Hormone Therapy for Musculoskeletal Health

(ARMOR Trial)

Overseen By Kristin J Koltun, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 4

Sponsor: Bradley Nindl

Must not be taking: Estrogens, Androgens, Bisphosphonates, others

Disqualifiers: Heart condition, Hypertension, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how hormone treatment can enhance muscle, tendon, and bone health, as well as physical and mental performance, particularly under stress. The focus is on preventing injuries common among military personnel. Participants will be divided into groups, with some receiving hormone treatments like testosterone (such as Testosterone gel, or AndroGel) or estrogen (such as the Estradiol/Levonorgestrel Transdermal System, or Climara Pro), while others continue their usual routines. Individuals who exercise regularly and have no recent injuries or major health issues may be suitable for this trial. As a Phase 4 trial, this research involves treatments that are already FDA-approved and effective, aiming to understand how they benefit more patients.

Will I have to stop taking my current medications?

The trial requires participants to either not be taking prescription medications or be willing to stop taking them before and during the study, unless approved by the study physician.

What is the safety track record for these treatments?

Research shows that the treatments in this trial have varying safety levels based on existing data. Studies indicate that the testosterone gel is generally safe for men with low testosterone, though it can cause side effects such as increased blood pressure and changes in mood or behavior.

The estradiol/levonorgestrel patch, known as Climara Pro, carries warnings about potential risks, including a higher chance of heart problems, certain cancers, and blood clots, especially for those using it for menopause symptoms.

Goserelin, also called Zoladex, can lead to side effects like hot flashes and loss of bone strength, potentially causing osteoporosis. It may also raise calcium levels in the blood, which can harm the kidneys, heart, and bones.

While these treatments are usually well-tolerated, they have specific risks. Prospective participants should consider their personal health and consult a healthcare provider before joining a trial. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores new ways to enhance musculoskeletal health using hormone therapies and stress training. Unlike typical treatments that focus on either hormone replacement or physical training independently, this trial combines both approaches. The study is unique in its use of Goserelin (Zoladex) to suppress natural hormone production, followed by the application of testosterone gel or a Climara Pro patch to carefully control and replace hormones in men and women, respectively. The approach of integrating hormone manipulation with military-style physical training might offer insights into optimizing physical performance and recovery, potentially benefiting both military personnel and civilians with musculoskeletal concerns.

What evidence suggests that this trial's treatments could be effective for musculoskeletal health?

Research has shown that hormone treatments can improve bone and muscle health. In this trial, some male participants will receive testosterone gel, which increases bone strength by boosting bone mineral density. Studies have also reported that testosterone gel enhances muscle mass and bone health in men. Female participants will receive the estradiol/levonorgestrel patch, which helps maintain and increase bone strength, crucial for strong bones. Early research suggests that this hormone therapy might also enhance physical performance by improving muscle strength and endurance. These treatments have proven effective in other health conditions, indicating they could help reduce injuries in military personnel. ^{1 6 7 8 9}

Who Is on the Research Team?

Bradley C Nindl, PhD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for military personnel who may be at risk of musculoskeletal injuries and have low testosterone levels. Participants should be in good health, able to undergo physical and mental stress tests, and willing to use hormonal treatments like patches or gels.

Inclusion Criteria

Able to commit to study duration

Agrees to adhere to study requirements

Body mass index (BMI) 18-30 kg/m2

Exclusion Criteria

I have a condition related to my hormones or metabolism.

Serum 25-hydroxyvitamin D < 20 ng/mL

I have a history of blood clots or clotting disorders.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multi-Stressor Training

Participants undergo a 4-week exercise training program consisting of 5 consecutive days of strenuous physical training followed by 2 days of recovery

4 weeks

Daily training sessions

Hormonal Intervention

Participants receive hormonal treatments such as Zoladex and AndroGel or placebo patches to study the effects on muscle, tendon, and bone function

Concurrent with training phase

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol / Levonorgestrel Transdermal System [Climara Pro]
• Goserelin 3.6 MG
• Testosterone gel (AndroGel 1.25g)
• Testosterone gel (AndroGel 5g)

Trial Overview The study is testing the effects of hormone treatments (testosterone gel, estradiol/levonorgestrel patch) versus a placebo on muscle, tendon, bone function, and stress resilience. It includes multi-stressor training sessions and monitoring changes in body composition.

How Is the Trial Designed?

Group I: SUPPRESS (women): Multi-stressor training + Zoladex + Placebo patch Experimental Treatment 3 Interventions

In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, women in the SUPRESS group will receive a placebo transdermal patch.

Group II: SUPPRESS (men): Multi-Stressor Training + Zoladex + AndroGel 1.25g Experimental Treatment 3 Interventions

In addition to participating in the multi-stressor training program, male participants randomized to the GnRH suppressed (SUPPRESS) group will be administered a long-acting GnRH agonist (Zoladex) by trained medical professionals to suppress endogenous gonadal steroids. Following GnRH agonist administration, men will be administered 1.25g/day (SUPPRESS) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.

Group III: REPLACE (women): Multi-Stressor Training + Zoladex + Climara Pro Patch Experimental Treatment 3 Interventions

Following GnRH agonist administration, women, the REPLACE group will receive a transdermal estradiol (0.045 mg/day) + levonorgestrel (0.015 mg/day) patch (Climara Pro, Bayer, NJ) to be placed on a clean, dry area of the skin on the lower

Group IV: REPLACE (men): Multi-Stressor Training + Zoladex + AndroGel 5g Experimental Treatment 3 Interventions

Following GnRH agonist administration, men will be administered 5g/day (REPLACE) of topical 1% testosterone gel (AndroGel, Abbvie, North Chicago, IL) to be applied to the shoulders, upper arms, and/or stomach area daily.

Group V: CONTROL (men + women) Active Control 1 Intervention

The control group will maintain their habitual exercise, diet, and sleep patterns, all of which will be monitored throughout the study.

Group VI: STRESS (men + women): Multi-Stressor Training Active Control 1 Intervention

Research volunteers will be randomized into the stress exposure group (STRESS) will undergo a 4-week exercise training program consisting of 5 consecutive days of strenuous physical training followed by 2 days of recovery (energy balance, no structured exercise). The exercise training program will consist of military-relevant physical training exercises (e.g., load carriage, aerobic and resistance exercises) that progressively increase in duration and intensity to increase exercise energy expenditure. Participants will perform multiple exercises per day using a variety of endurance and muscle loading modalities designed to mimic movements typically observed during real-life military operations.

Estradiol / Levonorgestrel Transdermal System [Climara Pro] is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Climara Pro for:

• Menopause symptoms
• Prevention of postmenopausal osteoporosis

Approved in European Union as Climara Pro for:

• Hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women
• Prevention of osteoporosis in postmenopausal women at high risk of future fractures

Approved in Canada as Climara Pro for:

• Menopause symptoms
• Prevention of osteoporosis in postmenopausal women

Who Is Running the Clinical Trial?

Bradley Nindl

Lead Sponsor

Trials

1

Recruited

120+

U.S. Army Medical Research and Development Command

Collaborator

Trials

296

Recruited

249,000+

Published Research Related to This Trial

Transdermal testosterone patches are being developed for women, particularly for treating sexual dysfunction in menopausal women, and are currently in phase III clinical trials.

Preliminary phase II studies indicate that the testosterone matrix patch is effective and safe for women with sexual dysfunction, showing promise as a new method for androgen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transdermal testosterone for women: a new physiological approach for androgen therapy. Mazer, NA., Shifren, JL.[2013]

In a study involving 29 hypogonadal subjects, Testim (a new 1% testosterone topical gel) demonstrated significantly higher peak serum levels (C(max)) of total testosterone, dihydrotestosterone, and free testosterone compared to AndroGel, with increases of 30%, 19%, and 38%, respectively.

Testim also showed greater overall exposure (AUC(0-24)) to testosterone than AndroGel, indicating that Testim has higher bioavailability, making it a potentially more effective option for testosterone replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim, compared to AndroGel. Marbury, T., Hamill, E., Bachand, R., et al.[2013]

Cellegy Pharmaceuticals is developing Fortigel, a 2% testosterone topical gel that aims to provide a convenient and less irritating alternative to injectable testosterone and existing dermal patches, with a focus on discreet application.

