Clinical Trials Register

Summary
EudraCT Number:	2015-001785-26
Sponsor's Protocol Code Number:	14-505
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:	2015-09-17
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

2015-001785-26

A.3

Full title of the trial

Prospective, Open-label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor who Have Acute Major Bleeding (ANNEXA-4).

A.3.1

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

A study to confirm that andexanet alfa helps to stop severe/ life threatening bleeding in patients, taking a type of anticoagulants called Factor Xa inhibitors.

A.3.2

Name or abbreviated title of the trial where available

ANNEXA-4

A.4.1

Sponsor's protocol code number

14-505

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02329327

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	Portola 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	Portola 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	Portola Pharmaceuticals, Inc.
B.5.2	Functional name of contact point	Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	270 East Grand Avenue,
B.5.3.2	Town/ city	South San Francisco
B.5.3.3	Post code	CA 94080
B.5.3.4	Country	United States
B.5.4	Telephone number	0016502467039
B.5.6	E-mail	clinicaltrials@Portola.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 (R)
D.2.1.1.2	Name of the Marketing Authorisation holder	Portola Netherlands B.V.
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 100mg vial
D.3.2	Product code	PRT064445
D.3.4	Pharmaceutical form	Lyophilisate 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.3.9.2	Current sponsor code	PRT064445
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 milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
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	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 (R)
D.2.1.1.2	Name of the Marketing Authorisation holder	Portola Netherlands B.V.
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 200mg vial
D.3.2	Product code	PRT064445
D.3.4	Pharmaceutical form	Lyophilisate 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.3.9.2	Current sponsor code	PRT064445
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 milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
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

Uncontrolled bleeding in patients who have taken either a direct factor Xa inhibitor (novel oral anticoagulants) or an indirect factor Xa inhibitor (low molecular weight heparins).

E.1.1.1

Medical condition in easily understood language

Serious bleeding complications in patients who have taken anticoagulant medicine, known as a factor Xa inhibitor.

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

Two Primary Objectives:
1. To demonstrate the decrease in anti-fXa activity following andexanet treatment.
2. To evaluate the haemostatic efficacy following andexanet treatment.

E.2.2

Secondary objectives of the trial

Secondary Objectives:
To assess the relationship between decrease in anti-fXa activity and achievement of haemostatic efficacy in patients receiving a fXa inhibitor who have acute major bleeding and reduced fXa activity.

Exploratory Objectives:
•For patients receiving apixaban, edoxaban or rivaroxaban, to evaluate the decrease in the free fraction of the fXa inhibitor
To evaluate:
• The use of red blood cell transfusions
• The use of other blood products and haemostatic agents
• Effect on thrombin generation, level of TFPI, level of ATIII and level of anti-fIIa activity
• Haemostatic efficacy in ICH patients at high risk for haematoma expansion
• Occurrence of re-bleeding
• Change in clinical status for patients with ICH

Safety Objectives:
• Evaluate overall safety of andexanet, including: adverse events, adjudicated thrombotic events and deaths, vital signs, clinical lab measurements and antibodies to fX, fXa and andexanet
• Evaluate the 30-day all-cause mortality

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Either the patient or his or her medical proxy (or legally acceptable designee) has been adequately informed of the nature and risks of the study and has given written informed consent prior to Screening;
2) The patient must be at least 18 years old at the time of Screening;
3) The patient must have an acute overt major bleeding episode requiring urgent reversal of anticoagulation; Acute major bleeding requiring urgent reversal of anticoagulation is defined by at least ONE of the following:
- Acute overt bleeding that is potentially life-threatening, e.g., with signs or symptoms of haemodynamic compromise, such as severe hypotension, poor skin perfusion, mental confusion, low urine output that cannot be otherwise explained;
- Acute overt bleeding associated with a fall in haemoglobin level by ≥ 2 g/dL, OR a Hgb ≤ 8 g/dL if no baseline Hgb is available;
- Acute bleeding in a critical area or organ, such as, intra-spinal, pericardial or intracranial.
4) The patient, for whom the bleeding is intracranial or intraspinal must have undergone a CT or MRI scan demonstrating the bleeding.
5) The patient received or is believed to have received one of the following within 18 hours prior to andexanet administration: apixaban, rivaroxaban, edoxaban or enoxaparin (dose of enoxaparin ≥1mg/kg/d).
6) For patients with ICH, there must be a reasonable expectation that andexanet treatment will commence within 2 hours of the baseline imaging evaluation.

E.4

Principal exclusion criteria

1) The patient is scheduled to undergo surgery in less than 12 hours after end of andexanet infusion, with the exception of minimally invasive surgery/procedures (e.g., endoscopy, bronchoscopy, central lines, Burr holes);
2) A patient with ICH has any of the following:
− Glasgow coma score < 7
− Estimated intracerebral haematoma volume >60 cc as assessed by the CT or MRI.
3) Patients with visible, musculoskeletal, or intra-articular bleeding as the qualifying bleed.
4) The patient has an expected survival of less than 1 month;
5) The patient has a recent history (within 2 weeks) of a diagnosed thrombotic event (TE) as follows: venous thromboembolism (VTE; e.g., deep venous thrombosis, pulmonary embolism, cerebral venous thrombosis), myocardial infarction (including an isolated troponin elevation), disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris hospitalization, or severe peripheral vascular disease within 2 weeks prior to Screening;
6) The patient has severe sepsis or septic shock at the time of Screening;
7) The patient is pregnant or a lactating female;
8) The patient has received any of the following drugs or blood products within 7 days or Screening:
• Vitamin K antagonist (VKA) (e.g., warfarin);
• Dabigatran;
• Prothrombin Complex Concentrate products (PCC, e.g., Kcentra®) or recombinant factor VIIa (rfVIIa) (e.g., NovoSeven®);
• Whole blood, plasma fractions
Note: Administration of platelets or packed red blood cells (PRBCs) is not an exclusion criterion;
9) The patient was treated with an investigational drug <30 days prior to Screening.
10) Planned administration of PCC, fresh frozen plasma (FFP), or rfVIIa from Screening until within 12 hours after the end of the andexanet infusion.

