New Treatment Strategies and Epigenetic Biomarker for Management of Benign Prostatic Hyperplasia

NCT ID: NCT06944145

Last Updated: 2025-12-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 242 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-12-03
• Study Completion Date: 2030-08-31

Brief Summary

SRD5A2 is a critical enzyme for prostatic development and growth, and the SRD5A2 inhibitor, finasteride, is used to treat benign prostatic hyperplasia (BPH). SRD5A2 is absent in 30% of normal adult men, which explains the resistance of a subset of patients to this commonly prescribed drug. This project proposes new combination therapies (5-ARI+raloxifene) and evaluates novel non-invasive biomarkers, based on alternative pathways that lead to prostatic enlargement.

Detailed Description

Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction by age 80 secondary to benign prostatic hyperplasia (BPH). BPH, the most common proliferative abnormality in humans, negatively impact the quality of life of 210 million men globally, accounting for significant life years lost. This study proposes to clinically evaluate the mechanisms of resistance to 5α-reductase inhibitor, finasteride, one of the more common drugs used to manage BPH and associated LUTS. Ongoing work has focused on steroid 5α-reductase 2 (SRD5A2, aka: 5α-reductase 2 [5AR2]), the enzyme responsible for prostatic development and growth. Investigations have revealed that expression of SRD5A2 is variable, and in fact, 30% of men do not express SRD5A2 in prostate tissues. Previous work, shows that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Studies indicate that (1) methylation of the SRDA2 is regulated by direct binding of the DNA-methyl transferase 1 (DNMT1) protein to the SRD5A2 promoter; (2) the inflammatory mediators TNF-α, NF-kB, and IL-6 regulate DNMT1 binding and subsequent methylation of the SRD5A2 promoter region; (3) clinical conditions associated with increased inflammation, age, and obesity, are associated with decreased expression of SRD5A via epigenetic modification; (4) in the absence of prostatic SRD5A2, alternate estrogenic pathways are upregulated, leading to an androgenic-to-estrogenic switch in the prostate gland, thus creating alternate pathways for prostatic growth. Therefore, it is hypothesized that (1) non- invasive assessment of SRD5A2 methylation status in peripheral blood can be an excellent indicator for resistance to 5ARI therapy, and (2) in men demonstrating hypermethylation of SRD5A2 and low protein expression (patients suspected of being resistant to 5ARI therapy), combination therapy (Selective Estrogen Receptor Modulators [SERMs]+5ARI) will serve as a better treatment strategy. To demonstrate the clinical significance of epigenetic changes to SRD5A2 and confirm its role in regulating sensitivity to 5ARI treatment, and to examine the role of estrogenic signaling blockade, a clinical trial is proposed with: Specific Aim 1: To assess the role of combination therapy (5ARI + SERM) in the treatment of BPH and to determine whether methylation of SRD5A2 promoter is a predictor for response to therapy. Specific Aim 2: To prospectively evaluate whether non-invasive radiologic prostate inflammatory markers can predict circulating WBCs SRD5A2 promoter methylation.

Conditions

BPH (Benign Prostatic Hyperplasia); Lower Urinary Track Symptoms

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Finasteride + Inactive Placebo Monotherapy

Participants may be randomized into the Finasteride + Inactive Placebo Monotherapy arm.

Group Type: ACTIVE_COMPARATOR

Finasteride

Intervention Type: DRUG

Participants randomized to the Finasteride + Inactive Placebo Monotherapy arm will self-administer finasteride at 5 mg orally/day and placebo capsule daily.

Finasteride + Raloxifene Combination Therapy

Participants may be randomized into the Finasteride + Raloxifene Combination Therapy arm.

Group Type: EXPERIMENTAL

raloxifene

Intervention Type: DRUG

Participants in the Finasteride + Raloxifene Combination Therapy Arm will receive both Finasteride and Raloxifene as their intervention.

Participants randomized to the Finasteride + Raloxifene Combination Therapy arm will self-administer finasteride at 5 mg orally/day and raloxifene at 60 mg orally/day.

Finasteride

Intervention Type: DRUG

Participants randomized to the Finasteride + Inactive Placebo Monotherapy arm will self-administer finasteride at 5 mg orally/day and placebo capsule daily.

Interventions

raloxifene

Participants in the Finasteride + Raloxifene Combination Therapy Arm will receive both Finasteride and Raloxifene as their intervention.

Participants randomized to the Finasteride + Raloxifene Combination Therapy arm will self-administer finasteride at 5 mg orally/day and raloxifene at 60 mg orally/day.

Intervention Type: DRUG

Finasteride

Participants randomized to the Finasteride + Inactive Placebo Monotherapy arm will self-administer finasteride at 5 mg orally/day and placebo capsule daily.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. ≥18 yrs old on the day of study consent;

2. Finasteride has been recommended for treatment of BPH by a physician;

3. PSA <20ng/ml within the last six months;

4. Willingness to maintain any current genitourinary medications (e.g., beta agonists, alpha blockers, anticholinergics);

5. Patient is able and willing to provide written informed consent.

Exclusion Criteria

1. Active or past history of venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis;

2. Previous diagnosis with any prostatic malignancy or precancerous lesions (atypical glandular foci);

3. History of pelvic radiation;

4. Actively receiving intravesical therapy for bladder cancer;

5. Received treatment with any demethylating medications (azacitidine, decitabine, zebularine, guadecitabine, hydralazine);

6. Current use of warfarin;

7. Prior treatment with 5ARI medications (e.g., Finasteride or Dutasteride) in the last year;

8. Diagnosed with diabetes mellitus;

9. Diagnosed with any neurodegenerative diseases;

10. History of allergic reaction to any intravenous (IV) iron replacement products;

11. Currently taking cholestyramine medication;

12. Contraindications to MRI examination, which may include:

• Cardiac pacemaker
• Intracranial clips, metal implants, or external clips within 10mm of the head
• Previous metal injury in the eye or occupation risk to ferrous metal in the eye (e.g. metalworker)
• Claustrophobia that cannot be managed with benzodiazepine

• Minimum Eligible Age: 18 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Aria F. Olumi, MD

Chief, Division of Urology, BIDMC

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Aria Olumi, MD

Role: PRINCIPAL_INVESTIGATOR

Beth Israel Deaconess Medical Center

Locations

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Yulia Mulugeta

Role: CONTACT

ymuluget@bidmc.harvard.edu

617-632-8890

Facility Contacts

Yulia Mulugeta

Role: primary

ymuluget@bidmc.harvard.edu

617-632-8890

Other Identifiers

R01DK142211

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2025P000440

Identifier Type: -

Identifier Source: org_study_id