Thrombocythemia, Hemorrhagic
Conditions
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).
Interventions
DRUGAnagrelide
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.
DRUGHydroxyurea
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.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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%
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Platelet Count at Month 6 | Month 6 | Platelet count was evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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). |
| Change From Baseline in Platelet Counts at Month 3 and 36 | Baseline and Month 3 and 36 | Platelet count was evaluated throughout the study. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Bulgaria, France, Hungary, Poland, Portugal, Serbia
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Anagrelide 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. | 76 |
| Hydroxyurea 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. | 70 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 13 |
| Overall Study | Lack of Efficacy | 6 | 6 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 9 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 6 |
Baseline characteristics
| Characteristic | Anagrelide | Hydroxyurea | Total |
|---|---|---|---|
| Age, Continuous | 52.1 years STANDARD_DEVIATION 16.1 | 52.9 years STANDARD_DEVIATION 15.8 | 52.5 years STANDARD_DEVIATION 15.91 |
| Sex: Female, Male Female | 56 Participants | 45 Participants | 101 Participants |
| Sex: Female, Male Male | 20 Participants | 25 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 76 | 27 / 70 |
| serious Total, serious adverse events | 17 / 76 | 13 / 70 |
Outcome results
Primary
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.
Time frame: Baseline and Month 1, 2, 3, 6, 9, 12, 18, 24, 30 and 36
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Baseline | 66.4 percentage of ejection fraction | Standard Deviation 4.81 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 1 | 0.5 percentage of ejection fraction | Standard Deviation 4.68 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 2 | 1.2 percentage of ejection fraction | Standard Deviation 5.8 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 3 | 0.1 percentage of ejection fraction | Standard Deviation 5.31 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 6 | -0.5 percentage of ejection fraction | Standard Deviation 5.68 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 9 | -0.8 percentage of ejection fraction | Standard Deviation 4.78 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 12 | -0.8 percentage of ejection fraction | Standard Deviation 6.61 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 18 | -2.0 percentage of ejection fraction | Standard Deviation 5.54 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 24 | -1.8 percentage of ejection fraction | Standard Deviation 6.81 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 30 | -1.8 percentage of ejection fraction | Standard Deviation 5.84 |
| Anagrelide | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 36 | -1.7 percentage of ejection fraction | Standard Deviation 6.55 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 36 | -0.6 percentage of ejection fraction | Standard Deviation 5.46 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 12 | -0.6 percentage of ejection fraction | Standard Deviation 5.67 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 1 | -1.1 percentage of ejection fraction | Standard Deviation 4.73 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 30 | -0.2 percentage of ejection fraction | Standard Deviation 5.38 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 2 | 0 percentage of ejection fraction | Standard Deviation 5.03 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 18 | -1.2 percentage of ejection fraction | Standard Deviation 4.84 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 3 | -0.4 percentage of ejection fraction | Standard Deviation 3.94 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Baseline | 66.9 percentage of ejection fraction | Standard Deviation 4.59 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 6 | -0.6 percentage of ejection fraction | Standard Deviation 3.95 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 24 | -1.7 percentage of ejection fraction | Standard Deviation 6.17 |
| Hydroxyurea | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time | Change from baseline at Month 9 | -1.5 percentage of ejection fraction | Standard Deviation 5.15 |
Primary
Platelet Count at Month 6
Platelet count was evaluated.
Time frame: Month 6
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Anagrelide | Platelet Count at Month 6 | 418.6 10^9 platelets per liter | Standard Deviation 135.96 |
| Hydroxyurea | Platelet Count at Month 6 | 396.0 10^9 platelets per liter | Standard Deviation 144.07 |
95% CI: [-179.42, -21.49]
Secondary
Change From Baseline in Platelet Counts at Month 3 and 36
Platelet count was evaluated throughout the study.
Time frame: Baseline and Month 3 and 36
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anagrelide | Change From Baseline in Platelet Counts at Month 3 and 36 | Change from baseline at Month 3 | 575.3 10^9 platelets per liter | Standard Deviation 36.11 |
| Anagrelide | Change From Baseline in Platelet Counts at Month 3 and 36 | Change from baseline at Month 36 | 531.0 10^9 platelets per liter | Standard Deviation 42.14 |
| Hydroxyurea | Change From Baseline in Platelet Counts at Month 3 and 36 | Change from baseline at Month 3 | 462.2 10^9 platelets per liter | Standard Deviation 37.54 |
| Hydroxyurea | Change From Baseline in Platelet Counts at Month 3 and 36 | Change from baseline at Month 36 | 462.8 10^9 platelets per liter | Standard Deviation 43.81 |
Comparison: Month 395% CI: [-187.4, -38.83]
Comparison: Month 3695% CI: [-154.95, 18.43]
Secondary
Change From Baseline in Red Blood Cell Count Over Time
Red blood cell count was evaluated throughout the study.
