Effect of Anagrelide Hydrochloride on Any Changes in Heart Function in Healthy Volunteers

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01552928
• Collaborator: (none)
• Enrollment: 60
• Location: 1
• Arms: 4
• Actual Duration (Months): 3.9
• Patients Per Site Per Month: 15.5

Study Details

Study Description

Brief Summary

According to the ICH Guidance Document E14, all non-antiarrhythmic drugs should be evaluated for their ability to prolong the QT interval which represents the duration of ventricular depolarization and subsequent repolarization. The primary objective of the study is to assess the effect of anagrelide on QT/QTc interval following a therapeutic and supratherapeutic dose of anagrelide when compared to placebo and a positive control.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Anagrelide 0.5 mg; Drug: Anagrelide 2.5 mg; Drug: Moxifloxacin; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Randomized, Double-blind, Placebo- and Positive-controlled, 4-Period Crossover Trial to Assess the Effect of Anagrelide Hydrochloride on QT/QTc Interval in Healthy Men and Women.
• Actual Study Start Date: Mar 29, 2012
• Actual Primary Completion Date: Jul 25, 2012
• Actual Study Completion Date: Jul 25, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Anagrelide Therapeutic (0.5 mg)	Drug: Anagrelide 0.5 mg; 0.5mg Anagrelide single oral dose; Other Names: Agrylin, Xagrid
Experimental: Anagrelide Supratherapeutic (2.5 mg)	Drug: Anagrelide 2.5 mg; 2.5mg Anagrelide single oral dose
Active Comparator: Moxifloxacin	Drug: Moxifloxacin; 400 mg Moxifloxacin single oral dose
Placebo Comparator: Placebo	Drug: Placebo; Anagrelide placebo + Moxifloxacin placebo single oral dose

Outcome Measures

Primary Outcome Measures

1. Mean Difference Changes From Baseline Versus Placebo in QTcNi Intervals From Time-Matched Analysis by Largest Time Point [Over 12 hours post-dose]

   QT interval corrected for heart rate using the subject-specific method (QTcNi) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.

2. Mean Difference Changes From Baseline Versus Placebo in Heart Rate From Time-Matched Analysis by Largest Time Point [Over 12 hours post-dose]

   The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.

3. Mean Difference Changes From Baseline Versus Placebo in QTcF Intervals From Time-Matched Analysis by Largest Time Point [Over 12 hours post-dose]

   QT interval corrected for heart rate using Fridericia's method (QTcF) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.

4. Mean Difference Changes From Baseline Versus Placebo in QTcB Intervals From Time-Matched Analysis by Largest Time Point [Over 12 hours post-dose]

   QT interval corrected for heart rate using Bazett's method (QTcB) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.

5. Mean Difference Changes From Baseline Versus Placebo in QT Intervals From Time-Matched Analysis by Largest Time Point [Over 12 hours post-dose]

   The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.

Secondary Outcome Measures

1. Mean Difference Changes From Baseline Versus Placebo in QTcNi Intervals at Subject-Specific Time of Maximum Plasma Concentration (Tmax) [Over 12 hours post-dose]

   QT interval corrected for heart rate using the subject-specific method (QTcNi) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.

2. Mean Difference Changes From Baseline Versus Placebo in Heart Rate at Subject-Specific Tmax [Over 12 hours post-dose]

3. Mean Difference Changes From Baseline Versus Placebo in QTcF Intervals at Subject-Specific Tmax [Over 12 hours post-dose]

   QT interval corrected for heart rate using Fridericia's method (QTcF) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.

4. Mean Difference Changes From Baseline Versus Placebo in QTcB Intervals at Subject-Specific Tmax [Over 12 hours post-dose]

   QT interval corrected for heart rate using Bazett's method (QTcB) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.

5. Mean Difference Changes From Baseline Versus Placebo in QT Intervals at Subject-Specific Tmax [Over 12 hours post-dose]

   The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.

6. Maximum Plasma Concentration (Cmax) of 0.5 mg Anagrelide in Males and Females [Over 12 hours post-dose]

7. Maximum Plasma Concentration (Cmax) of 2.5 mg Anagrelide in Males and Females [Over 12 hours post-dose]

8. Maximum Plasma Concentration (Cmax) of Metabolite of 0.5 mg Anagrelide (BCH24426) in Males and Females [Over 12 hours post-dose]

9. Maximum Plasma Concentration (Cmax) of Metabolite of 2.5 mg Anagrelide (BCH24426) in Males and Females [Over 12 hours post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age 18-45 years inclusive at the time of consent. The date of signing informed consent is defined as the beginning of the screening period. This inclusion criteria will only be assessed at the screening visit.