E.5 End points

E.5.1

Primary end point(s)

The two primary endpoints are:
1)The percent change from baseline (pre-treatment with andexanet) in anti-fXa activity to the nadir from the evaluation period (where the evaluation period starts 5 minutes following the end of the andexanet bolus and ends 10 minutes after the end of the andexanet infusion).
AND
2) The achievement of haemostatic efficacy.

The primary endpoints, including the evaluation of hemostatic efficacy in specific study populations against specific comparators, will be ordered in a fixed sequence multiple comparisons (i.e., hierarchical) fashion as delineated in the SAP.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients receive andexanet as an IV bolus administered over ~15–30 minutes, followed immediately by a continuous infusion administered over ~120 minutes.
Primary endpoint 1:
Sample for anti-fXa activity is drawn at 2 timepoints; one at (or within 30 minutes after) the end of the bolus, and another at (or within 30 minutes prior to) the end of the infusion.
Primary Endpoint 2:
Haemostatic efficacy: MRI/CT; GCS , mRS and NIHSS for ICH (pre-bolus and at 1hr, 12hr, +7d after end of infusion (EI). Transfusion-corrected haemoglobin and haematocrit for non-visible bleeding (at 12hr); Echocardiogram for pericardial bleed (pre-bolus and at 12hr EI). Ultrasound or CT/MRI scan for intraspinal bleeding (pre-bolus and at 1hr, 12hr, +7d EI).

E.5.2

Secondary end point(s)

Secondary Endpoints:
The secondary efficacy objective is to assess the relationship between the two primary efficacy endpoints. No additional efficacy endpoint is defined to support the secondary efficacy objective.

Exploratory Endpoints:
• The number of patients receiving one or more red blood cell transfusions from the start of the andexanet bolus through 12 hours after the end of andexanet infusion.
• For patients receiving apixaban, rivaroxaban, or edoxaban, to evaluate the decrease in free fraction of the fXa inhibitor following andexanet administration.
• The number of red blood cell units transfused per patient from the start of the andexanet bolus through 12 hours after the end of the andexanet infusion.
• The use of non-study-prescribed blood products and/or hemostatic agents.
• The occurrence of re-bleeding following andexanet treatment. Re-bleeding is defined as follows: bleeding from the same anatomical site in patients within 24 hours of initial andexanet treatment and after achieving initial good/excellent hemostasis.
• Andexanet reversal of anticoagulant effect as measured through TG parameters (with, endogenous thrombin potential (ETP) as the primary measure), for both the Tissue Factor (TF)-initiated assay and the non-TF-initiated assay.
• TFPI levels, both free and total, pre- and post-administration of andexanet.
• ATIII levels, pre- and post-administration of andexanet.
• Anti-factor IIa levels, pre- and post-administration of andexanet (enoxaparin patients only).
• The achievement of hemostatic efficacy in ICH patients at high risk of hematoma expansion.
• Change from baseline in GCS (for ICH patients only).
• Change from baseline in mRS (for ICH patients only).
• Change from baseline in NIHSS (for ICH patients only).

Safety Measurements:
-Survival status, AEs, vital signs, and clinical laboratory measurements
-Centrally-adjudicated Treatment-Emergent Adverse Events
-Antibodies to andexanet, fX, and fXa

E.5.2.1

Timepoint(s) of evaluation of this end point

Exploratory:
-No. of red blood cell units transfused, use of non-study-prescribed hemostatic agents (start of bolus through 12 hr)
-Free fraction of the direct fXa inhibitor (pre-bolus and 4hr, 8hr 12hr)
-Re-bleeding within 24 hours
-TG parameters (with ETP as primary measure), for both the TF-initiated and non-TF-initiated assay (pre-bolus, end of bolus, end of infusion, 4hr, 8hr 12hr 24, 48, 72hr, +7days)
-ATIII and TFPI levels, pre- and post-administration of andexanet (-30 min EI, 4hr, 8hr 12hr 24, 48, 72hr, +7days)
-Anti-factor IIa levels, pre- and post-administration
-GCS, mRS and NIHSS (pre-bolus and at 1 hr, 12 hrs, and 30 days (for ICH only)).
Safety:
Antibodies to andexanet, fX, and fXa (pre-bolus and +7 days)
AEs (followed through Study Day 30 post-treatment visit.

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

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)

Yes

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

Belgium

Canada

France

Germany

Japan

Netherlands

Spain

United Kingdom

United States

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:

446

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 2015-09-17.

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients are experiencing serious/life-threatening bleeding such as intracranial haemorrhage, pericardial and intra-spinal bleeding. Due to the critical nature of the illness 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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

220

F.4.2.2

In the whole clinical trial

500

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)

Following study completion the decision regarding the patient's treatment will be determined by his/her physician in accordance to any available treatment as per the standard of care.

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

2015-10-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-05-30

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

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