MASTERS: Maintaining Suppression of Testosterone With Transdermal Estradiol Gel

• Sponsor: BHR Pharma, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02349386
• Collaborator: H2O Clinical LLC (Industry), Q2 Solutions (Industry)
• Enrollment: 34
• Locations: 12
• Arms: 4
• Actual Duration (Months): 30.4
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The objective of this clinical study is to evaluate the safety and efficacy of three different doses of BHR-200 (0.36% transdermal estradiol gel) compared to placebo for the maintenance of testosterone (T) suppression in men with advanced androgen-sensitive prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Cancer of the Prostate	Drug: BHR-200 (0.36% transdermal 17β-estradiol gel); Drug: Placebo	Phase 2

Detailed Description

This is a multi-center, randomized, double-blind, placebo-controlled, dose finding study in men with advanced androgen-sensitive prostate cancer. Patients who give informed consent will have screening evaluations, and if fulfilling the entry criteria, will be randomized to one of 4 treatment groups: 1mL, 2mL or 3mL of 0.36% BHR-200 (transdermal estradiol gel) or Placebo. Study drug will be initiated on the day they were scheduled to receive next depot GnRH agonist injection. Patients will be offered low-dose radiation to aid in the prevention of gynecomastia. Patients will apply the study drug once per day. The first dose of study gel will be applied under the supervision of the PI/designee. Subsequent doses will be self-administered daily by the patient until he is no longer chemically castrated (testosterone levels increase above 50 ng/dL), a rise over baseline PSA of > 0.5 ng/mL is observed, or he has completed 52 weeks of study drug administration. At the conclusion of study participation, patients will be advised to resume standard of care treatment under the supervision of their healthcare provider. While on treatment, patients will be evaluated at Day 1 and every 2 weeks, for the first 24 weeks and every 4 weeks thereafter with a final post-treatment follow-up visit 2 weeks (+/- 1 week) post last dose administration.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of BHR-200 (0.36% Transdermal Estradiol Gel) for the Maintenance of Testosterone Suppression in Men With Advanced Androgen-Sensitive Prostate Cancer
• Actual Study Start Date: Jul 1, 2015
• Actual Primary Completion Date: Jun 14, 2017
• Actual Study Completion Date: Jan 10, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BHR-200 Low Dose 3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks.	Drug: BHR-200 (0.36% transdermal 17β-estradiol gel); An absorptive hydroalcoholic gel preparation containing 17β-estradiol.; Other Names: BHR-200
Experimental: BHR-200 Mid Dose 6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks.	Drug: BHR-200 (0.36% transdermal 17β-estradiol gel); An absorptive hydroalcoholic gel preparation containing 17β-estradiol.; Other Names: BHR-200
Experimental: BHR-200 High Dose 9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks.	Drug: BHR-200 (0.36% transdermal 17β-estradiol gel); An absorptive hydroalcoholic gel preparation containing 17β-estradiol.; Other Names: BHR-200
Placebo Comparator: Placebo 1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks.	Drug: Placebo; An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.

Outcome Measures

Primary Outcome Measures

1. Maintenance of Testosterone Suppression at Week 12 [Week 12]

   Primary Efficacy Endpoint was the percentage of patients failing to maintain castrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 4 to 12.

Secondary Outcome Measures

1. Maintenance of Testosterone Suppression at Week 24 [Week 24]

   Pproportion of patients failing to maintaincastrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 4 to 24.

2. Number of Patients Reporting Thromboembolic Adverse Events [To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study]

   Number of patients and severity of thromboembolic adverse events

Other Outcome Measures

1. Luteinizing Hormone (LH) [Reported for Baseline, Week 12, Week 24, Week 36 and Week 48]

   Serum concentrations of luteinizing hormone (LH)

2. Sex Hormone Binding Globulin (SHBG) [Reported for Baseline, Week 12, Week 24, Week 36 and Week 48]

   Serum concentrations of sex hormone binding globulin (SHBG)

3. Prostate Specific Antigen (PSA) [To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study]

   Serum concentrations of prostate specific antigen (PSA)

4. Follicle-stimulating Hormone (FSH) [Reported for Baseline, Week 12, Week 24, Week 36 and Week 48]

   Serum concentrations of follicle-stimulating hormone (FSH)

5. Maintenance of Testosterone Suppression at Week 52/ End of Study [Double-blind 28-Week Optional Extension Study from Week 24 to Week 52/End of Study]

   Proportion of patients failing to maintain castrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 24 to 52/End of Study

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Males, Ages 18 and older

2. Body Mass Index (BMI) between 18 and 35 kg/m2 (inclusive)

3. Not currently hospitalized

4. Clinical indication of adenocarcinoma of the prostate evidenced by a biopsy report on record

5. At present receiving ADT treatment with a GnRH agonist for at least 2 months but not longer than 36 months without interruption - Note: If the patient received GnRH agonist treatment prior to the treatment described under 5, there must be evidence of a period without GnRH agonist treatment for a minimum of 2 months prior to starting the present treatment as is seen, for example with intermittent treatment regimens.

