Clinical Trials Register

Summary
EudraCT Number:	2010-019247-19
Sponsor's Protocol Code Number:	DRONE_C_04629
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2010-08-20
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

Denmark - DHMA

A.2

EudraCT number

2010-019247-19

A.3

Full title of the trial

A Randomized, international, multi-center, open-label study to document pharmacokinetics and optimal timing of initiation of dronedarone TreatmEnt following long-term aMIodarone in patients with paroxysmal or perSistent Atrial Fibrillation whatever the reason for the change of treatment

Et randomiseret, internationalt, multi-center, åbent klinisk forsøg til dokumentation af farmakokinetiske data og optimalt tidspunkt for opstart af behandling med dronedaron efter langtidsbehandling med amiodaron hos patienter med paroksysmal eller persisterende atrieflimmer uanset årsagen til behandlingsskift.

A.3.2

Name or abbreviated title of the trial where available

ARTEMIS AF Long-Term

A.4.1

Sponsor's protocol code number

DRONE_C_04629

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01199081

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	sanofi aventis groupe
B.1.3.4	Country	France
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	Yes
D.2.1.1.1	Trade name	Multaq
D.2.1.1.2	Name of the Marketing Authorisation holder	sanofi aventis
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.3.4	Pharmaceutical form	Film-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	DRONEDARONE
D.3.9.1	CAS number	141626360
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	400
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal or persistent atrial fibrillation

E.1.1.1

Medical condition in easily understood language

atrial fibrillation

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to explore dronedarone and SR35021 (active metabolite) PK profiles according to different timings of dronedarone initiation.

E.2.2

Secondary objectives of the trial

The secondary efficacy objectives are:

• To explore potential PK interaction between dronedarone and amiodarone,
• To evaluate the rate of AF recurrence one month and two months after randomization,
• To assess the safety of the change from amiodarone to dronedarone and dronedarone safety

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Pharmacogenetic sub-study, date: 03-May-2010, version 1

The objective of this sub-study is to investigate allelic variants of drug metabolism enzymes or drug transporters as intrinsic factors associated with PK or pharmacodynamic variability of the development compound.

E.3

Principal inclusion criteria

Inclusion criteria at screening:
I01. Male or female adults aged 18 years or more,

I02. Patients with paroxysmal or persistent AF having received at least 6 months of amiodarone before screening with at least the last 2 months at a regimen of 200 mg/day (during at least 5 days per week) prior to screening,

I03. Requiring a change from amiodarone treatment whatever the reason, but without liver, lung or thyroid toxicity related to previous use of amiodarone

I04.Patients with at least one cardiovascular risk factor (i.e. age > 70, hypertension, diabetes, prior cerebrovascular disease or left atrial diameter ≥ 50 mm
I05. Patients receiving effective anticoagulation according to ACC/AHA/ESC guidelines, verified by INR (target INR > 2),

I06. QTcB < 500 ms on 12-lead ECG,

I07. Signed written informed consent.

Inclusion Criteria: to be checked before randomization

I08. Patients in sinus rhythm (Note: if cardioversion is performed on Day 1 prior to randomization, then the patient must be in sinus rhythm for at least an hour before randomization),

I09. Patients under effective anticoagulation according to ACC/AHA/ESC AF treatment Guidelines, verified by INR ( target > 2),
INR should be closely monitored after initiating dronedarone in patients taking vitamin K antagonist as per their label.

I10. QTcB < 500 ms and PR < 280 ms on 12-lead ECG,

I11. Outpatient and Inpatient (except patients hospitalized during screening period for SAE).

E.4

Principal exclusion criteria

Exclusion criteria at screening:

E01. Contraindication to oral anticoagulation,

E02. Documented AF episode motivating inclusion in the study after an acute condition known to cause AF (e.g. alcohol intake, thyrotoxicosis, acute infection, pericarditis, pulmonary embolism, cardiac surgery),

E03. Patients with permanent AF defined as patients with an AF duration ≥ 6 months (or duration unknown) and attempts to restore sinus rhythm no longer considered by the physician.

E04. Bradycardia < 50 beats per minute (bpm) at rest on the 12-lead ECG,

E05.•History of, or current heart failure or left ventricular systolic function
•Patients with unstable hemodynamic conditions

E06. Women of childbearing potential without adequate birth control (e.g. oral contraception or intra-uterine device [IUD]) or not menopaused, not sterile or not hysterectomized,

E07. Pregnant women,

E08. Breastfeeding women,

E09. Previous (2 preceding months) or current participation in another clinical trial with an investigational drug or with an investigational device,

E10. Clinically relevant hematologic, underlying hepatobiliary disease, gastrointestinal, pulmonary, endocrinologic, psychiatric, neurological or dermatological disease,

E11. Severe hepatic impairment,

E12. Severe renal impairment (creatinine clearance < 30 mL/min),

E13. Serum potassium <3.5 millimol/liter (mmol/l) (in patients with hypokalemia, potassium deficiency must be corrected before randomization) or > 5.5 mmol/l,

