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Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension (T3PAH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03528902
Recruitment Status : Recruiting
First Posted : May 18, 2018
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Eric Austin, Vanderbilt University Medical Center

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.

Condition or disease Intervention/treatment Phase
Hypertension Pulmonary Arterial Hypertension Familial Primary Pulmonary Hypertension Primary Pulmonary Hypertension Lung Diseases Tamoxifen Estrogen Receptor Antagonist Hormone Antagonists Estrogens Drug: Tamoxifen Drug: Placebo Oral Tablet Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : June 30, 2023


Arm Intervention/treatment
Experimental: Tamoxifen
20 mg po TID for 24 weeks
Drug: Tamoxifen
Tamoxifen 20 mg po daily for 24 weeks.

Placebo Comparator: Placebo
Placebo arm
Drug: Placebo Oral Tablet
Placebo




Primary Outcome Measures :
  1. Transthoracic echocardiogram (ECHO)-based change in the Tricuspid Annular Plane Systolic Excursion (TAPSE) measurement [ Time Frame: 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 Outcome Measures :
  1. Six minute walk test distance (6MWTD) [ Time Frame: 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.


  2. Quality of life will be assessed using the SF36 questionnaire. This will be administered at baseline and 12 and 24 weeks. [ Time Frame: 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.


  3. Quality of life will be assessed using emPHasis-10 questionnaire. This will be administered at baseline and 12 and 24 weeks. [ Time Frame: 24 weeks ]
    Change in score from Week 0 to Week 24.


Other Outcome Measures:
  1. Plasma BNP [ Time Frame: 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.

  2. HgbA1c [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03528902


Contacts
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Contact: Shannon Cordell, RN 615.343.8277 shannon.eason@vumc.org
Contact: Alisha Lindsey, RRT, MSHA 615.322.3412 alisha.lindsey@vumc.org

Locations
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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Shannon Cordell, RN    615-343-8277    shannon.eason@vanderbilt.edu   
Contact: Errine Garnett, MS    615-343-4252    errine.t.garnett@vanderbilt.edu   
Principal Investigator: Eric D Austin, MD, MSc         
Principal Investigator: James E Loyd, MD         
Sub-Investigator: Anna R Hemnes, MD         
Sub-Investigator: Evan Brittain, MD, MSc         
Sponsors and Collaborators
Vanderbilt University Medical Center
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Responsible Party: Eric Austin, Associate Professor of Pediatrics, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03528902    
Other Study ID Numbers: 180241
First Posted: May 18, 2018    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: 2 years after study completion.
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lung Diseases
Hypertension, Pulmonary
Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Respiratory Tract Diseases
Tamoxifen
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents