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Anagrelide Retard in Essential Thrombocythemia (TEAM-ET)

Primary Purpose

Essential Thrombocythemia

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Anagrelide retard
Thromboreductin
Sponsored by
AOP Orphan Pharmaceuticals AG
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Essential Thrombocythemia focused on measuring myeloproliferative neoplasm, essential thrombocythemia, high risk patients, anagrelide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • willing and able to give written informed consent prior to any study specific procedures and able to comply with the trial protocol
  • confirmed diagnosis of ET according to 2008 WHO diagnostic criteria* (Swerdlow et al, 2008), defined as meeting all four criteria
  • at high risk of experiencing ET-related events, indicated for Thromboreductin® treatment as defined by one or more of the following criteria: age ≥ 60 years, platelet counts ≥ 1000 G/L, increase of platelet count ≥ 300 G/L within 3 months, severe thrombohemorrhagic or ischemic symptoms in anamnesis
  • either currently treated with anagrelide
  • or ET treatment naive
  • or anagrelide naive

Exclusion Criteria:

  • Diagnosis of any myeloproliferative disorder other than ET
  • Any known cause for a secondary thrombocytosis
  • ET currently well controlled by another cytoreductive treatment than Anagrelide 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; Green and Weiss, 1992)
  • Clinically significant abnormal laboratory values (excluding markers for ET) in investigator's opinion
  • 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
  • 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.
  • 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.

Sites / Locations

  • AOP Orphan Investigational Site Austria 2
  • AOP Orphan Investigational Site Austria 1
  • AOP Orphan Investigational Site Austria 3
  • AOP Orphan Investigational Site Bulgaria 1
  • AOP Orphan Investigational Site Bulgaria 2
  • AOP Orphan Investigational Site Lithuania 1
  • AOP Orphan Investigational Site Lithuania 2
  • AOP Orphan Investigational Site Poland 5
  • AOP Orphan Insvestigational Site Poland 6
  • AOP Orphan Investigational Site Poland 4
  • AOP Orphan Investigational Site Poland 3
  • AOP Orphan Investigational Site Poland 2
  • AOP Orphan Investigational Site Poland 1
  • AOP Orphan Investigational Site Russia 1
  • AOP Orphan Investigational Site Russia 2
  • AOP Orphan Investigational Site Russia 5
  • AOP Orphan Investigational Site Russia 4
  • AOP Orphan Investigational Site Russia 6
  • AOP Orphan Investigational Site Russia 3

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Anagrelide retard

Thromboreductin

Arm Description

Anagrelide Retard prolonged-release formulation

Anagrelide immediate release formulation

Outcomes

Primary Outcome Measures

Platelet count
Mean value from three measurements

Secondary Outcome Measures

platelet response
Time from randomization to entering maintenance period
Study drug administration
Change in platelet counts in the titration period
Time from randomization until withdrawal
Incidence, causality and intensity of adverse events
Incidence, intensity and outcomes of events leading to dose reduction or temporary or permanent treatment discontinuation
Need of medications to treat adverse events
ECG abnormalities
Ejection fraction
ECHO normal/abnormal

Full Information

First Posted
February 13, 2014
Last Updated
July 27, 2015
Sponsor
AOP Orphan Pharmaceuticals AG
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1. Study Identification

Unique Protocol Identification Number
NCT02076815
Brief Title
Anagrelide Retard in Essential Thrombocythemia
Acronym
TEAM-ET
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2015
Overall Recruitment Status
Completed
Study Start Date
February 2014 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
April 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AOP Orphan Pharmaceuticals AG

