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Clinical Trial Results:
A phase III, randomized, multicenter, subject- and sponsor-blinded, placebo controlled study to compare the efficacy and safety of “Anagrelide retard” versus placebo in “at risk” subjects with Essential Thrombocythaemia

Summary
EudraCT number	2009-017095-24
Trial protocol	AT SK SI LT BG
Global end of trial date	12 Jan 2015

Results information
Results version number	v1(current)
This version publication date	27 May 2021
First version publication date	27 May 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AOP13007

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

AOP Orphan Pharmaceuticals AG

Sponsor organisation address

Wilhelminenstraße 91/IIf, Vienna, Austria,

Public contact

Dr. Michael Zörer, AOP Orphan Pharmaceuticals AG, 0043 1503 72 44 46, michael.zoerer@aoporphan.com

Scientific contact

Dr. Michael Zörer, AOP Orphan Pharmaceuticals AG, 0043 1503 72 44 46, michael.zoerer@aoporphan.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 Jan 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Jan 2015

Global end of trial reached?

Yes

Global end of trial date

12 Jan 2015

Was the trial ended prematurely?

Main objective of the trial

To determine whether "Anagrelide retard" compared to placebo will reduce the rate of ET-related complications in subjects with potential risk for ET-related Events

Protection of trial subjects

Clinical significant deviations from physical examination, vital signs, ECG, ECHO, laboratory parameters as well as therapy tolerance and adverse events will be evaluated by the investigator for the assessment of subject’s safety. Patients should be monitored during treatment for evidence of cardiovascular effects that may require further cardiovascular examination and investigation. Hypokalaemia or hypomagnesaemia must be corrected prior to Anagrelide administration and should be monitored periodically duringFinal therapy. Furthermore, serum calcium should be monitored periodically on treatment. Careful evaluation of the subject’s diaries by the investigator on every visit will help to detect unreported adverse events. For evaluation of Quality of Life (QoL) under test drug as compared to placebo, the SF-36 Questionnaire will be used. Written informed consent was obtained from all subjects prior to entry into the study. The investigator explained to each subject, orally and in writing (subject information sheet), the nature, significance, risks and implications of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Mar 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

1 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 30

Country: Number of subjects enrolled

Romania: 12

Country: Number of subjects enrolled

Slovakia: 3

Country: Number of subjects enrolled

Austria: 12

Country: Number of subjects enrolled

Bulgaria: 10

Country: Number of subjects enrolled

Lithuania: 5

Country: Number of subjects enrolled

Ukraine: 11

Country: Number of subjects enrolled

Russian Federation: 59

Country: Number of subjects enrolled

Croatia: 4

Worldwide total number of subjects

146

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

146

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

All subjects who enter into the screening period of the study (defined as the point at which the subject signs the informed consent) will receive a unique screening no before any study procedures are performed. This no will be used to identify the subject throughout the entire trial and must be used on all study documentation related that subject.

Period 1 title

Main Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind ^[1]

Roles blinded

Subject, Monitor, Data analyst, Assessor

Blinding implementation details

This was a subject and sponsor-blinded clinical study, the investigator was not blinded to treatment. The sponsor functions (including medical monitor, pharmacovigilance manager, clinical project manager, trial data manager and trial statistician) were blinded until after the database lock. Randomization scheme was prepared by an independent statistician (not otherwise involved in the study), and was stored securely with no access to it by the sponsor functions mentioned above.

Are arms mutually exclusive

Yes

Anagrelide retard

Arm description

Arm type

Experimental

Investigational medicinal product name

Anagrelide retard 2mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Titration Phase (Visit 2 – Visit 6, i.e. 4 weeks): Week 1: 1x1 tablet/d of “Anagrelide retard” (1 tablet = 2mg; total dose = 2mg/d) or placebo was administered in week 1. Week 2 “Anagrelide retard”: Dosing was titrated up according to response (platelet reduction) to 4 mg/day (= 2x1 tablet) in week 2. Week 3 – Week 4 “Anagrelide retard” In week 3 and 4, dose was either increased or decreased to maintain platelets in the normal or close to normal range. The maximum dose was 4 tablets (= 8mg Anagrelide retard) per day. Maintenance Phase (Visit 7 – Visit 10, i.e. up to 11 months) “Anagrelide retard” During maintenance phase (month 2 – month 12) doses of treatment were adjusted to the highest tolerated level which was able to maintain the platelet count within the normal range.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Titration Phase (Visit 2 – Visit 6, i.e. 4 weeks) Week 1: 1x1 tablet/d of placebo was administered in week 1. Week 2 2x1 tablet/d of placebo was administered in week 2. Week 3 – Week 4 In week 3 and week 4 the maximum dose was 4 tablets per day. Maintenance Phase (Visit 7 – Visit 10, i.e. up to 11 months) In order to guarantee blinding of subjects, the number of placebo tablets to be taken by the subject varied during maintenance period: month 2 - month 3: 2x1 tablet/d month 3 - month 6: 3x1 tablet/d month 6 - month 9: 4x1 tablet/d month 9 - month 12: 4x1 tablet/d Tablets were taken once daily after a high-fat meal intake (breakfast or lunch).The subjects were given dietary advice about high fat meals.

Notes
[1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
Justification: This was a subject and sponsor-blinded clinical study, the investigator was not blinded to treatment. The sponsor functions (including medical monitor, pharmacovigilance manager, clinical project manager, trial data manager and trial statistician) were blinded until after the database lock. Randomization scheme was prepared by an independent statistician (not otherwise involved in the study), and was stored securely with no access to it by the sponsor functions mentioned above.

