Pulmonary Arterial Hypertension
Conditions
Brief summary
The main purpose of this clinical trial is to examine the feasibility and effects of fulvestrant in post-menopausal women with pulmonary arterial hypertension (PAH). The study will evaluate how well the drug is tolerated. The study will evaluate changes in circulating hematopoietic progenitor cells, plasma hormone levels, NT-proBNP, and other plasma biomarkers after the administration of fulvestrant. Changes in tricuspid annular plane systolic excursion, stroke volume index, right ventricular fractional area change, and other echo parameters after fulvestrant administration will be evaluated as well as changes in distance walked in six minutes.
Interventions
DRUGFulvestrant
Fulvestrant 500 mg administered intramuscularly into the buttocks slowly as two 5 mL injections, one in each buttock, on days 0, 14, 28 and 56. Fulvestrant 250 mg (one 5 mL injection) will be used in patients with Child-Pugh Class B liver disease.
Sponsors
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Previous documentation of mean pulmonary artery pressure \> 25 mm Hg with a pulmonary capillary wedge pressure (or left ventricular end-diastolic pressure) \< 16 mm Hg and pulmonary vascular resistance \> 3 WU at any time before study entry. * Diagnosis of PAH which is idiopathic, heritable, drug- or toxin-induced, or associated with connective tissue disease, congenital heart disease, portal hypertension, or HIV infection. * Most recent pulmonary function tests with FEV1/FVC \>50% AND either a) total lung capacity \> 70% predicted or b) total lung capacity between 60% and 70% predicted with no more than mild interstitial lung disease on computerized tomography scan of the chest. * Female, post-menopausal state, defined as: * \> 50 years old and a) have not menstruated during the preceding 12 months or b) have follicle-stimulating hormone (FSH) levels \> 40 IU/L or * \< 50 years and FSH \> 40 IU/L or * having had a bilateral oophorectomy. * Informed consent.
Exclusion criteria
* Age \< 18. * Treatment with estrogen or anti-hormone therapy (tamoxifen, anastrozole, etc.) * WHO Class IV functional status. * History of breast cancer. * Clinically significant untreated sleep apnea. * Left-sided valvular disease (more than moderate mitral valve stenosis or insufficiency or aortic stenosis or insufficiency), pulmonary artery or valve stenosis, or ejection fraction \< 45% on echocardiography. * Initiation of PAH therapy (prostacyclin analogues or receptor agonists, endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators) within three months of enrollment; the dose must be stable for at least 3 months prior to Baseline Visit. PAH therapy which is stopped and then restarted or has dose changes which are not related to initiation and uptitration will be allowed within 3 months prior to the Baseline Visit. * Hormone therapy. * Use of warfarin or other anticoagulant (use of aspirin is permitted). * Platelet count \<100,000. * Renal failure (creatinine \>/= 2.0). * Child-Pugh Class C cirrhosis. * Current or recent (\< 6 months) chronic heavy alcohol consumption. * Current use of another investigational drug (non-FDA approved) for PAH.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline of Plasma Estradiol Levels | Baseline to 9 weeks | Plasma estradiol levels are obtained and measured from blood samples collected from each participant. Difference in change from baseline to 9 weeks in plasma estradiol levels |
| Change From Baseline of Tricuspid Annular Plane Systolic Excursion (TAPSE) | Baseline to 9 weeks | Measure obtained from echocardiogram completed on participants Difference in change from baseline to 9 weeks in TAPSE |
| Change From Baseline of Six Minute Walk Distance | Baseline to 9 weeks | Measure obtained from six minute walk test completed by participants Difference in change from baseline to 9 weeks in the six minute walk test distance |
| Change From Baseline of Plasma NT-proBNP Level | Baseline to 9 weeks | Plasma NT-proBNP levels are obtained and measured from blood samples collected from each participant. Difference in change from baseline to 9 weeks in plasma NT-proBNP levels |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fulvestrant 500 mg administered intramuscularly (as two 5 mL injections) on days 0, 14, 28 and 56
Fulvestrant: Fulvestrant 500 mg administered intramuscularly into the buttocks slowly as two 5 mL injections, one in each buttock, on days 0, 14, 28 and 56. Fulvestrant 250 mg (one 5 mL injection) will be used in patients with Child-Pugh Class B liver disease. | 5 |
| Total | 5 |
Baseline characteristics
| Characteristic | Fulvestrant |
|---|---|
| Age, Continuous | 55 years |
| Childs-Pugh Class A | 5 Participants |
| Childs-Pugh Class B or C | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 5 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 0 Participants |
| World Health Organization functional class Class I | 0 Participants |
| World Health Organization functional class Class II | 4 Participants |
| World Health Organization functional class Class III | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 5 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
Change From Baseline of Plasma Estradiol Levels
Plasma estradiol levels are obtained and measured from blood samples collected from each participant. Difference in change from baseline to 9 weeks in plasma estradiol levels
Time frame: Baseline to 9 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant | Change From Baseline of Plasma Estradiol Levels | -1.26 pg/ml |
Primary
Change From Baseline of Plasma NT-proBNP Level
Plasma NT-proBNP levels are obtained and measured from blood samples collected from each participant. Difference in change from baseline to 9 weeks in plasma NT-proBNP levels
Time frame: Baseline to 9 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant | Change From Baseline of Plasma NT-proBNP Level | 42.1 pg/ml |
Primary
Change From Baseline of Six Minute Walk Distance
Measure obtained from six minute walk test completed by participants Difference in change from baseline to 9 weeks in the six minute walk test distance
Time frame: Baseline to 9 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant | Change From Baseline of Six Minute Walk Distance | 31 meters |
Primary
Change From Baseline of Tricuspid Annular Plane Systolic Excursion (TAPSE)
Measure obtained from echocardiogram completed on participants Difference in change from baseline to 9 weeks in TAPSE
Time frame: Baseline to 9 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fulvestrant | Change From Baseline of Tricuspid Annular Plane Systolic Excursion (TAPSE) | 2 millimeter |