Clinical Trials Register

Summary
EudraCT Number:	2006-005351-14
Sponsor's Protocol Code Number:	CV185-035
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-03-04
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

Spain - AEMPS

A.2

EudraCT number

2006-005351-14

A.3

Full title of the trial

Estudio multicéntrico, aleatorizado, doble ciego, con control activo y de grupos paralelos, fase III, para evaluar la eficacia y seguridad de Apixaban en pacientes sometidos a cirugía programada para la implantación de prótesis total de cadera

A Phase 3, Randomized, Double-blind, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Safety and Efficacy of Apixaban in Subjects Undergoing Elective Total Hip Replacement Surgery.

Y enmienda farmacogenética en sangre 01-Específica de centro (Versión 1.0, fecha 27-Nov-2006)

And Pharmacogenetics Blood Sample Amendment 01 - Site Specific (Version 1.0, Date 27-Nov-2006).

A.4.1

Sponsor's protocol code number

CV185-035

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Bristol-Myers Squibb International Corporation
B.1.3.4	Country	Belgium
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	No
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	Apixaban
D.3.2	Product code	BMS-562247-01
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.9.2	Current sponsor code	BMS-562247-01 (laboratory code)
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Clexane
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Deutschland GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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
D.3.2	Product code	enoxaparin sodium
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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.3.10	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	40 mg/0.4 mL
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Film-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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Pacientes sometidos a cirugía programada para la implantación de prótesis total de cadera

Subjects undergoing elective total hip replacement (THR) surgery

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10051055
E.1.2	Term	Deep vein thrombosis

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10037377
E.1.2	Term	Pulmonary embolism

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 compare the effect of oral (PO) apixaban 2.5 mg BID versus subcutaneous (SC) enoxaparin 40 mg QD on the composite endpoint of adjudicated asymptomatic and symptomatic deep-vein thrombosis (DVT), non-fatal pulmonary embolism (PE) and all cause death during 35 days of double-blind treatment in subjects undergoing elective total hip replacement surgery.

E.2.2

Secondary objectives of the trial

1/ compare the effect of oral apixaban 2.5 mg BID vs SC enoxaparin 40 mg QD on the composite of adjudicated proximal DVT, non-fatal PE & VTE-related death during 35 days of DB treatment.
2/ assess the effect of oral apixaban 2.5 mg BID vs SC enoxaparin 40 mg QD on:
• composite of adjudicated asymptomatic & symptomatic DVT, non-fatal PE & VTE-related death during 35 days of DB treatment
• composite of adjudicated proximal DVT, non-fatal PE and all cause death after 35 days of DB treatment.
• single adjudicated endpoints of distal DVT, proximal DVT, non-fatal PE, VTE related deaths, and all-cause death during 35 days of DB treatment
• adjudicated major bleeding events during 35 days of DB treatment
• composite of adjudicated major and clinically relevant non-major bleeding events during 35 days of DB treatment
• adjudicated clinically relevant non-major bleeding during 35 days of DB treatment
3/ assess overall safety & tolerability of both treatment arms

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Signed written informed consent

Target population
2) Subjects undergoing elective unilateral total hip replacement or a revision of at least one component of a total hip replacement.
3) Subject must be willing and able to undergo bilateral ascending contrast venography.
Unless Investigator/radiologist can assure that a bilateral venogram can be performed, subjects exceeding 300 lbs. (136 kg) and/or BMI ≥ 35 kg/m2 are to be excluded because of technical limitations due to body habitus.

Age and Sex
4) Men and women, of any race, at least 18 (or legal age of consent if greater) years of age
5) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the treatment period of the study in such a manner that the risk of pregnancy is minimized.

E.4

Principal exclusion criteria

Sex and Reproductive Status
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire treatment period of the study
2) Women who are pregnant or breastfeeding
3) Women with a positive pregnancy test on enrollment or prior to investigational product administration

Target Disease Exceptions
4) Known or suspected, acquired or bleeding or coagulation disorder in the subject or a first degree relative
5) Known or suspected history of heparin-induced thrombocytopenia
6) Known coagulopathy
7) Active bleeding or at high risk for bleeding

Medical History and Concurrent Diseases
8) Brain, spinal, ophthalmologic, or major surgery or trauma within the past 90 days
9) Active hepatobiliary disease
10) Alcohol and/or substance abuse within the past year
11) Any condition, in the opinion of the Investigator, for which surgery or administration of an anticoagulant is contraindicated

Physical and Laboratory Test Findings
12) Two consecutive blood pressure readings within 15-30 minutes with supine SBP > 180 mm Hg or supine DBP > 105 mm Hg
13) Hemoglobin < 10 g/dL
14) Platelet count < 100,000/mm3
15) Creatinine clearance < 30 mL/min as estimated by the method of Cockcroft and Gault (see protocol Section 6.3.4)
16) Active hepatobiliary disease, based on an ALT or AST > 2xULN or a Total Bilirubin ≥ 1.5xULN (unless an alternative causative factor [e.g., Gilbert’s syndrome] is identified)

Allergies and Adverse Drug Reactions
17) Hypersensitivity to unfractionated heparin (UFH), low molecular weight heparin (LMWH), porcine products, or iodinated contrast medium (for venogram)

Prohibited Treatments and/or Therapies
18) Need for ongoing treatment with a parenteral or oral anticoagulant (e.g., subjects with mechanical valves, warfarin eligible atrial fibrillation)
19) Current use of dextrans or fibrinolytics
20) Treatment with medications affecting coagulation or platelet function unless they
can be withdrawn as follows:
• Unfractionated heparin, LMWH, warfarin (or any other VKA), glycoprotein IIb/IIIa inhibitors (e.g., abciximab, eptifibatide, tirofiban) within 4 days before surgery
• Clopidogrel, ticlopidine, dipyridamole, sulfinpyrazone within 7 days before surgery
• Non-selective NSAIDs with a T1/2 greater than 17 hours within 7 days before surgery
• Fondaparinux within 7 days before surgery
• Acetylsalicylic acid > 165 mg within 4 days before surgery
21) Planned indwelling intrathecal or epidural catheter that can not be removed at least 5 hours prior to first dose of post-operative study drug.

Other Exclusion Criteria
22) Prisoners or subjects who are compulsorily detained
23) Subjects who have been previously randomized into an apixaban clinical trial
24) Administration of any investigational drug currently or within 30 days prior to
enrollment into this study

E.5 End points

E.5.1

Primary end point(s)

Composite of adjudicated asymptomatic and symptomatic DVT, non-fatal PE and all-cause death following 35 days of double-blind treatment in subjects undergoing elective total hip replacement surgery.

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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)

Yes

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

Information not present in EudraCT

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

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

LPLV

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	206
F.4.2	For a multinational trial
F.4.2.1	In the EEA	1540
F.4.2.2	In the whole clinical trial	4424

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

2007-07-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-06-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2009-09-05

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