Effects of TNF Blockade on Human BPH/LUTS

Overview

Specific Aim 1. To evaluate the efficacy of TNF antagonist action in BPH/LUTS Specific Aim 2. Define the consequences of TNF antagonist therapy on prostate tissue Specific Aim 3. Identify genetic predictors to stratify patients with differential response to TNF-antagonist therapy.

Detailed description

The purpose of this study is to investigate whether an anti-inflammatory drug commonly used for a range of autoimmune diseases may be useful to provide symptomatic relief, prostate shrinkage, and/or decrease prostatic inflammation in patients with benign prostatic hyperplasia (BPH), sometimes described as prostatic enlargement.

BPH includes a significant amount of inflammation. Prior studies show that there are common links between autoimmune diseases, inflammation, and BPH. TNF-antagonists such as adalimumab are anti-inflammatory drugs commonly prescribed to treat autoimmune diseases. NorthShore researchers, including Drs. Glaser, Hayward, and Helfand, showed that these drugs reduced the incidence of BPH in patients with autoimmune diseases.

In this study, the investigators will study the TNF-antagonist adalimumab in patients with BPH who do not have autoimmune diseases. Adalimumab used in this study is investigational because it is not approved by the FDA for BPH. However, adalimumab is an approved, widely-prescribed, and commonly used drug utilized in a variety of conditions including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It has a well-studied side effect profile and was approved for use by the FDA in 2008. The purpose of this study is to determine whether adalimumab is an effective way to reduce symptoms and/or prostatic inflammation in BPH patients without autoimmune diseases. If this research is successful it may open up a new method of therapy for patients with BPH and associated symptoms.

This study will include a total of 70 subjects. Of those subjects, all 70 will be from NorthShore University HealthSystem ("NorthShore").

Interventions

• Drug Adalimumab
  Adalimumab will be delivered subcutaneously (under the skin) at a dose of 40mg every 2 weeks for a total of 6 doses.

Primary outcome measures

• International Prostate Symptom Score [Time frame: The past 30 days]
• Safety as measured by Clavien-Dindo grading system [Time frame: Through study completion (Week 24)]

Secondary outcome measures (8)

• LURN Symptom Index 29 (LURN SI-29) [Time frame: The past 7 days]
• The Patient-Reported Outcomes Measurement Information System (PROMIS-29) Profile v2.1 [Time frame: The past 7 days]
• Patient Global Impression of Improvement (PGI-I) [Time frame: Through study completion (Week 24)]
• 3-Day Voiding Diary [Time frame: Recorded on three separate days]
• Change in maximum flow rate (uroflowmetry) [Time frame: Through study completion (Week 24)]
• Change in PVR (post-void residual) [Time frame: Through study completion (Week 24)]
• Change in prostate volume [Time frame: 12 weeks]
• Change in systemic markers of inflammation (ESR, CRP) [Time frame: 12 weeks]

Eligibility criteria

Inclusion criteria

• Male sex
• Age 45-80 years
• Diagnosed by physician with BPH
• Prostate volume ≥ 60mL
• IPSS ≥ 8
• Able and willing to complete questionnaires
• Able and willing to provide informed consent
• Able to read, write, and speak in English
• No prior treatment with TNF inhibitor (adalimumab, etanercept, infliximab, certolizumab, golimumab)
• No plans to move from study area in the next 6 months

Deferral Criteria:

• Microscopic hematuria without appropriate workup per AUA/Society of Urodynamics, Female Pelvic Medicine \& Urogenital Reconstruction (SUFU) Guidelines
• Positive urine culture

