Hormone Therapy for Musculoskeletal Health

(ARMOR Trial)

Overseen By Kristin J Koltun, PhD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

Sponsor: Bradley Nindl

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

Disqualifiers: Heart condition, Hypertension, Diabetes, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Non-combat-related muscle, tendon and bone injuries are the most common injuries suffered by military personnel, particularly in new recruits. These injuries impact military readiness and are responsible for roughly 60% of limited duty days, 65% of soldiers who are unable to deploy, and nearly $500 million in medical cost to the government annually in the Army alone. Drug interventions must be studied and developed to prevent these negative outcomes and prepare military personnel for the demands of military service. At the current time, military leadership has identified critical gaps in understanding how to minimize these injuries and train soldiers with drug intervention serving among those gaps. The goal of this study is to determine how a hormonal intervention can change muscle, tendon, and bone function as well as physical and psychological performance in response to mental and physical stress. To do so, we will examine sex hormone (testosterone, estrogen) levels, muscle, tendon, and bone images, blood samples, and physical and mental performance. We will look at things like changes in hormone levels, chemicals released from active skeletal muscles, and your body composition. The results from this study will be used to improve physical readiness training in the military with the goal of reducing injuries.

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 data supports the effectiveness of the drug Estradiol / Levonorgestrel Transdermal System [Climara Pro] and Testosterone gel (AndroGel) for musculoskeletal health?

Research shows that long-term use of Testosterone gel (AndroGel) in men with low testosterone levels improves bone mineral density, which is important for musculoskeletal health. Additionally, the estradiol transdermal system (Climara) is effective for estrogen replacement therapy, which can also support bone health. ^{1 2 3 4 5}

Is hormone therapy for musculoskeletal health generally safe for humans?

Testosterone gel treatments like AndroGel have been shown to be generally safe, with mild skin irritation being the most common side effect. However, there is a need for monitoring for prostate issues and blood changes, as some cases of prostate cancer and increased blood counts have been reported. ^{1 2 3 4 6}

How does this drug differ from other treatments for musculoskeletal health?

This drug combines hormone therapy with a transdermal (through the skin) delivery system, using a combination of estradiol, levonorgestrel, goserelin, and testosterone gel, which is unique in providing sustained hormone levels and potentially improving musculoskeletal health. The use of transdermal testosterone gel, like AndroGel, offers a more consistent hormone level compared to injections, which can cause fluctuations. ^{1 2 3 4 7}

Research Team

Bradley C Nindl, PhD

Principal Investigator

University of Pittsburgh

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

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

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.

Participant Groups

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 Canada for the following indications:

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim, compared to AndroGel. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

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

3. United States 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Prospective study of topical testosterone gel (AndroGel) versus intramuscular testosterone in testosterone-deficient HIV-infected men. [2013]

5. New Zealand pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

A new 2% testosterone gel formulation: a comparison with currently available topical preparations. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Transdermal testosterone for women: a new physiological approach for androgen therapy. [2013]