Number of subjects in period 1	Anagrelide retard	Placebo
Started	77	69
Completed	60	52
Not completed	17	17
Adverse event, serious fatal	1	1
sponsor decision	-	1
Lack of efficacy: AE that constitutes ET-related	4	4
Consent withdrawn by subject	1	4
Adverse event, non-fatal	3	-
Administrative reasons	2	-
Pregnancy	1	-
patient relocated to another country	-	1
unstable platelet count	1	-
Lost to follow-up	2	-
Lack of efficacy: insufficient platelet reduction	2	6

Baseline characteristics

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Reporting group title

Anagrelide retard

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	Anagrelide retard	Placebo	Total
Number of subjects	77	69	146
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	77	69	146
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
SA
Units: years
arithmetic mean (standard deviation)	40.9 ± 11.25	45.2 ± 10.57	-
Gender categorical
Units: Subjects
Female	57	51	108
Male	20	18	38
JAK2 status
Day 0, ITT
Units: Subjects
positive	47	44	91
negative	28	25	53
not recorded	2	0	2
Body Mass Index
Units: kilogram(s)/square meter
arithmetic mean (standard deviation)	24.68 ± 4.6444	26.036 ± 4.5731	-
Duration of ET
SA
Units: Days
median (standard deviation)	75 ± 577.36	78 ± 510.39	-

Subject analysis set title

Safety Set (SA) - Anagrelide Retard

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Set (SA): All subjects who had at least one dose of treatment and one contact with the investigator afterwards are analyzed for safety. - Anagrelide Retard

Subject analysis set title

Intent-to-Treat Set (ITT) - Anagrelide retard

Subject analysis set type

Intention-to-treat

Subject analysis set description

Intent-to-Treat Set (ITT): all subjects who had at least one dose of treatment and also at least one observation visit with efficacy assessment under medication were evaluated as the 'intention to treat' (ITT) population. Subjects were excluded from the ITT population if a severe protocol violation occurred (e.g. true diagnosis was not ET). - Anagrelide retard

Subject analysis set title

Per-protocol Set 1 (PP1) - Anagrelide Retard

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol Set 1 (PP1): Subjects who were included in the ITT population and completed the study without showing major protocol deviations were included in the per protocol population (PP1). Note that subjects who discontinued due to lack of efficacy (increase of platelets and/or ET-related event were not excluded from the PP1 population even if other major protocol deviations occurred. - Anagrelide Retard

Subject analysis set title

Per-protocol Set 2 (PP2) - Anagrelide retard

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol Set 2 (PP2): An additional PP data set for exploratory purposes (PP2) that in addition to PP1 specifications excluded those subjects who had central laboratory bone marrow biopsy findings that suggested a diagnosis differing from ET. - Anagrelide retard

Subject analysis set title

Safety Set (SA) - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Set (SA): All subjects who had at least one dose of treatment and one contact with the investigator afterwards are analyzed for safety. - Placebo

Subject analysis set title

Intent-to-Treat Set (ITT) - Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Per-protocol Set 1 (PP1) - Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol Set 1 (PP1) - Placebo

Subject analysis set title

Per-protocol Set 2 (PP2) - Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis sets values	Safety Set (SA) - Anagrelide Retard	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Safety Set (SA) - Placebo	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects	77	77	53	42	69	69	47	33
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0
Adults (18-64 years)	77	77	53	42	69	69	47	33
From 65-84 years	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0
Age continuous
SA
Units: years
arithmetic mean (standard deviation)	40.9 ± 11.25	±	42.6 ± 11.53	42 ± 11.48	45.2 ± 10.57	±	46.6 ± 10.24	46.4 ± 10.17
Gender categorical
Units: Subjects
Female	57	57	40	32	51	51	39	28
Male	20	20	13	10	18	18	8	5
JAK2 status
Day 0, ITT
Units: Subjects
positive	47	47	32	26	44	44	27	18
negative	28	28	19	14	25	25	20	15
not recorded	2	2	2	2	0	0	0	0
Body Mass Index
Units: kilogram(s)/square meter
arithmetic mean (standard deviation)	24.68 ± 4.6444	24.68 ± 4.6444	±	±	26.036 ± 4.5731	26.036 ± 4.5731	±	±
Duration of ET
SA
Units: Days
median (standard deviation)	75 ± 577.36	75 ± 577.36	±	±	78 ± 510.39	78 ± 510.39	±	±

End points

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Reporting group title

Anagrelide retard

Reporting group description

Reporting group title

Placebo

Reporting group description

Subject analysis set title

Safety Set (SA) - Anagrelide Retard

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Set (SA): All subjects who had at least one dose of treatment and one contact with the investigator afterwards are analyzed for safety. - Anagrelide Retard

Subject analysis set title

Intent-to-Treat Set (ITT) - Anagrelide retard

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Per-protocol Set 1 (PP1) - Anagrelide Retard

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Per-protocol Set 2 (PP2) - Anagrelide retard

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

Safety Set (SA) - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Set (SA): All subjects who had at least one dose of treatment and one contact with the investigator afterwards are analyzed for safety. - Placebo

Subject analysis set title

Intent-to-Treat Set (ITT) - Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject analysis set title

Per-protocol Set 1 (PP1) - Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Per-protocol Set 1 (PP1) - Placebo

Subject analysis set title

Per-protocol Set 2 (PP2) - Placebo

Subject analysis set type

Per protocol

Subject analysis set description

Primary: Time to first ET-related event assessed by EAC adjudication and platelet criteria

