Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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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
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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.

Official Title
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Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

Conditions
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Tamoxifen, Estrogens, Hypertension, Pulmonary Arterial Hypertension, Familial Primary Pulmonary Hypertension, Primary Pulmonary Hypertension, Lung Diseases, Estrogen Receptor Antagonist, Hormone Antagonists

Intervention / Treatment
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* Drug: Tamoxifen
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tamoxifen<br>20 mg po TID for 24 weeks | Drug: Tamoxifen<br>* Tamoxifen 20 mg po daily for 24 weeks.<br>|
| Placebo Comparator: Placebo<br>Placebo arm | Drug: Placebo Oral Tablet<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 weeks | 
| 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 and emPHasis-10 questionnaires. These will be administered at baseline and 12 and 24 weeks. | 24 weeks | 
| Quality of life will be assessed using emPHasis-10 questionnaire. This will be administered at baseline and 12 and 24 weeks. | Change in score from Week 0 to Week 24. | 24 weeks |