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

Pulmonary Arterial Hypertension (PAH) includes a heterogeneous group of clinical entities
sharing similar clinical and pathological features that have been subcategorized as
idiopathic PAH (IPAH, formerly known as "primary pulmonary hypertension" or PPH), familial
PAH, pulmonary hypertension related to connective tissue diseases (such as systemic
sclerosis), portopulmonary hypertension and pulmonary hypertension related to HIV infection,
drugs and toxins (10). PAH is clinically defined by a resting mean pulmonary artery
pressure ≥ 25 mmHg and pulmonary artery wedge pressure ≤ 15 mmHg in the absence of left
heart disease, underlying parenchymal lung disease, thromboembolic disease or other causes
of pulmonary hypertension.

PAH is characterized by increased pulmonary vascular resistance due to remodeling and
occlusion of the pulmonary arterioles. Left untreated, PAH leads irremediably to right
ventricular (RV) hypertrophy, pressure overload and dilation resulting in death within 2-3
years (11). For the past two decades, it has been appreciated that the integrity of the RV
function, rather than the degree of pulmonary vascular injury, is the major determinant of
symptoms and mortality in patients with PAH. RV dysfunction at time of presentation, as
reflected by an elevation in right atrial pressure (RAP), the presence of pericardial
effusion or depressed cardiac output (CO), is a powerful prognosticator of death (12).

Current PAH therapies consist of prostacyclin analogues, endothelin receptor antagonists
(ETRA) and phosphodiesterase type V (PDE V) inhibitors (13). All have been shown to be
effective in improving exercise capacity as measured by the 6 MWD in short term (12 - 16
week) randomized, placebo-controlled clinical trials. However, the clinical response is
highly variable and mortality remains high (14). Moreover, the majority of subjects enrolled
in these trials have had IPAH. Over the past 10 years, the Johns Hopkins Pulmonary
Hypertension Program and Scleroderma Center have worked closely to address the daunting
clinical challenge of PAH associated with scleroderma or systemic sclerosis (PAH-SSc).
Previous work from our group (15;16) and others (17-19) has clearly demonstrated a markedly
worse prognosis in PAH-SSc compared with IPAH despite similar treatments. An intriguing and
consistent finding when comparing these two groups is that whereas mPAP is, on average,
lower in PAH-SSc, markers of RV dysfunction (e.g. CO and RAP) are similar, raising the
possibility of maladaptive RV response to pressure overload and/or intrinsic myocardial
disease. Current PAH therapies target pathways that have been implicated in the remodeling
of the pulmonary vasculature (PV). However, there is no clear evidence that these therapies
have altered PV and/or RV remodeling or offered significant beneficial effects in patients
with PAH-SSc in whom mortality remains exceedingly high. In addition, their effects on RV
dysfunction and RV-PV interaction remain poorly characterized.

We hypothesize that improvement in PAH-SSc will only be achieved with therapy directly
targeted at RV-PV dysfunction. Sildenafil and tadalafil inhibit phosphodiesterase type 5
(PDE5) which is abundant in the lung and is the main enzyme responsible for cGMP hydrolysis.
The resulting increase in cGMP probably mediates the relaxant and anti-hypertrophic actions
of nitric oxide and natriuretic peptides in vascular tissues, and exerts a direct
anti-hypertrophic action on cardiac muscle as demonstrated in compelling preliminary
experiments by investigators of the NHLBI-funded Hopkins Scientific Center of Clinically
Oriented Research (SCCOR) in Pulmonary Vascular Disease. In these experiments, sildenafil
was capable of preventing and reversing RV hypertrophy and dysfunction in a model of
pulmonary artery banding, similar to its effects on the left ventricle with aortic banding
(20), indicating a direct beneficial action on RV remodeling.

Both sildenafil (21) and tadalafil (22) have been demonstrated to be effective in PAH and
are FDA approved for this indication. The endothelin-receptor antagonists, bosentan (23) and
ambrisentan (24), are also FDA-labeled for this indication and represent alternative options
for oral therapy of PAH (25). A small randomized study comparing sildenafil with bosentan
suggested that sildenafil was superior in reducing RV mass and improving exercise capacity
in patients with PAH (26). Recently, the results of a large multi-center randomized,
controlled trial of tadalafil therapy for PAH have been presented. The data indicate, that
similar to sildenafil, tadalafil at doses of 20 and 40 mg per day, improved exercise
capacity. In addition, tadalafil 40 mg per day improved pulmonary hemodynamics, quality of
life and reduced the incidence of clinical worsening.

This study aims to compare the effects of tadalafil therapy, ambrisentan therapy and the
combination of both agents in PAH-SSc on PVR and RV mass. It will also assess novel markers
of RV function by cardiac MRI and echocardiography, as well as the conventional endpoints,
including 6 MWD and functional class. The trial is unique in that it will enroll only
PAH-SSc patients, the PAH subgroup with the poorest outcomes and will be considerably longer
in duration (36 weeks) than previous studies. In addition, the effects of first line
combination therapy with an ETRA/PDE V inhibitor will be compared with single agent
regimens.

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.