Clinical Trials Register

Summary
EudraCT Number:	2004-004061-15
Sponsor's Protocol Code Number:	SPD422-403
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-03-20
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

Bulgarian Drug Agency

A.2

EudraCT number

2004-004061-15

A.3

Full title of the trial

A Phase IIIb, randomised, open label study to compare the safety, efficacy and tolerability of anagrelide hydrochloride versus hydroxyurea in high-risk essential thrombocythaemia patients.

A.3.1

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

A study to compare the safety and effectiveness of anagrelide and hydroxyurea in high-risk essential thrombocythaemia patients.

A.3.2

Name or abbreviated title of the trial where available

COMET

A.4.1

Sponsor's protocol code number

SPD422-403

A.5.4

Other Identifiers

Name:

CT2004-004-061-15

Number:

Not available

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	Shire Pharmaceutical Development Ltd.
B.1.3.4	Country	United Kingdom
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	Shire Pharmaceuticals
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Not available
B.5.2	Functional name of contact point	Not available
B.5.3	Address:
B.5.3.1	Street Address	Not available
B.5.3.2	Town/ city	Not available
B.5.3.3	Post code	Not available

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	Xagrid
D.2.1.1.2	Name of the Marketing Authorisation holder	Shire Pharmaceutical Contracts Ltd
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/00/010
D.3 Description of the IMP
D.3.1	Product name	Xagrid
D.3.4	Pharmaceutical form	Capsule, hard
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	Anagrelide hydrochloride
D.3.9.1	CAS number	58579-51-4
D.3.9.2	Current sponsor code	SPD-422-404
D.3.9.3	Other descriptive name	COMET
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	0.5
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	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	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	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	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	Hydrea
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb
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.3.1	Product name	Hydrea
D.3.4	Pharmaceutical form	Capsule, hard
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	Hydroxycarbamide
D.3.9.1	CAS number	127-07-1
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	500
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

Essential thrombocythaemia

E.1.1.1

Medical condition in easily understood language

ET is a disorder of the bone marrow, which causes too many platelets to be produced. There is a risk of problems such as blood clots forming unnecessarily and excessive bleeding.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	PT
E.1.2	Classification code	10015493
E.1.2	Term	Essential thrombocythaemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To compare the safety of anagrelide and hydroxyurea in short and long term usage of up to three years with particular reference to cardiovascular safety (as assessed by echocardiogram).

E.2.2

Secondary objectives of the trial

To compare the efficacy of angrelide and hydroxyurea in terms of platelet count after 6 months of treatment.

To compare the efficacy of anagrelide and hydroxyurea in terms of platelet count after 3 months of treatment.

To compare the efficacy of anagrelide and hydroxyurea in terms of the number of patients achieving a complete response.

To compare the cytoreductive impact of anagrelide and hydroxyurea on white blood cell and red blood cell lines.

To investigate the tolerability of anagrelide and hydroxyurea in short term and long term usage of up to three years.

To investigate the effects of anagrelide and hydroxyurea on incidence of disease related thrombotic and haemorrhagic events.

To compare the average time to response following treatment with anagrelide or hydroxyurea.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must have given written informed consent to participate in the study.
Patients must be aged ≥ 18 years.
Previously untreated with a cytotreductive agent.
Confirmed diagnosis of ET - High Risk Profile.
Satisfactory Medical assessment with no clinically significant and relevant abnormalities.
If patients are female and of childbearing potential they must have a negative serum pregnancy test prior to entering the study and must agree to use effective birth control for the duration of the study. Pregnant or lactating women are excluded from participation.
Patients must be able, willing and likely to comply with the study procedures and restrictions.

E.4

Principal exclusion criteria

Patients with a diagnosis of any other myeloproliferative disorder (MPD).
Any known cause for a secondary thrombocytosis.
Previous or current treatment with cytoreductive therapy.
Anticoagulant therapies.
Anti-aggregant therapies, including aspirin. (Aspirin or other anti-aggregant therapy is allowed up to the point of randomisation).
Known or suspected intolerance to study materials.
Known or suspected Heart Disease.
Left Ventricular Ejection Fraction (LVEF) <55%.
Treatment with any medications known to alter ventricular ejection fraction.
Life threatening malignancy or neoplasia which in the opinion of the investigator is unrelated to thrombocythaemia.
Severe renal impairment defined as creatinine clearance <30ml/min, or severe hepatic impairment defined as elevated transaminases >5xULN.
Clinically significant abnormal laboratory values (excluding markers of essential thrombocythaemia) will exclude the patient from the study as will known infection with hepatitis B, hepatitis C or HIV.
Patients with a history of drug/alcohol abuse (within the previous 2 years).
Patients must not have participated in another investigational study within 30 days prior to enrolment or for a longer duration if specified in local regulations.

E.5 End points

E.5.1

Primary end point(s)

The primary outcome for this study is the safety measurement LVEF. LVEF will be measured at predefined intervals (pre-treatment and Months 1,2,3,6,9,12,18,24,30 and 36) during the study and the response (slope) in LVEF for each patients will be obtained using linear regression. LVEF will be modelled as a linear function of time with a separate slope and intercept for each patient.

The mean slope for each treatment group, the difference in the mean slopes between the two treatment groups, and the associated two-sided 95% confidence intervals will be presented. If the 95% CI for difference lies entirely below 2%/year then it will be concluded that the effect of anagrelide on LVEF is no worse than that observed for hydroxyurea.

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety with particular reference to cardiovascular safety of anagrelide and hydroxyurea will be performed in short and long term usage of up to 3 years

E.5.2

Secondary end point(s)

-Mean platelet count at 3 months.
- Mean and percentage platelet count reduction from baseline at 3 and 6 months
- The proportion of patients achieving a complete or partial response will be summarised by treatment group
- The median time to response will be summarised using Kaplan-Meier methodology.The minimum and maximum time to response along with a 95% CI will also be
presented.
- Incidence of disease related thrombotic and haemorrhagic events will be summarised by treatment group at baseline and post-baseline.

E.5.2.1

Timepoint(s) of evaluation of this end point

Mean platelet count at 3 months.
- Mean and percentage platelet count reduction from baseline at 3 and 6 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

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

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

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

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

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.8.2.3.1

Comparator description

Hydroxyurea

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

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

Last visit of the 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

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	25
F.4.2	For a multinational trial
F.4.2.1	In the EEA	154
F.4.2.2	In the whole clinical trial	184

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

2008-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-03-25

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

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