FK506 (Tacrolimus) in Pulmonary Arterial Hypertension (TransformPAH)

This study has been terminated.
(Prematurely stopped due to limited funding/slow patient recruitment in single academic center. Follow-up multicenter phase IIb efficacy trial is planned.)
Stanford University
Information provided by (Responsible Party):
Edda Spiekerkoetter, Stanford University Identifier:
First received: July 18, 2012
Last updated: January 5, 2015
Last verified: January 2015

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.

Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: Placebo
Drug: FK506 level < 2 ng/ml
Drug: FK506 level 2-3 ng/ml
Drug: FK506 level 3-5 ng/ml
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Single-Center Randomized Controlled Phase II Study of Safety and Efficacy of FK-506 (Tacrolimus) in Pulmonary Arterial Hypertension

Resource links provided by NLM:

Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Safety of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
    Number of patients with adverse events

Secondary Outcome Measures:
  • Efficacy of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]

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

    • Number of patients who die, who get transplanted, who need escalation of therapies, who have worsening of NYHA/WHO classification by at least 1 point, who require hospitalization for right heart failure.

  • Efficacy of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Change in 6MWD in meter

  • Efficacy of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Change in NT-Pro-BNP at 16 weeks in ng/l

  • Efficacy of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Change in Uric Acid at 16 weeks in micromol/l

  • Efficacy of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    % Change in DLCO at 16 weeks

  • Efficacy of low-dose FK-506 in PAH [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Change in novel RV parameters by echocardiography: Change in RV size in mm, RA size in mm, RV function in percent, TAPSE in cm, RVSP in mmHg

Other Outcome Measures:
  • Biomarkers [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
    Predictive biomarkers of response to treatment

Enrollment: 23
Study Start Date: July 2012
Study Completion Date: August 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo Drug: Placebo
placebo pill
Experimental: FK506 level < 2 Drug: FK506 level < 2 ng/ml
FK506 goal trough blood level < 2 ng/ml
Experimental: FK506 level 2-3 Drug: FK506 level 2-3 ng/ml
FK506 goal trough blood level 2-3 ng/ml
Experimental: FK506 level 3-5 Drug: FK506 level 3-5 ng/ml
FK506 goal trough blood level 3-5 ng/ml

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

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Age ≥ 18 and < 70 years
  2. 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).
  3. 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).
  4. Previous Right Heart Catheterization that documented:

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

Exclusion Criteria:

  1. WHO Group II - V Pulmonary Hypertension.
  2. 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).
  3. Current active treatment with the dual endothelin receptor antagonist bosentan.
  4. TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
  5. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted
  6. Significant left-sided heart disease (based on screening Echocardiogram):

    1. Significant aortic or mitral valve disease
    2. Diastolic dysfunction ≥ Grade II
    3. LV systolic function < 45%
    4. Pericardial constriction
    5. Restrictive cardiomyopathy
    6. Significant coronary disease with demonstrable ischemia.
  7. Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation).
  8. Current atrial arrhythmias not under optimal control.
  9. Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm
  10. Severe hypotension: SBP < 80 mmHg.
  11. Pregnant or breast-feeding.
  12. Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions.
  13. Active cyclosporine use.
  14. Known allergy or hypersensitivity to FK-506.
  15. Planned initiation of cardiac or pulmonary rehabilitation during period of study.
  16. Human Immunodeficiency Virus infection.
  17. Moderate to severe hepatic dysfunction with a Pugh score >10.
  18. Hyperkalemia defined as Potassium > 5.1 mEq/L at screening .
  19. Known active infection requiring antibiotic, antifungal, or antiviral therapies.
  20. 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.
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Please refer to this study by its identifier: NCT01647945

United States, California
Stanford University
Stanford, California, United States, 94305
Sponsors and Collaborators
Edda Spiekerkoetter
Stanford University
Principal Investigator: Edda Spiekerkoetter, MD Stanford University
Principal Investigator: Roham Zamanian, MD Stanford University
  More Information

Additional Information:
Responsible Party: Edda Spiekerkoetter, Assistant Professor of Medicine, Stanford University Identifier: NCT01647945     History of Changes
Other Study ID Numbers: PAH-70522 
Study First Received: July 18, 2012
Last Updated: January 5, 2015
Health Authority: United States: Institutional Review Board

Keywords provided by Stanford University:
PAH WHO group 1

Additional relevant MeSH terms:
Familial Primary Pulmonary Hypertension
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Calcineurin Inhibitors
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs processed this record on May 26, 2016