Clinical Trials Register

Summary
EudraCT Number:	2017-003342-25
Sponsor's Protocol Code Number:	P170604J
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-07-31
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

UK - MHRA

A.2

EudraCT number

2017-003342-25

A.3

Full title of the trial

Long-term treatment of cancer associated venous thromboembolism: reduced vs full dose of apixaban : API-CAT STUDY for APIxaban Cancer Associated Thrombosis

A.3.1

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

Long-term treatment of cancer associated venous thromboembolism: reduced vs full dose of apixaban : API-CAT STUDY for APIxaban Cancer Associated Thrombosis

A.3.2

Name or abbreviated title of the trial where available

API-CAT

A.4.1

Sponsor's protocol code number

P170604J

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03692065

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	ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
B.1.3.4	Country	France
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	Bristol Myers Squibb SARL
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
B.5.2	Functional name of contact point	DRCI Hôpital St Louis
B.5.3	Address:
B.5.3.1	Street Address	1 av. Claude Vellefaux
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.6	E-mail	aurelie.zindjirdjian@aphp.fr

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	ELIQUIS 5mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb/Pfizer EEIG
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	ELIQUIS 5mg
D.3.4	Pharmaceutical form	Coated tablet
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	APIXABAN
D.3.9.1	CAS number	503612-47-3
D.3.9.4	EV Substance Code	AS1
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	5
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.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	ELIQUIS 2,5mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb/Pfizer EEIG
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	ELIQUIS 2,5mg
D.3.4	Pharmaceutical form	Coated tablet
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	APIXABAN
D.3.9.1	CAS number	503612-47-3
D.3.9.4	EV Substance Code	AS2
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	2.5
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	Coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated tablet
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

Any cancer diagnosed histologically (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor or intra-cerebral metastasis) with objectively documented index event of symptomatic or incidental proximal DVT or symptomatic or incidental PE, afterat least 6 months of anticoagulant therapy for the treatment of the index event, with no objectively documented symptomatic recurrence of VTE between the index event and randomization.

E.1.1.1

Medical condition in easily understood language

Venous thrombosis or pulmonary embolism, with cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10076654
E.1.2	Term	Cancer-associated thrombosis
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

We would like to investigate whether, at least 6 months after the onset of a deep vein thrombosis or pulmonary embolism and for a duration of 12 months, an orally administered anticoagulant, apixaban (marketed under the name Eliquis), is at least as effective and possibly better tolerated as the standard treatment with the full dosage of apixaban.

E.2.2

Secondary objectives of the trial

In addition to the main aim, we try to find out, whether a low-dose regimen of apixaban (2.5 mg bid) is safer than a full dose regimen of apixaban (5 mg bid) in patients with active cancer who have completed at least 6 months of anticoagulant therapy for their thrombosis.

Furtermore, we will compare the reduced dose to the full dose in terms of other safety measures, such as recurrece of symptomatic VTE, death and major bleeding.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Signed Written Informed Consent

- Any cancer diagnosed histologically (other than basal-cell or squamous-cell carcinoma of the skin, primary brain tumor or intra-cerebral metastasis

- Active cancer defined as the presence of measurable disease or ongoing (or planned) chemotherapy, radiotherapy, hormonotherapy, targeted therapy, immunotherapy at inclusion.

- Objectively documented index event of :
symptomatic or incidental proximal lower-limb, iliac, inferior cava vena DVT or symptomatic or incidental PE in a segmental or larger pulmonary artery
(1) Proximal DVT is defined as DVT that involves at least the popliteal vein or a more proximal vein, demonstrated by imaging with compression ultrasound (CUS), including grey-scale or color-coded Doppler, or ascending contrast venography or contrast enhanced computed tomography or magnetic resonance imaging.
(2) PE has to be demonstrated by imaging as follows:
an intraluminal filling defect in segmental or more proximal branches on contrast enhanced chest computed tomography or on computed tomography pulmonary angiography ; or
an intraluminal filling defect or a sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram; or
a perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)
(3) Incidental VTE is defined as proximal DVT or PE detected by imaging incidentally when a patient undergoes imaging studies as standard of care for the management of his or her malignancy or other reasons but not for a VTE suspicion(e.g. cancer diagnosis or staging).