• Subject is willing to comply with any applicable contraceptive requirements of the protocol and is: male, or non-pregnant non lactating female, or females must be at least 90 days post-partum or nulliparous.

• Satisfactory medical assessment with no clinically or relevant abnormalities in medical history, physical examination, vital signs, ECG, and clinical laboratory evaluation as assessed by the investigator.

Exclusion Criteria:

• Current or recurrent disease that could affect the action, absorption, or disposition of the investigational product, or could affect clinical or laboratory assessments.

a- Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to fully complete the study, or any condition that presents undue risk from the investigational product or procedures.

• Significant illness, as judged by the Investigator, within 2 weeks of the first dose of investigational product.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Biotrial	Rueil-Malmaison		France

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01552928
• Other Study ID Numbers: SPD422-111; 2011-005288-26
• First Posted: Mar 13, 2012
• Last Update Posted: Jun 9, 2021
• Last Verified: May 1, 2021

• Additional relevant MeSH terms: Moxifloxacin; Anagrelide

Study Results

Participant Flow

Arm/Group Title	Anag 0.5 mg, Then Anag 2.5 mg, Then Placebo, Then Mox 400 mg	Anag 2.5 mg, Then Mox 400 mg, Then Anag 0.5 mg, Then Placebo	Mox 400 mg, Then Placebo, Then Anag 2.5 mg, Then Anag 0.5 mg	Placebo, Then Anag 0.5 mg, Then Mox 400 mg, Then Anag 2.5 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide on Day 1 for Period 1; then a single oral dose of 2.5 mg of anagrelide on Day 1 for Period 2; then a single oral dose of placebo on Day 1 for Period 3; then a single oral dose of 400 mg of moxifloxacin on Day 1 for Period 4.	A single oral dose of 2.5 mg of anagrelide on Day 1 for Period 1; then a single oral dose of 400 mg of moxifloxacin on Day 1 for Period 2; then a single oral dose of 0.5 mg of anagrelide on Day 1 for Period 3; then a single oral dose of placebo on Day 1 for Period 4.	A single oral dose of 400 mg of moxifloxacin on Day 1 for Period 1; then a single oral dose of placebo on Day 1 for Period 2; then a single oral dose of 2.5 mg of anagrelide on Day 1 for Period 3; then a single oral dose of 0.5 mg of anagrelide on Day 1 for Period 4.	A single oral dose of placebo on Day 1 for Period 1; then a single oral dose of 0.5 mg of anagrelide on Day 1 for Period 2; then a single oral dose of 400 mg of moxifloxacin on Day 1 for Period 3; then a single oral dose of 2.5 mg of anagrelide on Day 1 for Period 4.
Period Title: Period 1
STARTED	14	15	15	16
COMPLETED	14	15	15	16
NOT COMPLETED	0	0	0	0
Period Title: Period 1
STARTED	14	15	15	16
COMPLETED	14	15	15	16
NOT COMPLETED	0	0	0	0
Period Title: Period 1
STARTED	14	15	15	16
COMPLETED	14	15	14	16
NOT COMPLETED	0	0	1	0
Period Title: Period 1
STARTED	14	15	14	16
COMPLETED	14	15	14	16
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Anag 0.5 mg, Then Anag 2.5 mg, Then Placebo, Then Mox 400 mg	Anag 2.5 mg, Then Mox 400 mg, Then Anag 0.5 mg, Then Placebo	Mox 400 mg, Then Placebo, Then Anag 2.5 mg, Then Anag 0.5 mg	Placebo, Then Anag 0.5 mg, Then Mox 400 mg, Then Anag 2.5 mg	Total
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide on Day 1 for Period 1; then a single oral dose of 2.5 mg of anagrelide on Day 1 for Period 2; then a single oral dose of placebo on Day 1 for Period 3; then a single oral dose of 400 mg of moxifloxacin on Day 1 for Period 4.	A single oral dose of 2.5 mg of anagrelide on Day 1 for Period 1; then a single oral dose of 400 mg of moxifloxacin on Day 1 for Period 2; then a single oral dose of 0.5 mg of anagrelide on Day 1 for Period 3; then a single oral dose of placebo on Day 1 for Period 4.	A single oral dose of 400 mg of moxifloxacin on Day 1 for Period 1; then a single oral dose of placebo on Day 1 for Period 2; then a single oral dose of 2.5 mg of anagrelide on Day 1 for Period 3; then a single oral dose of 0.5 mg of anagrelide on Day 1 for Period 4.	A single oral dose of placebo on Day 1 for Period 1; then a single oral dose of 0.5 mg of anagrelide on Day 1 for Period 2; then a single oral dose of 400 mg of moxifloxacin on Day 1 for Period 3; then a single oral dose of 2.5 mg of anagrelide on Day 1 for Period 4.	Total of all reporting groups
Overall Participants	14	15	15	16	60
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 100%	15 100%	15 100%	16 100%	60 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	28.1 (6.44)	28.4 (7.7)	29.5 (5.83)	30.4 (8.02)	29.2 (6.96)
Sex: Female, Male (Count of Participants)
Female	6 42.9%	6 40%	6 40%	7 43.8%	25 41.7%
Male	8 57.1%	9 60%	9 60%	9 56.3%	35 58.3%
Region of Enrollment (Count of Participants)
FRANCE	14 100%	15 100%	15 100%	16 100%	60 100%

Outcome Measures

1. Secondary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QTcNi Intervals at Subject-Specific Time of Maximum Plasma Concentration (Tmax)
Description	QT interval corrected for heart rate using the subject-specific method (QTcNi) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	51	55	55
Least Squares Mean (90% Confidence Interval) [msec]	4.4	8.2	11.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in Heart Rate at Subject-Specific Tmax
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	51	55	55
Least Squares Mean (90% Confidence Interval) [beats per minute]	4.5	21.8	2.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QTcF Intervals at Subject-Specific Tmax
Description	QT interval corrected for heart rate using Fridericia's method (QTcF) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	51	55	55
Least Squares Mean (90% Confidence Interval) [msec]	3.7	4.5	10.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QTcB Intervals at Subject-Specific Tmax
Description	QT interval corrected for heart rate using Bazett's method (QTcB) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	51	55	55
Least Squares Mean (90% Confidence Interval) [msec]	8.5	25.5	14.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QT Intervals at Subject-Specific Tmax
Description	The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	51	55	55
Least Squares Mean (90% Confidence Interval) [msec]	-6.1	-34.3	4.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of 0.5 mg Anagrelide in Males and Females
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set consists of all subjects in the Safety Analysis Set who had evaluable concentration-time profiles for anagrelide, BCH24426, or moxifloxacin.

Arm/Group Title	Anagrelide 0.5 mg (Males)	Anagrelide 0.5 mg (Females)
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 0.5 mg of anagrelide
Measure Participants	34	25
Geometric Mean (Standard Deviation) [ng/ml]	2.083 (0.975)	3.64 (1.959)

7. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of 2.5 mg Anagrelide in Males and Females
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set consists of all subjects in the Safety Analysis Set who had evaluable concentration-time profiles for anagrelide, BCH24426, or moxifloxacin.

Arm/Group Title	Anagrelide 2.5mg (Males)	Anagrelide 2.5mg (Females)
Arm/Group Description	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide
Measure Participants	35	25
Geometric Mean (Standard Deviation) [ng/ml]	10.592 (4.871)	16.378 (10.224)

8. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Metabolite of 0.5 mg Anagrelide (BCH24426) in Males and Females
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set consists of all subjects in the Safety Analysis Set who had evaluable concentration-time profiles for anagrelide, BCH24426, or moxifloxacin.

Arm/Group Title	BCH24426 (Males)	BCH24426 (Females)
Arm/Group Description	Metabolite from a single oral dose of 0.5 mg of anagrelide	Metabolite from a single oral dose of 0.5 mg of anagrelide
Measure Participants	34	25
Geometric Mean (Standard Deviation) [ng/ml]	3.731 (1.257)	4.534 (1.405)

9. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Metabolite of 2.5 mg Anagrelide (BCH24426) in Males and Females
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set consists of all subjects in the Safety Analysis Set who had evaluable concentration-time profiles for anagrelide, BCH24426, or moxifloxacin.