E14. Magnesemia < 0.8 mml/l (in patient with hypo-magnesemia, magnesium deficiency must be corrected before randomization),

E15. Unstable angina pectoris (ischemic symptoms during the last 7 days) or recent myocardial infarction (MI) (< 6 weeks),

E16. First degree family history of sudden cardiac death below age 50 years in the absence of coronary heart disease,

E17. Patients with a second or third degree Atrio-Ventricular block, with a complete bundle branch block, a distal block, a sinus node dysfunction, atrial conduction defects or a sick sinus syndrome (except when a functioning pacemaker is in place)

E18. Ongoing potentially severe symptoms when in AF such as angina pectoris, transient ischemic attacks, stroke, syncope, as judged by the investigator,

E19. Wolff-Parkinson-White Syndrome,

E20. Previous catheter ablation for atrial fibrillation,

E21. Catheter ablation scheduled in the next 10 weeks,

E22. Previous history of amiodarone intolerance or toxicity,

E23. History of thyroid dysfunction,

E24. Hypersensitivity to dronedarone or any of the excipients,

E25. Patients previously treated with class I or class III anti-arrhythmic drugs (including sotalol) other than amiodarone if the anti-arrhythmic drug was taken less than one week before the day of screening (If taken more than one week before screening, the patient can be included),

E26. Patients in whom a contraindicated concomitant treatment is mandatory

Exclusion criteria to be checked before randomization:

E27. Bradycardia < 50 bpm on the 12-lead ECG before randomization,

E28. •History of, or current heart failure or left ventricular systolic dysfunction
•Patients with unstable hemodynamic conditions

E29. Serum potassium <3.5 millimol/liter (mmol/l) (in patients with hypokalemia, potassium deficiency must be corrected before randomization) or > 5.5 mmol/l,

E30. Magnesemia < 0.8 mml/l (in patient with hypo-magnesemia, magnesium deficiency must be corrected before randomization),

E31. Women of childbearing potential without adequate birth control (e.g. oral contraception or intra-uterine device [IUD]) or not menopaused, not sterile or not hysterectomized,

E32. Severe hepatic impairment.

E33. Patients with permanent AF defined as patients with an AF duration ≥ 6 months (or duration unknown) and attempts to restore sinus rhythm no longer considered by the physician
E34. Patients in whom a contraindicated concomitant treatment with dronedarone is mandatory (see above list of treatments),

E35. Treatments with other class I or class III anti-arrhythmic drugs other than amiodarone (including sotalol) since screening visit.

E.5 End points

E.5.1

Primary end point(s)

Pharmacokinetics criteria:
Plasma levels of dronedarone and its metabolite SR35021 (AUC0-12hours and Cmax).

E.5.1.1

Timepoint(s) of evaluation of this end point

Plasma levels of dronedarone and its metabolite SR35021 (AUC0-12hours and Cmax).
• at randomization (baseline),
• 3 hours after the first dose of dronedarone,
• after one week of treatment with dronedarone (before dronedarone dose),
• after two weeks of treatment with dronedarone (before dronedarone dose),
• after four weeks of treatment with dronedarone (before dronedarone dose).

E.5.2

Secondary end point(s)

Secondary PK endpoint:
Plasma levels of amiodarone and its metabolite desethylamiodarone (AUC0-12hours and
Cmax)
Efficacy criterion:
AF recurrence documented by at least two consecutive scheduled or unscheduled 12-lead ECGs approximately 10 minutes apart and both showing AF
Safety Criteria:
Secondary safety endpoints:
• Symptomatic bradycardia with HR at rest < 50 beats per minute,
• Symptomatic tachycardia at rest defined as HR > 120 beats per minute,
• Laboratory test (haematology, creatinine, INR, thyroid function tests and hepatic laboratory assessment: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Bilirubin
• ECG parameters,
• Adverse events, adverse events of special interest (AESIs), SAEs.

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary PK endpoint:
• at randomization (baseline),
• 3 hours after the first dose of dronedarone,
• after one week of treatment with dronedarone (before dronedarone dose),
• after two weeks of treatment with dronedarone (before dronedarone dose),
• after four weeks of treatment with dronedarone (before dronedarone dose).
Efficacy criterion:
AF recurrence at one month and at two months
Secondary safety endpoints:
Bradycardia/tachycardia: from V4 to V9
Laboratory test
haematology:V1 and V9.
creatinine:V1, V6 and V9.
INR:V2, V3, V4, V6, V7, V8 and V9.
thyroid function tests:at V1 and V9.
hepatic laboratory assessment: at V3, V4, V6, V8 and V9.
ECG parameters:at each visit
Adverse events, adverse events of special interest (AESIs), SAEs: all along the study

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

Yes

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Information not present in EudraCT

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

Yes

E.8.2.3.1

Comparator description

Arm C

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.8.5

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

Colombia

Czech Republic

Denmark

France

Germany

Greece

Mexico

Spain

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 of 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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
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	14
F.4.2	For a multinational trial
F.4.2.1	In the EEA	82
F.4.2.2	In the whole clinical trial	105

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

2010-09-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-08-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-04-18

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