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End point title

Time to first ET-related event assessed by EAC adjudication and platelet criteria

End point description

Following platelet related will be considered as events for the confirmatory analysis of the study: platelet counts > 1000 G/l as ET-related events together with the following additional specifications: - One single platelet count above 1000 G/l will suffice to qualify as ET related event. - Platelet counts > 1000 G/l will be considered irrespectively of the patient’s platelet count when entering the study. - Platelet counts > 1000 G/l will also qualify as ET-related event when having occurred in the titration phase. Increase of platelet count > 300 G/L within 3 months together with all the following additional specifications - the highest value following the increase is above the upper limit of normal (400 G/L) - the increased platelet value should be maintained during the subsequent visit to indicate durability of the increase and not a temporary phenomenon during dose adaptation, where the subsequent visit does not need to be within 3 months where the increase was observed

End point type

Primary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: Ratio
arithmetic mean (confidence interval 95%)	0.87 (0.74 to 0.94)	0.89 (0.73 to 0.95)	0.85 (0.67 to 0.94)	0.69 (0.16 to 0.79)	0.65 (0.45 to 0.78)	0.62 (0.39 to 0.79)

KM model with re-assessed pletelet criteria ITT

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.16

upper limit

0.79

KM model with re-assessed platelet criteria PP1

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

0.71

KM model with re-assessed platelet criteria PP2

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0029

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

0.88

Primary: Time to first ET-related event by EAC and platelet criteria (as originally planned)

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End point title

Time to first ET-related event by EAC and platelet criteria (as originally planned)

End point description

End point type

Primary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: Ratio
arithmetic mean (confidence interval 95%)	0.79 (0.65 to 0.88)	0.79 (0.62 to 0.89)	0.76 (0.56 to 0.88)	0.66 (0.5 to 0.78)	0.62 (0.43 to 0.77)	0.59 (0.36 to 0.76)

Kaplan-Meier model-ITT

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0124

Method

Fisher exact

Parameter type

Hazard ratio (HR)

Point estimate

0.52

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

1.03

Kaplan-Meier model-PP1

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0153

Method

Fisher exact

Parameter type

Hazard ratio (HR)

Point estimate

0.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

1.07

Kaplan-Meier model-PP2

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0404

Method

Fisher exact

Parameter type

Hazard ratio (HR)

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.24

upper limit

1.24

Secondary: Time to 1st ET-related event assessed by the EAC adjudication

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End point title

Time to 1st ET-related event assessed by the EAC adjudication

End point description

Information on ET-related events will be taken from the EAC adjudication only, without considering the platelet criteria. The censoring mechanism will therefore include all patients being EAC adjudicated as having an ET-related event as failures; all other patients will be censored.

End point type

Secondary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: Ratio
arithmetic mean (confidence interval 95%)	0.88 (0.78 to 0.94)	0.89 (0.76 to 0.95)	0.85 (0.7 to 0.93)	0.82 (0.71 to 0.9)	0.78 (0.63 to 0.87)	0.78 (0.59 to 0.89)

Kaplan-Meier model ITT

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1089

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

1.35

Kaplan-Meier model PP1

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0585

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

1.21

Kaplan-Meier model PP2

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2179

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

1.81

Secondary: Time to 1st ET-related event by re-assessed platelet criteria

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End point title

Time to 1st ET-related event by re-assessed platelet criteria

End point description

Time to 1st ET-related event using platelet criteria will be analyzed using the same models as for the primary efficacy parameter. Information on ET-related events will be taken from the two platelet criteria, whichever comes first; whereas neglecting the EAC adjudication. The censoring mechanism will therefore include all patients as having an ET-related event if one of the platelet criteria has been fulfilled as failures, all other patients will be censored.

End point type

Secondary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: Ratio
arithmetic mean (confidence interval 95%)	0.98 (0.89 to 1)	1 (1 to 1)	1 (1 to 1)	0.82 (0.7 to 0.9)	0.81 (0.66 to 0.9)	0.8 (0.6 to 0.91)

Kaplan-Meier model ITT

Statistical analysis description

Information on ET-related events will be taken from the two platelet criteria, whichever comes first; whereas neglecting the EAC adjudication. The censoring mechanism will therefore include all patients as having an ET-related event if one of the platelet criteria has been fulfilled as failures, all other patients will be censored.

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 2.5

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.09

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.4

Kaplan-Meier model PP1

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.42

Kaplan-Meier model PP2

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

0.44

Secondary: Time to 1st ET-related event by Investigator and re-assessed platelet criteria

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End point title

Time to 1st ET-related event by Investigator and re-assessed platelet criteria

End point description

Time to 1st ET-related event using both investigator adjudication and platelet criteria will be analyzed using the same models as for the primary efficacy parameter. Information on ET-related events will be taken from the CRF entries made by the investigators and the two platelet criteria, whichever comes first. The censoring mechanism will therefore include all patients as having an ET-related event if determined by the investigator as such or if one of the platelet criteria has been fulfilled as failures, all other patients will be censored.

End point type

Secondary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: Ratio
arithmetic mean (confidence interval 95%)	0.86 (0.75 to 0.92)	0.88 (0.76 to 0.95)	0.85 (0.7 to 0.93)	0.74 (0.61 to 0.83)	0.69 (0.53 to 0.81)	0.69 (0.5 to 0.82)

Kaplan-Meier model ITT

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0044

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

0.81

Kaplan-Meier model PP1

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0009

Method

Mantel-Haenszel

Parameter type

Hazard ratio (HR)

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.11

upper limit

0.65

Secondary: Change to baseline of platelet count

Top of page

End point title

Change to baseline of platelet count

End point description

The results at regular Visit 2 = Day 0 serve as baseline; if not available, the results of regular Visit 1 = Screening are used.