6. Able to initiate Screening procedures 2 weeks prior to the next scheduled injection with a GnRH agonist

7. Willing to discontinue current ADT regimen for the duration of the study

8. T level less than 50 ng/dL at Screening

9. WHO/ECOG performance status of 0 or 1

10. Life expectancy of at least 1 year

11. Adequate renal function demonstrated by having normal blood urea nitrogen (BUN) and Creatinine Screening lab values

Exclusion Criteria:

1. History or presence of allergic or adverse response to estradiol

2. Presence of symptomatic metastatic disease, risk of spinal cord compression or urinary obstruction

3. History within the past 2 years of deep vein thrombosis (DVT), pulmonary embolism (PE2), a known thrombophilic disorder (eg.protein C, protein S, or antithrombin deficiency), or cerebrovascular accident (CVA)

4. History within the past 2 years of myocardial infarction or a coronary vascular procedure (e.g. percutaneous coronary intervention, coronary artery bypass graft)

5. History of congestive heart failure

6. Use of any investigational drug, biologic, or device within 28 days prior to the first dose of study gel

7. Use of any of the following known inducers or inhibitors of cytochrome P450 3A4 (CYP3A4): phenobarbital, carbamazepine, rifampin, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, St. John's Wort preparations (Hypericum perforatum), and grapefruit juice

8. Hematological parameters (Hematocrit or Hemoglobin) outside 20% of the upper or lower limits of normal at Screening

9. Active skin rash, sunburn, or other skin disorder on the upper arm(s) that requires treatment or may affect skin absorption of study gel

10. Resting uncontrolled hypertension (HTN) (160/100 mmHg) at Screening

11. Co-existent malignancy or a history of malignancy during the past 5 years, with the exception of basal and/or squamous cell carcinoma of the skin

12. Any other significant concurrent illness or disease or condition that in the opinion of the Investigator might interfere with the patient's ability to receive the treatment outlined in the protocol or might put him at additional risk

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Urological Associates of Southern Arizona	Tucson	Arizona	United States	85741
2	South Florida Medical Research	Aventura	Florida	United States	33180
3	Advanced Urology Institute	Daytona Beach	Florida	United States	32114
4	Adult Pediatric Urology, PC	Council Bluffs	Iowa	United States	51501
5	Adult Pediatric Urology, PC	Omaha	Nebraska	United States	68114
6	Delaware Valley Urology	Voorhees	New Jersey	United States	08043
7	AccumetRX Clinical Trials	Albuquerque	New Mexico	United States	87109
8	Associated Medical Professionals of NY (AMP of NY)	Syracuse	New York	United States	13210
9	Eastern Urological Associates	Greenville	North Carolina	United States	27834
10	Urologic Consultants of Southeastern Pennsylvania (UCSEPA)	Bala-Cynwyd	Pennsylvania	United States	19044
11	Carolina Urologic Research Center	Myrtle Beach	South Carolina	United States	29572
12	Urology Clinics of North Texas	Dallas	Texas	United States	75231

Sponsors and Collaborators

• BHR Pharma, LLC
• H2O Clinical LLC
• Q2 Solutions

Investigators

• Study Director: Roland Gerritsen van der Hoop, MD, PhD, BHR Pharma, LLC

Study Documents (Full-Text)

