FK506 (Tacrolimus) in Pulmonary Arterial Hypertension

Study Overview
=================
Brief Summary
-----------------
Mutations in bone morphogenetic protein receptor 2 (BMPR2) are present in >80% of familial and  20% of sporadic pulmonary arterial hypertension (PAH) patients. Furthermore dysfunctional BMP signaling is a general feature of pulmonary hypertension even in non-familial PAH. We therefore hypothesized that increasing BMP signaling might prevent and reverse the disease. We screened > 3500 FDA approved drugs for their propensity to increase BMP signaling and found FK506 (Tacrolimus) to be a strong activator of BMP signaling. Tacrolimus restored normal function of pulmonary artery endothelial cells, prevented and reversed experimental PAH in mice and rats. Given that Tacrolimus is already FDA approved with a known side-effect profile, it is an ideal candidate drug to use in patients with pulmonary arterial hypertension. The aims of our trial are: Establish the Safety of FK506 in patients with PAH. Evaluate the Efficacy of FK506 in PAH Identify ideal candidates for future FK506 phase III clinical trial.

Detailed Description
-----------------
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: 1) 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

Official Title
-----------------
Single-Center Randomized Controlled Phase II Study of Safety and Efficacy of FK-506 (Tacrolimus) in Pulmonary Arterial Hypertension

Conditions
-----------------
Pulmonary Arterial Hypertension

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: FK506 level < 2 ng/ml
* Drug: FK506 level 2-3 ng/ml
* Drug: FK506 level 3-5 ng/ml


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* placebo pill<br>|
| Experimental: FK506 level < 2<br> | Drug: FK506 level < 2 ng/ml<br>* FK506 goal trough blood level < 2 ng/ml<br>|
| Experimental: FK506 level 2-3<br> | Drug: FK506 level 2-3 ng/ml<br>* FK506 goal trough blood level 2-3 ng/ml<br>|
| Experimental: FK506 level 3-5<br> | Drug: FK506 level 3-5 ng/ml<br>* FK506 goal trough blood level 3-5 ng/ml<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Low-dose FK-506 in PAH | Total number of adverse events measured between baseline and end of study at 18 weeks as reported by study subjects such as nausea/diarrhea, URI, sinus congestion, infection, fluid retention/edema, cough, headache, bronchitis, fatigue, drug reaction/hives, flushing, anxiety, tremor, fever, shingles, SOB, insomnia, pain | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Combined Clinical Events | Combined Clinical Events @ 16 weeks: Number of patients who died Number of patients who got transplanted Number of patients who needed escalation of therapies Number of patients who had worsening of NYHA/WHO classification by at least 1 point Number of patients who require hospitalization for right heart failure Low numbers would suggest either efficacy of the study drug or slowly progression of disease that is studied during the 16 week study period or short observation period or small study population | Baseline to 16 weeks | 
| Efficacy of Low-dose FK-506 in Pulmonary Arterial Hypertension (PAH) Measured by Change in 6-min Walk Distance (6MWD) | Change in 6MWD in meter between baseline and 16 weeks A large number would indicate an increase in exercise capacity | baseline to 16 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PAH WHO group 1