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is determine whether Anagrelide Retard is non-inferior to anagrelide immediate release form in treatment of essential thrombocythemia. Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterised by a sustained increase in platelet counts above the normal value (> 450 x 109/L) and increased megakaryopoiesis in the bone marrow, without secondary causes of thrombocytosis. Anagrelide hydrochloride selectively reduces platelet numbers by inhibiting megakaryocyte development and maturation in humans, without affecting other cell lineages. Anagrelide Retard is a new, prolonged release (PR) tablet formulation of anagrelide developed by AOP Orphan Pharmaceuticals AG. The rationale for developing this new formulation is based on the assumption of having a better tolerability while maintaining an efficacy comparable to that of the immediate release formulation. The effects of Anagrelide Retard and Thromboreductin® will be compared in terms of mean platelet count measured by a central laboratory/centralized method at 3 time points during the maintenance phase.
Detailed Description
This is a randomised, multicentre, double-blind, active controlled study to compare the efficacy and safety of two different anagrelide formulations in patients with high-risk essential thrombocythemia (ET). 100 patients, either Anagrelide-treated or Anagrelide-naïve, with an indication to receive Thromboreductin® treatment, will be randomized into one of the two investigational medicinal product (IMP) groups (Anagrelide Retard or Thromboreductin®). Treatment allocation will be balanced within stratum (treated/naive) and age classes by central randomization. Naive patients will start with dose level 2 of the IMPs (i.e., 1 mg Thromboreductin® or 2 mg Anagrelide Retard). Anagrelide-treated patients will be switched to the dose level which is closest to the pre-study anagrelide dose at study start. Dose modifications in the titration phase will be done on a weekly basis (up to a maximum of 12 weeks) until "stable platelet counts" on two consecutive visits is achieved. The periods of the study participation per patient are as follows: Screening (up to 7 days prior to randomization), ending with randomization/first IMP dose (Baseline Visit) Titration period (weekly visits for up to 12 weeks): to achieve "stable platelet counts" on two consecutive measurements (i.e. weekly visits) Maintenance period (weekly visits for 4 weeks): primary endpoint relevant period. The maintenance period for a patient starts at the visit with the second successive platelet count ≤400 G/L (or <600 G/L, if the dose cannot be increased any more due to intolerance or because the maximal dose allowed has already been reached) if the second platelet value measured lies in the range within ± 30% of the value measured at the previous visit. End of study (EoS) safety follow-up visit (28 days after the last maintenance visit/EoT for early termination).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Essential Thrombocythemia
Keywords
myeloproliferative neoplasm, essential thrombocythemia, high risk patients, anagrelide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
106 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Anagrelide retard
Arm Type
Experimental
Arm Description
Anagrelide Retard prolonged-release formulation
Arm Title
Thromboreductin
Arm Type
Active Comparator
Arm Description
Anagrelide immediate release formulation
Intervention Type
Drug
Intervention Name(s)
Anagrelide retard
Other Intervention Name(s)
Anagrelide retard 2 mg film coated tablet, ANAT2
Intervention Description
Overencapsulated tablets or matched placebo, twice daily, 2-12 weeks titration to achieve stable platelet count, followed by 4 more weeks
Intervention Type
Drug
Intervention Name(s)
Thromboreductin
Other Intervention Name(s)
Anagrelide 0.5 mg capsule, ANAC05
Intervention Description
Overencapsulated capsule, twice daily, 2-12 weeks titration to achieve the stable platelet count, followed by 4 more weeks
Primary Outcome Measure Information:
Title
Platelet count
Description
Mean value from three measurements
Time Frame
weeks 13-17
Secondary Outcome Measure Information:
Title
platelet response
Time Frame
weeks 13-17
Title
Time from randomization to entering maintenance period
Time Frame
up to 12 weeks
Title
Study drug administration
Time Frame
weeks 1-17
Title
Change in platelet counts in the titration period
Time Frame
baseline, week 12
Title
Time from randomization until withdrawal
