Anagrelide Retard in Essential Thrombocythemia

Essential Thrombocythemia Clinical Trial

— 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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02076815
• Other study ID #: AOP18007
• Secondary ID: 2013-003410-41
• Status: Completed
• Phase: Phase 3
• First received: February 13, 2014
• Last updated: July 27, 2015
• Start date: February 2014
• Est. completion date: April 2015

Study information

• Verified date: July 2015
• Source: AOP Orphan Pharmaceuticals AG
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Austrian Medicines and Medical Devices AgencyAustria : Federal Ministry for Labour, Health, and Social AffairsAustria: EthikkommissionBulgaria: Bulgarian Drug AgencyBulgaria: Ethics committeeBulgaria: Ministry of HealthLithuania: Bioethics CommitteeLithuania: State Medicine Control Agency - Ministry of HealthPoland: Ethics CommitteePoland: The Central Register of Clinical TrialsRussia: Ethics CommitteeRussia: FSI Scientific Center of Expertise of Medical ApplicationRussia: Ministry of Health of the Russian Federation
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: April 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Essential Thrombocythemia
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• Anagrelide retard
Overencapsulated tablets or matched placebo, twice daily, 2-12 weeks titration to achieve stable platelet count, followed by 4 more weeks
• Thromboreductin
Overencapsulated capsule, twice daily, 2-12 weeks titration to achieve the stable platelet count, followed by 4 more weeks

Locations

Country	Name	City	State
Austria	AOP Orphan Investigational Site Austria 2	Linz
Austria	AOP Orphan Investigational Site Austria 1	Vienna
Austria	AOP Orphan Investigational Site Austria 3	Wels
Bulgaria	AOP Orphan Investigational Site Bulgaria 1	Pleven
Bulgaria	AOP Orphan Investigational Site Bulgaria 2	Sofia
Lithuania	AOP Orphan Investigational Site Lithuania 1	Kaunas
Lithuania	AOP Orphan Investigational Site Lithuania 2	Klaipeda
Poland	AOP Orphan Investigational Site Poland 5	Bialystok
Poland	AOP Orphan Insvestigational Site Poland 6	Gdansk
Poland	AOP Orphan Investigational Site Poland 4	Katowice
Poland	AOP Orphan Investigational Site Poland 3	Lublin
Poland	AOP Orphan Investigational Site Poland 2	Torun
Poland	AOP Orphan Investigational Site Poland 1	Warsaw
Russian Federation	AOP Orphan Investigational Site Russia 1	Moscow
Russian Federation	AOP Orphan Investigational Site Russia 2	Saint-Petersburg
Russian Federation	AOP Orphan Investigational Site Russia 4	Saint-Petersburg
Russian Federation	AOP Orphan Investigational Site Russia 5	Saint-Petersburg
Russian Federation	AOP Orphan Investigational Site Russia 6	Volgograd
Russian Federation	AOP Orphan Investigational Site Russia 3	Yaroslavl

Sponsors (1)

Lead Sponsor	Collaborator
AOP Orphan Pharmaceuticals AG

Countries where clinical trial is conducted

Austria,  Bulgaria,  Lithuania,  Poland,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of Life		at week 1 and week 13	No
Other	Plasma anagrelide concentration		At week 13, 15 and 17	No
Other	Plasma anagrelide concentration		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)	No
Primary	Platelet count	Mean value from three measurements	weeks 13-17	No
Secondary	platelet response		weeks 13-17	No
Secondary	Time from randomization to entering maintenance period		up to 12 weeks	No
Secondary	Study drug administration		weeks 1-17	No
Secondary	Change in platelet counts in the titration period		baseline, week 12	No
Secondary	Time from randomization until withdrawal		up to 17 weeks	No
Secondary	Incidence, causality and intensity of adverse events		weeks 0-21	Yes
Secondary	Incidence, intensity and outcomes of events leading to dose reduction or temporary or permanent treatment discontinuation		weeks 1-18	Yes
Secondary	Need of medications to treat adverse events		weeks 0-21	Yes
Secondary	ECG abnormalities		weeks 0-18	Yes
Secondary	Ejection fraction		baseline, week 17, week 21	Yes
Secondary	ECHO normal/abnormal		baseline, week 17, week 21	Yes