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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Eli Lilly and Company
Johns Hopkins University
The Cleveland Clinic
University of Texas
Information provided by (Responsible Party):
UT Clinical Records Management, United Therapeutics
ClinicalTrials.gov Identifier:
NCT01042158
First received: January 4, 2010
Last updated: July 16, 2014
Last verified: July 2014
  Purpose

This will be a 36-week, randomized, double-blind, parallel group study comparing the effects of tadalafil monotherapy, ambrisentan monotherapy and combination therapy with tadalafil and ambrisentan in patients with PAH-SSc. Standard outcome measures such as six-minute walk distance (6MWD), 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-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 monotherapy
Drug: Ambrisentan monotherapy
Drug: tadalafil and ambrisentan
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
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 United Therapeutics:

Primary Outcome Measures:
  • To compare the effects of ambrisentan monotherapy, tadalafil monotherapy and the combination in patients with PAH-SSc on right ventricular mass as assessed by cardiac MRI and pulmonary vascular resistance (PVR) by right heart catheterization. [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To evaluate the safety of combination therapy with ambrisentan and tadalafil in PAH-SSc. [ Time Frame: 36 weeks ] [ Designated as safety issue: Yes ]
  • To compare the change in: i. 6 MWD ii. Resting hemodynamics iii. Pressure/flow slopes with submaximal exercise iv. TAPSE by echocardiography v. Heart rate variability vi. Quality of life vii. Borg score viii. NYHA class [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 63
Study Start Date: January 2010
Estimated Study Completion Date: February 2015
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tadalafil monotherapy Drug: Tadalafil monotherapy
tadalafil 20 mg once daily (qd) and placebo qd. Up-titration of study medications will occur at week 4 (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. If the subject is still experiencing an intolerable adverse event, then the investigator will withdraw the subject from the study.
Other Name: Adcirca
Active Comparator: Ambrisentan monotherapy Drug: Ambrisentan monotherapy
ambrisentan 5 mgs daily and placebo qd. Up-titration of study medications will occur at week 4 (ambrisentan 10 mgs daily). 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 5mg of ambrisentan. If the subject is still experiencing an intolerable adverse event, then the investigator will withdraw the subject from the study.
Other Name: Letairis
Active Comparator: Tadalafil and ambrisentan Drug: tadalafil and ambrisentan
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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. 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.
  3. Subjects will be older than 18 years of age with a diagnosis of PAH-SSc.
  4. Subjects will be NYHA functional class II or III.
  5. 6 minute walk distance ≥ 100 meters and ≤ 500 meters at screening and baseline.
  6. Negative urine pregnancy test for women of childbearing age at screening and baseline visits.
  7. Ability and willingness to provide written informed consent

Exclusion Criteria:

  1. Right heart catheterization reveals evidence of pulmonary venous hypertension (pulmonary capillary wedge pressure > 15 mm Hg).
  2. 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.
  3. 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
  4. Portal hypertension.
  5. Severe obstructive sleep apnea.
  6. Chronic thromboembolic disease.
  7. Positive antibodies to the human immunodeficiency virus.
  8. History of anorexigen use including phen-fen.
  9. Any other disease known to be associated with pulmonary hypertension.
  10. Subjects with other etiology for pulmonary hypertension besides PAH-SSc.
  11. Subjects with liver function abnormalities (ALT or AST > 3 times the upper limit of normal at screening or at baseline) or chronic liver disease.
  12. Advanced kidney failure (GFR < 30 ml/min at screening or at baseline).
  13. Acute decompensation of underlying illness or hospitalization for pulmonary hypertension within 4 weeks prior to enrollment.
  14. Prior chronic therapy with an endothelin-receptor antagonist, PDE V inhibitor, or a prostacyclin analogue.
  15. History of hypersensitivity reaction or adverse effect related to ambrisentan or tadalafil.
  16. History of implantable permanent pacemaker or any metallic objects in the body.
  17. Participation in a clinical study involving an investigational drug or device within four weeks before the screening visit.
  18. Pregnant or lactating women.
  19. Concomitant use of nitrates (any form) either regularly or intermittently
  20. Concomitant use of potent CYP3A inhibitors (eg, ritonavir, ketoconazole, itraconazole)
  21. Any additional contraindications and precautions specified in the package inserts for Tadalafil (Adcirca) and Ambrisentan (Letairis) not listed above.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01042158

Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
United Therapeutics
Eli Lilly and Company
Johns Hopkins University
The Cleveland Clinic
University of Texas
Investigators
Principal Investigator: Paul Hassoun, MD Johns Hopkins University
  More Information

No publications provided

Responsible Party: UT Clinical Records Management, Paul Hassoun, MD, Johns Hopkins University, United Therapeutics
ClinicalTrials.gov Identifier: NCT01042158     History of Changes
Other Study ID Numbers: TAD-PH-001, P50HL084946
Study First Received: January 4, 2010
Last Updated: July 16, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by United Therapeutics:
Tadalafil
Ambrisentan
Quality of Life

Additional relevant MeSH terms:
Hypertension, Pulmonary
Connective Tissue Diseases
Scleroderma, Systemic
Scleroderma, Diffuse
Hypertension
Sclerosis
Lung Diseases
Respiratory Tract Diseases
Skin Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Tadalafil
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014