FK506 (Tacrolimus) in Pulmonary Arterial Hypertension (TransformPAH)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified July 2012 by Stanford University.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Stanford University
Information provided by (Responsible Party):
Edda Spiekerkoetter, Stanford University
ClinicalTrials.gov Identifier:
NCT01647945
First received: July 18, 2012
Last updated: July 19, 2012
Last verified: July 2012
  Purpose

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


Estimated Enrollment: 40
Study Start Date: July 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 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
  Eligibility

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

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01647945

Contacts
Contact: Val Scott, RN (650) 725-8082 valscott@stanford.edu
Contact: Patricia Del Rosario, RN (650) 721-2408 pdelrosa@stanford.edu

Locations
United States, California
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Edda Spiekerkoetter, MD    650-724-1493    eddas@stanford.edu   
Principal Investigator: Edda Spiekerkoetter, MD         
Principal Investigator: Roham Zamanian, MD         
Sponsors and Collaborators
Edda Spiekerkoetter
Stanford University
Investigators
Principal Investigator: Edda Spiekerkoetter, MD Stanford University
Principal Investigator: Roham Zamanian, MD Stanford University
  More Information

Additional Information:
No publications provided

Responsible Party: Edda Spiekerkoetter, Assistant Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT01647945     History of Changes
Other Study ID Numbers: PAH-70522
Study First Received: July 18, 2012
Last Updated: July 19, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Stanford University:
PAH WHO group 1

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Tacrolimus
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 22, 2014