Exclusion criteria

• Female sex or intersex
• Age < 45 or > 80 years
• Being a prisoner or detainee
• Urinary retention with need for catheterization
• Gross hematuria
• Contraindication to treatment with adalimumab (e.g., presence of sepsis or active infection, active tuberculosis, Hepatitis B infection, invasive fungal infection, lymphoma, leukemia or other active malignancy, congestive heart failure, significant hematologic abnormality, allergy to adalimumab or its components, anti-drug antibodies, congestive heart failure)
• Diagnosis of autoimmune disease (rheumatoid arthritis, plaque psoriasis, ulcerative colitis, Crohn's disease, hidradenitis suppurativa, spondyloarthritis)
• Interstitial cystitis
• Pelvic or endoscopic genitourinary surgery within the preceding 6 months (not including diagnostic cystoscopy)
• History of lower urinary tract or pelvic malignancy including prostate cancer; history of pelvic radiation therapy
• Ongoing symptomatic urethral stricture
• Current chemotherapy or other cancer therapy
• Severe neurological or psychiatric disorder that would prevent study participation (e.g., bipolar disorder, psychotic disorder, Alzheimer's Disease)
• Current moderate or severe substance use disorder

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• NorthShore University HealthSystem — Glenview

Publications

• Vickman RE, Aaron-Brooks L, Zhang R, Lanman NA, Lapin B, Gil V, Greenberg M, Sasaki T, Cresswell GM, Broman MM, Paez JS, Petkewicz J, Talaty P, Helfand BT, Glaser AP, Wang CH, Franco OE, Ratliff TL, Nastiuk KL, Crawford SE, Hayward SW. TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease. Nat Commun. 2022 Apr 19;13(1):2133. doi: 10.1038/s41 PMID 35440548
• Kramer G, Mitteregger D, Marberger M. Is benign prostatic hyperplasia (BPH) an immune inflammatory disease? Eur Urol. 2007 May;51(5):1202-16. doi: 10.1016/j.eururo.2006.12.011. Epub 2006 Dec 11. PMID 17182170
• Glaser AP, Mansfield S, Smith AR, Helfand BT, Lai HH, Sarma A, Yang CC, Taddeo M, Clemens JQ, Cameron AP, Flynn KE, Andreev V, Fraser MO, Erickson BA, Kirkali Z, Griffith JW; LURN Study Group. Impact of Sleep Disturbance, Physical Function, Depression and Anxiety on Male Lower Urinary Tract Symptoms: Results from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN). J Urol. 2022 PMID 35212573
• Liu G, Andreev VP, Helmuth ME, Yang CC, Lai HH, Smith AR, Wiseman JB, Merion RM, Erickson BA, Cella D, Griffith JW, Gore JL, DeLancey JOL, Kirkali Z; LURN Study Group. Symptom Based Clustering of Men in the LURN Observational Cohort Study. J Urol. 2019 Dec;202(6):1230-1239. doi: 10.1097/JU.0000000000000354. Epub 2019 May 23. PMID 31120372
• Helfand BT, Smith AR, Lai HH, Yang CC, Gore JL, Erickson BA, Kreder KJ, Cameron AP, Weinfurt KP, Griffith JW, Lentz A, Talaty P, Andreev VP, Kirkali Z; LURN. Prevalence and Characteristics of Urinary Incontinence in a Treatment Seeking Male Prospective Cohort: Results from the LURN Study. J Urol. 2018 Aug;200(2):397-404. doi: 10.1016/j.juro.2018.02.075. Epub 2018 Mar 1. PMID 29477718
• Helfand BT, Glaser AP, Kasraeian A, Sterious S, Talaty P, Alcantara M, Alcantara KM, Higgins A, Ghiraldi E, Elterman D. Men with lower urinary tract symptoms secondary to BPH undergoing Aquablation with very large prostates (> 150 mL). Can J Urol. 2021 Dec;28(6):10884-10888. PMID 34895392
• Helfand BT, Kasraeian A, Sterious S, Glaser AP, Talaty P, Alcantara M, Alcantara KM, Higgins A, Ghiraldi E, Elterman DS. How I do it: Aquablation in very large prostates (> 150 mL). Can J Urol. 2022 Apr;29(2):11111-11115. PMID 35429430
• McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, Taylor AM, Waldstreicher J. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. Finasteride Long-Term Efficacy and Safety Study Group. N Engl J Med. 1998 Feb 26;338(9):557-63. doi: 10.10 PMID 9475762

Identifiers

NCT: NCT06062875 · EH22-232 · R01DK135516

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