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A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (ATPAHSS)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01042158
First Posted: January 5, 2010
Last Update Posted: September 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Eli Lilly and Company
United Therapeutics
The Cleveland Clinic
University of Texas
Stanford University
Information provided by (Responsible Party):
Johns Hopkins University
  Purpose
This will be a 36-week, single group, open label study assessing the effects of Tadalafil plus Ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with the scleroderma spectrum of disease (PAH-SSD). Standard outcome measures such as six-minute walk distance (6MWD), New York heart Association (NYHA) classification, and hemodynamic measurements will be assessed, as well as novel functional measures of RV-PV function including the transthoracic echocardiogram parameter tricuspid annular plane systolic ejection (TAPSE), contrast-enhanced cardiac MRI and heart rate variability assessed by Holter monitoring. This design (excluding a placebo arm) was selected for ethical concerns and to provide optimal efficiency and active therapy to all study subjects. It also allows for comparisons between the two monotherapies and with combination therapy.

Condition Intervention Phase
Pulmonary Arterial Hypertension Systemic Sclerosis Scleroderma Spectrum of Diseases Connective Tissue Disease Pulmonary Hypertension Drug: tadalafil and ambrisentan upfront combination therapy Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis

Resource links provided by NLM:


Further study details as provided by Johns Hopkins University:

Primary Outcome Measures:
  • Right Ventricular (RV) Mass [ Time Frame: baseline and 36 weeks ]
    Assessment of change in Right ventricular mass was done via standard volumetric cine images of the right heart at baseline and comparing it to that at the end of 36 weeks using Cardiac Magnetic Resonance Imaging studies.

  • Pulmonary Vascular Resistance (PVR) [ Time Frame: baseline 36 weeks ]
    Change in Pulmonary Vascular Resistance (PVR) was ascertained via Right Heart Catheterization (RHC) measurement of the difference between the PVR at baseline and 36 weeks


Secondary Outcome Measures:
  • Tricuspid Annular Plane Systolic Excursion (TAPSE) [ Time Frame: baseline and 36 weeks ]
    The extent of displacement of the tricuspid valves, termed as Tricuspid Annular Plane Systolic Excursion (TAPSE) was measured using a trans-thoracic echocardiogram following Right heart catheterization.

  • 6-minute Walk Distance [ Time Frame: baseline and 36 weeks ]
    patients were made to take a walk of normal speed to cover a distance in 6 minutes and distance covered was recorded. This was done at baseline (week o) and then repeated t 36 weeks.


Enrollment: 25
Study Start Date: January 2010
Study Completion Date: November 2014
Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Tadalafil and ambrisentan upfront therapy
This will be a 36-week, single group, open label study assessing the effects of Tadalafil plus Ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with the scleroderma spectrum of disease (PAH-SSD).
Drug: tadalafil and ambrisentan upfront combination therapy
tadalafil 20 mg qd and ambrisentan 5 mg qd. Up-titration of study medications will occur at week 4 (ambrisentan 10 mgs daily and tadalafil 40 mg qd). If a subject experiences an intolerable adverse event as a result of an uptitration in the study drug dose, the dose of study drug maybe down titrated to 20 mg of tadalafil and/or 5mg of ambrisentan. If the subject is still experiencing an intolerable adverse event, then the investigator will withdraw the subject from the study.
Other Names:
  • Adcirca
  • Letairis

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • A right heart catheterization done at baseline with a mean pulmonary artery pressure (mPAP) ≥ 25mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15mmHg, and pulmonary vascular resistance (PVR) ≥3 Woods units.
  • Scleroderma defined as systemic sclerosis with diffuse or limited scleroderma meeting the American College of Rheumatology (ACR) criteria (33). Cases will be included if they meet clinical features that satisfy ACR criteria for a diagnosis of scleroderma or the presence of three of five features of the CREST syndrome are identified; or there is the presence of definite Raynaud's phenomenon, abnormal nail fold capillaries typical of scleroderma and the presence of a specific scleroderma related auto-antibody. Limited skin involvement is defined as skin tightening distal to elbows and knees with or without facial involvement; and diffuse skin involvement, tightening proximal to these joints or truncal involvement.
  • Subjects will be older than 18 years of age with a diagnosis of PAH-SSc.
  • Subjects will be NYHA functional class II or III.
  • 6 minute walk distance ≥ 100 meters and ≤ 500 meters at screening and baseline.
  • Negative urine pregnancy test for women of childbearing age at screening and baseline visits.
  • Ability and willingness to provide written informed consent

Exclusion Criteria:

  • Right heart catheterization reveals evidence of pulmonary venous hypertension (pulmonary capillary wedge pressure > 15 mm Hg).
  • Significant chronic obstructive: Forced expiratory volume in 1 second to forced expiratory volume ratio < 70% and a forced expiratory volume in 1 second less than 60% of predicted.
  • Interstitial lung disease

    1. Based on a combination of pulmonary function tests and chest radiography.
    2. Patients will be excluded if they have a total lung capacity less than 60% of predicted and included if the total lung capacity was ≥ 70%. Patients with a total lung capacity between 60 and 70% of predicted are included if their computed tomography scan demonstrates only minimal interstitial fibrosis
  • Portal hypertension.
  • Severe obstructive sleep apnea.
  • Chronic thromboembolic disease.
  • Positive antibodies to the human immunodeficiency virus.
  • History of anorexigen use including fen-phen.
  • Any other disease known to be associated with pulmonary hypertension.
  • Subjects with other etiology for pulmonary hypertension besides PAH-SSc.
  • Subjects with liver function abnormalities (ALT or Aspartate Aminotransferase (AST) > 3 times the upper limit of normal at screening or at baseline) or chronic liver disease.
  • Advanced kidney failure (GFR < 30 ml/min at screening or at baseline).
  • Acute decompensation of underlying illness or hospitalization for pulmonary hypertension within 4 weeks prior to enrollment.
  • Prior chronic therapy with an endothelin-receptor antagonist, PDE V inhibitor, or a prostacyclin analogue.
  • History of hypersensitivity reaction or adverse effect related to ambrisentan or tadalafil.
  • History of implantable permanent pacemaker or any metallic objects in the body.
  • Participation in a clinical study involving an investigational drug or device within four weeks before the screening visit.
  • Pregnant or lactating women.
  • Concomitant use of nitrates (any form) either regularly or intermittently
  • Concomitant use of potent Cytochrome P3A (CYP3A) inhibitors (eg, ritonavir, ketoconazole, itraconazole)
  • Any additional contraindications and precautions specified in the package inserts for Tadalafil (Adcirca) and Ambrisentan (Letairis) not listed above.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01042158


Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Eli Lilly and Company
United Therapeutics
The Cleveland Clinic
University of Texas
Stanford University
Investigators
Principal Investigator: Paul Hassoun, MD Johns Hopkins University
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT01042158     History of Changes
Other Study ID Numbers: TAD-PH-001
P50HL084946 ( U.S. NIH Grant/Contract )
First Submitted: January 4, 2010
First Posted: January 5, 2010
Results First Submitted: July 13, 2017
Results First Posted: September 12, 2017
Last Update Posted: September 12, 2017
Last Verified: August 2017

Keywords provided by Johns Hopkins University:
Tadalafil
Ambrisentan
Quality of Life

Additional relevant MeSH terms:
Hypertension
Sclerosis
Hypertension, Pulmonary
Familial Primary Pulmonary Hypertension
Scleroderma, Systemic
Scleroderma, Diffuse
Connective Tissue Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Skin Diseases
Tadalafil
Ambrisentan
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Antihypertensive Agents