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Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension (T3PAH)

Primary Purpose

Hypertension, Pulmonary Arterial Hypertension, Familial Primary Pulmonary Hypertension

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Tamoxifen

Placebo Oral Tablet

About this trial

This is an interventional treatment trial for Hypertension

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Tamoxifen

Placebo

Arm Description

20 mg po TID for 24 weeks

Placebo arm

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

Full Information

NCT ID

NCT03528902

First Posted

March 21, 2018

Last Updated

July 31, 2023

Sponsor

Vanderbilt University Medical Center

1. Study Identification

Unique Protocol Identification Number

NCT03528902

Brief Title

Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

Acronym

T3PAH

Official Title

Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

October 1, 2018 (Actual)

Primary Completion Date

June 14, 2023 (Actual)

Study Completion Date

June 14, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Vanderbilt University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

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

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Tamoxifen

Arm Type

Experimental

Arm Description

20 mg po TID for 24 weeks

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo arm

Intervention Type

Drug

Intervention Name(s)

Tamoxifen

Intervention Description

Tamoxifen 20 mg po daily for 24 weeks.

Intervention Type

Drug

Intervention Name(s)

Placebo Oral Tablet

Intervention Description

Placebo

Primary Outcome Measure Information:

Title

Transthoracic echocardiogram (ECHO)-based change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) measurement

Description

Time Frame

24 weeks

Secondary Outcome Measure Information:

Title

Six minute walk test distance (6MWTD)

Description

Time Frame

24 weeks

Title

Quality of life will be assessed using the SF36 questionnaire. This will be administered at baseline and 12 and 24 weeks.

Description

Time Frame

24 weeks

Title

Quality of life will be assessed using emPHasis-10 questionnaire. This will be administered at baseline and 12 and 24 weeks.

Description

Change in score from Week 0 to Week 24.

Time Frame

24 weeks

Other Pre-specified Outcome Measures:

Title

Plasma BNP

Description

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

Title

HgbA1c

Description

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Facility Information:

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Since the data that will be produced involves patients with a disease process that is much in need of new treatment options and the investigators agree that data sharing is essential for expedited translation of research results into patient treatment options. A detailed data sharing plan is in place and available upon request. In brief: It is our plan to make data available at the time it is accepted for publication of the main findings from the final dataset through the use of a data enclave of our own design that would restrict our Data Analyst from sharing any information that would breach participant confidentiality. Potential researchers will contact the PI to discuss specific needs and how the data will be utilized. A formal approval process is in place to evaluate and complete such requests.

IPD Sharing Time Frame

2 years after study completion.

IPD Sharing Access Criteria

Criteria include: detailed written description of the project for which the data would be used. acknowledge in any publication resulting from the data, the source of the data, crediting the program support. agree to submit all papers or reports submitted for publication to the PI for review prior to submission.

Learn more about this trial

Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension

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