Trial Outcomes & Findings for Effect of Pharmacologic Interaction Between ERAs and PDE-5 Inhibitors on Medication Serum Levels and Clinical Disease Status in Patients With PAH (NCT NCT02484807)

Results Overview

comparison of different combination treatment arms (mean ± standard deviation), measurement of endothelin receptor antagonist plasma concentrations and PDE-5I plasma concentrations, results given es multiple of the expected mean plasma concentration (MOM). Due to technical setup measurement of plasma concentrations of macitentan was not possible. The expected mean concentration ranges (MOM) refer to data extracted from published plasma concentration-time profiles measured during monotherapy with sildenafil, tadalafil, bosentan, and ambrisentan and served as comparative values. Each individually measured drug concentration was set in proportion to the expected mean concentration and expressed as a multiple of the expected mean (MoM), with values \<1 denoting lower and values \>1 higher values than the expected mean.

Recruitment status

COMPLETED

Target enrollment

125 participants

Primary outcome timeframe

baseline vs. measurement after 3-6 months

Results posted on

2020-02-05

Participant Flow

March 2015 - September 2015

Participant milestones

Participant milestones
Measure	Bosentan + Sildenafil Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Overall Study STARTED	39	7	19	21	33	6
Overall Study COMPLETED	39	7	19	21	33	6
Overall Study NOT COMPLETED	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effect of Pharmacologic Interaction Between ERAs and PDE-5 Inhibitors on Medication Serum Levels and Clinical Disease Status in Patients With PAH

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bosentan + Sildenafil n=39 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil n=7 Participants Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil n=19 Participants Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil n=21 Participants Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil n=33 Participants Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil n=6 Participants Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups	Total n=125 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Age, Categorical Between 18 and 65 years	23 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants	7 Participants n=4 Participants	14 Participants n=21 Participants	2 Participants n=10 Participants	56 Participants n=115 Participants
Age, Categorical >=65 years	16 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants	14 Participants n=4 Participants	19 Participants n=21 Participants	4 Participants n=10 Participants	69 Participants n=115 Participants
Age, Continuous	56 years STANDARD_DEVIATION 16 • n=5 Participants	56 years STANDARD_DEVIATION 18 • n=7 Participants	61 years STANDARD_DEVIATION 19 • n=5 Participants	63 years STANDARD_DEVIATION 13 • n=4 Participants	65 years STANDARD_DEVIATION 13 • n=21 Participants	64 years STANDARD_DEVIATION 21 • n=10 Participants	61 years STANDARD_DEVIATION 16 • n=115 Participants
Sex: Female, Male Female	29 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants	12 Participants n=4 Participants	19 Participants n=21 Participants	4 Participants n=10 Participants	84 Participants n=115 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	9 Participants n=4 Participants	14 Participants n=21 Participants	2 Participants n=10 Participants	41 Participants n=115 Participants
Region of Enrollment Germany	39 participants n=5 Participants	7 participants n=7 Participants	19 participants n=5 Participants	21 participants n=4 Participants	33 participants n=21 Participants	6 participants n=10 Participants	125 participants n=115 Participants

PRIMARY outcome

Timeframe: baseline vs. measurement after 3-6 months

comparison of different combination treatment arms (mean ± standard deviation), measurement of endothelin receptor antagonist plasma concentrations and PDE-5I plasma concentrations, results given es multiple of the expected mean plasma concentration (MOM). Due to technical setup measurement of plasma concentrations of macitentan was not possible. The expected mean concentration ranges (MOM) refer to data extracted from published plasma concentration-time profiles measured during monotherapy with sildenafil, tadalafil, bosentan, and ambrisentan and served as comparative values. Each individually measured drug concentration was set in proportion to the expected mean concentration and expressed as a multiple of the expected mean (MoM), with values \<1 denoting lower and values \>1 higher values than the expected mean.

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil n=39 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil n=7 Participants Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil n=19 Participants Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil n=21 Participants Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil n=33 Participants Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil n=6 Participants Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Characterisation of Medication Levels ERA concentrations	5.54 MOM Standard Deviation 3.24	2.18 MOM Standard Deviation 1.23	1.81 MOM Standard Deviation 0.82	1.53 MOM Standard Deviation 0.84	NA MOM Standard Deviation NA measurement of Macitentan Plasma concentrations not possible due to technical limitations	NA MOM Standard Deviation NA measurement of Macitentan Plasma concentrations not possible due to technical limitations
Characterisation of Medication Levels PDE-5I concentrations	0.44 MOM Standard Deviation 0.42	0.89 MOM Standard Deviation 0.53	1.30 MOM Standard Deviation 0.97	1.67 MOM Standard Deviation 0.63	1.16 MOM Standard Deviation 0.87	1.59 MOM Standard Deviation 0.99

SECONDARY outcome

Timeframe: baseline vs. measurement 3-6 months after switch

Population: 20 of 39 patients receiving bosentan /sildenafil were switched to macitentan. sildenafil concentrations were compared before and after switch.