End point type

Secondary

End point timeframe

screening to month 12

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77 ^[1]	53 ^[2]	42 ^[3]	69 ^[4]	47 ^[5]	33 ^[6]
Units: G/L
arithmetic mean (standard deviation)
Day 7	-218.836 ± 154.9862	-234.117 ± 136.5971	-226.814 ± 145.3837	-6.116 ± 72.3912	136.5971 ± 77.0207	-3.545 ± 82.7825
Day 14	-388.965 ± 229.0479	-421.809 ± 198.5606	-418.283 ± 212.708	-25.372 ± 87.8962	-32.702 ± 86.1442	-30.884 ± 92.6846
Day 21	-324.161 ± 229.4759	-345.728 ± 213.9435	-349.11 ± 220.5995	-23.362 ± 78.8303	-27.15 ± 80.6909	-35.031 ± 90.279
Day 28	-387.251 ± 205.521	-407.345 ± 174.4643	-418.817 ± 160.4846	-21.219 ± 91.5135	-27.489 ± 88.7393	-12.281 ± 80.6755
Month 3	-394.381 ± 198.0757	741.404 ± 148.5678	-395.756 ± 163.3204	-38.254 ± 113.6795	-59.489 ± 106.3604	-45.156 ± 103.879
Month 6	-399.519 ± 196.2274	-386.506 ± 175.8822	-386.174 ± 186.9479	-18.282 ± 103.8526	-29.452 ± 109.099	-16.61 ± 91.453
Month 9	-393.844 ± 203.91	-383.657 ± 198.313	-393.505 ± 211.5138	-24.388 ± 120.7491	-42.334 ± 127.5186	-29.472 ± 130.4681
Month 12	-356.641 ± 229.7164	-377.404 ± 207.4387	-394.205 ± 203.8863	-10.942 ± 129.3443	-17.282 ± 139.7283	-8.926 ± 128.9752

Notes
[1] - n day 7: 76 n day 14: 75 n day 21 and 28: 74 n month 3: 69 n month 6: 63 n month 9 + 12 : 61
[2] - n month 3: 52 n month 6, 9 + 12 : 49
[3] - n month 3: 41 n month 6: 39 n month 9 + 12 : 38
[4] - n day 14: 68 n day 21:66 n day 28:64 n month 3: 63 n month 6: 60 n month 9: 56 n month 12: 52
[5] - n day 14 and 21: 46 n day 28: 45 n month 3: 45 n month 6: 44 n month 9: 41 n month 12: 39
[6] - n day 14, 21, 28: 32 n month 3: 32 n month 6: 31 n month 9: 29 n month 12: 27

No statistical analyses for this end point

Secondary: Maintaining of best individual response by best individual response

Top of page

End point title

Maintaining of best individual response by best individual response

End point description

Complete response is defined as platelet count < 400 G/L in absence of ET-related events (EAC rated) during the previous 3 months (90 days) Partial response is defined as platelet count < 600 G/L OR platelet count reduction of more than 200 G/L from baseline value No response is defined as any response that does not satisfy complete or partial response The results at regular Visit 2 = Day 0 serve as baseline; if not available, the results of regular Visit 1 = Screening are used Maintaining if BIR is defined as presence of BIR at the last documented visit in the study, if BIR was achieved before the last documented visit in the study

End point type

Secondary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo
Number of subjects analysed	77	53	69	47
Units: Number of Patients
Complete Response no	24	18	6	2
Complete Response yes	38	30	6	1
Partial Response no	4	2	17	14
Partial Response yes	5	2	6	5
No response no	4	0	2	1
No Response yes	0	0	34	24

Descriptive statistics ITT Complete response

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.066

Method

Fisher exact

Confidence interval

Descriptive statistics PP1 Complete response

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.553

Method

Fisher exact

Confidence interval

Descriptive statistics ITT Partial res...

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.213

Method

Fisher exact

Confidence interval

Descriptive statistics PP1 Partial res...

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.289

Method

Fisher exact

Confidence interval

Descriptive statistics ITT No res...

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Fisher exact

Confidence interval

Secondary: Number of subjects changing risk status to high risk

Top of page

End point title

Number of subjects changing risk status to high risk

End point description

Change to high risk status (platelets >= 1.000 G/L, increase of platelets > 300 G/L, or occurrence of any ET-related event) as assessed by the investigator

End point type

Secondary

End point timeframe

overall study

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: Number of subjects
no	68	47	36	51	32	22
yes	9	6	6	8	25	11

Change in risk status ITT

Statistical analysis description

Number of patients changing at least once the risk status to high risk according to the criteria above will be presented with counts and percentages for each treatment group. Rates between treatment groups will be compared using Fisher’s exact test, odds ratios and the two-sided 95% confidence intervals for odds ratios.