Time Frame
up to 17 weeks
Title
Incidence, causality and intensity of adverse events
Time Frame
weeks 0-21
Title
Incidence, intensity and outcomes of events leading to dose reduction or temporary or permanent treatment discontinuation
Time Frame
weeks 1-18
Title
Need of medications to treat adverse events
Time Frame
weeks 0-21
Title
ECG abnormalities
Time Frame
weeks 0-18
Title
Ejection fraction
Time Frame
baseline, week 17, week 21
Title
ECHO normal/abnormal
Time Frame
baseline, week 17, week 21
Other Pre-specified Outcome Measures:
Title
Quality of Life
Time Frame
at week 1 and week 13
Title
Plasma anagrelide concentration
Time Frame
At week 13, 15 and 17
Title
Plasma anagrelide concentration
Time Frame
1 min prior study treatment intake (morning dose), and 0.5, 1, 2, 3, 4, 6, 8, 10,12 (followed by evening dose), 13, 14, 15, 16, 18, 20, 24 hours after study treatment intake (morning dose)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: willing and able to give written informed consent prior to any study specific procedures and able to comply with the trial protocol confirmed diagnosis of ET according to 2008 WHO diagnostic criteria* (Swerdlow et al, 2008), defined as meeting all four criteria at high risk of experiencing ET-related events, indicated for Thromboreductin® treatment as defined by one or more of the following criteria: age ≥ 60 years, platelet counts ≥ 1000 G/L, increase of platelet count ≥ 300 G/L within 3 months, severe thrombohemorrhagic or ischemic symptoms in anamnesis either currently treated with anagrelide or ET treatment naive or anagrelide naive Exclusion Criteria: Diagnosis of any myeloproliferative disorder other than ET Any known cause for a secondary thrombocytosis ET currently well controlled by another cytoreductive treatment than Anagrelide 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; Green and Weiss, 1992) Clinically significant abnormal laboratory values (excluding markers for ET) in investigator's opinion 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 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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Heinz Gisslinger, Prof., MD
Organizational Affiliation
Vienna Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
AOP Orphan Investigational Site Austria 2
City
Linz
ZIP/Postal Code
A-4040
Country
Austria
Facility Name
AOP Orphan Investigational Site Austria 1
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
AOP Orphan Investigational Site Austria 3
City
Wels
ZIP/Postal Code
A-4600
Country
Austria
Facility Name
AOP Orphan Investigational Site Bulgaria 1
City
Pleven
ZIP/Postal Code
5800
Country
Bulgaria
Facility Name
AOP Orphan Investigational Site Bulgaria 2
City
Sofia
ZIP/Postal Code
1407
Country
Bulgaria
Facility Name
AOP Orphan Investigational Site Lithuania 1
City
Kaunas
ZIP/Postal Code
LT-50009
Country
Lithuania
Facility Name
AOP Orphan Investigational Site Lithuania 2
City
Klaipeda
ZIP/Postal Code
LT-92288
Country
Lithuania
Facility Name
AOP Orphan Investigational Site Poland 5
City
Bialystok
ZIP/Postal Code
15-276
Country
Poland
Facility Name
AOP Orphan Insvestigational Site Poland 6
City
Gdansk
ZIP/Postal Code
80-952
Country
Poland
Facility Name
AOP Orphan Investigational Site Poland 4
City
Katowice
ZIP/Postal Code
40-027
Country
Poland
Facility Name
AOP Orphan Investigational Site Poland 3
City
Lublin
ZIP/Postal Code
20-081
Country
Poland
Facility Name
AOP Orphan Investigational Site Poland 2
City
Torun
ZIP/Postal Code
87-100
Country
Poland
Facility Name
AOP Orphan Investigational Site Poland 1
City
Warsaw
ZIP/Postal Code
02-776
Country
Poland
Facility Name
AOP Orphan Investigational Site Russia 1
City
Moscow
ZIP/Postal Code
125167
Country
Russian Federation
Facility Name
AOP Orphan Investigational Site Russia 2
City
Saint-Petersburg
ZIP/Postal Code
191024
Country
Russian Federation
Facility Name
AOP Orphan Investigational Site Russia 5
City
Saint-Petersburg
ZIP/Postal Code
194291
Country
Russian Federation
Facility Name
AOP Orphan Investigational Site Russia 4
City
Saint-Petersburg
ZIP/Postal Code
196084
Country
Russian Federation
Facility Name
AOP Orphan Investigational Site Russia 6
City
Volgograd
ZIP/Postal Code
400138
Country
Russian Federation
Facility Name
AOP Orphan Investigational Site Russia 3
City
Yaroslavl
ZIP/Postal Code
150062
Country
Russian Federation

12. IPD Sharing Statement

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Anagrelide Retard in Essential Thrombocythemia

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