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5-Alpha Reductase 2 as a Marker of Resistance to 5ARI Therapy

Primary Purpose

Benign Prostatic Hyperplasia, Prostate Hyperplasia, Prostate Disease

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Finasteride
Sponsored by
Beth Israel Deaconess Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Benign Prostatic Hyperplasia focused on measuring Finasteride, 5 Alpha Reductase

Eligibility Criteria

50 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Male (physiological);
  • Age ≥ 50;
  • Eligible for treatment with 5ARI therapy;
  • Presence of lower urinary tract symptoms secondary to BPH;
  • Prostate size >40cc by digital rectal examination;
  • Absence of prostate nodule, tenderness or firmness;
  • Mildly elevated PSA's >2.5 ng/ml and ≤ 20 ng/ml;
  • Undergoing clinically indicated prostate biopsy for elevated PSA.

Exclusion Criteria:

  • Diagnosis of any prostatic malignancy or precancerous lesions (atypical glandular foci and prostatic intraepithelial neoplasia);
  • Treatment with 5ARI (Finasteride or Dutasteride) within six months of study enrollment;
  • Current urinary tract infection;
  • Previous pelvic radiation;
  • Previous treatment with demethylating drugs;
  • Diagnosis of multiple sclerosis, Alzheimer's, Parkinson's, neurological deficits in the judgment of the investigator;
  • Unable or unwilling to undergo MRI due to implants, claustrophobia, etc.

Sites / Locations

  • Beth Israel Deaconess Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Finasteride Treatment

Arm Description

Patients who are eligible will be given 5ARI therapy, Finasteride, for medical management of Benign Prostatic Hyperplasia (BPH) symptoms. Only patients with lower urinary tract symptoms (LUTS) as assessed by American Urologic Association (AUA) urinary symptom score > than 8, (suggestive of moderate LUTS) prostate size > 40cc, no prostate nodule/tenderness/firmness and increased PSA between 4-10ng/ml requiring prostate biopsy will be enrolled. Then, they will have prostate MRIs/needle biopsies and blood/urine collection followed by treatment with Finasteride (standard of care). They will be followed in urology clinic for assessment of LUTS every 6 months and Finasteride responsiveness at the 12-month time point. Prostate biopsy samples will be evaluated for SRD5A2 gene expression/methylation, hormonal androgen/estrogen levels (which will be repeated in blood samples). Prostate MRIs will assess size/inflammatory changes at the start and 3-year time points.

Outcomes

Primary Outcome Measures

Finasteride treatment effect on lower urinary tract symptom improvement by urinary symptom score
Validated questions of the AUA Urinary Symptom Score will be used every 6 months to assess efficacy of Finasteride treatment in improving lower urinary tract symptoms in the patient population. Based on previous randomized trials, it will be determined whether the patient is responsive or resistant to the treatment dependent on changes in their AUA Urinary Symptom Score at the first 12 month mark. For patients who are resistant to Finasteride, other medical or surgical treatments will be offered, and the patients will be removed from the study.

Secondary Outcome Measures

Full Information

First Posted
February 10, 2020
Last Updated
March 13, 2023
Sponsor
Beth Israel Deaconess Medical Center
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT04288427
Brief Title
5-Alpha Reductase 2 as a Marker of Resistance to 5ARI Therapy
Official Title
5-Alpha Reductase 2 as a Marker of Resistance to 5ARI Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 25, 2020 (Actual)
Primary Completion Date
November 30, 2024 (Anticipated)
Study Completion Date
April 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Beth Israel Deaconess Medical Center
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No