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.033

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

2.6667

Confidence interval

level

95%

sides

2-sided

lower limit

1.1076

upper limit

6.4205

Change in risk status PP1

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.014

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

3.6719

Confidence interval

level

95%

sides

2-sided

lower limit

1.2876

upper limit

10.471

Change in risk status PP2

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.059

Method

Fisher exact

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.9717

upper limit

9.2618

Secondary: JAK2 mutational status by visit

Top of page

End point title

JAK2 mutational status by visit

End point description

JAK status according to results from central laboratory

End point type

Secondary

End point timeframe

Day 0 to months 12

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77 ^[7]	53 ^[8]	42 ^[9]	69 ^[10]	47 ^[11]	33 ^[12]
Units: Number of patients
Day 0 negative	28	19	14	25	20	15
Day 0 positive	47	32	26	44	27	18
Month 12/WD negative	27	18	14	21	17	14
Month 12/WD positive	43	32	25	40	27	18

Notes
[7] - n = 70 at month 12
[8] - n = 50 at month 12
[9] - n = 39 at month 12
[10] - n = 61 at month 12
[11] - n = 44 at month 12
[12] - n = 32 at month12

No statistical analyses for this end point

Secondary: Quality of life measured by the SF-36v2® questionnaire

Top of page

End point title

Quality of life measured by the SF-36v2® questionnaire

End point description

change to baseline (visit 2, day 0) score 0-100

End point type

Secondary

End point timeframe

Visit 2, day 0 Visit 8, month 6

End point values	Intent-to-Treat Set (ITT) - Anagrelide retard	Per-protocol Set 1 (PP1) - Anagrelide Retard	Per-protocol Set 2 (PP2) - Anagrelide retard	Intent-to-Treat Set (ITT) - Placebo	Per-protocol Set 1 (PP1) - Placebo	Per-protocol Set 2 (PP2) - Placebo
Number of subjects analysed	77	53	42	69	47	33
Units: QoL-Score
arithmetic mean (standard deviation)
General health	0.65 ± 16.048	0.04 ± 15.782	0.73 ± 14.047	-0.2 ± 13.471	0.02 ± 11.063	-1.25 ± 10.451
mental health	3.03 ± 16.132	4.27 ± 16.535	3.92 ± 17.084	0.58 ± 15.128	2.31 ± 14.09	0.36 ± 11.049
physical functioning	15.128 ± 13.731	1.82 ± 14.491	0.12 ± 9.832	0.82 ± 9.698	2 ± 7.274	1.47 ± 6.798
Role limitation emotional	4.37 ± 22.184	6.42 ± 23.835	6.53 ± 25.62	0.95 ± 15.729	2.13 ± 14.998	-0.14 ± 12.324
Role limitation physical	1.47 ± 20.615	1.35 ± 21.61	1.75 ± 20.761	0.56 ± 17.241	6.16 ± 16.377	2.46 ± 15.529
Social functioning	1.23 ± 16.41	0.52 ± 16.901	3.38 ± 17.091	-0.66 ± 17.266	2.13 ± 15.027	3.02 ± 12.789
Vitality	3.42 ± 18.297	3.39 ± 19.38	3.04 ± 19.073	1.97 ± 17.875	2.34 ± 16.608	-0.22 ± 13.659
bodily pain	4.79 ± 21.146	4.67 ± 22.028	5.15 ± 19.638	-1.02 ± 18.925	1.05 ± 17.073	0.69 ± 13.411

Bodily pain ITT Verum

Statistical analysis description

The SF-36v2® health questionnaire will be analysed following the instructions as described in Ware, J. E., Jr., Kosinski, M., Bjorner, J. B., Turner-Bowker, D. M., Gandek, B., & Maruish, M. E. (2007). User’s manual for the SF-36v2® Health Survey (2nd ed.). Lincoln, RI: QualityMetric Incorporated.

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.115 ^[13]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[13] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Bodily pain ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.693 ^[14]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[14] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

General Health ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.979 ^[15]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[15] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

General Health ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.541 ^[16]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[16] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Mental Health ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.047 ^[17]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[17] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Mental Health ITT Verum Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.656 ^[18]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[18] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Physical functioning ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.439 ^[19]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[19] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Physical functioning ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.422 ^[20]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[20] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation Emotional ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.072 ^[21]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[21] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation Emotional ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.7 ^[22]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[22] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation Physical ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.71 ^[23]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[23] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation Physical ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.374 ^[24]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[24] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Social functioning ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.528 ^[25]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[25] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Social functioning ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.964 ^[26]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[26] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Vitality ITT Placebo

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Placebo v Intent-to-Treat Set (ITT) - Anagrelide retard

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.341 ^[27]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[27] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Vitality ITT Verum

Statistical analysis description

Comparison groups

Intent-to-Treat Set (ITT) - Anagrelide retard v Intent-to-Treat Set (ITT) - Placebo

Number of subjects included in analysis

146

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.097 ^[28]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[28] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Bodily Pain PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.214 ^[29]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[29] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Bodily Pain PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.734 ^[30]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[30] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

General Health PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.592 ^[31]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[31] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

General Health PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.962 ^[32]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[32] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Mental Health PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.361 ^[33]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[33] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Mental Health PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.016 ^[34]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[34] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Physical functioning PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.415 ^[35]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[35] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Physical functioning PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.098 ^[36]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[36] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation emotional PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.387 ^[37]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[37] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation emotional PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.028 ^[38]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[38] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation physical PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard v Per-protocol Set 1 (PP1) - Placebo

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.374 ^[39]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[39] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation physical PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.019 ^[40]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[40] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Social functioning PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.43 ^[41]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[41] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Social functioning PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.854 ^[42]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[42] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Vitality PP1 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.17 ^[43]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[43] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Vitality PP1 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 1 (PP1) - Placebo v Per-protocol Set 1 (PP1) - Anagrelide Retard

Number of subjects included in analysis

100

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.626 ^[44]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[44] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Bodily Pain PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.719 ^[45]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[45] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

General Health PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.543 ^[46]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[46] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

