The Pharmacokinetics of Anagrelide in Elderly and Young Patients With Essential Thrombocythaemia (ET)

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00413634
• Collaborator: (none)
• Enrollment: 24
• Locations: 5
• Arms: 2
• Actual Duration (Months): 14.3
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Age related differences in response to a drug could arise from variation in pharmacokinetic (PK) and/or pharmacodynamic (PD) profiles between age groups. Whilst the efficacy and safety profile of anagrelide is well established through a well-documented clinical trial programme in patients of all ages, no formal studies have been carried out to investigate whether the PK profile of anagrelide and its metabolites is altered with age.

This study is designed to allow comparisons to be made in terms of pharmacokinetics of anagrelide and its metabolites between elderly (≥ 65 years) and young (18-50 years) ET patients

Condition or Disease	Intervention/Treatment	Phase
Essential Thrombocythaemia	Drug: anagrelide hydrochloride; Drug: anagrelide hydrochloride	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open-label, Multicentre, Pharmacokinetic, Pharmacodynamic and Safety Study of Anagrelide Hydrochloride in Young (18-50 Years) and Elderly (≥ 65 Years) Patients With Essential Thrombocythaemia.
• Actual Study Start Date: Nov 13, 2006
• Actual Primary Completion Date: Jan 22, 2008
• Actual Study Completion Date: Jan 22, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Younger Participants (18-50 years)	Drug: anagrelide hydrochloride; Anagrelide hydrochloride 0.5 mg per capsule; participants will be stable on an anagrelide treatment regimen and will take capsules from their own prescription except on the PK day when the participant specific anagrelide dose will be administered from a controlled study specific supply.
Experimental: Elderly Participants (≥65 years)	Drug: anagrelide hydrochloride; Anagrelide hydrochloride 0.5 mg per capsule; participants will be stable on an anagrelide regimen and will take capsules from their own prescription except on the PK day when the participant specific anagrelide dose will be administered from a controlled study specific supply.

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) of Agrylin [over 1 day]

2. Time of Maximum Plasma Concentration (Tmax) of Agrylin [over 1 day]

3. Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Agrylin [over 1 day]

4. Terminal Half-life (T 1/2) of Agrylin [over 1 day]

5. Total Clearance (CL/F) of Agrylin [over 1 day]

6. Volume of Distribution (Vz/F) of Agrylin [over 1 day]

7. Cmax of Active Metabolite [over 1 day]

   An active metabolite has therapeutic activity similar to the parent compound and must be considered in therapeutic pharmacokinetics.

8. Tmax of Active Metabolite [over 1 day]

9. AUC of Active Metabolite [over 1 day]

10. T 1/2 of Active Metabolite [over 1 day]

11. CL/F of Active Metabolite [over 1 day]

12. Vz/F of Active Metabolite [over 1 day]

Secondary Outcome Measures

1. Platelet Count [over 1 day]

   Platelet counts in patients with ET receiving Agrylin

2. Heart Rate [over 1 day]

   Heart rates in patients with ET receiving Agrylin

3. Systolic Blood Pressure [over 1 day]

   Systolic blood pressures in patients with ET receiving Agrylin

4. Diastolic Blood Pressure [over 1 day]

   Diastolic blood pressures in patients with ET receiving Agrylin

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Young patients aged 18-50 years inclusive or Elderly patients aged 65 years and over

• Patients must have a confirmed diagnosis of ET.

• Currently receiving anagrelide hydrochloride at a stable maintenance dose < 5 mg/day for at least 4 weeks.

Exclusion Criteria:

• Diagnosis of any other myeloproliferative disorder.

• Current use of tobacco in any form (e.g. smoking or chewing)

• Treatment with any known enzyme altering agents (barbiturates, phenothiazines, cimetidine etc.) within 30 days prior to or during the study.

