FK506 (Tacrolimus) in Pulmonary Arterial Hypertension

NCT01647945 | Completed Phase 2 Results DMC

• 1 other identifier: PAH-70522
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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. 1.Establish the Safety of FK506 in patients with PAH.
2. 2.Evaluate the Efficacy of FK506 in PAH
3. 3.Identify ideal candidates for future FK506 phase III clinical trial.

Conditions

Pulmonary Arterial Hypertension

Keywords

PAH WHO group 1

Outcome Measures

Primary Outcomes (1)

• 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

  18 weeks

Secondary Outcomes (2)

• Number of Combined Clinical Events

  Baseline to 16 weeks

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

  baseline to 16 weeks

Study Arms (4)

Placebo

PLACEBO COMPARATOR

Drug: Placebo

FK506 level < 2

EXPERIMENTAL

Drug: FK506 level < 2 ng/ml

FK506 level 2-3

EXPERIMENTAL

Drug: FK506 level 2-3 ng/ml

FK506 level 3-5

EXPERIMENTAL

Drug: FK506 level 3-5 ng/ml

Interventions

Placebo DRUG

placebo pill

Placebo

FK506 level < 2 ng/ml DRUG

FK506 goal trough blood level \< 2 ng/ml

FK506 level < 2

FK506 level 2-3 ng/ml DRUG

FK506 goal trough blood level 2-3 ng/ml

FK506 level 2-3

FK506 level 3-5 ng/ml DRUG

FK506 goal trough blood level 3-5 ng/ml

FK506 level 3-5

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Edda Spiekerkoetter: lead
• Stanford University: collaborator

Study Sites (1)

Stanford University

Stanford, California, 94305, United States

Location

Related Publications (1)

• 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.

  PMID: 28893866 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

Due to slow patient recruitment in single academic center we recruited fewer patients than originally expected. Follow-up multicenter phase IIb efficacy trial is planned

Results Point of Contact

• Title: Dr. Edda Spiekerkoetter
• Organization: Stanford University

eddas@stanford.edu

650-724-1493

Study Officials

• Edda Spiekerkoetter, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

• Roham Zamanian, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: July 18, 2012
• First Posted: July 24, 2012
• Study Start: July 1, 2012
• Primary Completion: May 1, 2014
• Study Completion: August 1, 2014
• Last Updated: October 5, 2016
• Results First Posted: October 5, 2016

Record last verified: 2016-08

Locations

US (1)