General Health PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.52 ^[47]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[47] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Mental Health PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.036 ^[48]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[48] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Mental Health PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.959 ^[49]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[49] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Physical functioning PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.345 ^[50]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[50] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Physical functioning PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.962 ^[51]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[51] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation emotional PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.093 ^[52]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[52] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation emotional PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.807 ^[53]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[53] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation physical PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.193 ^[54]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[54] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Limitation physical PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.323 ^[55]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[55] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Social functioning PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.228 ^[56]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[56] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Social functioning PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.253 ^[57]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[57] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Vitality PP2 Placebo

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Placebo v Per-protocol Set 2 (PP2) - Anagrelide retard

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.554 ^[58]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[58] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Vitality PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.222 ^[59]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[59] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Bodily Pain PP2 Verum

Statistical analysis description

Comparison groups

Per-protocol Set 2 (PP2) - Anagrelide retard v Per-protocol Set 2 (PP2) - Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.248 ^[60]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[60] - p-value of paired Wilcoxon signed rank test for paired differences (two-sided)

Adverse events

Top of page

Timeframe for reporting adverse events

main and safety extension

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Anagrelide retard

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Anagrelide retard	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 77 (11.69%)	4 / 69 (5.80%)
number of deaths (all causes)	1	0
number of deaths resulting from adverse events	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Clear cell renal cell carcinoma
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma
Additional description: Lung adenocarcinoma
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Prostate cancer
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Burns second degree
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Appendicectomy
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatic operation
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Ischaemic stroke
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Migraine
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Volvulus
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Anagrelide retard	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	68 / 77 (88.31%)	48 / 69 (69.57%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Vascular disorders
Hot flush
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Pallor
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Vascular pain
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Vasodilatation
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Hypotension
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	2	0
Flushing
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	2	0
Erythromelalgia
subjects affected / exposed	0 / 77 (0.00%)	2 / 69 (2.90%)
occurrences all number	0	3
Peripheral vascular disorder
subjects affected / exposed	1 / 77 (1.30%)	2 / 69 (2.90%)
occurrences all number	1	5
Haematoma
subjects affected / exposed	2 / 77 (2.60%)	2 / 69 (2.90%)
occurrences all number	2	3
Surgical and medical procedures
Hypertension
subjects affected / exposed	8 / 77 (10.39%)	6 / 69 (8.70%)
occurrences all number	11	6
Prostatic operation
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Eyelid operation
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Knee arthroplasty
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Tooth extraction
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 77 (6.49%)	4 / 69 (5.80%)
occurrences all number	6	7
Asthenia
subjects affected / exposed	6 / 77 (7.79%)	2 / 69 (2.90%)
occurrences all number	9	3
Chest pain
subjects affected / exposed	4 / 77 (5.19%)	2 / 69 (2.90%)
occurrences all number	4	2
Oedema peripheral
subjects affected / exposed	2 / 77 (2.60%)	2 / 69 (2.90%)
occurrences all number	3	2
Influenza like illness
subjects affected / exposed	1 / 77 (1.30%)	2 / 69 (2.90%)
occurrences all number	1	2
Pyrexia
subjects affected / exposed	3 / 77 (3.90%)	0 / 69 (0.00%)
occurrences all number	3	0
Chills
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	2
Oedema
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	3	0
Exercise tolerance decreased
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Feeling hot
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Malaise
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Peripheral swelling
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	3	0
Benign prostatic hyperplasia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Menopausal symptoms
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Menorrhagia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Sexual dysfunction
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 77 (3.90%)	0 / 69 (0.00%)
occurrences all number	5	0
Oropharyngeal pain
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Dyspnoea
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	2	0
Dyspnoea exertional
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Dysphonia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Epistaxis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Nasal oedema
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Pleurisy
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Apathy
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Insomnia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Sleep disorder
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	2	0
Investigations
Platelet count increased
subjects affected / exposed	1 / 77 (1.30%)	6 / 69 (8.70%)
occurrences all number	1	6
N-terminal prohormone brain natriuretic peptide increased
subjects affected / exposed	4 / 77 (5.19%)	0 / 69 (0.00%)
occurrences all number	4	0
Platelet count decreased
subjects affected / exposed	4 / 77 (5.19%)	0 / 69 (0.00%)
occurrences all number	5	0
Ejection fraction decreased
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	2
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Blood pressure increased
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Breath sounds
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Carotid pulse increased
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	2	0
Electrocardiogram PQ interval shortened
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Haematocrit increased
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Haemoglobin decreased
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Hepatic enzyme increased
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 77 (2.60%)	2 / 69 (2.90%)
