Trial Outcomes & Findings for Pharmacokinetic Effects of QTI571 on Sildenafil and Bosentan in Pulmonary Arterial Hypertension Participants (NCT NCT01392469)

Last Updated: 2021-06-21

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

21 participants

Primary outcome timeframe

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

Results posted on

2021-06-21

Participant Flow

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

Participant milestones

Participant milestones
Measure	Imatinib+ Bosentan+ Sildenafil 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 Study STARTED	21
Overall Study COMPLETED	17
Overall Study NOT COMPLETED	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Imatinib+ Bosentan+ Sildenafil 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 Study Adverse Event	2
Overall Study Withdrawal by Subject	1
Overall Study Protocol Violation	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Imatinib+ Bosentan+ Sildenafil n=21 Participants 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.
Age, Continuous	54.4 years STANDARD_DEVIATION 13.44 • n=5 Participants
Sex: Female, Male Female	15 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: 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.

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=17 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=17 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) n=17 Participants 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.
Geometric Mean Ratio of Dose Normalized Area Under the Curve From Time Zero to Tau (AUCtau) for Bosentan Before and After Imatinib Administrations	93.3 hr*ng/mL/mg Geometric Coefficient of Variation 49.9	109 hr*ng/mL/mg Geometric Coefficient of Variation 52.0	131 hr*ng/mL/mg Geometric Coefficient of Variation 38.0

PRIMARY outcome

Timeframe: 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

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=17 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=17 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) n=17 Participants 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.
Geometric Mean Ratio of Dose Normalized AUCtau for Sildenafil Before and After Imatinib Administrations	7.22 hr*ng/mL/mg Geometric Coefficient of Variation 60.6	9.82 hr*ng/mL/mg Geometric Coefficient of Variation 42.5	12.3 hr*ng/mL/mg Geometric Coefficient of Variation 40.9

PRIMARY outcome

Timeframe: 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

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=17 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=17 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) n=17 Participants 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.
Geometric Mean Ratio of Dose Normalized Maximum Plasma Concentration (Cmax) for Bosentan Before and After Imatinib Administrations	21.9 ng/mL/mg Geometric Coefficient of Variation 48.8	21.8 ng/mL/mg Geometric Coefficient of Variation 60.3	23.4 ng/mL/mg Geometric Coefficient of Variation 44.7

PRIMARY outcome

Timeframe: 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

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=17 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=17 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) n=17 Participants 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.
Geometric Mean Ratio of Dose Normalized Cmax for Sildenafil Before and After Imatinib Administrations	2.44 ng/mL/mg Geometric Coefficient of Variation 68.6	3.14 ng/mL/mg Geometric Coefficient of Variation 52.4	3.81 ng/mL/mg Geometric Coefficient of Variation 52.9

SECONDARY outcome

Timeframe: From time of first administration of study drug until end of study (up to approximately 18 months)

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

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.

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=21 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=19 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 2) n=18 Participants 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.
Number of Participants With At Least One or More Adverse Events (AEs)	10 Participants	9 Participants	16 Participants

SECONDARY outcome

Timeframe: 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

Population: 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.

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=17 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=17 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 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.
Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) Imatinib Cmax/Dose	7.55 ng/ml/mg Standard Deviation 4.18	6.71 ng/ml/mg Standard Deviation 3.39	—
Dose Normalized Cmax of Imatinib and CGP74588 (Active Metabolite of Imatinib) CGP74588 Cmax/Dose	1.37 ng/ml/mg Standard Deviation 0.538	1.39 ng/ml/mg Standard Deviation 0.575	—

SECONDARY outcome

Timeframe: 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

Population: 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.

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil (Reference) n=17 Participants 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	Imatinib (200 mg/Day) + Bosentan + Sildenafil (Test 1) n=17 Participants 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.	Imatinib (400 mg/Day) + Bosentan + Sildenafil (Test 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.
Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) Imatinib AUCtau/Dose	90.9 hr*ng/mL/mg Standard Deviation 49.3	88.4 hr*ng/mL/mg Standard Deviation 36.0	—
Dose Normalized AUCtau of Imatinib and CGP74588 (Active Metabolite of Imatinib) CGP74588 AUCtau/Dose	19.3 hr*ng/mL/mg Standard Deviation 9.69	20.6 hr*ng/mL/mg Standard Deviation 9.07	—

Adverse Events

Bosentan + Sildenafil

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Imatinib (200 mg/Day) + Bosentan + Sildenafil

Serious events: 2 serious events

Other events: 9 other events

Deaths: 0 deaths

Imatinib (400 mg/Day) + Bosentan+ Sildenafil

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Total Participants

Serious events: 2 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Bosentan + Sildenafil n=21 participants at risk Participants received treatment with bosentan 125 mg twice daily and sildenafil thrice daily for 8 days in treatment period 1	Imatinib (200 mg/Day) + Bosentan + Sildenafil n=19 participants at risk 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.	Imatinib (400 mg/Day) + Bosentan+ Sildenafil n=18 participants at risk 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.	Total Participants n=21 participants at risk
Cardiac disorders Atrial flutter	0.00% 0/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	0.00% 0/19 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	5.6% 1/18 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	4.8% 1/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement
Cardiac disorders Cardiac failure congestive	0.00% 0/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	5.3% 1/19 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	0.00% 0/18 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	4.8% 1/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement
Infections and infestations Viral infection	0.00% 0/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	5.3% 1/19 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	0.00% 0/18 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	4.8% 1/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement
Skin and subcutaneous tissue disorders Rash	0.00% 0/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	0.00% 0/19 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	5.6% 1/18 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement	4.8% 1/21 • From time of first administration of study drug until end of study (up to approximately 18 months) Safety analysis set included all participants who received at least one dose of the study drug with at least one post-baseline measurement

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER