Sex Hormone Supplementation and Rotator Cuff Repair: A Preliminary Randomized Trial

Study Overview
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Brief Summary
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Shoulder tendon tears are a common cause of shoulder pain and disability and after surgery the repaired tendon often does not heal. In this pilot study, men with low sex hormone levels will be randomly assigned to receive sex hormone therapy or placebo pills while healing from tendon repair surgery in their shoulder. Sex hormone therapy increases sex hormone levels, and the investigators will test whether these increased sex hormone levels show promise in improving tendon healing and patient shoulder function and pain.

Detailed Description
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The rotator cuff is a system of tendons in the shoulder that stabilize the ball within the socket. These tendons frequently tear with age, which causes pain, weakness, and dysfunction in the shoulder. While these tears can be surgically repaired, they do not always heal. Our data suggest that deficiency of testosterone and estrogen can contribute to both tearing of the rotator cuff and failure of healing after rotator cuff repair. Testosterone can be converted into estrogen in the body through the aromatase enzyme, which is in both tendons and bones, as well as other tissues. Both testosterone and estrogen can improve bone quality. While testosterone is frequently prescribed for testosterone deficiency, when it is given your body no longer has the drive to make testosterone. So when the treatment is withdrawn testosterone levels can go very low until feedback mechanisms in the body motivate it to make more. As a result, testosterone is not usually given temporarily. For temporary treatment clomiphene avoids this issue. Clomiphene works at the feedback mechanisms within the body to trick the body into thinking testosterone and estrogen levels are low and thus to motivate it to make more testosterone and estrogen. However, clomiphene can only be given continuously to men, because women's estrogen levels regularly cycle up and down on a monthly basis and clomiphene interferes with this cycle. The purpose of this study is to determine whether clomiphene treatment decreases pain and improves function, increases tendon healing, and improves bone quality with rotator cuff repair in men. We hypothesize that clomiphene treatment will decrease pain and improve function, improve tendon healing, and improve bone quality with rotator cuff repair in men. This is a placebo-controlled study, so a control group of patients will received placebo pills, i.e. sugar pills, instead of clomiphene. This is a randomized study, so patients enrolled in the study will be randomly assigned to the clomiphene group or the placebo group. This is a blinded study, so both the patients enrolled in the will not know whether they are in the clomiphene or the control group. This is a double-blinded study, so the doctors performing the surgeries and the study will not know whether each specific patient is in the clomiphene or the control group. Study participants will first start the clomiphene treatment one month before surgery and will continue the treatment for six months after surgery. Both before surgery and six months after surgery, study participants will fill out study questionnaires about shoulder pain and function. Both before surgery and six months after surgery, study participants will undergo an magnetic resonance imaging study to examine the rotator cuff tendons as well as the bone quality within the shoulder. The magnetic resonance imaging study after surgery is provided free to study participants. Study participants will be compensated for completing the study. These results are important because may lead to a better understanding of the problem, more effective treatment, and improved clinical outcomes for future patients.

Official Title
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Sex Hormone Supplementation and Rotator Cuff Repair: A Preliminary Randomized Trial

Conditions
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Rotator Cuff Tears

Intervention / Treatment
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* Drug: Clomiphene Citrate
* Procedure: Rotator Cuff Repair


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria A plan for a primary rotator cuff repair Male sex >1 cm tear width, full thickness supraspinatus/infraspinatus tear Exclusion Criteria Active infection Pre-operative testosterone supplementation Known diagnosis of secondary testicular failure or testosterone deficiency Medically unfit for operative intervention Revision surgery Unwillingness to participate in the study, including post-operative imaging Inability to read or comprehend written instructions Prisoner Concomitant patch augmentation or tendon-transfer Untreated prostate cancer Liver disease Pituitary or hypothalamic dysfunction

