Clinical Trials Register

Summary
EudraCT Number:	2006-004275-35
Sponsor's Protocol Code Number:	DFI6174
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-01-11
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

France - ANSM

A.2

EudraCT number

2006-004275-35

A.3

Full title of the trial

A randomized, double-blind, placebo-controlled, parallel group trial of HMR1766 assessing the efficacy and safety of 3 doses of HMR1766 (25, 100, 200 mg OD) versus placebo with cilostazol, 100 mg BID as a calibrator, administered for 26 weeks in patients with Peripheral Arterial Disease (PAD) Fontaine stage II.

A.3.2

Name or abbreviated title of the trial where available

ACCELA

A.4.1

Sponsor's protocol code number

DFI6174

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	sanofi-aventis recherche & développement
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	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	Ataciguat
D.3.2	Product code	HMR1766
D.3.4	Pharmaceutical form	Capsule, soft
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.3.9.1	CAS number	254976-06-2
D.3.9.2	Current sponsor code	HMR1766
D.3.9.3	Other descriptive name	Ataciguat
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	25
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	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	PLETAL
D.2.1.1.2	Name of the Marketing Authorisation holder	Otsuka Pharmaceutical Europe Ltd
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	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	cilostazol
D.3.9.1	CAS number	73963-72-1
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	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: 3
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	Ataciguat
D.3.2	Product code	HMR1766
D.3.4	Pharmaceutical form	Capsule, soft
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.3.9.1	CAS number	254976-06-2
D.3.9.2	Current sponsor code	HMR1766
D.3.9.3	Other descriptive name	Ataciguat
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	50
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	Capsule, soft
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	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

Peripheral Arterial Disease (PAD) Fontaine stage II (intermittent claudication)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	8.1
E.1.2	Level	LLT
E.1.2	Classification code	10022562
E.1.2	Term	Intermittent claudication

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 demonstrate the efficacy of 6 months treatment with HMR1766 for improvement in walking distance in patients with intermittent claudication (Fontaine II stage PAD).

E.2.2

Secondary objectives of the trial

· To assess the safety and tolerability of HMR1766.
· To assess steady state PK in a subset of about 90 patients, in selected sites.
· To build a population PK model in all study patients.

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

Title: PK substudy
Date: 8 Septembre 2006
Related objective: assess steady state PK in a subset of about 90 patients, in selected sites (Canada, France, Germany, Austria, South Africa, and the US)

E.3

Principal inclusion criteria

Inclusion criteria at screening period

Diagnosis of intermittent claudication (PAD Fontaine stage II):
1. Patient with stable symptoms of intermittent claudication of the lower extremities, secondary to chronic occlusive arterial disease from atherosclerosis etiology (symptoms present for 6 months or longer and not significantly changed within the past 3 months);
and
2. ICD (Initial claudication distance) of 30 to 250 m at screening constant workload treadmill test.

Confirmation of underlying PAD:
3. Ankle/Brachial Index (ABI) of 0.90 to 0.5 or for patients with an ABI greater than 1.3 (due to non-compressible arteries), a Toe-Brachial Index (TBI) of less than 0.7.

Inclusion criteria at randomization

Confirmation of symptom stability:
4. Mean ICD of 30 to 250 m calculated by averaging the constant workload treadmill test performed at the end of the run-in phase and the previous one performed at screening.
5. The maximum change (measured in log) in the claudication distance should not exceed 0.25 between those two ICD measurements, as per international recommendation.
6. The patient is not allowed to smoke 3 hours before treadmill / ABI tests.

Appropriate background therapy:
7. The patients must have optimal cardiovascular risk prevention and appropriate management of PAD, including clopidogrel 75mg per day, during the study treatment period.

E.4

Principal exclusion criteria

Exclusion criteria at screening / randomization visits

1. Patient not having provided written informed consent.
2. Patient participated in investigational clinical trials in the last 2 months prior screening.
3. Pregnant or breast-feeding woman or woman without documented birth control measures for at least 3 months prior to randomization.

Potentially non-atherosclerotic and/or severe stage disease not amenable to medical therapy:

4. Age below 40 years and/or onset of symptoms of PAD before the age of 40 years.
5. Non-atherosclerotic peripheral arteriopathy (e.g. Buerger’s disease, aneurismal states, popliteal entrapment syndrome).
6. Acute peripheral ischemia e.g. thrombosis in situ, trauma, paradoxical embolism of venous thrombi.
7. Critical limb ischemia (equivalent to Fontaine stages III and IV), manifested by ischemic rest pain or trophic lesions.

Recent (within 3 months prior to screening) pharmacological treatment likely to interfere with study endpoints:

8. Recent initiations or discontinuation of treatment by vasoactive agents (e.g. pentoxifylline, beraprost sodium, papaverine, isoxsuprine, nylidrin, cyclandelate and niacin derivatives). Patients treated by cilostazol within 3 months prior to screening will also be excluded.
9. Concomitant treatment with sildenafil or other drug of the same class, from start of the run-in phase, until the end of the trial.

Recent (within 3 months prior to screening or during the run-in phase) changes in local and/or general conditions likely to interfere with study endpoints:

10. Recent lower-extremity surgical or endovascular arterial reconstructions or sympathectomy, or recent deep venous thrombosis.
11. Recent change in the level of compliance to supervised or unsupervised program of exercise training and smoking status.
12. Recent occurrence of at least one of the following: acute myocardial infarction (MI), unstable angina (UA), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), transient ischemic attack (TIA) or stroke; symptomatic cardiac arrhythmias or significant conduction disturbances.

Presence of medical and/or social conditions that would either interfere with participation in the trial, or lead to inability to complete the trial:

13. Conditions other than claudication, limiting their exercise capacity, likely to jeopardize completion and/or safety of the treadmill testing, according to investigator’s judgment.
14. Planned cardiac or vascular surgery or angioplasty or any major surgery within the next 6 months.
15. Severe concomitant disease such that the patient is not expected to survive 6 months.
16. Receipt of any investigational treatment (drug or device) within the previous 2 months.
17. Inadequate control of hypercholesterolemia and diabetes mellitus.
18. Geographic or social factors making study participation impractical.

Contra-indications to the use of clopidogrel, cilostazol, or conditions likely to affect
pharmacokinetics of cilostazol and/or comedication:

19. Contra-indication to the use of clopidogrel.
20. CHF of any severity.
21. History of drug allergy to cilostazol or HMR1766.
22. Severe hepatic disease (hepatic enzymes>3times ULN).
23. Severe renal failure (serum creatinine greater than 2.5 mg/dL).
24. Requirement for systemic administration of inhibitors of CYP3A4 such as ketoconazole, itraconazole, erythromycin, diltiazem, as well as substrates of CYP2C9 such as warfarin, fluvastatin.

E.5 End points

E.5.1

Primary end point(s)

Efficacy endpoint
. Primary:
percent change in claudication distance (ICD) measured at the 26-week test, compared with baseline value.

. Secondary:
Percent change in absolute claudication distance (ACD) at the 26-week test, compared with the value at baseline.

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

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

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)

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

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

Yes

E.8.2.3.1

Comparator description

cilostazol used as a calibrator

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

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

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

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	30
F.4.2	For a multinational trial
F.4.2.1	In the EEA	190
F.4.2.2	In the whole clinical trial	550

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

2007-01-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-04-06

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-10-08

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