Clinical data presented at a major urological meeting indicated that Fortigel successfully restored testosterone levels to the physiological range in 92% of hypogonadal men who completed the trial, highlighting its efficacy as a hormone replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Testosterone-topical fortigel - cellegy: fortigel, tostrex. [2018]

In a study of 163 hypogonadal men using AndroGel (testosterone gel) for up to 42 months, treatment effectively normalized testosterone levels and improved sexual function and mood, while also increasing lean body mass and bone mineral density.

While there were some mild side effects like skin irritation, the treatment was generally safe, with no significant adverse changes in blood counts or biochemistry, although monitoring for prostate health is recommended due to potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. Wang, C., Cunningham, G., Dobs, A., et al.[2022]

In a study of 30 HIV-infected men, daily application of testosterone gel resulted in more stable serum testosterone levels compared to intramuscular injections, which caused significant fluctuations in testosterone concentrations.

The use of testosterone gel also led to improved quality of life scores, indicating better physical and emotional well-being compared to the intramuscular injection method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective study of topical testosterone gel (AndroGel) versus intramuscular testosterone in testosterone-deficient HIV-infected men. Scott, JD., Wolfe, PR., Anderson, P., et al.[2013]

The 7-day estradiol transdermal patch (Climara) effectively reduces hot flushes in women, with a mean decline of 74.6% for the higher dose compared to 64.5% for the lower dose, showing comparable efficacy to traditional hormone therapies.

The Climara patch is well tolerated, with a low withdrawal rate due to adverse events (8.9%), primarily related to skin reactions, and it demonstrated better adhesion compared to other patches, making it a practical option for estrogen replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy. Gordon, SF.[2019]

Testosterone gel formulations effectively restore testosterone levels to mid-normal physiological ranges within 24 hours, improving the quality of life for patients with hypogonadism.

While testosterone gels have a favorable efficacy and safety profile compared to other forms of testosterone replacement therapy, there is a risk of secondary exposure, which remains a challenge for their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new 2% testosterone gel formulation: a comparison with currently available topical preparations. Arver, S., Stief, C., de la Rosette, J., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5423263/

The Effects of Transdermal Estrogen Delivery on Bone ... In conclusion, it seems that one-two years of transdermal estrogen delivery can increase bone density, preserve BMD, and successfully protect the bone structure ...

2. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/021258s012lbl.pdf

CLIMARA PRO® (estradiol/levonorgestrel transdermal system) The Women's Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke ...

3. hcp.climarapro.com hcp.climarapro.com/postmenopausal-osteoporosis

Postmenopausal Osteoporosis | Climara Pro® | HCP Climara Pro (estradiol/levonorgestrel transdermal system) is indicated for treatment of moderate to severe vasomotor symptoms due to menopause.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6686188/

Oestrogen replacement improves bone mineral density in ... Transdermal estradiol over 12 months improves BMD in young OAA, particularly compared with an ethinyl estradiol-containing contraceptive pill/oral ...

5. ohsu.edu ohsu.edu/sites/default/files/2019-01/HRT_final-report_update-3_OCT_07.pdf

Drug Class Review on Hormone Therapy for ... Main outcomes/results. Estradiol patch/levonorgestrel. Warming ... An estradiol matrix transdermal system for the prevention of postmenopausal bone loss.

6. mayoclinic.org mayoclinic.org/drugs-supplements/estradiol-and-levonorgestrel-transdermal-route/description/drg-20112971

Estradiol and levonorgestrel (transdermal route) Estradiol and levonorgestrel combination skin patch is used treat moderate to severe symptoms of menopause (eg, feelings of warmth in the face, neck, and chest)

7. hcp.climarapro.com hcp.climarapro.com/about-climara-pro

About Climara Pro® (estradiol/levonorgestrel transdermal ... Climara Pro (estradiol/levonorgestrel transdermal system) is indicated for treatment of moderate to severe vasomotor symptoms due to menopause.

8. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eabc0fb3-da2a-482f-83a7-99b1e823a150

CLIMARA PRO- estradiol and levonorgestrel patch - DailyMed The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein ...

9. goodrx.com goodrx.com/climara-pro/what-is?srsltid=AfmBOorKaoLCXuk2d40XpX73Urt8j1Yp7ssstaGLi5aXOJVDfYKWBA_-

Climara Pro: Uses, Alternatives, Side Effects & More Climara Pro is a patch that's applied to the skin once a week. It's approved to prevent osteoporosis in people who've gone through menopause.