occurrences all number	2	2
Injury
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Ligament sprain
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Procedural pain
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Cardiac disorders
Palpitations
subjects affected / exposed	23 / 77 (29.87%)	9 / 69 (13.04%)
occurrences all number	39	15
Acute myocardial infarction
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Arrhythmia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Atrioventricular block second degree
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Extrasystoles
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Nervous system disorders
Headache
subjects affected / exposed	36 / 77 (46.75%)	21 / 69 (30.43%)
occurrences all number	82	66
Dizziness
subjects affected / exposed	6 / 77 (7.79%)	4 / 69 (5.80%)
occurrences all number	8	7
Hypoaesthesia
subjects affected / exposed	5 / 77 (6.49%)	2 / 69 (2.90%)
occurrences all number	14	2
Paraesthesia
subjects affected / exposed	1 / 77 (1.30%)	3 / 69 (4.35%)
occurrences all number	1	5
Somnolence
subjects affected / exposed	3 / 77 (3.90%)	1 / 69 (1.45%)
occurrences all number	4	2
Transient ischaemic attack
subjects affected / exposed	1 / 77 (1.30%)	2 / 69 (2.90%)
occurrences all number	1	2
Migraine
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Head discomfort
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Dystonia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Encephalopathy
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Neuritis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Syncope
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
VIIIth nerve paralysis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 77 (6.49%)	2 / 69 (2.90%)
occurrences all number	7	3
Thrombocytopenia
subjects affected / exposed	7 / 77 (9.09%)	0 / 69 (0.00%)
occurrences all number	12	0
Thrombocytosis
subjects affected / exposed	1 / 77 (1.30%)	4 / 69 (5.80%)
occurrences all number	1	4
Iron deficiency anaemia
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	3	0
Anaemia folate deficiency
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Polycythaemia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Splenomegaly
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	7 / 77 (9.09%)	3 / 69 (4.35%)
occurrences all number	7	3
Tinnitus
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Eye disorders
Visual impairment
subjects affected / exposed	2 / 77 (2.60%)	2 / 69 (2.90%)
occurrences all number	2	2
Conjunctivitis allergic
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Eye oedema
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Scintillating scotoma
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Vision blurred
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Gastrointestinal disorders
Nausea
subjects affected / exposed	7 / 77 (9.09%)	5 / 69 (7.25%)
occurrences all number	8	10
Abdominal pain upper
subjects affected / exposed	7 / 77 (9.09%)	2 / 69 (2.90%)
occurrences all number	13	8
Diarrhoea
subjects affected / exposed	6 / 77 (7.79%)	2 / 69 (2.90%)
occurrences all number	7	5
Vomiting
subjects affected / exposed	5 / 77 (6.49%)	1 / 69 (1.45%)
occurrences all number	6	4
Abdominal pain
subjects affected / exposed	3 / 77 (3.90%)	2 / 69 (2.90%)
occurrences all number	15	2
Gastrointestinal disorder
subjects affected / exposed	3 / 77 (3.90%)	0 / 69 (0.00%)
occurrences all number	6	0
Abdominal distension
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	2	0
Dyspepsia
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Abdominal discomfort
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Epigastric discomfort
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Flatulence
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Gastric ulcer
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Gastritis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Gingival bleeding
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Stomatitis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Hepatocellular injury
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Hepatomegaly
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	4 / 77 (5.19%)	1 / 69 (1.45%)
occurrences all number	5	1
Night sweats
subjects affected / exposed	1 / 77 (1.30%)	3 / 69 (4.35%)
occurrences all number	1	3
Hyperhidrosis
subjects affected / exposed	2 / 77 (2.60%)	1 / 69 (1.45%)
occurrences all number	3	1
Alopecia
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Dermatitis allergic
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	2
Erythema
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	2	1
Skin depigmentation
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	2	0
Dermatitis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Rash
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Telangiectasia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Nephrolithiasis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Urinary bladder haemorrhage
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	3 / 77 (3.90%)	4 / 69 (5.80%)
occurrences all number	8	4
Myalgia
subjects affected / exposed	4 / 77 (5.19%)	1 / 69 (1.45%)
occurrences all number	6	4
Arthralgia
subjects affected / exposed	1 / 77 (1.30%)	3 / 69 (4.35%)
occurrences all number	1	20
Back pain
subjects affected / exposed	3 / 77 (3.90%)	1 / 69 (1.45%)
occurrences all number	6	1
Joint swelling
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	2
Musculoskeletal chest pain
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	2	4
Bone pain
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Costochondritis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Muscle spasms
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	2	0
Pain in jaw
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	3
Plantar fasciitis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 77 (5.19%)	5 / 69 (7.25%)
occurrences all number	4	10
Urinary tract infection
subjects affected / exposed	1 / 77 (1.30%)	3 / 69 (4.35%)
occurrences all number	3	4
Bronchitis
subjects affected / exposed	2 / 77 (2.60%)	1 / 69 (1.45%)
occurrences all number	2	1
Pharyngitis
subjects affected / exposed	2 / 77 (2.60%)	1 / 69 (1.45%)
occurrences all number	3	1
Tracheitis
subjects affected / exposed	1 / 77 (1.30%)	2 / 69 (2.90%)
occurrences all number	1	2
Upper respiratory tract infection
subjects affected / exposed	1 / 77 (1.30%)	2 / 69 (2.90%)
occurrences all number	2	2
Cystitis
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	5	1
Rhinitis
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	2	1
Acute tonsillitis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Gingivitis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Influenza
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Onychomycosis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Oral herpes
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Pulpitis dental
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Scarlet fever
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Sinusitis
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Subcutaneous abscess
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Tonsillitis
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Tooth infection
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Muscle strain
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	2 / 77 (2.60%)	1 / 69 (1.45%)
occurrences all number	2	1
Hypokalaemia
subjects affected / exposed	2 / 77 (2.60%)	1 / 69 (1.45%)
occurrences all number	3	2
Hypophosphataemia
subjects affected / exposed	1 / 77 (1.30%)	2 / 69 (2.90%)
occurrences all number	1	4
Hypercholesterolaemia
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Hyperkalaemia
subjects affected / exposed	2 / 77 (2.60%)	0 / 69 (0.00%)
occurrences all number	2	0
Hypoalbuminaemia
subjects affected / exposed	1 / 77 (1.30%)	1 / 69 (1.45%)
occurrences all number	1	1
Hyperglycaemia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Hyperuricosuria
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Hypocalcaemia
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1
Hypoproteinaemia
subjects affected / exposed	1 / 77 (1.30%)	0 / 69 (0.00%)
occurrences all number	1	0
Vitamin D deficiency
subjects affected / exposed	0 / 77 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

