Estradiol Supplementation and Rotator Cuff Repair

Menopause Clinical Trial

— ESTRCR  

Official title:

Estradiol Supplementation and Rotator Cuff Repair: A Preliminary Randomized Trial

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06318403
• Other study ID #: 177012
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: April 2025
• Est. completion date: May 2028

Study information

• Verified date: March 2024
• Source: University of Utah
• Contact: Peter Chalmers, MD
• Phone: 8015870063
• Email: chalmerspractice[@]hsc.utah.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rotator cuff tears in the shoulder are common, often cause pain and disability, often fail to heal with surgery, and both tears and failure of healing are associated with estradiol deficiency. In this study, women who have gone through menopause will be randomized to either estradiol patches or placebo patches after repair of the rotator cuff. The purpose of this study is to determine whether estradiol patches show promise in improving shoulder pain, strength, and function when given with rotator cuff repair.

Description:

Injuries to the rotator cuff are among the most common musculoskeletal complaints and are increasing in incidence. Multiple studies have demonstrated that rotator cuff repair (RCR) improves outcomes for rotator cuff tears. Over 500,000 RCRs are performed in the US annually. When both surgical and non-operative treatment are included, rotator cuff injuries cost the United States over $5 billion dollars annually. After RCR, tendon healing fails to occur in >20% of patients. Improving tendon healing is thus a critical barrier to success. The field has arrived at a consensus that improving tendon biology is the key to improving tendon healing. Our prior human and animal research demonstrates that estradiol deficiency contributes to rotator cuff injuries and estradiol supplementation improves RCR healing. With this study we propose to translate these promising and compelling preliminary findings into improved clinical care of patients with rotator cuff injuries. Estradiol deficiency can be treated with hormone therapy (HT), which is widely utilized, well-tolerated, inexpensive, and FDA approved. In this study, we will conduct a phase II study of the preliminary efficacy and feasibility of HT within the setting of RCR. We will conduct a randomized, placebo-controlled, double-blinded clinical trial. Post-menopausal women aged 40-80 will be included. Postoperatively, we will evaluate validated patient-reported outcomes and tendon healing utilizing magnetic resonance imaging. We hypothesize that outcomes and healing will be better in the HT group than the control group. Through this study we will also determine the feasibility of studying systemic HT in the setting of RCR. Although there is extensive clinical experience with HT in human women, there is none with RCR surgery. If preliminary efficacy is demonstrated, a future large, multi-center randomized clinical trial will be warranted. Thus, within our randomized controlled trial we will determine recruitment and retention rates, compliance with treatment, response to treatment of serum hormone levels, and adverse events. We hypothesize that compliance and response rates will be high while adverse events will be infrequent and equally common with estradiol patches and placebo patches. If our hypotheses are confirmed, then rationale will exist to translate this promising approach to improved healing and outcomes after RCR into a future, larger, well-powered, multi-centered randomized clinical trial with longer follow-up. Such a study could improve the treatment of people with rotator cuff injuries, thereby decreasing a source of significant disability. If our hypotheses are confirmed, it would shift the paradigm on the treatment of problems with tendons and their attachments to bone throughout the body.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 58
• Est. completion date: May 2028
• Est. primary completion date: March 2028
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 40 Years to 80 Years

Eligibility

Inclusion Criteria

1. A plan for a primary rotator cuff repair

2. Female sex (assigned sex at birth)

3. >1 cm tear width, full thickness supraspinatus/infraspinatus tear

4. Post-menopausal, as defined by at least six months since last menses

Exclusion Criteria

1. Active infection

2. Pre-operative estradiol supplementation

3. Medically unfit for operative intervention

4. Revision surgery

5. Unwillingness to participate in the study, including post-operative imaging

6. Inability to read or comprehend written instructions

7. Prisoner

8. Concomitant patch augmentation or tendon-transfer

9. Breast cancer or a history of breast cancer or other estradiol-dependent neoplasia

10. Liver disease as documented in the medical record

11. Active venous thromboembolic disease, such as deep venous thrombosis, pulmonary embolism, a history of these conditions, or a known predisposition to these disorders (such as Protein C, protein S, or antithrombin deficiency)

12. Active arterial thromboembolic disease, such as stroke, myocardiac infarction, a history of these conditions, or a known predisposition to these disorders

13. Isolated subscapularis tears

14. known anaphylactic reaction or hypersensitivity to estradiol, adhesive, or transdermal patches

Related Conditions & MeSH terms

• Menopause
• Menopause Related Conditions
• Rotator Cuff Injuries
• Rotator Cuff Syndrome
• Rotator Cuff Tears

Intervention

Drug:
• Transdermal estrogen
All patients will receive patches with identical labeling from our pharmacy, to be applied twice weekly. In the study group, these will contain 0.025 mg/day of estradiol. In the control group, these will be placebo. These will be applied twice weekly for three months beginning at the time of surgery and extending for three months after surgery.