Time frame: Baseline and Month 6, 12, 18, 24, 30 and 36
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 12 | -0.246 10^12 cells per liter | Standard Deviation 0.4292 |
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 24 | -0.299 10^12 cells per liter | Standard Deviation 0.5811 |
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 6 | -0.227 10^12 cells per liter | Standard Deviation 0.4134 |
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 30 | -0.295 10^12 cells per liter | Standard Deviation 0.5713 |
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 18 | -0.225 10^12 cells per liter | Standard Deviation 0.4224 |
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 36 | -0.366 10^12 cells per liter | Standard Deviation 0.4328 |
| Anagrelide | Change From Baseline in Red Blood Cell Count Over Time | Baseline | 4.757 10^12 cells per liter | Standard Deviation 0.5897 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 36 | -1.362 10^12 cells per liter | Standard Deviation 0.6586 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Baseline | 4.787 10^12 cells per liter | Standard Deviation 0.6002 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 6 | -1.467 10^12 cells per liter | Standard Deviation 0.6563 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 12 | -1.398 10^12 cells per liter | Standard Deviation 0.5744 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 18 | -1.323 10^12 cells per liter | Standard Deviation 0.7278 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 24 | -1.281 10^12 cells per liter | Standard Deviation 0.7219 |
| Hydroxyurea | Change From Baseline in Red Blood Cell Count Over Time | Change from baseline at Month 30 | -1.339 10^12 cells per liter | Standard Deviation 0.6509 |
Secondary
Change From Baseline in White Blood Cell Count Over Time
White blood cell count was evaluated throughout the study.
Time frame: Baseline and Month 6, 12, 18, 24, 30 and 36
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 12 | -1.00 10^9 cells per liter | Standard Deviation 2.001 |
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 24 | -1.24 10^9 cells per liter | Standard Deviation 2.283 |
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 6 | -0.38 10^9 cells per liter | Standard Deviation 4.257 |
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 30 | -1.00 10^9 cells per liter | Standard Deviation 2.316 |
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 18 | -1.18 10^9 cells per liter | Standard Deviation 2.184 |
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 36 | -1.63 10^9 cells per liter | Standard Deviation 2.234 |
| Anagrelide | Change From Baseline in White Blood Cell Count Over Time | Baseline | 9.13 10^9 cells per liter | Standard Deviation 2.159 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 36 | -4.46 10^9 cells per liter | Standard Deviation 3.312 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Baseline | 10.20 10^9 cells per liter | Standard Deviation 3.491 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 6 | -5.02 10^9 cells per liter | Standard Deviation 2.525 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 12 | -4.79 10^9 cells per liter | Standard Deviation 2.779 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 18 | -4.46 10^9 cells per liter | Standard Deviation 2.664 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 24 | -4.82 10^9 cells per liter | Standard Deviation 2.692 |
| Hydroxyurea | Change From Baseline in White Blood Cell Count Over Time | Change from baseline at Month 30 | -4.59 10^9 cells per liter | Standard Deviation 3.391 |
Secondary
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.
Time frame: From the signing of informed consent until the last study-related visit (Month 36)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Anagrelide | Number of Participants With Thrombotic and Haemorrhagic Events | 30 participants |
| Hydroxyurea | Number of Participants With Thrombotic and Haemorrhagic Events | 16 participants |
Secondary
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.
Time frame: Baseline up to Month 36
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Anagrelide | Percentage of Participants With Complete Response | 58.9 percenatge of participants |
| Hydroxyurea | Percentage of Participants With Complete Response | 58.8 percenatge of participants |
Secondary
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.
Time frame: Baseline up to Month 36
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Anagrelide | Percentage of Participants With Partial Response | 21.9 percentage of participants |
| Hydroxyurea | Percentage of Participants With Partial Response | 27.9 percentage of participants |
Secondary
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).
Time frame: Baseline up to Month 36
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Anagrelide | Time to Complete Response | 177.0 days |
| Hydroxyurea | Time to Complete Response | 123.0 days |
Secondary
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).
Time frame: Baseline up to Month 36
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Anagrelide | Time to Partial Response | 61.0 days |
| Hydroxyurea | Time to Partial Response | 47.0 days |