Change of medication serum levels after clinically indicated medication adaptation in patients who received Bosentan + Sildenafil in the beginning and changed the ERA to Macitentan 1. change of mean levels ± standard deviation 2. frequency of borderline medication serum levels or medication levels out of the therapeutic window The expected mean concentration ranges (MOM) refer to data extracted from published plasma concentration-time profiles measured during monotherapy with sildenafil, tadalafil, bosentan, and ambrisentan and served as comparative values. Each individually measured drug concentration was set in proportion to the expected mean concentration and expressed as a multiple of the expected mean (MoM), with values \<1 denoting lower and values \>1 higher values than the expected mean.

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil n=20 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Impact of Medication Adjustment sildenafil concentrations before switch	0.42 MOM Standard Deviation 0.32	—	—	—	—	—
Impact of Medication Adjustment sildenafil concentrations after switch	1.59 MOM Standard Deviation 1.46	—	—	—	—	—

SECONDARY outcome

Timeframe: baseline vs. measurement 3-6 months after switch

* Changes of medication levels after adjustment of combination therapy if clinically indicated * correlation with clinical routine parameters indicating clinical disease status

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil n=20 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Clinical Relevance 6 Minute Walking Distance 6 minute walking distance before switch	396 meters Standard Deviation 118	—	—	—	—	—
Clinical Relevance 6 Minute Walking Distance 6 minute walking distance after switch	436 meters Standard Deviation 108	—	—	—	—	—

SECONDARY outcome

Timeframe: baseline vs. measurement after 3-6 months

* Changes of medication levels after adjustment of combination therapy if clinically indicated * correlation with clinical routine parameters indicating clinical disease status

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil n=20 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Clinical Relevance NTproBNP NTproBNP before switch	2204 ng/ml Standard Deviation 3823	—	—	—	—	—
Clinical Relevance NTproBNP NTproBNP after switch	1181 ng/ml Standard Deviation 2899	—	—	—	—	—

SECONDARY outcome

Timeframe: baseline vs. measurement after 3-6 months

* Changes of medication levels after adjustment of combination therapy if clinically indicated * correlation with clinical routine parameters indicating clinical disease status

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil n=20 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Clinical Relevance Echocardiography Systolic Pulmonary Arterial Pressure (sPAP) sPAP before switch	60.6 mmHg Standard Deviation 21.4	—	—	—	—	—
Clinical Relevance Echocardiography Systolic Pulmonary Arterial Pressure (sPAP) sPAP after switch	60.2 mmHg Standard Deviation 20.0	—	—	—	—	—

SECONDARY outcome

Timeframe: baseline vs. measurement after 3-6 months

* Changes of medication levels after adjustment of combination therapy if clinically indicated * correlation with clinical routine parameters indicating clinical disease status

Outcome measures

Outcome measures
Measure	Bosentan + Sildenafil n=20 Participants Combination treatment with Bosentan + Sildenafil at baseline no intervention, only observation of different groups	Bosentan + Tadalafil Combination treatment with Bosentan + Tadalafil at baseline no intervention, only observation of different groups	Ambrisentan + Sildenafil Combination treatment with Ambrisentan + Sildenafil at baseline no intervention, only observation of different groups	Ambrisentan + Tadalafil Combination treatment with Ambrisentan + Tadalafil at baseline no intervention, only observation of different groups	Macitentan + Sildenafil Combination treatment with Macitentan + Sildenafil at baseline no intervention, only observation of different groups	Macitentan + Tadalafil Combination treatment with Macitentan + Tadalafil at baseline no intervention, only observation of different groups
Clinical Relevance Echocardiography Tricuspid Annular Plane Systolic Excursion (TAPSE) TAPSE before switch	21.9 mm Standard Deviation 5.4	—	—	—	—	—
Clinical Relevance Echocardiography Tricuspid Annular Plane Systolic Excursion (TAPSE) TAPSE after switch	21.5 mm Standard Deviation 5.9	—	—	—	—	—

SECONDARY outcome

Timeframe: baseline vs. measurement after 3-6 months

* Changes of medication levels after adjustment of combination therapy if clinically indicated * correlation with clinical routine parameters indicating clinical disease status