Pulmonary Arterial Hypertension
Conditions
Keywords
Randomized Controlled Trial, clinical trial, anastrozole, pulmonary hypertension, pulmonary arterial hypertension, PAH
Brief summary
The primary objectives of this study are to determine whether the study drug, anastrozole may improve six minute walk distance at six months compared to placebo and to assess safety and side effects up to twelve months in pulmonary arterial hypertension (PAH).
Interventions
DRUGAnastrozole
Anastrozole is an aromatase inhibitor indicated for: * adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer * first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer * treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.
DRUGPlacebo Oral Tablet
matching placebo tablet
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins University
University of Colorado, Denver
Rhode Island Hospital
Stanford University
Vanderbilt University
Washington University School of Medicine
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
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 PVR \> 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 and receiving treatment for PAH. * 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. * Ability to perform six minute walk testing without significant limitations in musculoskeletal function or coordination. * If 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. * Current treatment with estrogen, hormone therapy, or anti-hormone therapy (tamoxifen, fulvestrant, etc.) * WHO Class IV functional status. * History of invasive 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 most recent echocardiography (within 1 year). * Initiation of PAH therapy (prostacyclin analogues, endothelin-1 receptor antagonists, phosphodiesterase-5 inhibitors, riociguat, selexipag) within three months of enrollment; the dose must be stable for at least three 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. * Hospitalized or acutely ill. * Renal failure (creatinine ≥ 2.0). * Hypercalcemia. * Severe osteoporosis: T score -2.5 to -3.4 without bone modifying treatment OR T score = - 3.5 or lower * Child-Pugh Class C cirrhosis. * Current or recent (\< 3 months) chronic heavy alcohol consumption. * Enrollment in a clinical trial or concurrent use of another investigational drug or device within 30 days of screening visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Six-minute Walk Distance | 6 months | Change in the distance walked in six minutes adjusted for baseline value and sex |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma NT-proBNP | 6months | Change in log10 NT-proBNP adjusted for baseline value and sex |
| Change in the Medical Outcomes Study Questionnaire Short Form-36 (SF36) Physical Component Summary (PCS) Score Adjusted for Baseline Value and Sex. | 6months | Change in the Medical Outcomes Study Questionnaire Short Form-36 (SF36) physical component summary (PCS) score adjusted for baseline value and sex. SF36 PCS score is a subjective measure of physical health status, with scores ranging from 0 to 100. Higher scores represent better health status. |
| Change in the emPHasis-10 Score Adjusted for Baseline Value and Sex | 6months | Change in the emPHasis-10 score adjusted for baseline value and sex. EmPHasis-10 is a pulmonary hypertension-specific measure of quality of life which is scored from 0-50, with higher scores indicating worse quality of life. |
| Change in Right Ventricular Function: Tricuspid Annular Systolic Plane Excursion (TAPSE) | 6 months | Change in tricuspid annular systolic plane excursion (TAPSE) adjusted for baseline value and sex. TAPSE is a measure of right ventricular function that is measured via cardiac echography |
| Number of Participants With a Clinical Worsening Event Between Anastrozole and Placebo Groups | 12 months | Number of participants with a clinical worsening event. Clinical worsening was defined as the addition of new PAH therapies or dose increases in previously stable PAH therapy for increased symptoms, hospitalization for PAH progression and/or right-sided heart failure, lung transplantation, atrial septostomy, or all-cause death.' Unit of Measure is retained as 'Participants. |
| Change in Bone Mineral Density: Lumbar Spine Between Anastrozole and Placebo Groups | 12 months | Change in lumbar spine bone mineral density adjusted for baseline value and sex between anastrozole and placebo groups |
| Change in Actigraphy-measured Physical Activity: Change in 7-day Median Daily Vector Magnitude Count | 6months | Actigraphy-measured vector magnitude count is an estimate of physical activity intensity. The total vector magnitude counts per day was measured over 7 days using an actigraphy device, and the median value over the 7 days was obtained. This outcome measure is the change in the 7-day median value from baseline to follow-up, adjusted for the baseline value, sex, and actigraphy device wear time. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anastrozole 1mg (1 tablet)taken by mouth once a day for one year
Anastrozole: Anastrozole is an aromatase inhibitor indicated for:
* adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer
* first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer
* treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. | 43 |
| Placebo 1 tablet taken by mouth once a day for one year
Placebo Oral Tablet: matching placebo tablet | 41 |
| Total | 84 |
Baseline characteristics
| Characteristic | Anastrozole | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 11.8 | 59.4 years STANDARD_DEVIATION 11 | 60.3 years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 77 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) White | 31 Participants | 64 Participants | 33 Participants |
| Sex: Female, Male Female | 26 Participants | 51 Participants | 25 Participants |
| Sex: Female, Male Male | 17 Participants | 33 Participants | 16 Participants |
| Six-minute walk distance | 442.8 meters STANDARD_DEVIATION 119.5 | 429.8 meters STANDARD_DEVIATION 117.5 | 416.3 meters STANDARD_DEVIATION 115.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 3 / 41 |
| other Total, other adverse events | 38 / 43 | 38 / 41 |
| serious Total, serious adverse events | 16 / 43 | 10 / 41 |
Outcome results
Primary
Change in Six-minute Walk Distance
Change in the distance walked in six minutes adjusted for baseline value and sex
Time frame: 6 months
Population: Some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data. Includes non-missing six-minute walk distance at 6 months
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in Six-minute Walk Distance | 1.53 meters |
| Placebo | Change in Six-minute Walk Distance | 9.45 meters |
Secondary
Change in Actigraphy-measured Physical Activity: Change in 7-day Median Daily Vector Magnitude Count
Actigraphy-measured vector magnitude count is an estimate of physical activity intensity. The total vector magnitude counts per day was measured over 7 days using an actigraphy device, and the median value over the 7 days was obtained. This outcome measure is the change in the 7-day median value from baseline to follow-up, adjusted for the baseline value, sex, and actigraphy device wear time.
