FK506 (Tacrolimus) in Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Study type: Interventional
Phase: Phase 2

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
    

Intervention name(s): Placebo; FK506 level < 2 ng/ml; FK506 level 2-3 ng/ml; FK506 level 3-5 ng/ml
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): placebo pill; FK506 goal trough blood level < 2 ng/ml; FK506 goal trough blood level 2-3 ng/ml; FK506 goal trough blood level 3-5 ng/ml
Intervention MeSH terms: Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: PAH WHO group 1