Arm/Group Title	BCH24426 (Males)	BCH24426 (Females)
Arm/Group Description	Metabolite from a single oral dose of 2.5 mg of anagrelide	Metabolite from a single oral dose of 2.5 mg of anagrelide
Measure Participants	35	25
Geometric Mean (Standard Deviation) [ng/ml]	18.927 (6.016)	23.785 (7.952)

10. Primary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QTcNi Intervals From Time-Matched Analysis by Largest Time Point
Description	QT interval corrected for heart rate using the subject-specific method (QTcNi) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	50	55	53
Least Squares Mean (90% Confidence Interval) [msec]	7.0	13.0	12.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

11. Primary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in Heart Rate From Time-Matched Analysis by Largest Time Point
Description	The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	50	54	53
Least Squares Mean (90% Confidence Interval) [beats per minute]	7.8	29.1	4.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	ANCOVA
	Comments

12. Primary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QTcF Intervals From Time-Matched Analysis by Largest Time Point
Description	QT interval corrected for heart rate using Fridericia's method (QTcF) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	50	55	53
Least Squares Mean (90% Confidence Interval) [msec]	5.0	10.0	11.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

13. Primary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QTcB Intervals From Time-Matched Analysis by Largest Time Point
Description	QT interval corrected for heart rate using Bazett's method (QTcB) at the subject-specific time of maximum plasma concentration. The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	50	56	55
Least Squares Mean (90% Confidence Interval) [msec]	-2.9	-18.1	-2.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.078
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.156
	Comments
	Method	ANCOVA
	Comments

14. Primary Outcome

Title	Mean Difference Changes From Baseline Versus Placebo in QT Intervals From Time-Matched Analysis by Largest Time Point
Description	The QT interval is the time it takes for the ventricles of the heart to contract and relax. Data were subtracted from the placebo value. The largest time point refers to the estimated largest mean difference between each treatment and placebo among all time points. Values for different treatments can come from different time points.
Time Frame	Over 12 hours post-dose

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consists of subjects in the Safety Analysis Set who had at least 1 electrocardiogram (ECG). Safety Analysis Set consists of subjects who received at least 1 dose of investigational product and had at least 1 post-dose safety assessment.

Arm/Group Title	Anagrelide 0.5 mg	Anagrelide 2.5 mg	Moxifloxacin 400 mg
Arm/Group Description	A single oral dose of 0.5 mg of anagrelide	A single oral dose of 2.5 mg of anagrelide	A single oral dose of 400 mg of moxifloxacin
Measure Participants	49	54	56
Least Squares Mean (90% Confidence Interval) [msec]	1.7	-2.4	9.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.439
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Anagrelide 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.274
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Moxifloxacin 400 mg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	Anagrelide 0.5mg		Anagrelide 2.5mg		Moxifloxacin 400mg		Placebo
Arm/Group Description
All Cause Mortality
	Anagrelide 0.5mg		Anagrelide 2.5mg		Moxifloxacin 400mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Anagrelide 0.5mg		Anagrelide 2.5mg		Moxifloxacin 400mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/60 (0%)		0/60 (0%)		0/60 (0%)
Other (Not Including Serious) Adverse Events
	Anagrelide 0.5mg		Anagrelide 2.5mg		Moxifloxacin 400mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/59 (22%)		49/60 (81.7%)		2/60 (3.3%)		0/60 (0%)
Cardiac disorders
Tachycardia	0/59 (0%)	0	3/60 (5%)	3	0/60 (0%)	0	0/60 (0%)	0
Gastrointestinal disorders
Constipation	3/59 (5.1%)	3	1/60 (1.7%)	1	0/60 (0%)	0	0/60 (0%)	0
Nausea	2/59 (3.4%)	2	17/60 (28.3%)	17	1/60 (1.7%)	1	0/60 (0%)	0
Vomiting	0/59 (0%)	0	5/60 (8.3%)	5	0/60 (0%)	0	0/60 (0%)	0
Nervous system disorders
Dizziness	2/59 (3.4%)	2	14/60 (23.3%)	14	0/60 (0%)	0	0/60 (0%)	0
Headache	12/59 (20.3%)	13	44/60 (73.3%)	44	1/60 (1.7%)	1	0/60 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/59 (0%)	0	5/60 (8.3%)	5	0/60 (0%)	0	0/60 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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