23 Aug 2010

-Investigator was not blinded since a platelet reduction by Anagrelide retard could have a potential unblinding effect. The Sponsor was blinded. -Stratified randomization of the subjects according to their JAK2 mutational status. Hypothesis: JAK2 mutation positivity may be an independent risk factor for thrombosis in myeloproliferative. - EAC was established. The treatment allocation status was blinded for the subject, but open for the primary site investigators. - DMC had to review the unblinded cumulating data, advises the sponsor regarding safety of current and future participants. DMC responsible for monitoring safety data, reviewing AEs. The DMC was responsible for the interim safety review and the study conduct. - Risk factors at inclusion criteria were modified: “essential hypertension” replaced the hypertension definition of WHO grades and hormone replacement therapy and hormonal contraception were added. - The exclusion criterion “diabetes mellitus” was modified to “poorly controlled” diabetes mellitus - Definition of the primary endpoint relevant ET-related event was modified. A clinically significant ET-related event was defined as a disease-related event which implied a change of the subject risk status to the high risk group. - Blinded AEs/ SAEs management, including blinded SUSARs reporting was added. -subjects to be treated for a maximum of 3 years as long as they do not experience their 1st clinically significant ET-related event. - Laboratory tests were split into local and central. - Use of version of the Declaration of Helsinki of October 1996. - The causality assessment for drug-event relationship was changed to “Yes, related/ No, unrelated” judgment. - References added: ARETA Study Working Guideline for idv staff, ARETA Study Working Guideline for Harrison, DMC and EAC Charter. - Measurement of prothrombin time and NT-proBNP.

11 Mar 2014

1) Introduction of the analysis based on the CALR and MPL mutational status as potentially relevant to predict disease prognosis and treatment outcomes. 2) Inclusion of progressive thrombocytosis as a risk changing event into the ET-related event definitions as the primary endpoint (i.e. platelet criterion) 3) Intensification of the ECG monitoring schedule in the study (additional ECGs scheduled at months 1, 3, 6 and 9. 4) Magnesium was included into the list of biochemical parameters to be measured at regular intervals. 5) Early withdrawal visits were preponed for all active subjects in case of study completion after stage I analysis at the earliest date possible. 6) Specification on post study care (after study completion) for subjects, who received active drug during the study.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A phase III, randomized, multicenter, subject- and sponsor-blinded, placebo controlled study to compare the efficacy and safety of “Anagrelide retard” versus placebo in “at risk” subjects with Essential Thrombocythaemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to first ET-related event assessed by EAC adjudication and platelet criteria

Primary: Time to first ET-related event assessed by EAC adjudication and platelet criteria

Primary: Time to first ET-related event by EAC and platelet criteria (as originally planned)

Primary: Time to first ET-related event by EAC and platelet criteria (as originally planned)

Secondary: Time to 1st ET-related event assessed by the EAC adjudication

Secondary: Time to 1st ET-related event assessed by the EAC adjudication

Secondary: Time to 1st ET-related event by re-assessed platelet criteria

Secondary: Time to 1st ET-related event by re-assessed platelet criteria

Secondary: Time to 1st ET-related event by Investigator and re-assessed platelet criteria

Secondary: Time to 1st ET-related event by Investigator and re-assessed platelet criteria

Secondary: Change to baseline of platelet count

Secondary: Change to baseline of platelet count

Secondary: Maintaining of best individual response by best individual response

Secondary: Maintaining of best individual response by best individual response

Secondary: Number of subjects changing risk status to high risk

Secondary: Number of subjects changing risk status to high risk

Secondary: JAK2 mutational status by visit

Secondary: JAK2 mutational status by visit

Secondary: Quality of life measured by the SF-36v2® questionnaire

Secondary: Quality of life measured by the SF-36v2® questionnaire

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A phase III, randomized, multicenter, subject- and sponsor-blinded, placebo controlled study to compare the efficacy and safety of “Anagrelide retard” versus placebo in “at risk” subjects with Essential Thrombocythaemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Time to first ET-related event assessed by EAC adjudication and platelet criteria

Primary: Time to first ET-related event assessed by EAC adjudication and platelet criteria

Primary: Time to first ET-related event by EAC and platelet criteria (as originally planned)

Primary: Time to first ET-related event by EAC and platelet criteria (as originally planned)

Secondary: Time to 1st ET-related event assessed by the EAC adjudication

Secondary: Time to 1st ET-related event assessed by the EAC adjudication

Secondary: Time to 1st ET-related event by re-assessed platelet criteria

Secondary: Time to 1st ET-related event by re-assessed platelet criteria

Secondary: Time to 1st ET-related event by Investigator and re-assessed platelet criteria

Secondary: Time to 1st ET-related event by Investigator and re-assessed platelet criteria

Secondary: Change to baseline of platelet count

Secondary: Change to baseline of platelet count

Secondary: Maintaining of best individual response by best individual response

Secondary: Maintaining of best individual response by best individual response

Secondary: Number of subjects changing risk status to high risk

Secondary: Number of subjects changing risk status to high risk

Secondary: JAK2 mutational status by visit

Secondary: JAK2 mutational status by visit

Secondary: Quality of life measured by the SF-36v2® questionnaire

Secondary: Quality of life measured by the SF-36v2® questionnaire

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A phase III, randomized, multicenter, subject- and sponsor-blinded, placebo controlled study to compare the efficacy and safety of “Anagrelide retard” versus placebo in “at risk” subjects with Essential Thrombocythaemia