• Study Protocol - Jun 13, 2016
• Statistical Analysis Plan - Aug 19, 2017

More Information

Publications

• Bland LB, Garzotto M, DeLoughery TG, Ryan CW, Schuff KG, Wersinger EM, Lemmon D, Beer TM. Phase II study of transdermal estradiol in androgen-independent prostate carcinoma. Cancer. 2005 Feb 15;103(4):717-23.
• Cox RL, Crawford ED. Estrogens in the treatment of prostate cancer. J Urol. 1995 Dec;154(6):1991-8. Review.
• Langley RE, Cafferty FH, Alhasso AA, Rosen SD, Sundaram SK, Freeman SC, Pollock P, Jinks RC, Godsland IF, Kockelbergh R, Clarke NW, Kynaston HG, Parmar MK, Abel PD. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). Lancet Oncol. 2013 Apr;14(4):306-16. doi: 10.1016/S1470-2045(13)70025-1. Epub 2013 Mar 4.
• Langley RE, Godsland IF, Kynaston H, Clarke NW, Rosen SD, Morgan RC, Pollock P, Kockelbergh R, Lalani el-N, Dearnaley D, Parmar M, Abel PD. Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer. BJU Int. 2008 Aug;102(4):442-5. doi: 10.1111/j.1464-410X.2008.07583.x. Epub 2008 Apr 16.
• Lycette JL, Bland LB, Garzotto M, Beer TM. Parenteral estrogens for prostate cancer: can a new route of administration overcome old toxicities? Clin Genitourin Cancer. 2006 Dec;5(3):198-205. Review.
• Ockrim J, Lalani el-N, Abel P. Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy. Nat Clin Pract Oncol. 2006 Oct;3(10):552-63. Review.
• Ockrim JL, Abel PD. Long term androgen deprivation therapy in prostate cancer. BMJ. 2008 Sep 22;337:a1361. doi: 10.1136/bmj.a1361.
• Ockrim JL, Lalani el-N, Kakkar AK, Abel PD. Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism. J Urol. 2005 Aug;174(2):527-33; discussion 532-3.
• Ockrim JL, Lalani EN, Laniado ME, Carter SS, Abel PD. Transdermal estradiol therapy for advanced prostate cancer--forward to the past? J Urol. 2003 May;169(5):1735-7.
• Sayed Y, Taxel P. The use of estrogen therapy in men. Curr Opin Pharmacol. 2003 Dec;3(6):650-4. Review.

• Responsible Party: BHR Pharma, LLC
• ClinicalTrials.gov Identifier: NCT02349386
• Other Study ID Numbers: BHR-200-201
• First Posted: Jan 28, 2015
• Last Update Posted: Mar 31, 2022
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Prostatic Neoplasms; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Period Title: 24-Week Double-Blind Main Study
STARTED	9	8	9	8
COMPLETED	3	2	4	0
NOT COMPLETED	6	6	5	8
Period Title: 24-Week Double-Blind Main Study
STARTED	3	2	4	0
COMPLETED	1	2	1	0
NOT COMPLETED	2	0	3	0

Baseline Characteristics

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo	Total
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.	Total of all reporting groups
Overall Participants	9	8	9	8	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 22.2%	2 25%	1 11.1%	1 12.5%	6 17.6%
>=65 years	7 77.8%	6 75%	8 88.9%	7 87.5%	28 82.4%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%
Male	9 100%	8 100%	9 100%	8 100%	34 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 33.3%	3 37.5%	1 11.1%	1 12.5%	8 23.5%
White	6 66.7%	5 62.5%	8 88.9%	7 87.5%	26 76.5%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	9 100%	8 100%	9 100%	8 100%	34 100%

Outcome Measures

1. Primary Outcome

Title	Maintenance of Testosterone Suppression at Week 12
Description	Primary Efficacy Endpoint was the percentage of patients failing to maintain castrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 4 to 12.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) population contains all patients who are randomized into the study. All efficacy parameters were analyzed using the ITT population. In the case of a patient who was randomized but did not take the study drug, the analysis was done for this patient using the randomized treatment.

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	8	8	8	7
Count of Participants [Participants]	3 33.3%	3 37.5%	5 55.6%	2 25%

2. Secondary Outcome

Title	Maintenance of Testosterone Suppression at Week 24
Description	Pproportion of patients failing to maintaincastrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 4 to 24.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) population contains all patients who are randomized into the study. All efficacy parameters were analyzed using the ITT population. In the case of a patient who was randomized but did not take the study drug, the analysis was done for this patient using the randomized treatment.

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	8	8	5	6
Count of Participants [Participants]	3 33.3%	2 25%	3 33.3%	0 0%

3. Secondary Outcome

Title	Number of Patients Reporting Thromboembolic Adverse Events
Description	Number of patients and severity of thromboembolic adverse events
Time Frame	To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	9	8	9	8
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%

4. Other Pre-specified Outcome

Title	Luteinizing Hormone (LH)
Description	Serum concentrations of luteinizing hormone (LH)
Time Frame	Reported for Baseline, Week 12, Week 24, Week 36 and Week 48

Outcome Measure Data

Analysis Population Description

Safety population: contains all patients who received at least one dose of study drug.

