Estrogen Receptor Antagonist, Estrogens, Familial Primary Pulmonary Hypertension, Hormone Antagonists, Hypertension, Lung Diseases, Primary Pulmonary Hypertension, Pulmonary Arterial Hypertension, Tamoxifen
Conditions
Brief summary
The main purpose of this clinical trial is to examine the feasibility and effects of tamoxifen in subjects with pulmonary arterial hypertension (PAH). The study will evaluate how well the drug is tolerated, and its impact on functional condition and selected biomarkers. Changes in tricuspid annular plane systolic excursion (TAPSE) and other parameters determined by transthoracic echocardiography will be evaluated as well as changes in additional metrics such as six minute walk test distance, quality of life assessments, and hormone levels.
Detailed description
Pulmonary arterial hypertension (PAH) is characterized by progressive loss of function by the pulmonary vascular bed due to a variety of factors including obliterative vascular lesions, vasoconstriction, and thrombotic occlusion of the pulmonary arteries. Ultimately, right-sided heart failure ensues with severe limitation of exercise and eventual progression to death or lung transplantation. While there are multiple FDA-approved therapies for PAH representing 3 major pathways of interest, no treatments are curative, and have additional limitations including high expense, multiple side effects, and dosing inconveniences. The strongest established risk factor for the progressively fatal disease pulmonary arterial hypertension (PAH) is female sex (\ 3:1 female:male ratio). We and others have found higher circulating estrogen levels, and enhanced estrogen signaling, in PAH patients. Preclinical work by our group and others supports the concept that anti-estrogen therapy, is effective for both prevention and treatment in PAH. Recent and ongoing clinical studies are underway to assess these approaches in humans, including a recent study demonstrating the safety of estrogen reduction in postmenopausal women. Tamoxifen is the most commonly used selective estrogen receptor modulator (SERM). Due to its extensive use in humans for over three decades, it has an excellent safety profile and its long-term sequelae are well characterized. Furthermore, it is a generic drug which has been FDA-approved for treatment and prevention of breast cancer, particularly those with estrogen receptor-positive neoplasms. To help to determine whether tamoxifen may be a safe and effective treatment for PAH in women and men, we will conduct a single-center, randomized, double-blind, placebo-controlled Phase II study of subjects with PAH. All subjects will also be treated with background standard of care therapy at the discretion of their PAH care physician.
Interventions
DRUGTamoxifen
Tamoxifen 20 mg po daily for 24 weeks.
DRUGPlacebo Oral Tablet
Placebo
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Single-center, randomized, double-blind, placebo-controlled Phase II study of 24 subjects with PAH. Eligible subjects will be randomized to treatment with a 1:1 ratio using a permuted-block randomization algorithm.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Previous documentation of mean pulmonary artery pressure greater than or equal to 25 mm Hg with a pulmonary capillary wedge pressure (or left ventricular end-diastolic pressure) less than or equal to15 mm Hg and PVR greater than or equal to 3 WU at any time before study entry, consistent Group 1 PAH classified by accepted international classification. * Diagnosis of PAH which is idiopathic, heritable, drug- or toxin-induced, or associated with connective tissue disease. * Age 18 years and older. * WHO Functional Class I, II, or III status. * Ability to perform a six minute walk test without significant limitations in musculoskeletal function or coordination, with distance greater than or equal to 150m and less than or equal to 550m. * Informed consent.
