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

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00202644
• Collaborator: (none)
• Enrollment: 150
• Locations: 15
• Arms: 2
• Actual Duration (Months): 119
• Patients Per Site: 10
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Thrombocythemia, Hemorrhagic	Drug: Anagrelide; Drug: Hydroxyurea	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: Jan 13, 2006
• Actual Primary Completion Date: Dec 15, 2015
• Actual Study Completion Date: Dec 15, 2015

Arms and Interventions

Arm	Intervention/Treatment
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.
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.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time [Baseline and Month 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36]

   The LVEF was measured by echocardiography and considered a sufficiently sensitive measure to evaluate any changes in cardiac function.

2. Platelet Count at Month 6 [Month 6]

   Platelet count was evaluated.

Secondary Outcome Measures

1. Change From Baseline in Platelet Counts at Month 3 and 36 [Baseline and Month 3 and 36]

   Platelet count was evaluated throughout the study.

2. Percentage of Participants With Complete Response [Baseline up to Month 36]

   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.

3. Percentage of Participants With Partial Response [Baseline up to Month 36]

   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.

4. Time to Complete Response [Baseline up to Month 36]

   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).

5. Time to Partial Response [Baseline up to Month 36]

   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).

6. Number of Participants With Thrombotic and Haemorrhagic Events [From the signing of informed consent until the last study-related visit (Month 36)]

   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.

7. Change From Baseline in White Blood Cell Count Over Time [Baseline and Month 6, 12, 18, 24, 30 and 36]

   White blood cell count was evaluated throughout the study.

8. Change From Baseline in Red Blood Cell Count Over Time [Baseline and Month 6, 12, 18, 24, 30 and 36]

   Red blood cell count was evaluated throughout the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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%

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00202644
• Other Study ID Numbers: SPD422-403; 2004-004061-15
• First Posted: Sep 20, 2005
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• Additional relevant MeSH terms: Thrombocytosis; Thrombocythemia, Essential; Hydroxyurea; Anagrelide

Study Results

Participant Flow

Pre-assignment Detail	A total of 183 participants were screened, 149 participants were randomized at 29 sites across 10 countries. Four (4) participants randomized but withdrawn prior to treatment and 1 participant not randomized but treated.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Period Title: Overall Study
STARTED	76	70
COMPLETED	41	43
NOT COMPLETED	35	27

Baseline Characteristics

Arm/Group Title	Anagrelide	Hydroxyurea	Total
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.	Total of all reporting groups
Overall Participants	76	70	146
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.1 (16.10)	52.9 (15.80)	52.5 (15.91)
Sex: Female, Male (Count of Participants)
Female	56 73.7%	45 64.3%	101 69.2%
Male	20 26.3%	25 35.7%	45 30.8%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of participants analysed for specified category at the specified time points in each arm respectively.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Baseline	66.4 (4.81)	66.9 (4.59)
Change from baseline at Month 1	0.5 (4.68)	-1.1 (4.73)
Change from baseline at Month 2	1.2 (5.80)	0 (5.03)
Change from baseline at Month 3	0.1 (5.31)	-0.4 (3.94)
Change from baseline at Month 6	-0.5 (5.68)	-0.6 (3.95)
Change from baseline at Month 9	-0.8 (4.78)	-1.5 (5.15)
Change from baseline at Month 12	-0.8 (6.61)	-0.6 (5.67)
Change from baseline at Month 18	-2.0 (5.54)	-1.2 (4.84)
Change from baseline at Month 24	-1.8 (6.81)	-1.7 (6.17)
Change from baseline at Month 30	-1.8 (5.84)	-0.2 (5.38)
Change from baseline at Month 36	-1.7 (6.55)	-0.6 (5.46)

2. Primary Outcome

Title	Platelet Count at Month 6
Description	Platelet count was evaluated.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, N = Number of participants analysed in each arm for this outcome measure.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	60	58
Mean (Standard Deviation) [10^9 platelets per liter]	418.6 (135.96)	396.0 (144.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide, Hydroxyurea
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Noninferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-100.5
	Confidence Interval	(2-Sided) 95%; -179.42 to -21.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 39.93
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Platelet Counts at Month 3 and 36
Description	Platelet count was evaluated throughout the study.
Time Frame	Baseline and Month 3 and 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded with last observation carried forward (LOCF). Here, n=number of participants analysed for specified category at specified time points in each arm respectively.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Change from baseline at Month 3	575.3 (36.11)	462.2 (37.54)
Change from baseline at Month 36	531.0 (42.14)	462.8 (43.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide, Hydroxyurea
	Comments	Month 3
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Noninferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-113.1
	Confidence Interval	(2-Sided) 95%; -187.40 to -38.83
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 37.56
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide, Hydroxyurea
	Comments	Month 36
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	Noninferiority of anagrelide could be concluded if lower limit of 95% Confidence Interval for the difference between treatment groups (Hydroxyurea - Anagrelide) was > -100 x 10^9/Liter.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean
	Estimated Value	-68.3
	Confidence Interval	(2-Sided) 95%; -154.95 to 18.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 43.83
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Complete Response
Description	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.
Time Frame	Baseline up to Month 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Number [percenatge of participants]	58.9 77.5%	58.8 84%