5. Study Description

Brief Summary
The study is being conducted to learn why some patients with Benign Prostatic Hyperplasia (BPH) do not respond to a commonly used treatment drug, Finasteride. The hope is to find ways to predict which patients will not respond to Finasteride so that, in the future, these patients can be identified prior to offering this treatment and they can be offered alternative treatment strategies in its place. The aim is to see if noninvasive techniques such as MRI can detect inflammation of the prostate to assist with early detection of those who will and who will not respond to Finasteride.
Detailed Description
Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction by age 80, rendering benign prostatic hyperplasia (BPH) the most common proliferative abnormality in humans. LUTS secondary to BPH negatively impact the quality of life of 210 million men globally, accounting for significant life years lost, in addition to costing the US healthcare system over $4 billion per year. Medical therapy for the management of BPH, which includes α-adrenergic blockers (e.g., doxazosin, terazosin, tamsulosin or alfuzosin) and 5α reductase inhibitors (5ARI, i.e., finasteride or dutasteride) targets both stromal and epithelial cells in the prostate gland. Utilization of 5ARI remains ineffective in many patients, leading to invasive therapies in many patients. 5ARI's are the only class of BPH-related drugs that reduce prostate size for the alleviation of LUTS. However, the Medical Therapy of Prostatic Symptoms (MTOPS) trial, which randomized 3047 men, showed that 34% of BPH patients did not respond to individualized treatment with finasteride or doxazosin, while combining the 5ARI and α-blocker relieved LUTS in 66% of BPH patients. Resistance to 5ARI therapy is a major factor limiting the effectiveness of these agents in the management of BPH. Therefore, understanding the molecular pathogenesis of 5ARI resistance is a High-Priority Recommendation of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Prostate Research Strategic Plan. However, it is not yet possible to predict responders vs. non-responders to 5ARI therapy, which creates a significant gap in our ability to effectively manage patients with BPH. 5α reductase (5-AR) plays a critical role in the normal development of the human prostate and in the pathogenesis and progression of prostatic diseases. There are three types of 5-AR isozymes, Steroid 5 Alpha-Reductase 1, 2 3 (SRD5A1, SRD5A2 and SRD5A3), which are encoded by three distinct corresponding genes, SRD5A1, SRD5A2 and SRD5A3. Many studies suggest that all three 5-AR enzymes are expressed in prostate tissues; however, SRD5A2 is the predominant enzyme responsible for prostate development and growth. In addition, since the most commonly prescribed 5ARI, finasteride, is an inhibitor of SRD5A2, regulation of SRD5A2 will remain the focus of this study. It was previously shown that the mechanism of somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes in the promoter region of the SRD5A2 gene. DNA methylation is one of the most common epigenetic mechanisms affecting gene expression. Methylation of Cytosine-Phosphate-Guanine (CpG) islands has been associated with the regulation of genes during development, cancer initiation, and metastasis. Since the prostate is the only solid organ that grows during adulthood as a result of androgen exposure, it can be considered a benign tumor growth throughout adulthood. Therefore, similar to the neoplastic initiation and progression of many cancers, including prostate cancer, epigenetic changes and variable expression of SRD5A2 in benign prostate tissue is a plausible molecular mechanism. Finasteride, the most commonly prescribed 5ARI, is an inhibitor of SRD5A2. Finasteride has been shown in several large clinical trials to reduce prostate size by 20%, improve urinary flow rate, and improve urinary bothersome symptom scores in men suffering from bladder outlet obstruction caused by BPH. Despite their widespread use and clinical effectiveness, 25% to 30% of patients are resistant to the therapeutic effects of 5ARIs and another 5% to 7% of patients develop worsening symptoms and ultimately may require surgery. Given their age and comorbidities, these patients are often not ideal candidates for surgery. Therefore, understanding the mechanisms of 5ARI treatment failure may pave the way for the development of new medical therapies appropriately targeted to these specific patient groups and is a desirable way to move forward with precision medicine. This proposed work is based on the premise that epigenetic changes to SRD5A2 account for the significant number of patients who are unresponsive to 5ARI therapy. The goal is to assess SRD5A2 methylation and expression as a gene signature to predict which patients will respond to 5ARI therapy. The information gained from this proposal will pave the way toward the development of predictive biomarker assays that can be used to evaluate resistance to BPH-related therapies and allow clinicians to select alternate therapies for managing the most common proliferative disorder affecting men worldwide.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Benign Prostatic Hyperplasia, Prostate Hyperplasia, Prostate Disease, Prostate Hypertrophy, Prostate Pain, Lower Urinary Tract Symptoms, Urinary Obstruction, Urinary Tract Disease
Keywords
Finasteride, 5 Alpha Reductase

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Finasteride Treatment
Arm Type
Experimental
Arm Description
Patients who are eligible will be given 5ARI therapy, Finasteride, for medical management of Benign Prostatic Hyperplasia (BPH) symptoms. Only patients with lower urinary tract symptoms (LUTS) as assessed by American Urologic Association (AUA) urinary symptom score > than 8, (suggestive of moderate LUTS) prostate size > 40cc, no prostate nodule/tenderness/firmness and increased PSA between 4-10ng/ml requiring prostate biopsy will be enrolled. Then, they will have prostate MRIs/needle biopsies and blood/urine collection followed by treatment with Finasteride (standard of care). They will be followed in urology clinic for assessment of LUTS every 6 months and Finasteride responsiveness at the 12-month time point. Prostate biopsy samples will be evaluated for SRD5A2 gene expression/methylation, hormonal androgen/estrogen levels (which will be repeated in blood samples). Prostate MRIs will assess size/inflammatory changes at the start and 3-year time points.
Intervention Type
Drug
Intervention Name(s)
Finasteride
Other Intervention Name(s)
Sequential Time Point Study
Intervention Description
Patients who are candidates to receive 5ARI therapy, Finasteride, for clinical medical management of lower urinary tract symptoms will begin treatment once deemed eligible. They will be assess every 6 months for changes in urinary symptom scores and their responsiveness to the Finasteride treatment will be assessed at the 12-month time point. MRIs of prostate taken at the start of study and at the 3 year time point will assess prostate size and changes in size as well as degree of inflammatory changes. Gene expression of SRD5A2 as well as methylation pattern will be tested on prostate tissue samples, where hormonal androgen/estrogen levels will also be assessed as they are in blood samples.
Primary Outcome Measure Information:
Title
Finasteride treatment effect on lower urinary tract symptom improvement by urinary symptom score
Description
Validated questions of the AUA Urinary Symptom Score will be used every 6 months to assess efficacy of Finasteride treatment in improving lower urinary tract symptoms in the patient population. Based on previous randomized trials, it will be determined whether the patient is responsive or resistant to the treatment dependent on changes in their AUA Urinary Symptom Score at the first 12 month mark. For patients who are resistant to Finasteride, other medical or surgical treatments will be offered, and the patients will be removed from the study.
Time Frame
Assessment of Finasteride responsiveness through changes in urinary symptoms will be completed at 6 month intervals during clinic visits, and treatment efficacy will be determined after the first 12 months.

10. Eligibility

Sex
Male
Gender Based
Yes
Gender Eligibility Description
Prostatic disease are limited to biologically male individuals.
Minimum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male (physiological); Age ≥ 50; Eligible for treatment with 5ARI therapy; Presence of lower urinary tract symptoms secondary to BPH; Prostate size >40cc by digital rectal examination; Absence of prostate nodule, tenderness or firmness; Mildly elevated PSA's >1.5 ng/ml and ≤ 40 ng/ml; Undergoing clinically indicated prostate biopsy for elevated prostate-specific antigen (PSA). Exclusion Criteria: Diagnosis of any prostatic malignancy or precancerous lesions (atypical glandular foci and prostatic intraepithelial neoplasia); Treatment with 5ARI (Finasteride or Dutasteride) within six months of study enrollment; Current urinary tract infection; Previous pelvic radiation; Previous treatment with demethylating drugs; Diagnosis of multiple sclerosis, Alzheimer's, Parkinson's, neurological deficits in the judgment of the investigator; Unable or unwilling to undergo MRI due to implants, claustrophobia, etc.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Abigail Escobar, BS
Phone
617-903-0153
Email
aescoba2@bidmc.harvard.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Christopher Mistretta, RN
Phone
617-632-8432
Email
cmistret@bidmc.harvard.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aria F. Olumi, MD
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Chris Mistretta, RN
Phone
978-821-0889
Email
cmistret@bidmc.harvard.edu
First Name & Middle Initial & Last Name & Degree
Abigail Escobar, B.S.
Phone
617-903-0153
Email
aescoba2@bidmc.harvard.edu
First Name & Middle Initial & Last Name & Degree
Aria Olumi, MD

12. IPD Sharing Statement

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5-Alpha Reductase 2 as a Marker of Resistance to 5ARI Therapy

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