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>All patients will receive non-labeled pills identical in appearance from our pharmacy, to be taking once every other day. In the control group, these will be placebo. These will be taken every other day for seven months beginning four week prior to surgery and extending for six months after surgery. | Procedure: Rotator Cuff Repair<br>* 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.<br>|
| Experimental: Clomiphene<br>All patients will receive non-labeled pills identical in appearance from our pharmacy, to be taking once every other day. In the study group, these will contain 50 mg of clomiphene citrate. These will be taken every other day for seven months beginning four week prior to surgery and extending for six months after surgery. | Drug: Clomiphene Citrate<br>* All patients will receive non-labeled pills identical in appearance from our pharmacy, to be taking once every other day. In the study group, these will contain 50 mg of clomiphene citrate. In the control group, these will be placebo. These will be taken every other day for seven months beginning four weeks prior to surgery and extending for six months after surgery. After enrollment patients will be randomized. Patient will be assigned to the 2 groups using a permuted block randomization scheme with blocks of size 2, 4, and 6. Prior to initiation of the study opaque sealed envelopes will be prepared and thoroughly shuffled and then used sequentially during the study. These randomization assignments will be available to the pharmacy in a web-based format or by cards in sealed envelopes. A nonparticipant in the study (the pharmacy at our institution) will administer this process.<br>Procedure: Rotator Cuff Repair<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Magnetic Resonance Imaging (MRI) tendon healing Post-op | MRI scans will be assessed by observers blinded to the patient's allocation. 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 to be healed. This will be the primary outcome of the study. The investigators have previously demonstrated this measurement to be reliable. | To be collected at 6 months (±4 weeks) post-operatively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| American Shoulder and Elbow Surgeons (ASES) Score 6 months | 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. Higher scores indicate a better outcome. | To be collected at 6 months (±4 weeks) post-operatively. | 
| Simple Shoulder Test (SST) Score Pre-op | 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. Higher scores indicate a better outcome. | To be collected within six months pre-operatively. | 
| Simple Shoulder Test (SST) Score 6 weeks | 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. Higher scores indicate a better outcome. | To be collected at six weeks (±2 weeks) post-operatively. | 
| Simple Shoulder Test (SST) Score 12 weeks | 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. Higher scores indicate a better outcome. | To be collected at 12 weeks (±2 weeks) post-operatively. | 
| Simple Shoulder Test (SST) Score 6 months | 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. Higher scores indicate a better outcome. | To be collected at 6 months (±4 weeks) post-operatively. | 
| Visual Analogue Score (VAS) for pain Pre-op | 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. Lower scores indicate a better outcome. | To be collected within six months pre-operatively. | 
| Visual Analogue Score (VAS) for pain 6 weeks | 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. Lower scores indicate a better outcome. | To be collected at six weeks (±2 weeks) post-operatively. | 
| Visual Analogue Score (VAS) for pain 12 weeks | 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. Lower scores indicate a better outcome. | To be collected at 12 weeks (±2 weeks) post-operatively. | 
| Visual Analogue Score (VAS) for pain 6 months | 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. Lower scores indicate a better outcome. | To be collected at 6 months (±4 weeks) post-operatively. | 
| Magnetic Resonance Imaging (MRI) proximal humeral bone quality Pre-op | Both the pre-operative and post-operative MRI scans will include a ultra-short time-echo (UTE) coronal sequence. On the UTE sequence, maximum humeral cortical thickness will be measured orthogonal to the axis of the shaft five, ten, and fifteen cm distal to the top the head, as we have previously demonstrated this measurement to be accurate and reliable. | To be collected within six months pre-operatively. | 
| Magnetic Resonance Imaging (MRI) proximal humeral bone quality Post-op | Both the pre-operative and post-operative MRI scans will include a ultra-short time-echo (UTE) coronal sequence. On the UTE sequence, maximum humeral cortical thickness will be measured orthogonal to the axis of the shaft five, ten, and fifteen cm distal to the top the head, as we have previously demonstrated this measurement to be accurate and reliable. | To be collected at 6 months (±4 weeks) post-operatively. | 
| Strength Assessment Pre-op | Rotator cuff strength, as measured with a handheld dynamometer, 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 a single research coordinator. | To be collected within six months pre-operatively. | 
| Strength Assessment 6 weeks | Rotator cuff strength, as measured with a handheld dynamometer, 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 a single research coordinator. | To be collected at six weeks (±2 weeks) post-operatively. | 
| Strength Assessment 12 weeks | Rotator cuff strength, as measured with a handheld dynamometer, 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 a single research coordinator. | To be collected at 12 weeks (±2 weeks) post-operatively. | 
| Strength Assessment 6 months | Rotator cuff strength, as measured with a handheld dynamometer, 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 a single research coordinator. | To be collected at 6 months (±4 weeks) post-operatively. | 
| Range of motion Pre-op | 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. These will be measured sequentially during a single continuous video, first with the video viewing from anteriorly while the subject abducts while standing against a wall, then while viewing from laterally while the subject elevates while standing adjacent to a wall, then while viewing from posteriorly while the subject internally rotates in adduction, and then while viewing from superiorly while the subject externally rotates while sitting in a chair. 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. | To be collected within six months pre-operatively. | 
| Range of motion 6 weeks | 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. These will be measured sequentially during a single continuous video, first with the video viewing from anteriorly while the subject abducts while standing against a wall, then while viewing from laterally while the subject elevates while standing adjacent to a wall, then while viewing from posteriorly while the subject internally rotates in adduction, and then while viewing from superiorly while the subject externally rotates while sitting in a chair. 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. | To be collected at six weeks (±2 weeks) post-operatively. | 
| Range of motion 12 weeks | 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. These will be measured sequentially during a single continuous video, first with the video viewing from anteriorly while the subject abducts while standing against a wall, then while viewing from laterally while the subject elevates while standing adjacent to a wall, then while viewing from posteriorly while the subject internally rotates in adduction, and then while viewing from superiorly while the subject externally rotates while sitting in a chair. 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. | To be collected at 12 weeks (±2 weeks) post-operatively. | 
| Range of motion 6 months | 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. These will be measured sequentially during a single continuous video, first with the video viewing from anteriorly while the subject abducts while standing against a wall, then while viewing from laterally while the subject elevates while standing adjacent to a wall, then while viewing from posteriorly while the subject internally rotates in adduction, and then while viewing from superiorly while the subject externally rotates while sitting in a chair. 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. | To be collected at 6 months (±4 weeks) post-operatively. | 
| American Shoulder and Elbow Surgeons (ASES) Score Pre-op | 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. Higher scores indicate a better outcome. | To be collected within six months pre-operatively. | 
| American Shoulder and Elbow Surgeons (ASES) Score 6 weeks | 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. Higher scores indicate a better outcome. | To be collected at six weeks (±2 weeks) post-operatively. | 
| American Shoulder and Elbow Surgeons (ASES) Score 12 weeks | 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. Higher scores indicate a better outcome. | To be collected at 12 weeks (±2 weeks) post-operatively. |