• Patients for whom use of another cytoreductive agent in addition to anagrelide is considered necessary for control of platelet count.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospitl Del Mar	Barcelona		Spain
2	Quintiles Hermelinen	Lulea		Sweden
3	Uppsala Akademiska Sjukhus	Uppsala		Sweden	75185
4	Quintiles AB Phase I Unit	Uppsala		Sweden
5	Belfast City Hospital	Belfast		United Kingdom

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• FDA-approved Label
• FDA Recall Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT00413634
• Other Study ID Numbers: SPD422-203; 2004-004058-20
• First Posted: Dec 20, 2006
• Last Update Posted: Jun 29, 2021
• Last Verified: Jun 1, 2021

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

Study Results

Participant Flow

Recruitment Details	Patients were between 18-50 years (young) and 65 or older (elderly) with a diagnosis of essential thrombocythemia (ET) and receiving a stable dose of anagrelide <=5mg/day for at least 4 weeks.
Pre-assignment Detail	The study comprised four phases: Screening (patients take their normal regimen of anagrelide), a run-in period (patients divided their normal anagrelide daily dose equally into two daily doses), Pharmacokinetics (PK) sampling day (patients take normal morning dose), and follow-up (patients were contacted by phone 30 days after PK visit).

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Period Title: Overall Study
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)	Total
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	0 0%	12 50%
>=65 years	0 0%	12 100%	12 50%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	39.2 (8.4)	69.2 (3.0)	54.2 (16.5)
Sex: Female, Male (Count of Participants)
Female	9 75%	8 66.7%	17 70.8%
Male	3 25%	4 33.3%	7 29.2%
Region of Enrollment (Count of Participants)
Germany	5 41.7%	10 83.3%	15 62.5%
United Kingdom	2 16.7%	1 8.3%	3 12.5%
Spain	1 8.3%	1 8.3%	2 8.3%
Sweden	2 16.7%	0 0%	2 8.3%
Serbia	2 16.7%	0 0%	2 8.3%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population (defined as all patients with post-dose drug concentration data)

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [ng/ml]	2.66 (0.99)	3.63 (1.44)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.092
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Platelet Count
Description	Platelet counts in patients with ET receiving Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

Safety population (defined as all patients who received study treatment)

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Baseline	488.8 (167.4)	548.5 (278.7)
2 hours post-dose	487.9 (168.1)	539.2 (258.6)
12 hours post-dose	473.2 (146.0)	540.3 (263.6)

3. Secondary Outcome

Title	Heart Rate
Description	Heart rates in patients with ET receiving Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Baseline	74.0 (9.6)	70.3 (8.4)
0.5 hours post-dose	72.4 (8.9)	77.7 (13.5)
1 hour post-dose	75.8 (5.5)	80.6 (11.7)
1.5 hours post-dose	78.1 (7.7)	82.7 (12.9)
2 hours post-dose	74.3 (7.0)	81.2 (13.8)
4 hours post-dose	75.0 (5.5)	74.7 (13.7)
6 hours post-dose	75.9 (8.6)	76.9 (11.4)
8 hours post-dose	75.5 (6.7)	76.3 (10.1)
12 hours post-dose	73.2 (6.0)	71.9 (8.1)

4. Primary Outcome

Title	Time of Maximum Plasma Concentration (Tmax) of Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [hours]	1.11 (0.39)	1.14 (0.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.857
	Comments
	Method	ANOVA
	Comments

5. Primary Outcome

Title	Area Under the Steady-state Plasma Concentration-time Curve (AUC) of Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [ng.h/ml]	6.4 (2.4)	10.3 (4.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	ANOVA
	Comments

6. Primary Outcome

Title	Terminal Half-life (T 1/2) of Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [hours]	1.3 (0.4)	1.4 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.378
	Comments
	Method	ANOVA
	Comments

7. Primary Outcome

Title	Total Clearance (CL/F) of Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [L/h]	156 (73)	97 (70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	ANOVA
	Comments

8. Primary Outcome

Title	Volume of Distribution (Vz/F) of Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [L]	286 (125)	195 (137)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	ANOVA
	Comments

9. Primary Outcome

Title	Cmax of Active Metabolite
Description	An active metabolite has therapeutic activity similar to the parent compound and must be considered in therapeutic pharmacokinetics.
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Active metabolite of Agrylin (BCH24426) in ages 18-50	Active metabolite of Agrylin (BCH24426) in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [ng/ml]	7.26 (3.74)	4.19 (3.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	ANOVA
	Comments

10. Primary Outcome

Title	Tmax of Active Metabolite
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Active metabolite of Agrylin (BCH24426) in ages 18-50	Active metabolite of Agrylin (BCH24426) in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [hours]	0.92 (0.26)	1.04 (0.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.557
	Comments
	Method	ANOVA
	Comments

11. Primary Outcome

Title	AUC of Active Metabolite
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Active metabolite of Agrylin (BCH24426) in ages 18-50	Active metabolite of Agrylin (BCH24426) in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [ng.h/ml]	27.6 (10.9)	17.4 (14.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	ANOVA
	Comments

12. Primary Outcome

Title	T 1/2 of Active Metabolite
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Active metabolite of Agrylin (BCH24426) in ages 18-50	Active metabolite of Agrylin (BCH24426) in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [hours]	2.7 (0.5)	3.5 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	ANOVA
	Comments

13. Primary Outcome

Title	CL/F of Active Metabolite
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Active metabolite of Agrylin (BCH24426) in ages 18-50	Active metabolite of Agrylin (BCH24426) in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [L/h]	36 (16)	57 (27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments
	Method	ANOVA
	Comments

14. Primary Outcome

Title	Vz/F of Active Metabolite
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Active metabolite of Agrylin (BCH24426) in ages 18-50	Active metabolite of Agrylin (BCH24426) in ages 65 and older
Measure Participants	12	12
Geometric Mean (Standard Deviation) [L]	139 (86)	277 (203)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Agrylin (Young), Agrylin (Elderly)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	ANOVA
	Comments

15. Secondary Outcome

Title	Systolic Blood Pressure
Description	Systolic blood pressures in patients with ET receiving Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Baseline	122.2 (9.6)	154.3 (19.6)
0.5 hours post-dose	122.7 (12.9)	145.2 (20.3)
1.0 hours post-dose	121.8 (11.7)	143.7 (21.8)
1.5 hours post-dose	122.3 (11.6)	140.1 (17.7)
2 hours post-dose	121.3 (12.3)	139.9 (19.8)
4 hours post-dose	122.2 (13.6)	133.7 (18.1)
6 hours post-dose	120.2 (16.1)	141.8 (19.5)
8 hours post-dose	123.6 (14.5)	136.3 (24.3)
12 hours post-dose	124.7 (13.6)	159.8 (28.6)

16. Secondary Outcome

Title	Diastolic Blood Pressure
Description	Diastolic blood pressures in patients with ET receiving Agrylin
Time Frame	over 1 day

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Agrylin (Young)	Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years	Anagrelide hydrochloride in ages 65 and older
Measure Participants	12	12
Baseline	76.9 (7.5)	81.4 (10.3)
0.5 hours post-dose	74.8 (7.3)	75.2 (9.9)
1 hour post-dose	72.4 (6.6)	72.6 (7.5)
1.5 hours post-dose	72.8 (6.7)	71.6 (9.5)
2 hours post-dose	71.3 (7.9)	72.8 (7.1)
4 hours post-dose	76.2 (6.0)	73.0 (9.5)
6 hours post-dose	73.4 (10.0)	71.3 (7.6)
8 hours post-dose	76.3 (6.2)	75.0 (11.3)
12 hours post-dose	76.3 (9.1)	84.2 (12.4)

Adverse Events

Arm/Group Title	Agrylin (Young)		Agrylin (Elderly)
Arm/Group Description	Anagrelide hydrochloride in ages 18-50 years		Anagrelide hydrochloride in ages 65 and older
All Cause Mortality
	Agrylin (Young)		Agrylin (Elderly)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Agrylin (Young)		Agrylin (Elderly)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Agrylin (Young)		Agrylin (Elderly)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/12 (25%)		0/12 (0%)
Infections and infestations
Nasopharyngitis	1/12 (8.3%)	1	0/12 (0%)	0
Urinary tract infection	1/12 (8.3%)	1	0/12 (0%)	0
Nervous system disorders
Headache	1/12 (8.3%)	1	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/12 (8.3%)	1	0/12 (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.