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	9	8	9	8
Baseline LH	0.380 (0.5700)	0.470 (0.5949)	0.190 (0.0000)	0.530 (0.9576)
Week 12 LH	0.227 (0.0635)	0.527 (0.5831)	1.597 (2.1889)	2.050 (2.1920)
Week 24 LH	0.997 (0.7267)	0.395 (0.2899)	0.393 (0.4050)
Week 36 LH	0.645 (0.6435)	0.345 (0.2192)	3.750 (4.7376)
Week 48 LH	0.600 (0)	0.300 (0.1414)	0.300 (0)

5. Other Pre-specified Outcome

Title	Sex Hormone Binding Globulin (SHBG)
Description	Serum concentrations of sex hormone binding globulin (SHBG)
Time Frame	Reported for Baseline, Week 12, Week 24, Week 36 and Week 48

Outcome Measure Data

Analysis Population Description

Safety population: contains all patients who received at least one dose of study drug.

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	9	8	9	8
Baseline SHBG	49.7 (17.65)	52.8 (22.48)	45.8 (15.64)	48.8 (24.09)
Week 12 SHBG	48.7 (18.01)	55.7 (3.06)	55.2 (10.62)	27.0 (2.83)
Week 24 SHBG	50.3 (15.63)	52.0 (4.24)	71.3 (8.62)
Week 36 SHBG	37.0 (7.07)	53.5 (3.54)	47.0 (12.73)
Week 48 SHBG	46.0 (0)	42.5 (7.78)	58.0 (0)

6. Other Pre-specified Outcome

Title	Prostate Specific Antigen (PSA)
Description	Serum concentrations of prostate specific antigen (PSA)
Time Frame	To Week 52/End of Study: Both 24-Week Main Study and Optional 28-Week Extension Study

Outcome Measure Data

Analysis Population Description

Safety population: contains all patients who received at least one dose of study drug.

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	9	8	9	8
Baseline PSA	0.374 (0.4572)	0.921 (1.1726)	8.058 (22.2814)	0.334 (0.5623)
Week 4 PSA	0.459 (0.6234)	1.483 (2.2501)	5.170 (13.1114)	0.481 (0.6153)
Week 8 PSA	0.545 (0.7978)	1.145 (1.6158)	4.995 (12.0050)	0.870 (0.9449)
Week 12 PSA	0.330 (0.3251)	0.227 (0.2367)	4.380 (10.4936)	1.395 (1.8455)
Week 16 PSA	0.297 (0.2684)	0.160 (0.1212)	6.960 (11.8992)	0.090 (0)
Week 20 PSA	0.330 (0.3251)	0.127 (0.0635)	5.345 (10.5033)
Week 24 PSA	0.363 (0.3099)	0.145 (0.0778)	4.745 (9.3033)
Week 28 PSA	0.430 (0.3110)	0.090 (0)	4.863 (8.2590)
Week 32 PSA	0.463 (0.3272)	0.145 (0.0778)	4.563 (7.7394)
Week 36 PSA	0.650 (0.0707)	0.145 (0.0778)	7.050 (9.5459)
Week 40 PSA	0.750 (0.2121)	0.145 (0.0778)	7.800 (0)
Week 44 PSA	0.500 (0)	0.145 (0.0778)	12.600 (0)
Week 48 PSA	0.700 (0)	0.145 (0.0778)	12.800 (0)
Week 52 PSA	0.700 (0)	0.145 (0.0778)	13.300 (0)

7. Other Pre-specified Outcome

Title	Follicle-stimulating Hormone (FSH)
Description	Serum concentrations of follicle-stimulating hormone (FSH)
Time Frame	Reported for Baseline, Week 12, Week 24, Week 36 and Week 48

Outcome Measure Data

Analysis Population Description

Safety population: contains all patients who received at least one dose of study drug.

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	9	8	8	8
Baseline FSH	4.478 (1.9911)	5.225 (1.8093)	3.963 (2.1354)	5.700 (2.0901)
Week 12 FSH	0.630 (0.2339)	0.493 (0.0058)	3.848 (5.0343)	9.450 (5.4447)
Week 24 FSH	1.600 (0.9165)	0.795 (0.4313)	0.848 (0.5219)
Week 36 FSH	2.050 (1.3435)	1.095 (0.8556)	10.600 (12.7279)
Week 48 FSH	2.00 (0)	0.795 (0.4313)	1.500 (0)

8. Other Pre-specified Outcome

Title	Maintenance of Testosterone Suppression at Week 52/ End of Study
Description	Proportion of patients failing to maintain castrate levels of T (T < 50 ng/dL). Testosterone suppression, defined as the absence of any T level measurement over 50 ng/dL during Weeks 24 to 52/End of Study
Time Frame	Double-blind 28-Week Optional Extension Study from Week 24 to Week 52/End of Study

