Effects of TNF Blockade on Human BPH/LUTS

Benign Prostatic Hyperplasia (BPH) Clinical Trial

Official title:

Effects of TNF Blockade on Human BPH/LUTS

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06062875
• Other study ID #: EH22-232
• Secondary ID: R01DK135516
• Status: Recruiting
• Phase: Phase 2
• Start date: January 24, 2024
• Est. completion date: June 1, 2028

Study information

• Verified date: April 2024
• Source: NorthShore University HealthSystem
• Contact: Rachel Pulido
• Phone: 224-364-7975
• Email: rpulido[@]northshore.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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").

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 70
• Est. completion date: June 1, 2028
• Est. primary completion date: April 1, 2028
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 45 Years to 80 Years

Eligibility

Inclusion Criteria:

• Male sex

• Age 45-80 years

• Diagnosed by physician with BPH

• Prostate volume = 60mL

• IPSS = 8

• Scheduled for BPH surgery (prostatic urethral lift, water vapor thermal therapy, transurethral resection of prostate, laser vaporization or enucleation, robotic waterjet treatment, or simple prostatectomy)

• 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

Related Conditions & MeSH terms

• Benign Prostatic Hyperplasia (BPH)
• Hyperplasia
• Prostatic Hyperplasia

Intervention

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

Locations

Country	Name	City	State
United States	NorthShore University HealthSystem	Glenview	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
NorthShore University HealthSystem	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

References & Publications (18)

Ahmed Ali U, Martin ST, Rao AD, Kiran RP. Impact of preoperative immunosuppressive agents on postoperative outcomes in Crohn's disease. Dis Colon Rectum. 2014 May;57(5):663-74. doi: 10.1097/DCR.0000000000000099. — View Citation

Bechara FG, Podda M, Prens EP, Horvath B, Giamarellos-Bourboulis EJ, Alavi A, Szepietowski JC, Kirby J, Geng Z, Jean C, Jemec GBE, Zouboulis CC. Efficacy and Safety of Adalimumab in Conjunction With Surgery in Moderate to Severe Hidradenitis Suppurativa: The SHARPS Randomized Clinical Trial. JAMA Surg. 2021 Nov 1;156(11):1001-1009. doi: 10.1001/jamasurg.2021.3655. — View Citation

Cohen BL, Fleshner P, Kane SV, Herfarth HH, Palekar N, Farraye FA, Leighton JA, Katz JA, Cohen RD, Gerich ME, Cross RK, Higgins PDR, Tinsley A, Glover S, Siegel CA, Bohl JL, Iskandar H, Ji J, Hu L, Sands BE. Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery. Gastroenterology. 2022 Jul;163(1):204-221. doi: 10.1053/j.gastro.2022.03.057. Epub 2022 Apr 10. — View Citation

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 Jul;208(1):155-163. doi: 10.1097/JU.0000000000002493. Epub 2022 Feb 25. — View Citation

He J, Guo Z, Huang Y, Wang Z, Huang L, Li B, Bai Z, Wang S, Xiang S, Gu C, Pan J. Comparisons of efficacy and complications between transrectal and transperineal prostate biopsy with or without antibiotic prophylaxis. Urol Oncol. 2022 May;40(5):191.e9-191.e14. doi: 10.1016/j.urolonc.2022.01.004. Epub 2022 Feb 12. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Hyman NH, Cheifetz AS. PUCCINI: Safety of Anti-TNF in the Perioperative Setting. Gastroenterology. 2022 Jul;163(1):44-46. doi: 10.1053/j.gastro.2022.04.050. Epub 2022 May 4. No abstract available. — View Citation

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. — View Citation

Lightner DJ, Wymer K, Sanchez J, Kavoussi L. Best Practice Statement on Urologic Procedures and Antimicrobial Prophylaxis. J Urol. 2020 Feb;203(2):351-356. doi: 10.1097/JU.0000000000000509. Epub 2019 Aug 23. — View Citation

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. — View Citation

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: 10.1056/NEJM199802263380901. — View Citation

McConnell JD, Roehrborn CG, Bautista OM, Andriole GL Jr, Dixon CM, Kusek JW, Lepor H, McVary KT, Nyberg LM Jr, Clarke HS, Crawford ED, Diokno A, Foley JP, Foster HE, Jacobs SC, Kaplan SA, Kreder KJ, Lieber MM, Lucia MS, Miller GJ, Menon M, Milam DF, Ramsdell JW, Schenkman NS, Slawin KM, Smith JA; Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med. 2003 Dec 18;349(25):2387-98. doi: 10.1056/NEJMoa030656. — View Citation

