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Trial record 1 of 1 for:    NCT01647945
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FK506 (Tacrolimus) in Pulmonary Arterial Hypertension (TransformPAH)

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ClinicalTrials.gov Identifier: NCT01647945
Recruitment Status : Completed
First Posted : July 24, 2012
Results First Posted : October 5, 2016
Last Update Posted : October 5, 2016
Stanford University
Information provided by (Responsible Party):
Edda Spiekerkoetter, Stanford University

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.

Condition or disease Intervention/treatment 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

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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
Study Start Date : July 2012
Actual Primary Completion Date : May 2014
Actual Study Completion Date : August 2014

Arm Intervention/treatment
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

Primary Outcome Measures :
  1. Safety of Low-dose FK-506 in PAH [ Time Frame: 18 weeks ]
    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

Secondary Outcome Measures :
  1. Number of Combined Clinical Events [ Time Frame: Baseline to 16 weeks ]

    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

  2. Efficacy of Low-dose FK-506 in Pulmonary Arterial Hypertension (PAH) Measured by Change in 6-min Walk Distance (6MWD) [ Time Frame: baseline to 16 weeks ]

    Change in 6MWD in meter between baseline and 16 weeks

    A large number would indicate an increase in exercise capacity

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01647945

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United States, California
Stanford University
Stanford, California, United States, 94305
Sponsors and Collaborators
Edda Spiekerkoetter
Stanford University
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Principal Investigator: Edda Spiekerkoetter, MD Stanford University
Principal Investigator: Roham Zamanian, MD Stanford University
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Edda Spiekerkoetter, Assistant Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT01647945    
Other Study ID Numbers: PAH-70522
First Posted: July 24, 2012    Key Record Dates
Results First Posted: October 5, 2016
Last Update Posted: October 5, 2016
Last Verified: August 2016
Keywords provided by Edda Spiekerkoetter, Stanford University:
PAH WHO group 1
Additional relevant MeSH terms:
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Pulmonary Arterial Hypertension
Familial Primary Pulmonary Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action