Clinical Trials Register

Summary
EudraCT Number:	2013-003410-41
Sponsor's Protocol Code Number:	AOP18007
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:	2014-01-22
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2013-003410-41

A.3

Full title of the trial

A phase III randomized, multicenter, double-blind, active controlled study to compare the efficacy and safety of two different anagrelide formulations in patients with Essential Thrombocythemia (TEAM-ET 2.0)

A.3.1

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

Safety and efficacy study for comparison of two different anagrelide formulations in patients with Essential Thrombocythemia

A.3.2

Name or abbreviated title of the trial where available

TEAM-ET 2.0

A.4.1

Sponsor's protocol code number

AOP18007

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	AOP Orphan Pharmaceuticals AG
B.1.3.4	Country	Austria
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	AOP Orphan Pharmaceuticals AG
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOP Orphan Pharmaceuticals AG
B.5.2	Functional name of contact point	Medical Affairs Manager
B.5.3	Address:
B.5.3.1	Street Address	Wilhelminenstraße 91/II f
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1160
B.5.3.4	Country	Austria
B.5.4	Telephone number	+4315037244918
B.5.5	Fax number	+431503724441
B.5.6	E-mail	team-et@aoporphan.com

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	Anagrelide Retard 2 mg film coated tablet (over-encapsulated for blinding)
D.3.2	Product code	ANAT2
D.3.4	Pharmaceutical form	Capsule
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
D.3.9.1	CAS number	58579-51-4
D.3.9.3	Other descriptive name	ANAGRELIDE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00523MIG
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
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	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	Thromboreductin 0.5 mg
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	Thromboreductin 0.5 mg (over-encapsulated for blinding)
D.3.2	Product code	ANACO5
D.3.4	Pharmaceutical form	Capsule
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
D.3.9.1	CAS number	58579-51-4
D.3.9.3	Other descriptive name	ANAGRELIDE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB00523MIG
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)	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	Capsule
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

male or femal patients with confirmed diagnosis of Essential Thrombocythemia

E.1.1.1

Medical condition in easily understood language

male or femal patients with confirmed diagnosis of Essential Thrombocythemia

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	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10015494
E.1.2	Term	Essential thrombocythemia
E.1.2	System Organ Class	100000004864

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 determine whether Anagrelide Retard is non-inferior to Thromboreductin® in terms of mean platelet count measured by a central laboratory/centralized method at 3 time points during the maintenance phase.

E.2.2

Secondary objectives of the trial

To compare the effects of Anagrelide Retard and Thromboreductin® on the following:
- platelet response status
- tolerability and safety

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Willing and able to give written informed consent prior to any study specific procedures and able to comply with this protocol.

• Male / female

• Age ≥18 years

• Confirmed diagnosis of ET according to 2008 World Health Organization (WHO) diagnostic criteria*, defined as meeting all four criteria as follows:

a. Sustained platelet count ≥450 G/L.
b. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes. No significant increase or left shift of neutrophil granulopoiesis or erythropoiesis. (Bone marrow examination should be available as source data and based on existing biopsies – no screening assessment.)
c. Not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-ABL1-positive chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
d. Demonstration of JAK2V617F or other clonal marker, or in the absence of JAK2V617F, no evidence for reactive thrombocytosis.

* If the diagnosis was made according to earlier criteria (for example, Polycythemia Vera Study Group [PVSG]), re-examination and confirmation of diagnosis according to 2008 WHO criteria must be done. In the source data a notice by investigator should be made: ‘Reclassified according to WHO 2008 criteria for ET’.

AND:
• at high risk of experiencing ET-related events, indicated for Thromboreductin® treatment as defined by one or more of the following criteria:

o Age ≥ 60 years
o Platelet counts ≥ 1000 G/L
o Increase of platelet count ≥ 300 G/L within 3 months
o Severe thrombohemorrhagic or ischemic symptoms in anamnesis

EITHER:
• Currently treated with anagrelide (Thromboreductin® or other locally available anagrelide formulations), meeting the definition of well controlled disease. Well controlled disease is defined as the absence at screening of any acute disease related symptoms, as well as the achievement of stable platelet counts (<600 G/L AND fluctuation of these values of not more than +/- 30 %, confirmed at the Screening Visit and one previous measurement within 3 months before Screening).

OR:
• Naive:
a. ET treatment naive: no cytoreductive treatment received yet
b. Anagrelide naive, defined as meeting ALL of the below mentioned criteria:
o Treatment received has to be another cytoreductive treatment than anagrelide (e.g. Hydroxyurea, Busulfan, Interferons).
o This cytoreductive treatment had to be terminated either due to intolerance or lack of reduction of the elevated platelet counts. Intolerance to hydroxyurea is defined according to LeukemiaNet European Collaboration (see Appendix 5). Intolerance to busulfan, interferon (IFN) or another cytoreductive treatment than anagrelide is defined as any NCI CTCAE 4.0 toxicity of ≥ grade 2 (see Appendix 7).
o Termination of treatment has to be at least four weeks before start of study medication/randomization.