Exclusion criteria
* Current treatment with estrogen, progesterone, or any form of sex hormone therapy. * Current treatment with anti-sex hormone therapy (e.g., anastrozole, fulvestrant, tamoxifen, leuprolide acetate (luporon) or other centrally-acting hormone agents. * WHO Functional Class IV status. * History of, or current, breast, uterine, ovarian, or testicular cancer. * Current pregnancy, or prior pregnancy within 3 months of enrollment. * 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. Of note, PAH therapy, including diuretics, which is stopped and then restarted or has dose changes which are not related to initiation and up titration will be allowed within 3 months prior to the Baseline Visit, and during the trial for subjects. * History of thromboembolic event. * Hospitalized or acutely ill. * Renal failure (creatinine over 2.0). * Hypercalcemia. * Severe osteoporosis (t score \< -2.0 OR t score \< -2.5 if on bone modifying treatment). * Current or recent (\< 3 months) chronic heavy alcohol consumption. * Enrollment in a clinical trial or concurrent use of another investigational drug (non FDA approved) or device therapy within 30 days of screening visit. * Enrollment in any pharmacologic clinical trial within one month of screening. * Due to potential drug interactions with tamoxifen, subjects using bosentan (CYP3A4) or selexipag (CYP2C8) will be excluded. * Due to the concerns of pregnancy during PAH and with tamoxifen use, subjects will be excluded who do not use at least two forms of contraception (e.g., IUD plus the use of a barrier contraceptive method).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Transthoracic Echocardiogram (ECHO)-Based Change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) Measurement | 24 weeks | Transthoracic echocardiograms (ECHOs) will be performed to measure the TAPSE value prior to Intervention at Week 0, as well as at the end of the study intervention (Week 24). The primary outcome measure will be the change in TAPSE, determined by echocardiogram, from Week 0 to Week 24. About TAPSE: Tricuspid annular plane systolic excursion (TAPSE) is a parameter of global right ventricular function which describes apex-to-base shortening of the ventricle. It is obtained by transthoracic echocardiogram, which can be performed on a resting subject without sedation in the outpatient setting. TAPSE correlates closely with the right ventricular ejection fraction, and has been determined to be both highly specific and easy to measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Six Minute Walk Test Distance (6MWTD) | 24 weeks | Change in 6MWTD from Week 0 to Week 24. The 6-minute walk test distance (6MWTD) is a widely accepted measure of exercise capacity and functional status. The 6MWTD is a clinical and research test obtained in a standardized manner according to American Thoracic Society (ATS) Guidelines. Briefly, the 6MWT is a sub-maximal exercise test on flat ground that is used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity over time. |
| Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | 24 weeks | Change in score from Week 0 to Week 24. Specifically, Quality of life will be assessed using two different accepted questionnaires for pulmonary hypertension patients, the SF36 questionnaires. These will be administered at baseline and 12 and 24 weeks. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. |
| Quality of Life Will be Assessed Using emPHasis-10 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | 24 weeks | This will be administered at baseline and 12 and 24 weeks. Change in score from Week 0 to Week 24 will be reported. emPHasis-10 scores range from 0 to 50, higher scores indicate worse quality of life |
Other
| Measure | Time frame | Description |
|---|---|---|
| Plasma BNP | 24 weeks | Change in Plasma BNP levels will be assessed from Week 0 to Week 24 during the study. These measurements are made from the plasma, and will require a blood draw from the research participant. |
| HgbA1c | 24 weeks | Change in hemoglobin A1c (HgbA1c) levels will be assessed from Week 0 to Week 24 during the study. These measurements are made from the plasma, and will require a blood draw from the research participant. |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred between 1/08/2018-12/28/2022
Participants by arm
| Arm | Count |
|---|---|
| Tamoxifen 20 mg po TID for 24 weeks
Tamoxifen: Tamoxifen 20 mg po daily for 24 weeks. | 9 |
| Placebo Placebo arm
Placebo Oral Tablet: Placebo daily for 24 weeks. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Tamoxifen | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 45.8 years STANDARD_DEVIATION 12.4 | 48.4 years STANDARD_DEVIATION 11.4 | 51 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 17 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 16 Participants | 8 Participants |
| Region of Enrollment United States | 9 participants | 18 participants | 9 participants |
| Sex: Female, Male Female | 9 Participants | 17 Participants | 8 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 5 / 9 | 5 / 9 |
| serious Total, serious adverse events | 0 / 9 | 2 / 9 |
Outcome results
Primary
Transthoracic Echocardiogram (ECHO)-Based Change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) Measurement
Transthoracic echocardiograms (ECHOs) will be performed to measure the TAPSE value prior to Intervention at Week 0, as well as at the end of the study intervention (Week 24). The primary outcome measure will be the change in TAPSE, determined by echocardiogram, from Week 0 to Week 24. About TAPSE: Tricuspid annular plane systolic excursion (TAPSE) is a parameter of global right ventricular function which describes apex-to-base shortening of the ventricle. It is obtained by transthoracic echocardiogram, which can be performed on a resting subject without sedation in the outpatient setting. TAPSE correlates closely with the right ventricular ejection fraction, and has been determined to be both highly specific and easy to measure.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tamoxifen | Transthoracic Echocardiogram (ECHO)-Based Change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) Measurement | Baseline | 2.244 mm | Standard Deviation 0.194 |
| Tamoxifen | Transthoracic Echocardiogram (ECHO)-Based Change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) Measurement | Week 24 | 2.300 mm | Standard Deviation 0.22 |
| Placebo | Transthoracic Echocardiogram (ECHO)-Based Change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) Measurement | Baseline | 2.244 mm | Standard Deviation 0.274 |
| Placebo | Transthoracic Echocardiogram (ECHO)-Based Change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) Measurement | Week 24 | 2.212 mm | Standard Deviation 0.352 |
Secondary
Quality of Life Will be Assessed Using emPHasis-10 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks.
