Conditions: Pulmonary Arterial Hypertension
Keywords: PAH WHO group 1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

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:

1. Establish the Safety of FK506 in patients with PAH.
2. Evaluate the Efficacy of FK506 in PAH
3. 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.

1. 10 patients: FK-506 blood level: 3 - 5 ng/ml
2. 10 patients: FK-506 blood level: 2 - 3 ng/ml
3. 10 patients: FK-506 level: \< 2.0 ng/ml
4. 10 patients: Placebo

Study Duration:

16 weeks

Primary Endpoints:

1\) Safety of low-dose FK506 in PAH

Secondary Objectives/Endpoints:

1. 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.
2. Change in 6MWD at 16 weeks
3. Change in NT-Pro-BNP at 16 weeks
4. Change in Uric Acid at 16 weeks
5. Change in DLCO at 16 weeks
6. Change in novel RV parameters by transthoracic echocardiography: Change in RV size, RA size, RV function, TAPSE, RVSP

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: Placebo intervention 2: FK506 level < 2 ng/ml intervention 3: FK506 level 2-3 ng/ml intervention 4: FK506 level 3-5 ng/ml
Intervention descriptions: intervention 1: placebo pill intervention 2: FK506 goal trough blood level \< 2 ng/ml intervention 3: FK506 goal trough blood level 2-3 ng/ml intervention 4: FK506 goal trough blood level 3-5 ng/ml

Protocol document: