Transdermal Estradiol and Exercise in Mitigating Adverse Effects of Androgen Deprivation Therapy for Prostate Cancer Radiation Therapy (ESTRACISE)

Transdermal Estradiol and Exercise in Mitigating Adverse Effects of Androgen Deprivation Therapy for Prostate Cancer Radiation Therapy: A Randomized Controlled Trial

The goal of the clinical trial is to find out whether transdermal estradiol will reduce the adverse effects of androgen deprivation therapy in prostate cancer patients.

The primary aim of this study is to estimate the efficacy of transdermal estradiol (E2) in reducing androgen deprivation therapy induced adverse effects on sexual function. A secondary aim of this study is to estimate the utility of E2 and the combination of E2 with supervised exercise in reducing other androgen deprivation therapy related adverse effects.

Participants (n=310) will use transdermal estradiol for 12 months concomitant to androgen deprivation therapy. The use of transdermal estradiol will start at the beginning of the trial, at the same time as androgen deprivation therapy. A subgroup of participants (n=120) will also be allocated to perform six months supervised resistance training.

Researchers will compare transdermal estradiol group to control group, and resistance training groups and non-training control groups.

Study Overview

• Status: Not yet recruiting
• Conditions: Prostate Cancer
• Intervention / Treatment: Drug: Transdermal estrogen; Behavioral: Resistance training; Drug: Active Comparator: Androgen deprivation therapy

Detailed Description

The current study is an open-label study examining a drug with known tolerability and safety profile (phase IIA trial). The study will recruit 310 prostate cancer patients with high-risk disease and scheduled for external beam radiation with adjuvant subcutaneous androgen deprivation therapy, leuprorelin (LHRH agonist).

Stratified randomization (n=310) will be done in a 1:1 fashion to the transdermal estradiol + androgen deprivation therapy arm or control arm (androgen deprivation therapy only). Stratified randomization will be based on two covariates, which are sexual dysfunction score and BMI. The use of the stratified randomization method will guarantee even distribution of covariates, which could likely affect the study outcomes. Additionally, a total of 120 participants who are willing to participate in the supervised resistance training program and have sufficient performance status (ECOG 0-1) will be randomized to the resistance training group or the non-training control group. A total of 30 men from each arm will be recruited to supervised training and 30 men from each arm the non-training control group. Participants of the ESTRACISE who do not participate in the exercise substudy will form a non-training group (n=95 per arm). The stratified randomization of the substudy participants in the training group or the non-training control group will be done in a 1:1 fashion before the start of the training period. Stratified randomization will be based on two main covariates, which are age and the self-reported physical activity level of the participant.

ESTRACISE participants allocated to the transdermal estradiol arm will use transdermal estradiol gel (E2) as a dose of 750 ug (EstroGel 0.6 mg/ml) in addition to androgen deprivation therapy for 12 months. Additionally, substudy participants allocated to the resistance training groups will be attending supervised group resistance training sessions twice a week for six months. The resistance training will start after six months of androgen deprivation therapy. Participants in the non-training groups are advised to stay physically active but they will do it at their own discretion.

According to the standard treatment protocol, all participants will receive androgen deprivation therapy as leuprorelin, subcutaneous injections at three months intervals for a minimum of one year, and standard external beam radiation for prostate cancer with standard clinical dosing and fractionation at the discretion of the radiation oncologist.

The research methodologies include questionnaires (expanded prostate cancer index composition 26, world health organization quality of life brief version, and patient health questionnaire), adverse event screening, medication compliance screening, computerized tomography (CT) of the thigh muscle, bioimpedance analysis (BIA), 3D-imaging of the body composition, body composition and bone mineral assessment by dual-energy x-ray absorptiometry (DXA), strength, functional capacity, physical activity measurements, and serum and plasma blood samples. In addition, muscle biopsies are collected from a subset of participants allocated in the resistance training (n=60) and non-training control groups (n=60). The primary measurement timepoints are baseline (0 months), after six months of androgen deprivation therapy, and after twelve months of androgen deprivation therapy.

Based on prior sample size estimation of primary outcome the n=310 should be more than adequate to detect statistically significant differences in the mean sexual domain score between the two study arms. The true difference in the mean is expected to be 10, with a probability (power) of 0.8, a Type 1 error probability of 0.05, and with dropout rate of 10%.

• Study Type: Interventional
• Enrollment (Estimated): 310
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Heikki Seikkula, MD, Docent; Phone Number: +358142691299; Email: heikki.seikkula@hyvaks.fi
• Study Contact Backup: Name: Ilkka Jussila, MSc.; Phone Number: +358142694546; Email: ilkka.jussila@outlook.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men with localized prostate cancer, and scheduled for external beam radiation with adjuvant subcutaneous androgen deprivation therapy, leuprorelin (LHRH agonist) for at least 12 months without any other endocrinology treatments for prostate cancer
• Adults (age over 18 years)
• Sufficient performance status (Eastern Cooperative Oncology Group, 0-1)
• Body mass index between 18.5 - 30.0
• Willingness to participate and signed consent

Exclusion Criteria:

• Patients with low-risk prostate cancer (ISUP Gleason grade 1)
• Patients with expected adjuvant androgen deprivation therapy for less than one year
• Distant bone, lymph node, or soft tissue metastasis
• Cardiac pacemaker
• Prior recent cardiovascular event or stroke (<12 months)
• Past or current venous thromboembolism
• Other untreated or unstable malignancy in risk of recurrence/progression (as judged by the treating physician)
• Concurrent glucocorticoid treatment
• Physical disabilities for regular exercise
• Any medication or condition considered as a contraindication to estradiol (allergy to adjuvant compounds (carbomer, trolamine), history with thromboembolic disorders (protein C, protein S, or antithrombin deficiency), porphyria, acute or previous liver disease, drugs with cytochrome P450 enzyme metabolism (anticonvulsants: phenobarbital, phenytoin, carbamazepine; anti-infectives: rifampicin, rifapentine, nevirapine, efavirenz; and St. John's wort)) or leuprorelin (allergy to adjuvant compounds (polylactic acid), Qt-time prolonging drugs (quinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide, methadone, moxifloxacin, antipsychotics)
• Known allergy to estradiol or leuprorelin
• Expected poor compliance or expected survival time of less than one year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Transdermal estradiol; Participants (n=155) receiving transdermal estradiol and androgen deprivation therapy.	Drug: Transdermal estrogen; Participants (n=155) receiving transdermal estradiol for 12 months.; Behavioral: Resistance training; Participants (n=30 in each arm) performing supervised resistance training for six months.
Active Comparator: Androgen deprivation therapy; Participants (n=155) receiving solely androgen deprivation therapy.	Behavioral: Resistance training; Participants (n=30 in each arm) performing supervised resistance training for six months.; Drug: Active Comparator: Androgen deprivation therapy; Participants (n=155) receiving solely androgen deprivation therapy for 12 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The efficacy of transdermal estradiol in mitigating the deterioration of EPIC-26 (The Expanded Prostate Cancer Index Composite) sexual function domain scores caused by androgen deprivation therapy.	Compared between the two arms. Scores scaled from 0 - 100, higher score means better sexual function.	Twelve and six months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The occurrence of androgen deprivation therapy induced adverse effects.	Compared between different groups. Assessed by CTCAE (Common Termionology Criteria for Adverse Events). Number of participants with androgen deprivation therapy related adverse events, and grading of adverse event from 1 - 5. Higher grading indicates worse adverse event.	Twelve and six months.
Number of participants with transdermal estradiol-related adverse events as assessed by CTCAE (Common Terminology Criteria for Adverse Events).	Transdermal estradiol arm. Number and grading of adverse events from 1 - 5. Higher grading means worse adverse event.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on one repetition maximum tests of both the leg press and barbell biceps curl, and maximal hand grip strength assessed with a dynamometer.	Compared between different groups. One repetition maximum tests and maximal hand grip strength assessed as kilograms or newtons. Higher kilograms or newtons indicates higher strength.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on explosive strength of the leg extensors assessed with a countermovement jump (CMJ).	Compared between different groups. From CMJ flight time is defined as milliseconds. Higher flight time in milliseconds represents higher jump height and explosive strength.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on 6-minute walk (functional capacity).	Compared between different groups. Walking distance and heart rate will be collected from 6-minute walk test. Higher walking distance with lower heart rate indicates better functional capacity.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on loaded 10-stair climb test (functional capacity).	Compared between different groups. Time taken to ascend and descend from 10-stair climb test. Less time taken to complete 10-stair climb test indicates better functional capacity.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on body composition.	Compared between different groups. More lean mass, and less fat mass indicates better body composition.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on bone mineral density.	Compared between different groups. Higher bone mineral density indicates better outcome.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on mid-thigh muscle mass.	Compared between different groups. Higher mid-thigh muscles cross-sectional area indicates higher mid-thigh muscle mass.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on mid-thigh fat mass.	Compared between different groups. Lower adipose tissue size indicates less mid-thigh fat mass.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on hormone (testosterone and estradiol) levels, and cancer (PSA) status.	Compared between different groups. Higher or lower hormones levels could indicate better outcome, depending on the arm of the participant, and overall status. Lower PSA concentration usually indicates better outcome.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on concentration of PVK, IL-6, TNF-α, AFOS, Alat, Krea, Cholesterol, LDL-C, HDL-C, and triglycerides).	Compared between different groups. Higher or lower concentration of biomarkers can indicate better outcome, depending on the exact biomarker.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on type I and II myofibers' cross-sectional area, myonuclei, myonuclear domain, the satellite cell count, androgen receptor and myostatin content	Compared between different groups. Higher type I and II myofibers' cross-sectional area indicates improved skeletal muscle characteristics. Higher myonuclei, myonuclear domain, satellitte cell count, and androgen and myostatin content usually indicates improved cellular function.	Twelve and six months.
Impact of transdermal estradiol with or without 6-month supervised resistance training on muscle cellular function (e.g., HSP70, alpha B-crystallin, HSP60, cytochrome c oxidase subunit IV proteins)	Compared between different groups. Higher or lower concentration of proteins could indicate improved or worsen muscle cellular function, depending on the exact protein.	Twelve and six months.
Number of participants with resistance training induced adverse events.	Compared between different groups. Assessed by CTCAE (Common Termionology Criteria for Adverse Events). Number of participants with androgen deprivation therapy related adverse events, and grading of adverse event from 1 - 5. Higher grading indicates worse adverse event.	Twelve and six months.
The World Health Organization Quality of Life Brief Version (WHOQOL-BREF).	Compared between different groups. Subdomain scores scaled from 0 to 100. Higher overall and subdomain score in WHOQOL-BREF indicates higher quality of life.	Twelve and six months.
The Patient Health Questionnaire score (PHQ-9) overall and subdomain score.	Compared between different groups. Scores scaled from 0 to 27. Higher overall score in PHQ-9 indicates more depressive symptoms.	Twelve and six months.

Collaborators and Investigators

• Sponsor: Central Finland Hospital District
• Collaborators: Tampere University; Tampere University Hospital; University of Jyvaskyla

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: November 20, 2023
• First Submitted That Met QC Criteria: February 20, 2024
• First Posted (Estimated): February 21, 2024

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Prostate cancer; Androgen deprivation therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens; Estrogens
• Other Study ID Numbers: ESTRACISE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No