Outcome Measure Data

Analysis Population Description

Intent-to-Treat

Arm/Group Title	BHR-200 Low Dose	BHR-200 Mid Dose	BHR-200 High Dose	Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.	1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
Measure Participants	3	2	4	0
Count of Participants [Participants]	1 11.1%	2 25%	2 22.2%	0 0%

Adverse Events

Time Frame	AEs were captured for the duration of the study. The reporting period began with the first dose of Study Drug (Study Day 1) and ends at Week 24 or the End of Study. For participants who opted to enroll in the 28-week open-label extension study, AE collection continued to Week 52 or the End of Study.
Arm/Group Title	BHR-200 Low Dose		BHR-200 Mid Dose		BHR-200 High Dose		Placebo
Arm/Group Description	3 mg estradiol per 1 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.		6 mg estradiol per 2 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.		9 mg estradiol per 3 mL 0.36% BHR-200 (transdermal 17β-estradiol gel) applied daily to the skin for up to 52 weeks. BHR-200 (0.36% transdermal 17β-estradiol gel): An absorptive hydroalcoholic gel preparation containing 17β-estradiol.		1, 2 or 3 mL of Placebo gel containing 0 mg estradiol applied daily for up to 52 weeks. Placebo: An absorptive hydroalcoholic gel preparation gel of the same ingredients as BHR-200, but without 17β-estradiol.
All Cause Mortality
	BHR-200 Low Dose		BHR-200 Mid Dose		BHR-200 High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Serious Adverse Events
	BHR-200 Low Dose		BHR-200 Mid Dose		BHR-200 High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/8 (0%)		2/9 (22.2%)		0/8 (0%)
Gastrointestinal disorders
Small intestinal obstruction	0/9 (0%)	0	0/8 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Surgical and medical procedures
Lymphoid tissue operation	0/9 (0%)	0	0/8 (0%)	0	1/9 (11.1%)	1	0/8 (0%)	0
Other (Not Including Serious) Adverse Events
	BHR-200 Low Dose		BHR-200 Mid Dose		BHR-200 High Dose		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/9 (77.8%)		5/8 (62.5%)		9/9 (100%)		4/8 (50%)
Blood and lymphatic system disorders
Anaemia	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Eye disorders
Diplopia	0/9 (0%)		0/8 (0%)		2/9 (22.2%)		0/8 (0%)
Gastrointestinal disorders
Abdominal pain upper	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Dry mouth	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Small intestinal obstruction	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
General disorders
Application site pain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Oedema peripheral	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Infections and infestations
Nasopharyngitis	1/9 (11.1%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Sinusitis	0/9 (0%)		1/8 (12.5%)		1/9 (11.1%)		0/8 (0%)
Urinary tract infection	0/9 (0%)		0/8 (0%)		2/9 (22.2%)		0/8 (0%)
Acute sinusitis	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Bronchiolitis	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Escherichia urinary tract infection	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Urinary tract infection enterococcal	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Injury, poisoning and procedural complications
Incisional hernia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Wrist fracture	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Investigations
Blood pressure increased	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Metabolism and nutrition disorders
Dehydration	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Hypercholesterolaemia	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Hypocalcaemia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Increased appetite	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Vitamin D deficiency	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Back pain	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Flank pain	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Muscle tightness	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Musculoskeletal pain	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Nervous system disorders
Burning sensation	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Headache	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Neuropathy peripheral	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Sciatica	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Syncope	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Psychiatric disorders
Depression	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Insomnia	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Renal and urinary disorders
Azotaemia	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Haematuria	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)
Nocturia	0/9 (0%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Urinary incontinence	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Urinary retention	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Reproductive system and breast disorders
Breast tenderness	2/9 (22.2%)		3/8 (37.5%)		1/9 (11.1%)		0/8 (0%)
Nipple pain	1/9 (11.1%)		1/8 (12.5%)		3/9 (33.3%)		0/8 (0%)
Breast enlargement	1/9 (11.1%)		1/8 (12.5%)		1/9 (11.1%)		0/8 (0%)
Gynaecomastia	1/9 (11.1%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Nipple disorder	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/9 (11.1%)		1/8 (12.5%)		0/9 (0%)		0/8 (0%)
Dyspnoea	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Rash	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		1/8 (12.5%)
Pruritus	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Surgical and medical procedures
Lymphoid tissue operation	0/9 (0%)		0/8 (0%)		1/9 (11.1%)		0/8 (0%)
Tooth extraction	0/9 (0%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Vascular disorders
Hypertension	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		1/8 (12.5%)
Hypotension	0/9 (0%)		0/8 (0%)		2/9 (22.2%)		0/8 (0%)
Hot flush	1/9 (11.1%)		0/8 (0%)		0/9 (0%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.