E.4

Principal exclusion criteria

• Diagnosis of any other myeloproliferative disorder
• Any known cause for a secondary thrombocytosis, e.g. thrombocytosis due to iron deficiency
• ET currently well controlled by another cytoreductive treatment than Anagrelide (e.g. hydroxyurea, busulfan, IFN) AND the opportunity to continue to receive this treatment
• ET currently treated with combination of any two of the following agents: anagrelide, hydroxyurea, interferons, busulfan
• Hypersensitivity to either active or non-active ingredients of anagrelide or to any other excipients of the investigational products
• Known hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
• Cardiovascular disease grade 3 with a negative benefit/risk assessment or grade 4 (South West Oncology Group, see Appendix 6)
• Clinically significant abnormal laboratory values (excluding markers for ET) in investigator’s opinion, including electrolyte imbalance
• Severe renal insufficiency (creatinine clearance <30 ml/min)
• Moderate to severe hepatic insufficiency (ALT or AST > 5 times upper normal limit [UNL])
• White blood count (WBC) ≥ 15 G/L at screening
• Diagnosis of any malignancy, other than ET (except basal cell and squamous cell carcinomas of the skin and carcinoma in situ of the cervix that have been completely excised and are considered cured), within the last 3 years, or coexisting, malignant, systemic disease
• Poorly controlled diabetes mellitus
• Known infection with hepatitis B, hepatitis C or HIV
• Pregnant or lactating women (pregnancy test to be performed within 7 days prior study treatment start)
• Women of childbearing potential or male patients, who have sexual intercourse with females of childbearing potential, not willing to use an effective method of contraception during the study. Effective methods for women are hormonal contraceptives, intrauterine devices (IUDs), surgical intervention, and sexual abstinence. Female patients with childbearing potential receiving oral hormonal contraception will have to apply an additional effective method of contraception during the study period. Effective methods for men are condoms and sexual abstinence.
• History of drug/alcohol abuse within the previous 2 years
• Participation in another investigational study within 4 weeks prior to informed consent signed or for a longer duration if specified in local regulations
• Any significant psychiatric disorder that, in the opinion of the investigator, might prohibit the understanding and giving of informed consent, or that might prevent the patient from completing the trial.

E.5 End points

E.5.1

Primary end point(s)

• Mean platelet count based on three measurements during the maintenance phase.

Optimal dosing (increase to achieve the target platelet level, decrease in case of toxicity, following the SmPC specifications of Thromboreductin® and the dosing rules for Anagrelide Retard) should be applied to each patient to reduce (for anagrelide naive patients) or maintain (for anagrelide pre-treated patients) the platelet count ≤400 G/L or, in cases in which further dose up-titration is not possible due to poor tolerability, at least below 600 G/L.

E.5.1.1

Timepoint(s) of evaluation of this end point

Mean platelet count based on three measurements during the maintenance phase; Visit 14, Visit 16 & Visit 18

E.5.2

Secondary end point(s)

Efficacy
• Platelet response status:
Responder: Response is defined as the attainment of platelet levels <600 G/L (response will be evaluated by taking the mean of three platelet counts from the central laboratory) during the maintenance treatment period.
Non responder: If platelet levels do not remain <600 G/L or missing values (e.g. drop-outs during titration and maintenance phase).

• Time from randomization to entering maintenance phase

• Study drug administration (the maintenance dose and the number of titrations)

• Change in platelet counts in the titration phase

• Time from randomization until withdrawal

Safety
• Incidence, causality and intensity of adverse events (AEs) according to common terminology criteria for adverse events (CTCAE 4.0), with additional special focus on cardiovascular, neurological and general disorders (adverse events of special interest, AESI: palpitation, tachycardia, headache, dizziness, nausea, vomiting, diarrhea, abdominal pain)
• Incidence, intensity and outcomes of events leading to dose reduction or temporary or permanent treatment discontinuation

• Need of medications (dose and duration) to treat AEs

• Electrocardiogram (ECG) abnormalities

• Ejection fraction and echocardiography (ECHO) overall conclusion (normal/abnormal)

Patient reported outcomes
• Quality of Life (EQ-5D-3L)

Pharmacokinetic measurements
There will be a mandatory PK sampling (at three visits during the maintenance period: Visits M1, M3 and M5) and an optional PK sampling (at the second visit in the maintenance period: Visit M2) to determine the concentration of anagrelide in plasma.

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy:
Evaluation of platelet status will be done throughout the Titration Period and the Maintainance Phase

Safety:
Evaluation of safety aspects status will be done throughout the complete study

Patient reported outcomes:
Evaluation of Quality of Life Questionnaire will be done throughout the Titration Period at Visit 2 and the Maintainance Phase at Visit 14 and at Visit 18.

Pharmacokinetic measurements:
There will be a mandatory PK sampling (at three visits during the maintenance period: Visits M1, M3 and M5) and an optional PK sampling (at the second visit in the maintenance period: Visit M2) to determine the concentration of anagrelide in plasma.

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

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)

Yes

E.8.2.2

Placebo

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

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

Austria

Bulgaria

Lithuania

Poland

Russian Federation

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

LVLS

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

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

112

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients, who benefit/ achieve well controlled ET during treatment in this study, can be further treated with an anagrelide formulation at the investigator's discretion as long as the patient benefits from treatment and until routinetreatment is accessible for the patient. Suitable patients will be switched toan anagrelide formulation at the EoT/last maintenance visit at the dose level equal to that received during the maintenance period

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

2014-02-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-04-14

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials