Pharmacokinetic Effects of QTI571 on Sildenafil and Bosentan in Pulmonary Arterial Hypertension Participants

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01392469
• Collaborator: (none)
• Enrollment: 21
• Locations: 11
• Arm: 1
• Actual Duration (Months): 18.2
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to investigate the effects of QTI571 (imatinib) on pharmacokinetics of bosentan and sildenafil at steady state when co-administered to participants with pulmonary arterial hypertension.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Imatinib; Drug: Sildenafil; Drug: Bosentan	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Non-Randomized, Multiple Dose, Three Treatment Period, Open-Label, Single Sequence, Single Group Study to Evaluate the Pharmacokinetic Effect of Two Doses of QTI571 (Imatinib) on the Co-administered Drugs Sildenafil and Bosentan in Pulmonary Arterial Hypertension (PAH) Patients
• Actual Study Start Date: Apr 20, 2011
• Actual Primary Completion Date: Oct 25, 2012
• Actual Study Completion Date: Oct 25, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Imatinib + Bosentan + Sildenafil Participants received treatment with bosentan 125 milligrams (mg) twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan. Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2. Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.

Drug: Imatinib; Film coated tablets, oral administration; Other Names: QTI571 ; Drug: Sildenafil; Oral Administration; Drug: Bosentan; Oral Administration

Outcome Measures

Primary Outcome Measures

1. Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations [Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose]

   AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized AUCtau of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).

2. Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations [Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose]

   AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized AUCtau of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).

3. Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations [Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose]

   Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized Cmax of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).

4. Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations [Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose]

   Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized Cmax of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals was then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).

Secondary Outcome Measures

1. Number of Participants With At Least One or More Adverse Events (AEs) [From time of first administration of study drug until end of study (up to approximately 18 months)]

   An adverse event was the appearance or worsening of any undesirable sign, symptom, or medical condition that occurred after starting the study drug even if the event was not considered to be related to study drug. Number of participants with AEs were reported by treatment period.

2. Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) [Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose]

3. Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) [Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants with Pulmonary arterial hypertension (PAH) in World Health Organization (WHO) Diagnostic Group 1, with pulmonary vascular resistance > 800 dyneseccm^-5,

• On stable doses of bosentan and sildenafil

Exclusion Criteria:

• Other diagnosis of PAH in World Health Organization (WHO) Diagnostic Group 1 such as congenital large or small unrepaired systemic to pulmonary shunts, portal hypertension, Human Immunodeficiency Virus (HIV) infection, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic teleangiectasia, hemoglobinopathies, myeloproliferative disorders, veno-occlusive pulmonary disease

• Significant lung diseases not related to PAH

• Significant cardiovascular system disorders, hematological system disorders, liver insufficiency

• Significant diseases in other organ system.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Tampa	Florida	United States	33606
2	Novartis Investigative Site	Weston	Florida	United States	33331
3	Novartis Investigative Site	Mineola	New York	United States	11501
4	Novartis Investigative Site	Darlinghurst	New South Wales	Australia	2010
5	Novartis Investigative Site	Bruxelles		Belgium	1070
6	Novartis Investigative Site	Leuven		Belgium	3000
7	Novartis Investigative Site	Berlin		Germany	12683
8	Novartis Investigative Site	Hannover		Germany	30625
9	Novartis Investigative Site	Roma	RM	Italy	00161
10	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
11	Novartis Investigative Site	London		United Kingdom	NW3 2PR

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01392469
• Other Study ID Numbers: CQTI571A2102; 2010-021344-17
• First Posted: Jul 12, 2011
• Last Update Posted: Jun 21, 2021
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Pulmonary Arterial Hypertension; Pulmonary Vascular Resistance; Imatinib; Bosentan; Sildenafil
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Imatinib Mesylate; Bosentan; Sildenafil Citrate

Study Results

Participant Flow

Recruitment Details	Participants with pulmonary arterial hypertension (PAH) were enrolled in the study at 8 investigation sites worldwide from 20 April 2011 to 25 October 2012.

Arm/Group Title	Imatinib+ Bosentan+ Sildenafil
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan. Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2. Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Period Title: Overall Study
STARTED	21
COMPLETED	17
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Imatinib+ Bosentan+ Sildenafil
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan. Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2. Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Overall Participants	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.4 (13.44)
Sex: Female, Male (Count of Participants)
Female	15 71.4%
Male	6 28.6%

Outcome Measures

1. Primary Outcome

Title	Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations
Description	AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized AUCtau of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time Frame	Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.

Arm/Group Title	Bosentan + Sildenafil (Reference)	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan	Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	17	17	17
Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL/mg]	93.3 (49.9)	109 (52.0)	131 (38.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 90%; 1.03 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 90%; 1.23 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations
Description	AUCtau was the area under the curve calculated to the end of the dosing interval, tau. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized AUCtau of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time Frame	Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.

Arm/Group Title	Bosentan + Sildenafil (Reference)	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan.	Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	17	17	17
Geometric Mean (Geometric Coefficient of Variation) [hr*ng/mL/mg]	7.22 (60.6)	9.82 (42.5)	12.3 (40.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 90%; 1.14 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.70
	Confidence Interval	(2-Sided) 90%; 1.43 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations
Description	Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of bosentan was performed on dose normalized Cmax of bosentan. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals were then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time Frame	Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.

Arm/Group Title	Bosentan + Sildenafil (Reference)	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan.	Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	17	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL/mg]	21.9 (48.8)	21.8 (60.3)	23.4 (44.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 90%; 0.82 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 90%; 0.88 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations
Description	Cmax was the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after dose administration. The effect of co-administration of imatinib at two doses (200 and 400 mg) on the pharmacokinetics of sildenafil was performed on dose normalized Cmax of sildenafil. A mixed effects linear model was fitted to the log-transformed PK parameters. This model included treatment (i.e., dose of imatinib) as a fixed effect, and participant as a random effect. Estimates for the treatment differences and associated 90% confidence intervals were obtained from the above model. These estimates and confidence intervals was then "back-transformed" to the original scale, giving, for each dose level of imatinib, the ratio of imatinib + co-administered sildenafil and bosentan (test) relative to the co-administered drugs alone (sildenafil + bosentan) (reference).
Time Frame	Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.

Arm/Group Title	Bosentan + Sildenafil (Reference)	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1. Participants were on the same sildenafil dose level (20, 40, 50 or 60 mg) they had been at study entry which was well tolerated in conjunction with bosentan.	Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	17	17	17
Geometric Mean (Geometric Coefficient of Variation) [ng/mL/mg]	2.44 (68.6)	3.14 (52.4)	3.81 (52.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 90%; 1.03 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bosentan + Sildenafil (Reference), Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (Test/Reference)
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 90%; 1.24 to 1.95
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants With At Least One or More Adverse Events (AEs)
Description	An adverse event was the appearance or worsening of any undesirable sign, symptom, or medical condition that occurred after starting the study drug even if the event was not considered to be related to study drug. Number of participants with AEs were reported by treatment period.
Time Frame	From time of first administration of study drug until end of study (up to approximately 18 months)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants enrolled and who received at least one dose of study drug (bosentan, sildenafil, or imatinib).

Arm/Group Title	Bosentan + Sildenafil	Imatinib (200 mg/Day) + Bosentan + Sildenafil	Imatinib (400 mg/Day) + Bosentan+ Sildenafil
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1	Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	21	19	18
Count of Participants [Participants]	10 47.6%	9 NaN	16 NaN

6. Secondary Outcome

Title	Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib)
Time Frame	Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.

Arm/Group Title	Imatinib (200 mg/Day) + Bosentan + Sildenafil	Imatinib (400 mg/Day) + Bosentan + Sildenafil
Arm/Group Description	Participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	17	17
Imatinib Cmax/Dose	7.55 (4.18)	6.71 (3.39)
CGP74588 Cmax/Dose	1.37 (0.538)	1.39 (0.575)

7. Secondary Outcome

Title	Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib)
Time Frame	Day 1: pre-dose, Day 8: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose, Day 9: pre-dose, Days 22 and 36: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

PK analysis set included all participants with data for at least one of the primary PK variables in at least one period and no major protocol deviations with impact on PK data.

Arm/Group Title	Imatinib (200 mg/Day) + Bosentan + Sildenafil	Imatinib (400 mg/Day) + Bosentan + Sildenafil
Arm/Group Description	Participants received concomitant treatment of oral imatinib 200 mg daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.	Participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
Measure Participants	17	17
Imatinib AUCtau/Dose	90.9 (49.3)	88.4 (36.0)
CGP74588 AUCtau/Dose	19.3 (9.69)	20.6 (9.07)

Adverse Events

Time Frame	From time of first administration of study drug until end of study (up to approximately 18 months)
Adverse Event Reporting Description	Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement
Arm/Group Title	Bosentan + Sildenafil		Imatinib (200 mg/Day) + Bosentan + Sildenafil		Imatinib (400 mg/Day) + Bosentan+ Sildenafil		Total Participants
Arm/Group Description	Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1		Following treatment period 1, the participants received concomitant treatment of oral imatinib 200 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 2.		Following treatment period 2, the participants received concomitant treatment of oral imatinib 400 mg tablet daily, bosentan 125 mg twice daily and sildenafil thrice daily for 14 days in treatment period 3.
All Cause Mortality
	Bosentan + Sildenafil		Imatinib (200 mg/Day) + Bosentan + Sildenafil		Imatinib (400 mg/Day) + Bosentan+ Sildenafil		Total Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/19 (0%)		0/18 (0%)		0/21 (0%)
Serious Adverse Events
	Bosentan + Sildenafil		Imatinib (200 mg/Day) + Bosentan + Sildenafil		Imatinib (400 mg/Day) + Bosentan+ Sildenafil		Total Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		2/19 (10.5%)		1/18 (5.6%)		2/21 (9.5%)
Cardiac disorders
Atrial flutter	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Cardiac failure congestive	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Infections and infestations
Viral infection	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Skin and subcutaneous tissue disorders
Rash	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	Bosentan + Sildenafil		Imatinib (200 mg/Day) + Bosentan + Sildenafil		Imatinib (400 mg/Day) + Bosentan+ Sildenafil		Total Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/21 (47.6%)		9/19 (47.4%)		16/18 (88.9%)		19/21 (90.5%)
Blood and lymphatic system disorders
Anaemia	1/21 (4.8%)		1/19 (5.3%)		3/18 (16.7%)		4/21 (19%)
Neutropenia	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Thrombocytopenia	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Cardiac disorders
Atrioventricular block first degree	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Extrasystoles	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Palpitations	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Tachycardia	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Ear and labyrinth disorders
Vertigo	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Endocrine disorders
Hypothyroidism	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Eye disorders
Eyelid oedema	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Periorbital oedema	0/21 (0%)		1/19 (5.3%)		1/18 (5.6%)		2/21 (9.5%)
Vision blurred	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Gastrointestinal disorders
Abdominal discomfort	0/21 (0%)		1/19 (5.3%)		1/18 (5.6%)		2/21 (9.5%)
Abdominal pain	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Ascites	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Diarrhoea	1/21 (4.8%)		5/19 (26.3%)		2/18 (11.1%)		7/21 (33.3%)
Dry mouth	0/21 (0%)		1/19 (5.3%)		1/18 (5.6%)		2/21 (9.5%)
Gingival bleeding	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Haemorrhoidal haemorrhage	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Nausea	1/21 (4.8%)		4/19 (21.1%)		2/18 (11.1%)		7/21 (33.3%)
Toothache	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Vomiting	0/21 (0%)		1/19 (5.3%)		4/18 (22.2%)		5/21 (23.8%)
General disorders
Chest discomfort	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Fatigue	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Oedema peripheral	2/21 (9.5%)		1/19 (5.3%)		3/18 (16.7%)		5/21 (23.8%)
Infections and infestations
Nasopharyngitis	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Rhinitis	0/21 (0%)		1/19 (5.3%)		1/18 (5.6%)		2/21 (9.5%)
Upper respiratory tract infection	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Urinary tract infection	0/21 (0%)		0/19 (0%)		2/18 (11.1%)		2/21 (9.5%)
Injury, poisoning and procedural complications
Accidental overdose	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Investigations
Blood bilirubin increased	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Blood creatinine increased	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Blood glucose increased	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Blood potassium decreased	0/21 (0%)		1/19 (5.3%)		3/18 (16.7%)		4/21 (19%)
Metabolism and nutrition disorders
Decreased appetite	0/21 (0%)		1/19 (5.3%)		1/18 (5.6%)		2/21 (9.5%)
Hypokalaemia	1/21 (4.8%)		0/19 (0%)		1/18 (5.6%)		2/21 (9.5%)
Iron deficiency	1/21 (4.8%)		0/19 (0%)		1/18 (5.6%)		2/21 (9.5%)
Musculoskeletal and connective tissue disorders
Back pain	0/21 (0%)		2/19 (10.5%)		0/18 (0%)		2/21 (9.5%)
Muscle spasms	0/21 (0%)		0/19 (0%)		2/18 (11.1%)		2/21 (9.5%)
Musculoskeletal pain	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Myalgia	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Pain in extremity	1/21 (4.8%)		2/19 (10.5%)		1/18 (5.6%)		2/21 (9.5%)
Nervous system disorders
Dizziness	3/21 (14.3%)		0/19 (0%)		0/18 (0%)		3/21 (14.3%)
Head discomfort	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Headache	1/21 (4.8%)		2/19 (10.5%)		1/18 (5.6%)		4/21 (19%)
Hypoaesthesia	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Paraesthesia	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Presyncope	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Psychiatric disorders
Insomnia	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Sleep disorder	1/21 (4.8%)		0/19 (0%)		0/18 (0%)		1/21 (4.8%)
Renal and urinary disorders
Renal failure	1/21 (4.8%)		0/19 (0%)		1/18 (5.6%)		2/21 (9.5%)
Respiratory, thoracic and mediastinal disorders
Cough	0/21 (0%)		1/19 (5.3%)		1/18 (5.6%)		2/21 (9.5%)
Dyspnoea	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Epistaxis	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Pleural effusion	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Skin and subcutaneous tissue disorders
Dry skin	0/21 (0%)		1/19 (5.3%)		0/18 (0%)		1/21 (4.8%)
Rash	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Telangiectasia	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)
Vascular disorders
Hypotension	0/21 (0%)		0/19 (0%)		1/18 (5.6%)		1/21 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.