A Study of Anagrelide and Hydroxyurea in High-Risk Essential Thrombocythemia Patients

A Phase IIIb, Randomized, Open Label Study to Compare the Safety, Efficacy and Tolerability of Anagrelide Hydrochloride Versus Hydroxyurea in High-Risk Essential Thrombocythaemia Patients.

Essential thrombocythaemia is a disorder of bone marrow, which causes too many platelets to be produced. Platelets are small cells carried around in the blood, which help form blood clots. When patients have too many platelets, there is a risk of blood clots forming unnecessarily and excessive bleeding. The aim of this study is to gain additional information on the safety profile of Anagrelide (Xagrid(r)) and Hydroxyurea (also known as hydroxycarbamide).

Study Overview

• Status: Completed
• Conditions: Thrombocythemia, Hemorrhagic
• Intervention / Treatment: Drug: Anagrelide; Drug: Hydroxyurea

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 4

Contacts and Locations

Study Locations

• Bulgaria
  • Pleven, Bulgaria, 5800
    • University Multiprofile Hospital for Active Treatment ''Dr Georgi Stranski'' - Pleven
  • Sofia, Bulgaria, 1303
    • University Multiprofile Hospital for active Treatment ''Alexandrovska'' Clinic of Haematology
  • Varna, Bulgaria, 9010
    • University Multiprofile Hospital for Active Treament ''Sv. Marina'' - Varna Haematology Clinic
• France
  • Paris, France
    • Hopital Saint Louis - Centre d'Investigation Clinique
  • Cedex 09
    • Angers, Cedex 09, France, 49933
      • CHU Angers Services des Maladies du Sang
• Hungary
  • Debrecen, Hungary, 4012
    • University of Debrecen Medical and Health Science Centre
  • Gyor, Hungary, 9024
    • Petz Aladar County Teaching Hospital
  • Gyula, Hungary, 5700
    • Pandy Kalman Hospital of Bekes County
  • Kaposvar, Hungary, 7400
    • Kaposi Mor Teaching Hospital
• Poland
  • Gdansk, Poland, 80-952
    • Uniwersyteckie Centrum Kliniczne Katedra i Klinika Hematologii i Transplantologii
  • Lublin, Poland, 21-081
    • Samodzielny Publiczny Szpital Kliniczny Nr 1
  • Warsaw, Poland, 02-097
    • Katedra i Klinika Onkologii i Chorob Wewnetrznych Akademii Medycznej
  • Warsaw, Poland, 02-776
    • Klinika Hematologii Instytut Hematologii i Transfuzjologi
• Portugal
  • Coimbra, Portugal, 3000-076
    • Hospitals da Universidade de Coimbra
• Serbia
  • Belgrade, Serbia, 11000
    • Institute for Haematology of Clinical Centre of Serbia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of essential thrombocythaemia - high risk profile
• Previously untreated with a cytoreductive agent
• Females of childbearing potential must have a negative urine pregnancy test prior to entering the study and must agree to use effective birth control for the duration of the study

Exclusion Criteria:

• Diagnosis of any other myeloproliferative disorder
• Any known cause for a secondary thrombocytosis
• Anti-coagulant and anti-aggregant therapies
• Known or suspected heart disease
• Left Ventricular Ejection Fraction < 55%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: B	Drug: Hydroxyurea; Hydroxyurea is 500mg hydroxycarbamide capsules; initial dose is 1000mg/day, administered in two divided doses (500mg/dose). Dose titrated to effect to achieve a response.
Experimental: A	Drug: Anagrelide; Anagrelide hydrochloride 0.5mg capsules;initial dose administered will be 1.0mg/day administered as 0.5mg bid. The dose will be titrated such that the total daily dose is incremented by no more than 0.5mg per week as required depending on platelet reduction versus adverse event profile.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time	The LVEF was measured by echocardiography and considered a sufficiently sensitive measure to evaluate any changes in cardiac function.	Baseline and Month 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36
Platelet Count at Month 6	Platelet count was evaluated.	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Platelet Counts at Month 3 and 36	Platelet count was evaluated throughout the study.	Baseline and Month 3 and 36
Percentage of Participants With Complete Response	A complete response was defined as a platelet count of less than (<) 400x10^9/Liter which was confirmed over 2 consecutive visits at least 28 days apart.	Baseline up to Month 36
Percentage of Participants With Partial Response	A partial response is defined as a platelet count of 400-600 x 10^9/Liter and a reduction in platelet count of at least 200 x 10^9/Liter from baseline which was confirmed over 2 consecutive visits at least 28 days apart.	Baseline up to Month 36
Time to Complete Response	Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a participant did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal).	Baseline up to Month 36
Time to Partial Response	Time in days from the date of the first dose of study medication to the date of the first visit at which response was classified. If a participant did not achieve response then they were censored at their last visit in the study (Month 36 or withdrawal).	Baseline up to Month 36
Number of Participants With Thrombotic and Haemorrhagic Events	Thrombohaemorrhagic events are a well-known complication of the underlying essential thrombocythemia (ET) and disease progression. Events such as arterial and venous thrombosis, serious haemorrhage (including gastrointestinal haemorrhage), and death from vascular causes have been reported in participants who received cytoreductive treatment.	From the signing of informed consent until the last study-related visit (Month 36)
Change From Baseline in White Blood Cell Count Over Time	White blood cell count was evaluated throughout the study.	Baseline and Month 6, 12, 18, 24, 30 and 36
Change From Baseline in Red Blood Cell Count Over Time	Red blood cell count was evaluated throughout the study.	Baseline and Month 6, 12, 18, 24, 30 and 36

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Birgegard G, Folkvaljon F, Garmo H, Holmberg L, Besses C, Griesshammer M, Gugliotta L, Wu J, Achenbach H, Kiladjian JJ, Harrison CN. Leukemic transformation and second cancers in 3649 patients with high-risk essential thrombocythemia in the EXELS study. Leuk Res. 2018 Nov;74:105-109. doi: 10.1016/j.leukres.2018.10.006. Epub 2018 Oct 11.
• Gotic M, Egyed M, Gercheva L, Warzocha K, Kvasnicka HM, Achenbach H, Wu J. Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia. Cardiovasc Toxicol. 2021 Mar;21(3):236-247. doi: 10.1007/s12012-020-09615-0. Epub 2020 Oct 29.

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2006
• Primary Completion (Actual): December 15, 2015
• Study Completion (Actual): December 15, 2015

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: September 14, 2005
• First Posted (Estimate): September 20, 2005

Study Record Updates

• Last Update Posted (Actual): June 2, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Myeloproliferative Disorders; Blood Coagulation Disorders; Blood Platelet Disorders; Thrombocytosis; Thrombocythemia, Essential; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Antineoplastic Agents; Antisickling Agents; Hydroxyurea; Anagrelide
• Other Study ID Numbers: SPD422-403; 2004-004061-15 (EudraCT Number)