5. Secondary Outcome

Title	Percentage of Participants With Partial Response
Description	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.
Time Frame	Baseline up to Month 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Number [percentage of participants]	21.9 28.8%	27.9 39.9%

6. Secondary Outcome

Title	Time to Complete Response
Description	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).
Time Frame	Baseline up to Month 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Median (95% Confidence Interval) [days]	177.0	123.0

7. Secondary Outcome

Title	Time to Partial Response
Description	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).
Time Frame	Baseline up to Month 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Median (95% Confidence Interval) [days]	61.0	47.0

8. Secondary Outcome

Title	Number of Participants With Thrombotic and Haemorrhagic Events
Description	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.
Time Frame	From the signing of informed consent until the last study-related visit (Month 36)

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Number [participants]	30 39.5%	16 22.9%

9. Secondary Outcome

Title	Change From Baseline in White Blood Cell Count Over Time
Description	White blood cell count was evaluated throughout the study.
Time Frame	Baseline and Month 6, 12, 18, 24, 30 and 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of participants analysed for specified category at the specified time points in each arm respectively.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Baseline	9.13 (2.159)	10.20 (3.491)
Change from baseline at Month 6	-0.38 (4.257)	-5.02 (2.525)
Change from baseline at Month 12	-1.00 (2.001)	-4.79 (2.779)
Change from baseline at Month 18	-1.18 (2.184)	-4.46 (2.664)
Change from baseline at Month 24	-1.24 (2.283)	-4.82 (2.692)
Change from baseline at Month 30	-1.00 (2.316)	-4.59 (3.391)
Change from baseline at Month 36	-1.63 (2.234)	-4.46 (3.312)

10. Secondary Outcome

Title	Change From Baseline in Red Blood Cell Count Over Time
Description	Red blood cell count was evaluated throughout the study.
Time Frame	Baseline and Month 6, 12, 18, 24, 30 and 36

Outcome Measure Data

Analysis Population Description

The FAS population included all randomized participants who received at least 1 dose of study medication and who had a pretreatment and at least 1 post baseline LVEF measurement recorded. Here, n = Number of participants analysed for specified category at the specified time points in each arm respectively.

Arm/Group Title	Anagrelide	Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.	Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
Measure Participants	73	68
Baseline	4.757 (0.5897)	4.787 (0.6002)
Change from baseline at Month 6	-0.227 (0.4134)	-1.467 (0.6563)
Change from baseline at Month 12	-0.246 (0.4292)	-1.398 (0.5744)
Change from baseline at Month 18	-0.225 (0.4224)	-1.323 (0.7278)
Change from baseline at Month 24	-0.299 (0.5811)	-1.281 (0.7219)
Change from baseline at Month 30	-0.295 (0.5713)	-1.339 (0.6509)
Change from baseline at Month 36	-0.366 (0.4328)	-1.362 (0.6586)