- At least 6 months of anticoagulant therapy at therapeutic dosage (whatever the drug and the dosing), or completed assigned a clinical trial study treatment, for the treatment of the index event; and patient still receiving anticoagulant treatment after occurrence or the VTE index event.

- No objectively documented symptomatic recurrence of VTE between the index event and randomization.

- Anticipated duration of anticoagulant treatment of at least 12 months at the time of randomization.

E.4

Principal exclusion criteria

- WOCBP who are unwilling or unable to use an acceptable method of birth control [such as oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (condoms)] to avoid pregnancy for the entire study

- Women who are pregnant or breastfeeding

- Women with a positive pregnancy test on enrollment or prior to investigational product administration

- Isolated sub-segmental incidental or symptomatic PE without associated DVT

- Isolated distal DVT of the legs

- Isolated upper-extremity DVT or superior vena cava thrombosis

- Isolated visceral thrombosis

- Isolated catheter thrombosis

- Objectively documented symptomatic recurrence of VTE after the index event under anticoagulant treatment

- VTE during anticoagulant treatment given at therapeutic dosage

- Subjects with indications for long-term treatment with a VKA, such as:
Mechanical heart valve
Antiphospholipid syndrome

- Subjects with indication for long-term anticoagulation with a VKA or a DOAC at therapeutic dosage

- Conditions increasing the risk of serious bleeding
intracranial or intraocular bleeding within the 6 months ;
major surgery within 2 weeks prior to randomization;
- overt major bleeding at time of randomization.

- Life expectancy < 12 months

- Eastern Cooperative Oncology Group (ECOG) level 3 or 4

- Bacterial endocarditis

- Uncontrolled hypertension: systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg

- Platelet count <75,000/mm3;

- Hemoglobin < 8g /dl

- Creatinine clearance < 30 ml /min based on the Cockcroft Gault equation; (see Section 5.9.2);

- Acute hepatitis, chronic active hepatitis, liver cirrhosis; or an alanine aminotransferase level 3 times or more and/or bilirubin level 2 times or more higher the upper limit of the normal range

- Subjects requiring ASA >165 mg/day at randomization or thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor).

- Subjects requiring dual anti-platelet therapy (such as ASA plus clopidogrel or ASA plus ticlopidine) at randomization. Subjects who transition from dual antiplatelet therapy to monotherapy prior to randomization will be eligible for the trial.

- Concomitant use of strong inhibitors of both cytochrome P-450 3A4 and P Glycoprotein (e.g., human immunodeficiency virus protease inhibitors or systemic ketoconazole) or strong inducers of both cytochrome P-450 3A4 and P Glycoprotein (e.g., rifampicin, carbamazepine, or phenytoin).

- Prisoners or subjects who are involuntarily incarcerated

- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

- Hypersensitivity to apixaban

- Subjects participating in another pharmaco therapeutic program with an experimental therapy that is known to affect the coagulation system

- Under 18 years old ;

- Patients under legal protection (guardianship)

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the incidence of an adjudicated composite of recurrent symptomatic VTE (proximal and/or distal DVT and/or symptomatic PE and/or upper limb or CVC thrombosis) or incidental VTE (proximal DVT or PE), or death due to PE during the treatment period.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

The key secondary outcome is the incidence of adjudicated major and clinically relevant non-major bleeding during the treatment period.

Other secondary endpoints:
Adjudicated composite of :
- Recurrent symptomatic VTE ;
- VTE related-death ;
- All-cause death: all deaths will be adjudicated by the ICAC and classified as either VTE-related, cancer death (including all deaths due to the underlying cancer), bleeding-related or others, including all deaths due to a clearly documented other cause, such as for example respiratory failure (e.g., terminal emphysema), infections/sepsis, etc. ;
- Adjudicated major bleeding.

E.5.2.1

Timepoint(s) of evaluation of this end point

13 months

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

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)

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

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)

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

155

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

France

Greece

Italy

Netherlands

Poland

Spain

Switzerland

United Kingdom

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

Last Visit Last Subject

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