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FK506 (Tacrolimus) in Pulmonary Arterial Hypertension (TransformPAH)

Primary Purpose

Pulmonary Arterial Hypertension

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Placebo

FK506 level < 2 ng/ml

FK506 level 2-3 ng/ml

FK506 level 3-5 ng/ml

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring PAH WHO group 1

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age ≥ 18 and < 70 years
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).
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).
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
WHO functional class I to IV as judged by the investigator.

Exclusion Criteria:

WHO Group II - V Pulmonary Hypertension.
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).
Current active treatment with the dual endothelin receptor antagonist bosentan.
TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease.
FEV1 / FVC < 70% predicted and FEV1 < 60% predicted
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.
Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation).
Current atrial arrhythmias not under optimal control.
Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm
Severe hypotension: SBP < 80 mmHg.
Pregnant or breast-feeding.
Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions.
Active cyclosporine use.
Known allergy or hypersensitivity to FK-506.
Planned initiation of cardiac or pulmonary rehabilitation during period of study.
Human Immunodeficiency Virus infection.
Moderate to severe hepatic dysfunction with a Pugh score >10.
Hyperkalemia defined as Potassium > 5.1 mEq/L at screening .
Known active infection requiring antibiotic, antifungal, or antiviral therapies.
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.

Sites / Locations

Stanford University

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

FK506 level < 2

FK506 level 2-3

FK506 level 3-5

Arm Description

Outcomes

Primary Outcome Measures

Safety of Low-dose FK-506 in PAH

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

Number of Combined Clinical Events

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

Efficacy of Low-dose FK-506 in Pulmonary Arterial Hypertension (PAH) Measured by Change in 6-min Walk Distance (6MWD)

Change in 6MWD in meter between baseline and 16 weeks A large number would indicate an increase in exercise capacity

Full Information

NCT ID

NCT01647945

First Posted

July 18, 2012

Last Updated

August 11, 2016

Sponsor

Edda Spiekerkoetter

Collaborators

Stanford University

1. Study Identification

Unique Protocol Identification Number

NCT01647945

Brief Title

FK506 (Tacrolimus) in Pulmonary Arterial Hypertension

Acronym

TransformPAH

Official Title

Single-Center Randomized Controlled Phase II Study of Safety and Efficacy of FK-506 (Tacrolimus) in Pulmonary Arterial Hypertension

Study Type

Interventional

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Completed

Study Start Date

July 2012 (undefined)

Primary Completion Date

May 2014 (Actual)

Study Completion Date

August 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Edda Spiekerkoetter

Collaborators

Stanford University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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: Establish the Safety of FK506 in patients with PAH. Evaluate the Efficacy of FK506 in PAH 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. 10 patients: FK-506 blood level: 3 - 5 ng/ml 10 patients: FK-506 blood level: 2 - 3 ng/ml 10 patients: FK-506 level: < 2.0 ng/ml 10 patients: Placebo Study Duration: 16 weeks Primary Endpoints: 1) Safety of low-dose FK506 in PAH Secondary Objectives/Endpoints: 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. Change in 6MWD at 16 weeks Change in NT-Pro-BNP at 16 weeks Change in Uric Acid at 16 weeks Change in DLCO at 16 weeks Change in novel RV parameters by transthoracic echocardiography: Change in RV size, RA size, RV function, TAPSE, RVSP

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Arterial Hypertension

Keywords

PAH WHO group 1

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

23 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Title

FK506 level < 2

Arm Type

Experimental

Arm Title

FK506 level 2-3

Arm Type

Experimental

Arm Title

FK506 level 3-5

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

placebo pill

Intervention Type

Drug

Intervention Name(s)

FK506 level < 2 ng/ml

Intervention Description

FK506 goal trough blood level < 2 ng/ml

Intervention Type

Drug

Intervention Name(s)

FK506 level 2-3 ng/ml

Intervention Description

FK506 goal trough blood level 2-3 ng/ml

Intervention Type

Drug

Intervention Name(s)

FK506 level 3-5 ng/ml

Intervention Description

FK506 goal trough blood level 3-5 ng/ml

Primary Outcome Measure Information:

Title

Safety of Low-dose FK-506 in PAH

Description

Time Frame

18 weeks

Secondary Outcome Measure Information:

Title

Number of Combined Clinical Events

Description

Time Frame

Baseline to 16 weeks

Title

Efficacy of Low-dose FK-506 in Pulmonary Arterial Hypertension (PAH) Measured by Change in 6-min Walk Distance (6MWD)

Description

Change in 6MWD in meter between baseline and 16 weeks A large number would indicate an increase in exercise capacity

Time Frame

baseline to 16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥ 18 and < 70 years 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). 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). Previous Right Heart Catheterization that documented: Mean PAP ≥ 25 mmHg. Pulmonary capillary wedge pressure < 15 mmHg. Pulmonary Vascular Resistance ≥ 3.0 Wood units or 240 dynes/sec/cm5 WHO functional class I to IV as judged by the investigator. Exclusion Criteria: WHO Group II - V Pulmonary Hypertension. 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). Current active treatment with the dual endothelin receptor antagonist bosentan. TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted Significant left-sided heart disease (based on screening Echocardiogram): Significant aortic or mitral valve disease Diastolic dysfunction ≥ Grade II LV systolic function < 45% Pericardial constriction Restrictive cardiomyopathy Significant coronary disease with demonstrable ischemia. Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation). Current atrial arrhythmias not under optimal control. Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm Severe hypotension: SBP < 80 mmHg. Pregnant or breast-feeding. Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions. Active cyclosporine use. Known allergy or hypersensitivity to FK-506. Planned initiation of cardiac or pulmonary rehabilitation during period of study. Human Immunodeficiency Virus infection. Moderate to severe hepatic dysfunction with a Pugh score >10. Hyperkalemia defined as Potassium > 5.1 mEq/L at screening . Known active infection requiring antibiotic, antifungal, or antiviral therapies. 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Edda Spiekerkoetter, MD

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Roham Zamanian, MD

Organizational Affiliation

Stanford University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Stanford University

City

Stanford

State/Province

California

ZIP/Postal Code

94305

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

28893866

Citation

Spiekerkoetter E, Sung YK, Sudheendra D, Scott V, Del Rosario P, Bill M, Haddad F, Long-Boyle J, Hedlin H, Zamanian RT. Randomised placebo-controlled safety and tolerability trial of FK506 (tacrolimus) for pulmonary arterial hypertension. Eur Respir J. 2017 Sep 11;50(3):1602449. doi: 10.1183/13993003.02449-2016. Print 2017 Sep.

Results Reference

derived

Links:

URL

http://wallcenter.stanford.edu

Description

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FK506 (Tacrolimus) in Pulmonary Arterial Hypertension

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