Adverse Events

Time Frame	From the signing of informed consent until the last study-related visit (Month 36)
Arm/Group Title	Anagrelide		Hydroxyurea
Arm/Group Description	Participants received Anagrelide hydrochloride 1.0 milligram (mg) per day administered orally as 0.5 mg capsule twice daily (bid) for 1 week. Then the dose was titrated such that the total daily dose is incremented by no more than 0.5 mg in any 1 week and the recommended maximum single dose could not exceed 2.5 mg as required depending on platelet reduction versus adverse event profile. Total daily dosage was not exceed 10 mg. Participants followed for up to 3 years.		Participants received Hydroxyurea as 1000 mg per day administered orally as 500 mg capsule twice daily and dose titrated to effect to achieve a response. Participants followed for up to 3 years.
All Cause Mortality
	Anagrelide		Hydroxyurea
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Anagrelide		Hydroxyurea
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/76 (22.4%)		13/70 (18.6%)
Blood and lymphatic system disorders
Anaemia	1/76 (1.3%)	1	0/70 (0%)	0
Iron deficiency anaemia	1/76 (1.3%)	1	0/70 (0%)	0
Pancytopenia	0/76 (0%)	0	1/70 (1.4%)	1
Cardiac disorders
Angina unstable	1/76 (1.3%)	1	0/70 (0%)	0
Left ventricular failure	1/76 (1.3%)	1	0/70 (0%)	0
Tachycardia	1/76 (1.3%)	1	0/70 (0%)	0
Gastrointestinal disorders
Anal fistula	0/76 (0%)	0	1/70 (1.4%)	2
Crohn's disease	1/76 (1.3%)	1	0/70 (0%)	0
Gastrointestinal haemorrhage	0/76 (0%)	0	1/70 (1.4%)	1
Inguinal hernia	0/76 (0%)	0	1/70 (1.4%)	1
Upper gastrointestinal haemorrhage	1/76 (1.3%)	1	0/70 (0%)	0
General disorders
Asthenia	1/76 (1.3%)	1	0/70 (0%)	0
Sudden death	1/76 (1.3%)	1	0/70 (0%)	0
Infections and infestations
Ear infection	1/76 (1.3%)	1	0/70 (0%)	0
Laryngitis	1/76 (1.3%)	1	0/70 (0%)	0
Sepsis	1/76 (1.3%)	1	0/70 (0%)	0
Injury, poisoning and procedural complications
Foot fracture	0/76 (0%)	0	1/70 (1.4%)	1
Traumatic amputation	0/76 (0%)	0	1/70 (1.4%)	1
Traumatic haematoma	1/76 (1.3%)	2	0/70 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	1/76 (1.3%)	1	0/70 (0%)	0
Type 2 diabetes mellitus	1/76 (1.3%)	1	0/70 (0%)	0
Musculoskeletal and connective tissue disorders
Scleroderma	0/76 (0%)	0	1/70 (1.4%)	1
Tendon calcification	0/76 (0%)	0	1/70 (1.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenoid cystic carcinoma	1/76 (1.3%)	1	0/70 (0%)	0
Bladder cancer	1/76 (1.3%)	1	0/70 (0%)	0
Breast cancer	0/76 (0%)	0	1/70 (1.4%)	1
Malignant melanoma	0/76 (0%)	0	1/70 (1.4%)	1
Peripheral nerve sheath tumour malignant	0/76 (0%)	0	1/70 (1.4%)	1
Nervous system disorders
Aphasia	1/76 (1.3%)	1	0/70 (0%)	0
Cerebral infarction	1/76 (1.3%)	2	0/70 (0%)	0
Ischaemic stroke	3/76 (3.9%)	3	0/70 (0%)	0
Neurological decompensation	1/76 (1.3%)	1	0/70 (0%)	0
Vasculitis cerebral	1/76 (1.3%)	1	0/70 (0%)	0
Reproductive system and breast disorders
Ovarian cyst	1/76 (1.3%)	1	0/70 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/76 (1.3%)	1	1/70 (1.4%)	1
Respiratory distress	1/76 (1.3%)	1	0/70 (0%)	0
Vascular disorders
Deep vein thrombosis	0/76 (0%)	0	1/70 (1.4%)	1
Hypertensive crisis	1/76 (1.3%)	1	0/70 (0%)	0
Peripheral artery thrombosis	1/76 (1.3%)	1	0/70 (0%)	0
Other (Not Including Serious) Adverse Events
	Anagrelide		Hydroxyurea
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/76 (60.5%)		27/70 (38.6%)
Blood and lymphatic system disorders
Anaemia	4/76 (5.3%)	6	8/70 (11.4%)	9
Leukopenia	1/76 (1.3%)	1	7/70 (10%)	7
Neutropenia	0/76 (0%)	0	5/70 (7.1%)	8
Cardiac disorders
Palpitations	18/76 (23.7%)	29	0/70 (0%)	0
Ear and labyrinth disorders
Vertigo	5/76 (6.6%)	5	0/70 (0%)	0
Gastrointestinal disorders
Diarrhoea	6/76 (7.9%)	7	3/70 (4.3%)	3
General disorders
Asthenia	5/76 (6.6%)	6	4/70 (5.7%)	6
Chest pain	4/76 (5.3%)	7	1/70 (1.4%)	1
Infections and infestations
Nasopharyngitis	2/76 (2.6%)	2	5/70 (7.1%)	8
Pharyngitis	2/76 (2.6%)	2	6/70 (8.6%)	8
Upper respiratory tract infection	4/76 (5.3%)	4	1/70 (1.4%)	1
Urinary tract infection	4/76 (5.3%)	8	2/70 (2.9%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	6/76 (7.9%)	7	2/70 (2.9%)	2
Nervous system disorders
Headache	19/76 (25%)	33	1/70 (1.4%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	4/76 (5.3%)	5	2/70 (2.9%)	2
Vascular disorders
Hypertension	9/76 (11.8%)	12	1/70 (1.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.