Procedure:
• Rotator Cuff Repair Surgery
The operative protocol will be standardized in all patients. Both the operative protocol and post-operative rehabilitation protocol will be per our standard of care, without alteration. An arthroscopic approach will be used. In all cases a double-row rotator cuff repair using triple-loaded anchor(s) on the medial row will be used. Post-operatively all patients will be placed in a sling for six weeks. Active range of motion exercises will begin at six weeks post-operatively and strengthening will be delayed until 12 weeks post-operatively. In all phases of care our peri-operative and post-operative protocol for study patients will be similar to our current clinical practice to ensure generalizability.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Utah

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serum Hormone Measurement	Nonadherence could result in cross-over, biasing towards the null hypothesis. We will assess compliance with serum laboratory values. Blood will be drawn and the following serum estradiol values will be collected. These values will be interpreted by co-investigator Dr. Corrine Welt, a board-certified endocrinologist with extensive experience with reproductive urology. To preserve participant blinding, the results of hormonal testing will not be available through the patient electronic portal unless it is deemed necessary for patient care by Dr. Welt. In addition, to preserve their blinding, the treating surgeons and the clinical research coordinators performing the post-operative assessments will not have access to the laboratory values. Dr. Welt will not perform any other patient evaluations, and thus cannot influence the results.	To be collected within 3 months pre-operatively, at 6 weeks (±1 week) after starting medication, and at 12 weeks (±2 weeks) after starting medication.
Other	Patch Count	Subjects will be asked how many patches they have used to determine patient compliance. Deviations from protocol will be recorded.	6 weeks (±2 weeks) post-operatively, 12 weeks (±2 week) post-operatively.
Other	Averse Event Assessment	At each visit patients will be queried regarding adverse events. Patients will asked about the following specific adverse events side effects: dyspepsia/gastritis, hypertension, flu-like symptoms, back-pain, headache, anxiety, insomnia, depression, breast tenderness, vaginal bleeding, hot flashes, venous insufficiency, vertigo, edema, deep venous thrombosis, application site reactions, abdominal pain, weight gain, emotional lability, bleeding, infection, complications from anesthesia, the need for further surgery. In addition, any post-operative injections will be recorded.	To be collected at every patient visit, including 6 weeks (±2 weeks) after surgery, 12 weeks (±2 weeks) after surgery, and 6 months (±4 weeks) after surgery.
Primary	American Shoulder and Elbow Surgeons (ASES) Score	The ASES score is a patient survey that creates a score on a 100 point scale incorporating questions regarding shoulder pain and shoulder function. This survey contains 11 questions and takes ~3 minutes to complete. The validity and reliability of this score has been previously validated.	To be collected within 3 months pre-operatively and at 6 weeks (±2 weeks), 12 weeks (±2 weeks), and 6 months (±4 weeks) post-operatively.
Secondary	Simple Shoulder Test (SST) Score	The SST score is a patient survey that creates a score on a 12-point scale incorporating questions regarding shoulder function. This survey contains 12 questions and takes ~3 minutes to complete. The validity and reliability of this score has been previously validated.	To be collected within 3 months pre-operatively and at 6 weeks (±2 weeks), 12 weeks (±2 weeks), and 6 months (±4 weeks) post-operatively.
Secondary	Visual Analogue Score (VAS) for pain	The VAS pain score is a patient survey that creates a score on a 10 point scale incorporating a single question regarding shoulder pain. This survey takes <1 minute to complete.	To be collected within 3 months pre-operatively and at 6 weeks (±2 weeks), 12 weeks (±2 weeks), and 6 months (±4 weeks) post-operatively.
Secondary	Magnetic Resonance Imaging (MRI) tendon healing	MRI scans will be assessed by observers blinded to the patient's allocation. On the pre-operative MRI, pre-operative tear width, pre-operative tear retraction, cuff muscle atrophy will be measured. For each patient, the post-operative MRI will be categorized as either "healed" or "non-healed". On post-operative MRI only those patients without tendon defects will be considered healed. This will be the primary outcome of the study. We have previously demonstrated these measurements to have good inter- and intra-observer reliability with kappa values of 0.632 and 0.581 respectively. All post-operative MRI scans will be 1.5 tesla non-arthrogram studies in which T2 imaging will be performed in the sagittal, coronal, and axial planes.	Within 3 months pre-operatively and at 6 months (±4 weeks) post-operatively.
Secondary	Strength Assessment	Rotator cuff strength, as measured with a handheld digital dynamometer (Lafayette instruments, Lafayette, IN), will be measured. Abduction strength will be measured at 30 degrees of flexion, 30 degrees of abduction, neutral rotation, and full elbow extension. External rotation strength will be measured with the arm in adduction, neutral rotation, and 90 degrees of elbow flexion. These measures will be performed by research coordinators trained to perform these assessments. We have previously demonstrated these measurements to have excellent inter-observer reliability, with abduction strength having an intra-class correlation coefficient (ICC) of 0.993 and external rotation strength having an ICC of 0.986.	To be collected within 3 months pre-operatively and at 6 weeks (±2 weeks), 12 weeks (±2 weeks), and 6 months (±4 weeks) post-operatively.
Secondary	Range of motion	Range of motion will be recorded. Research personnel experienced with the use of video will measure active abduction, active forward elevation, active internal rotation in adduction, and active external rotation in adduction. This protocol has been previously used in many publications. These videos will be saved using subject numbers and then evaluated using a digital protractor by a third-party observer blinded to the subjects group. This method of range of motion measurement has been previously demonstrated to have excellent inter-observer reliability.	To be collected within 3 months pre-operatively and at 6 weeks (±2 weeks), 12 weeks (±2 weeks), and 6 months (±4 weeks) post-operatively.