A FACTOR XA INHIBITOR WHO REQUIRE URGENT SURGERY (ANNEXA-S)

A.3.1

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

A phase 2 clinical trial to study effect of andexanet alfa for patients who require urgent surgery.

A.4.1

Sponsor's protocol code number

19-515

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	Alexion Pharmaceuticals, Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alexion Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Alexion Europe SAS
B.5.2	Functional name of contact point	European Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	103-105 Rue Anatole France
B.5.3.2	Town/ city	Levallois-Perret
B.5.3.3	Post code	92300
B.5.3.4	Country	France
B.5.4	Telephone number	+33147100615
B.5.5	Fax number	+33147100611
B.5.6	E-mail	clinicaltrials.eu@alexion.com

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	Ondexxya®
D.2.1.1.2	Name of the Marketing Authorisation holder	Alexion Europe SAS
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	andexanet alfa 200 mg vial
D.3.2	Product code	ALXN2070
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ANDEXANET ALFA
D.3.9.1	CAS number	1262449-58
D.3.9.2	Current sponsor code	ALXN2070
D.3.9.3	Other descriptive name	Recombinant Factor Xa Inhibitor Antidote
D.3.9.4	EV Substance Code	SUB181082
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	10
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.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

Need for FXa inhibitor reversal in patients undergoing urgent surgery.

E.1.1.1

Medical condition in easily understood language

Urgent need for surgery AND recent ingestion of blood thinners.

E.1.1.2

Therapeutic area

Not possible to specify

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	10075279
E.1.2	Term	Anticoagulant reversal therapy
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

• To evaluate the hemostatic efficacy following andexanet treatment.

E.2.2

Secondary objectives of the trial

• To evaluate the effect of andexanet on anti-fXa activity.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All of the following criteria must be met for the patient to be eligible:
1. Either the patient or their medical proxy (or legal designee) has given written informed consent.
2. Age ≥ 18 and < 85 years old.
3. Requires urgent surgical intervention that must occur within 12 hours of consent, for which reversal of anti-fXa activity is judged necessary.
4. Treatment with an oral FXa inhibitor (apixaban [last dose 2.5 mg or greater], rivaroxaban [last dose 10 mg or greater], edoxaban [last dose 30 mg or greater] or enoxaparin [≥ 1 mg/kg/d]):
5. ≤ 15 hours prior to start of surgery.
6. > 15 hours prior to start of surgery or unknown time from the last dose, if documented anti fXa activity is > 100 ng/mL (> 0.5 IU/mL for enoxaparin, or over the equivalent IU/mL threshold on a low molecular weight heparin assay; see Laboratory Manual) within 2 hours prior to consent. Note: Patients enrolled in this manner should receive a high-andexanet dosing regimen.
7. Have a negative pregnancy test documented prior to enrollment (for women of childbearing potential).
8. Willingness to use highly effective methods of contraception through 30 days following study drug dose (for female and male patients who are fertile).

E.4

Principal exclusion criteria

If a patient meets any of the following criteria, he or she is not eligible:
1. Surgery for which the risk of clinically meaningful uncontrolled or unmanageable bleeding is low.
2. Acute life-threatening bleeding (ISTH criteria) at the time of Screening:
a. The patient has acute-overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of hemodynamic compromise, such as severe hypotension, poor skin perfusion, mental confusion, low urine output that cannot be otherwise explained.
b. The patient has overt bleeding associated with a fall in hemoglobin level by ≥2g/dL, OR, a hemoglobin ≤8 g/dL if no baseline hemoglobin is available.
c. The patient has acute bleeding in a critical area or organ, such as pericardial, intracranial, or intraspinal.
3. Any surgical procedure that involves the intraoperative use of systemic, intravascular, unfractionated heparin.
4. Primary procedure for efficacy assessment is a non-surgical interventional procedure (e.g, lumbar puncture, skin biopsy, cardiac catheterization, endoscopic retrograde cholangio-pancreatography).
5. Expected survival of < 1 month due to comorbidity.
6. Known “Do Not Resuscitate” order or similar advanced directive.
7. The patient has a recent history (within 30 days prior to screening) of a diagnosed TE as follows: venous thromboembolism (including deep vein thrombosis, pulmonary embolism, intracardiac thrombus), myocardial infarction (including asymptomatic troponin elevations), disseminated intravascular coagulation, acute traumatic coagulopathy, cerebrovascular accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe peripheral vascular disease.
8. Acute decompensated heart failure or cardiogenic shock at the time of screening.
9. The patient has sepsis or septic or severe hemorrhagic shock at the time of Screening.
10. The patient has heparin-induced thrombocytopenia (with or without thrombosis).
11. Inherited coagulopathy (e.g., anti-phospholipid antibody syndrome, protein C/S deficiency, Factor V Leiden) at time of Screening.
12. Platelet count < 80,000/μL at the time of Screening.
13. Last dose of apixaban < 2.5 mg, rivaroxaban < 10 mg, edoxaban < 30 mg, or enoxaparin 40 mg.
14. The patient is pregnant or a lactating female.
15. The patient has received any of the following drugs or blood products within 7 days of enrollment:
o Vitamin K antagonists (e.g., warfarin).
o Dabigatran.
o Prothrombin complex concentrate products (e.g., Kcentra®) or recombinant factor
VIIa (e.g., NovoSeven®).
o Whole blood, plasma fractions.
Note: Administration of tranexamic acid, platelets or packed red blood cells is not an exclusion criterion.
16. The patient was treated with an investigational drug < 30 days prior to Screening.
17. Prior treatment with andexanet.
18. Known or suspected (i.e., presumed positive) COVID-19-related illness at the time of Screening.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the achievement of effective hemostasis, as determined by the surgeon’s assessment of intraoperative hemostasis and confirmed by adjudication by an independent EAC.

E.5.1.1

Timepoint(s) of evaluation of this end point

From start of surgery to the end of the procedure

E.5.2

Secondary end point(s)

The secondary efficacy endpoint is the percent change in anti-fXa activity from baseline to the evaluation period nadir.

E.5.2.1

Timepoint(s) of evaluation of this end point

The evaluation period starts 5 minutes after the end of the andexanet bolus and ends just prior to the end of the andexanet infusion

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

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.8.3

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Israel

Japan

United States

Austria

France

Germany

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

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

Due to the urgent surgery some patients will be unable to provide their own consent

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

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)

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

2020-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-01-25

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