This will be administered at baseline and 12 and 24 weeks. Change in score from Week 0 to Week 24 will be reported. emPHasis-10 scores range from 0 to 50, higher scores indicate worse quality of life
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tamoxifen | Quality of Life Will be Assessed Using emPHasis-10 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | Baseline | 25.7 units on a scale | Standard Deviation 13.9 |
| Tamoxifen | Quality of Life Will be Assessed Using emPHasis-10 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | Week 24 | 23.5 units on a scale | Standard Deviation 12.7 |
| Placebo | Quality of Life Will be Assessed Using emPHasis-10 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | Baseline | 14.3 units on a scale | Standard Deviation 11.7 |
| Placebo | Quality of Life Will be Assessed Using emPHasis-10 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | Week 24 | 15.9 units on a scale | Standard Deviation 13.7 |
Secondary
Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks.
Change in score from Week 0 to Week 24. Specifically, Quality of life will be assessed using two different accepted questionnaires for pulmonary hypertension patients, the SF36 questionnaires. These will be administered at baseline and 12 and 24 weeks. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_functioning (Baseline) | 55 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_health(Baseline) | 31.2 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | emotional_probs (Baseline) | 66.67 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | energy_fatigue (Baseline) | 37.5 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | well_being (Baseline) | 75 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | social_function (Baseline) | 62.5 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | pain (Baseline) | 67.5 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | gen_health(Baseline) | 40 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_functioning (Week 24) | 55 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_health (week 24) | 40.6 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | emotional_probs (Week 24) | 58.3 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | energy_fatigue (Week 24) | 59.4 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | well_being (Week 24) | 77.5 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | social_function (Week 24) | 81.2 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | pain (Week 24) | 67.5 score on a scale |
| Tamoxifen | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | gen_health (Week 24) | 37.5 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | gen_health (Week 24) | 40 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_functioning (Baseline) | 65 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_functioning (Week 24) | 65 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_health(Baseline) | 81.2 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | well_being (Week 24) | 90 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | emotional_probs (Baseline) | 100 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | physical_health (week 24) | 93.8 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | energy_fatigue (Baseline) | 62.5 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | pain (Week 24) | 77.5 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | well_being (Baseline) | 90 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | emotional_probs (Week 24) | 100 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | social_function (Baseline) | 100 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | social_function (Week 24) | 100 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | pain (Baseline) | 67.5 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | energy_fatigue (Week 24) | 62.5 score on a scale |
| Placebo | Quality of Life Will be Assessed Using the SF36 Questionnaire. This Will be Administered at Baseline and 12 and 24 Weeks. | gen_health(Baseline) | 50 score on a scale |
Secondary
Six Minute Walk Test Distance (6MWTD)
Change in 6MWTD from Week 0 to Week 24. The 6-minute walk test distance (6MWTD) is a widely accepted measure of exercise capacity and functional status. The 6MWTD is a clinical and research test obtained in a standardized manner according to American Thoracic Society (ATS) Guidelines. Briefly, the 6MWT is a sub-maximal exercise test on flat ground that is used to assess aerobic capacity and endurance. The distance covered over a time of 6 minutes is used as the outcome by which to compare changes in performance capacity over time.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tamoxifen | Six Minute Walk Test Distance (6MWTD) | Baseline | 375.3 Meters | Standard Deviation 78.4 |
| Tamoxifen | Six Minute Walk Test Distance (6MWTD) | Week 24 | 377.9 Meters | Standard Deviation 84.5 |
| Placebo | Six Minute Walk Test Distance (6MWTD) | Baseline | 415.2 Meters | Standard Deviation 87.5 |
| Placebo | Six Minute Walk Test Distance (6MWTD) | Week 24 | 405.5 Meters | Standard Deviation 156.4 |
Other Pre-specified
HgbA1c
Change in hemoglobin A1c (HgbA1c) levels will be assessed from Week 0 to Week 24 during the study. These measurements are made from the plasma, and will require a blood draw from the research participant.
Time frame: 24 weeks
Population: HgbA1c was not assessed due to assay issues.
Other Pre-specified
Plasma BNP
Change in Plasma BNP levels will be assessed from Week 0 to Week 24 during the study. These measurements are made from the plasma, and will require a blood draw from the research participant.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tamoxifen | Plasma BNP | Baseline | 30.4 pg/mL | Standard Deviation 31.3 |
| Tamoxifen | Plasma BNP | Week 24 | 101.3 pg/mL | Standard Deviation 150.9 |
| Placebo | Plasma BNP | Baseline | 79.1 pg/mL | Standard Deviation 110.5 |
| Placebo | Plasma BNP | Week 24 | 76.2 pg/mL | Standard Deviation 77.1 |