A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
Condition: Pulmonary Arterial Hypertension; Systemic Sclerosis; Scleroderma Spectrum of Diseases; Connective Tissue Disease; Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Scleroderma, Systemic; Scleroderma, Diffuse; Connective Tissue Diseases; Sclerosis
Intervention: tadalafil and ambrisentan upfront combination therapy
Intervention description: 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.
Intervention MeSH terms: Ambrisentan; Tadalafil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Tadalafil; Ambrisentan; Quality of Life

Summary:

      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.
    

Eligibility 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.