FK506 (Tacrolimus) in Pulmonary Arterial Hypertension (TransformPAH)
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.
|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 Design:||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|
- 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
- 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
- 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
|Study Start Date:||July 2012|
|Study Completion Date:||August 2014|
|Primary Completion Date:||May 2014 (Final data collection date for primary outcome measure)|
|Placebo Comparator: Placebo||
|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
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
1) Safety of low-dose FK506 in PAH
Combined Clinical Events/Time to Clinical Worsening @ 16 weeks:
- All cause mortality
- 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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01647945
|United States, California|
|Stanford, California, United States, 94305|
|Principal Investigator:||Edda Spiekerkoetter, MD||Stanford University|
|Principal Investigator:||Roham Zamanian, MD||Stanford University|