Quaresma AB, Yamamoto T, Kotze PG. Biologics and surgical outcomes in Crohn's disease: is there a direct relationship? Therap Adv Gastroenterol. 2020 Jul 16;13:1756284820931738. doi: 10.1177/1756284820931738. eCollection 2020. — View Citation

Roehrborn CG, Bruskewitz R, Nickel JC, McConnell JD, Saltzman B, Gittelman MC, Malek GH, Gottesman JE, Suryawanshi S, Drisko J, Meehan A, Waldstreicher J; Proscar Long-Term Efficacy and Safety Study Group. Sustained decrease in incidence of acute urinary retention and surgery with finasteride for 6 years in men with benign prostatic hyperplasia. J Urol. 2004 Mar;171(3):1194-8. doi: 10.1097/01.ju.0000112918.74410.94. — View Citation

Setia SA, Smith J, Cendo D, Yoder J, Gorin MA, Allaway MJ, Vourganti S. Outcomes of freehand transperineal prostate biopsy with omission of antibiotic prophylaxis. BJU Int. 2022 Jul;130(1):54-61. doi: 10.1111/bju.15590. Epub 2021 Dec 23. — View Citation

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/s41467-022-29719-1. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cellular consequences of adalimumab therapy on prostate tissue	We hypothesize that TNF-antagonist treatment will de-repress apoptosis, suppress proliferative pathways, and modify the immune cell profile in the prostate. In this aim we will employ flow cytometry and scRNA-seq analysis with pathway imputation, supplemented with immunohistochemistry and bulk RNA-seq, to characterize these changes at a cellular and tissue level.	Through study completion (Week 24)
Other	Genetic predictors to stratify patients with differential response to adalimumab	We hypothesize that genetic variants in 1) genes involved in the TNF-antagonist targeted pathways, 2) susceptibility to chronic inflammation, and 3) susceptibility to BPH influence the effectiveness of the therapy	Through study completion (Week 24)
Primary	International Prostate Symptom Score	The IPSS is a self-report measure used to assess urinary urgency, frequency, and voiding symptoms, and includes one disease-specific quality of life (QoL) question. IPSS scores ranges from 0 to 35, with higher scores indicating more severe urinary symptoms, and QoL ranges from 0 (delighted) to 6 (terrible).	The past 30 days
Primary	Safety as measured by Clavien-Dindo grading system	Frequency and severity of treatment related adverse events will be reported using the Clavien-Dindo severity grading system.	Through study completion (Week 24)
Secondary	LURN Symptom Index 29 (LURN SI-29)	This is a multidimensional 29-item questionnaire that assesses different lower urinary tract symptoms as well as single item about global bother.	The past 7 days
Secondary	The Patient-Reported Outcomes Measurement Information System (PROMIS-29) Profile v2.1	The PROMIS-29 Profile is a 29-item instrument that combines short assessments of eight core constructs of health-related quality of life (HRQoL): physical function (PF), sleep disturbance (SD), pain interference (PI) and pain intensity (PIN), fatigue (FA), anxiety (AN), depression (DE) and ability to participate in social roles and activities (SRAA).	The past 7 days
Secondary	Patient Global Impression of Improvement (PGI-I)	This is a single item that captures how much better or worse the person's condition is relative to when they began treatment. Scale ranges from "Very much worse" to "Very much better".	Through study completion (Week 24)
Secondary	3-Day Voiding Diary	The diary records the patient's daily fluid intake, frequency of urination throughout the day and night, instances of leakage, and the quantity of lost urine. Analyzing these findings against the standard criteria for regular bladder function could reveal potential issues and help confirm a diagnosis. The definition of normal benchmarks takes into account factors like age, gender, as well as various internal and external variables including fluid consumption and its nature.	Recorded on three separate days
Secondary	Change in maximum flow rate (uroflowmetry)	Uroflowmetry is a diagnostic test that measures the rate and pattern of urine flow during voiding to assess the functioning of the urinary tract. Changes in maximum flow rate (Qmax) will be compared.	Through study completion (Week 24)
Secondary	Change in PVR (post-void residual)	Bladder scanner to measure post-void residual	Through study completion (Week 24)
Secondary	Change in prostate volume	Prostate volume as calculated by MRI prostate before and after adalimumab/placebo treatment	12 weeks
Secondary	Change in systemic markers of inflammation (ESR, CRP)	Blood test for systemic markers of inflammation (erythrocyte sedimentation rate [ESR] and c-reactive protein [CRP]) before and after adalimumab/placebo treatment	12 weeks

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