NCT02484807

Brief Summary

The development of disease-targeted medication for the treatment of pulmonary arterial hypertension (PAH) has significantly improved within the last years, leading to the development of 10 approved agents. Combination treatment with Endothelin-Receptor-Antagonists (ERA) and Phosphodiesterase-Type-5-Inibitors (PDE-5-Inhibitor) has become increasingly important for the treatment of PAH. In a recent press release, the results of the AMBITION study reported that an upfront combination treatment immediately after diagnosis leads to a delayed disease progression \[4\]. Thus, the question if there is a clinically relevant pharmaco-dynamic drug-drug interaction is of rising interest.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
125

participants targeted

Target at P50-P75 for all trials

Timeline
Completed

Started May 2015

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

May 1, 2015

Completed
2 months until next milestone

First Submitted

Initial submission to the registry

June 24, 2015

Completed
6 days until next milestone

First Posted

Study publicly available on registry

June 30, 2015

Completed
1.4 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2016

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2016

Completed
3.2 years until next milestone

Results Posted

Study results publicly available

February 5, 2020

Completed
Last Updated

February 5, 2020

Status Verified

January 1, 2020

Enrollment Period

1.6 years

First QC Date

June 24, 2015

Results QC Date

July 19, 2017

Last Update Submit

January 24, 2020

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (1)

  • Characterisation of Medication Levels

    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.

    baseline vs. measurement after 3-6 months

Secondary Outcomes (6)

  • Impact of Medication Adjustment

    baseline vs. measurement 3-6 months after switch

  • Clinical Relevance 6 Minute Walking Distance

    baseline vs. measurement 3-6 months after switch

  • Clinical Relevance NTproBNP

    baseline vs. measurement after 3-6 months

  • Clinical Relevance Echocardiography Systolic Pulmonary Arterial Pressure (sPAP)

    baseline vs. measurement after 3-6 months

  • Clinical Relevance Echocardiography Tricuspid Annular Plane Systolic Excursion (TAPSE)

    baseline vs. measurement after 3-6 months

  • +1 more secondary outcomes

Study Arms (6)

Bosentan + Sildenafil

Combination treatment with Bosentan + Sildenafil at baseline

Other: no intervention, only observation of different groups

Bosentan + Tadalafil

Combination treatment with Bosentan + Tadalafil at baseline

Other: no intervention, only observation of different groups

Ambrisentan + Sildenafil

Combination treatment with Ambrisentan + Sildenafil at baseline

Other: no intervention, only observation of different groups

Ambrisentan + Tadalafil

Combination treatment with Ambrisentan + Tadalafil at baseline

Other: no intervention, only observation of different groups

Macitentan + Sildenafil

Combination treatment with Macitentan + Sildenafil at baseline

Other: no intervention, only observation of different groups

Macitentan + Tadalafil

Combination treatment with Macitentan + Tadalafil at baseline

Other: no intervention, only observation of different groups

Interventions

no intervention, only observation of different groupsOTHER
Ambrisentan + SildenafilAmbrisentan + TadalafilBosentan + SildenafilBosentan + TadalafilMacitentan + SildenafilMacitentan + Tadalafil

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)
Sampling MethodNon-Probability Sample
Study Population

patients with pulmonary arterial hypertension receiving disease-targeted combination therapy

You may qualify if:

  • Men and women ≥ 18 years old
  • Diagnosis of PAH according to ESC/ERS-guidelines: patients with manifest pulmonary arterial hypertension, mean pulmonary arterial pressure ≥25mmHg, measured by right heart catheterization.
  • Combination treatment with ERA (Bosentan, Ambrisentan or Macitentan) and PDE-5-Inhibitor (Sildenafil or Tadalafil) for more than 3 months.

You may not qualify if:

  • Underage patients
  • Pregnancy or lactation

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Centre for pulmonary hypertension, Thoraxclinic at the University Hospital Heidelberg

Heidelberg, 69126, Germany

Location

Related Publications (8)

  • Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009 Oct;30(20):2493-537. doi: 10.1093/eurheartj/ehp297. Epub 2009 Aug 27. No abstract available.

    PMID: 19713419BACKGROUND

  • Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004 Sep 30;351(14):1425-36. doi: 10.1056/NEJMra040291. No abstract available.

    PMID: 15459304BACKGROUND

  • Voelkel NF, Gomez-Arroyo J, Abbate A, Bogaard HJ, Nicolls MR. Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J. 2012 Dec;40(6):1555-65. doi: 10.1183/09031936.00046612. Epub 2012 Jun 27.

    PMID: 22743666BACKGROUND

  • Wrishko RE, Dingemanse J, Yu A, Darstein C, Phillips DL, Mitchell MI. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008 May;48(5):610-8. doi: 10.1177/0091270008315315. Epub 2008 Feb 27.

    PMID: 18305126BACKGROUND

  • Paul GA, Gibbs JS, Boobis AR, Abbas A, Wilkins MR. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005 Jul;60(1):107-12. doi: 10.1111/j.1365-2125.2005.02383.x.

    PMID: 15963102BACKGROUND

  • Weiss J, Theile D, Spalwisz A, Burhenne J, Riedel KD, Haefeli WE. Influence of sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan in LS180 cells. Biochem Pharmacol. 2013 Jan 15;85(2):265-73. doi: 10.1016/j.bcp.2012.11.020. Epub 2012 Dec 5.

    PMID: 23219525BACKGROUND

  • Weiss J, Theile D, Ruppell MA, Speck T, Spalwisz A, Haefeli WE. Interaction profile of macitentan, a new non-selective endothelin-1 receptor antagonist, in vitro. Eur J Pharmacol. 2013 Feb 15;701(1-3):168-75. doi: 10.1016/j.ejphar.2013.01.010. Epub 2013 Jan 23.

    PMID: 23353592BACKGROUND

  • Burgess G, Hoogkamer H, Collings L, Dingemanse J. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008 Jan;64(1):43-50. doi: 10.1007/s00228-007-0408-z. Epub 2007 Nov 27.

    PMID: 18040672BACKGROUND

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Hypertension, PulmonaryLung DiseasesRespiratory Tract Diseases

Limitations and Caveats

small sample size. Due to the fact that currently no established therapeutic plasma concentration ranges exist, no conclusion can be drawn whether lower or higher concentrations lead to treatment failure or adverse events.

Results Point of Contact

Title
Professor Dr. med. Ekkehard Grünig
Organization
Centre for pulmonary hypertension of the Thoraxclinic at the University Hospital Heidelberg
ekkehard.gruenig@med.uni-heidelberg.de
+4962213968053

Study Officials

  • Ekkehard Grünig, MD

    Thoraxclinic at the University Hospital Heidelberg

    PRINCIPAL INVESTIGATOR

Publication Agreements

PI is Sponsor Employee
No
Restriction Type
LTE60
Restrictive Agreement
Yes

Study Design

Study Type
observational
Observational Model
COHORT
Time Perspective
PROSPECTIVE
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Prof. Dr. med.

Study Record Dates

First Submitted

June 24, 2015

First Posted

June 30, 2015

Study Start

May 1, 2015

Primary Completion

December 1, 2016

Study Completion

December 1, 2016

Last Updated

February 5, 2020

Results First Posted

February 5, 2020

Record last verified: 2020-01

Locations

DE(1)