Time frame: 6months
Population: Please note that some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in Actigraphy-measured Physical Activity: Change in 7-day Median Daily Vector Magnitude Count | -0.43 counts per day(x10^5) |
| Placebo | Change in Actigraphy-measured Physical Activity: Change in 7-day Median Daily Vector Magnitude Count | -0.28 counts per day(x10^5) |
Secondary
Change in Bone Mineral Density: Lumbar Spine Between Anastrozole and Placebo Groups
Change in lumbar spine bone mineral density adjusted for baseline value and sex between anastrozole and placebo groups
Time frame: 12 months
Population: Please note that some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in Bone Mineral Density: Lumbar Spine Between Anastrozole and Placebo Groups | 0 g/cm^2 |
| Placebo | Change in Bone Mineral Density: Lumbar Spine Between Anastrozole and Placebo Groups | 0 g/cm^2 |
Secondary
Change in Plasma NT-proBNP
Change in log10 NT-proBNP adjusted for baseline value and sex
Time frame: 6months
Population: Please note that some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in Plasma NT-proBNP | 0.06 log10(pg/ml) |
| Placebo | Change in Plasma NT-proBNP | 0.04 log10(pg/ml) |
Secondary
Change in Right Ventricular Function: Tricuspid Annular Systolic Plane Excursion (TAPSE)
Change in tricuspid annular systolic plane excursion (TAPSE) adjusted for baseline value and sex. TAPSE is a measure of right ventricular function that is measured via cardiac echography
Time frame: 6 months
Population: Some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in Right Ventricular Function: Tricuspid Annular Systolic Plane Excursion (TAPSE) | -0.97 millimeters |
| Placebo | Change in Right Ventricular Function: Tricuspid Annular Systolic Plane Excursion (TAPSE) | -0.08 millimeters |
Secondary
Change in the emPHasis-10 Score Adjusted for Baseline Value and Sex
Change in the emPHasis-10 score adjusted for baseline value and sex. EmPHasis-10 is a pulmonary hypertension-specific measure of quality of life which is scored from 0-50, with higher scores indicating worse quality of life.
Time frame: 6months
Population: Please note that some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in the emPHasis-10 Score Adjusted for Baseline Value and Sex | -0.27 units on a scale |
| Placebo | Change in the emPHasis-10 Score Adjusted for Baseline Value and Sex | -0.51 units on a scale |
Secondary
Change in the Medical Outcomes Study Questionnaire Short Form-36 (SF36) Physical Component Summary (PCS) Score Adjusted for Baseline Value and Sex.
Change in the Medical Outcomes Study Questionnaire Short Form-36 (SF36) physical component summary (PCS) score adjusted for baseline value and sex. SF36 PCS score is a subjective measure of physical health status, with scores ranging from 0 to 100. Higher scores represent better health status.
Time frame: 6months
Population: Please note that some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Anastrozole | Change in the Medical Outcomes Study Questionnaire Short Form-36 (SF36) Physical Component Summary (PCS) Score Adjusted for Baseline Value and Sex. | 1.38 units on a scale |
| Placebo | Change in the Medical Outcomes Study Questionnaire Short Form-36 (SF36) Physical Component Summary (PCS) Score Adjusted for Baseline Value and Sex. | 0.02 units on a scale |
Secondary
Number of Participants With a Clinical Worsening Event Between Anastrozole and Placebo Groups
Number of participants with a clinical worsening event. Clinical worsening was defined as the addition of new PAH therapies or dose increases in previously stable PAH therapy for increased symptoms, hospitalization for PAH progression and/or right-sided heart failure, lung transplantation, atrial septostomy, or all-cause death.' Unit of Measure is retained as 'Participants.
Time frame: 12 months
Population: Please note that some participants are missing data at follow-up and the Analysis Population includes only participants with non-missing data
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anastrozole | Number of Participants With a Clinical Worsening Event Between Anastrozole and Placebo Groups | 7 Participants |
| Placebo | Number of Participants With a Clinical Worsening Event Between Anastrozole and Placebo Groups | 8 Participants |