FK506 (Tacrolimus) in Pulmonary Arterial Hypertension

Study Design:

Randomized, placebo-controlled, four arm clinical trial.

Sample Size: 10 subjects in each arm, Total enrollment = 40 patients.

• 10 patients: FK-506 blood level: 3 - 5 ng/ml
• 10 patients: FK-506 blood level: 2 - 3 ng/ml
• 10 patients: FK-506 level: < 2.0 ng/ml
• 10 patients: Placebo

Study Duration:

16 weeks

Primary Endpoints:

• Safety of low-dose FK506 in PAH

Secondary Objectives/Endpoints:

• Combined Clinical Events/Time to Clinical Worsening @ 16 weeks:

• All cause mortality
• Transplantation
• Atrial septostomy
• Need for escalation of therapies as deemed by site investigator
• Worsening of NYHA/WHO classification by at least 1 point.
• Hospitalization for right heart failure.
• Change in 6MWD at 16 weeks
• Change in NT-Pro-BNP at 16 weeks
• Change in Uric Acid at 16 weeks
• Change in DLCO at 16 weeks
• Change in novel RV parameters by transthoracic echocardiography: Change in RV size, RA size, RV function, TAPSE, RVSP

Inclusion criteria

• Age ≥ 18 and < 70 years
• Diagnosis of WHO Group I Pulmonary Arterial Hypertension (PAH) (Idiopathic (I)PAH, Heritable PAH (including Hereditary Hemorrhagic Telangiectasia), Associated (A)PAH (including collagen vascular disorders, drugs+toxins exposure, congenital heart disease, and portopulmonary disease).
• Stable on active PAH treatment including any prostacycline or phosphodiesterase inhibitors and the endothelin antagonist Ambrisentan alone or in combination (stability defined as: <10% change in 6MWD, no change in NYHA class, no hospitalization or addition of PAH therapy for at least 3 months).
• Previous Right Heart Catheterization that documented:

• Mean PAP ≥ 25 mmHg.
• Pulmonary capillary wedge pressure < 15 mmHg.
• Pulmonary Vascular Resistance ≥ 3.0 Wood units or 240 dynes/sec/cm5
• WHO functional class I to IV as judged by the investigator.

Exclusion criteria

• WHO Group II - V Pulmonary Hypertension.
• Current or prior experimental PAH treatments within the last 6 months (including but not limited to tyrosine kinase inhibitors, rho-kinase inhibitors, or cGMP modulators).
• Current active treatment with the dual endothelin receptor antagonist bosentan.
• TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
• FEV1 / FVC < 70% predicted and FEV1 < 60% predicted
• Significant left-sided heart disease (based on screening Echocardiogram):

• Significant aortic or mitral valve disease
• Diastolic dysfunction ≥ Grade II
• LV systolic function < 45%
• Pericardial constriction
• Restrictive cardiomyopathy
• Significant coronary disease with demonstrable ischemia.
• Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation).
• Current atrial arrhythmias not under optimal control.
• Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm
• Severe hypotension: SBP < 80 mmHg.
• Pregnant or breast-feeding.
• Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions.
• Active cyclosporine use.
• Known allergy or hypersensitivity to FK-506.
• Planned initiation of cardiac or pulmonary rehabilitation during period of study.
• Human Immunodeficiency Virus infection.
• Moderate to severe hepatic dysfunction with a Pugh score >10.
• Hyperkalemia defined as Potassium > 5.1 mEq/L at screening .
• Known active infection requiring antibiotic, antifungal, or antiviral therapies.
• Co-morbid conditions that would impair a patient's exercise performance and ability to assess WHO functional class, including but not limited to chronic low-back pain or peripheral musculoskeletal problems.