Open Randomized Clinical Trial to Evaluate the Effects of Intermittent Caloric Restriction in Patients With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

Study Overview
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Brief Summary
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Lower urinary tract symptoms (LUTS) include filling, emptying or post-voiding state alterations; producing symptomatology depending of the underline mechanism. Benign prostatic hyperplasia (BPH) is the most common underlying disease, which increases with age and significantly affects men over 50 years. There are currently no prevention or curative treatment guidelines, as their pathophysiological mechanism is not exactly known. Several factors have been implicated, such as hormones, aging, lifestyle or diet. BPH is associated with metabolic disorders, the basis of which is insulin resistance and its associated pathologies: diabetes, hypertension, obesity, dyslipidemia and metabolic syndrome. Patients without these metabolic signs have a lower incidence of BPH and / or LUTS. Insulin resistance (IR) is associated with greater proliferation and a reduction of cellular apoptosis at the prostate level; leading to an increase in prostate volume or symptoms. Likewise, the autonomic nervous system (ANS) imbalance, both in favor of sympathetic (emptying symptoms) or parasympathetic (filling symptoms), influences LUTS. SNA activity can be measured non-invasively, repetitively and effectively by measuring the heart rate variability (HRV). Caloric restriction with optimal nutrition (CRON, hereinafter only CR) is the most physiologically adapted nutritional alternative to our ancestral needs and has been shown in humans to reduce insulin resistance and associated pathologies. It has also been observed that CR improves the balance of the SNA and allows to improve LUTS. Proliferation inhibition and prostatic apoptosis induction, mediated through CR, by insulin-IGF-1 axis reduction and mTOR metabolic pathways inhibition, are the central axis of this project. CR will be used to reduce insulin resistance, IGF expression and inhibition of the PI3K / AKT / mTOR pathway, to reduce prostate cell proliferation and promote prostatic tissue apoptosis; in this way it will be possible to reduce its volume and improve the symptomatology. Additionally, CR will allow us to evaluate the potential benefits it has on certain metabolic diseases (diabetes, dyslipidemia, obesity, hypertension, etc.), anthropometric values (BMI, abdominal perimeter and skin folds) and autonomic nervous system functionality (HRV) .

Official Title
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Open Randomized Clinical Trial to Evaluate the Effects of Intermittent Caloric Restriction in Patients With Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

Conditions
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Prostatic Hyperplasia, Benign, Metabolic Syndrome

Intervention / Treatment
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* Behavioral: Caloric Restriction
* Behavioral: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signature of specific informed consent for this study. Metabolic syndrome according to WHO criteria Current intake food pattern > 14 hours of duration. Total PSA below 2,5 ng/mL or total PSA 4 - 10 ng/mL and free/total PSA > 25% IPSS score > 9 points Maximal flow rate < 15 cc/secs Prostatic volume > 40 cc. Exclusion Criteria: Active oncological disease; includes patients already treated without complete remission or in current active treatment. PSA 4 - 10 ng/mL and free/total PSA < 25% or PSA > 10 ng/mL Previous prostatic biopsy in the last 5 years. Treatment with prostatic phytotherapy in the last 4 weeks. BPH alphablocking treatment in the last 6 weeks. 5-alpha-reductase treatment in the last 6 months. Anticholinergic or betamimetics treatment in the last 4 weeks Eating, weight management disorder or previous bariatric surgery. Concurrent treatment with the following drugs in the fasting period: AAS and NSAIDs (except paracetamol). Concurrent treatment with any of the following steroids: prednisolone, budesonide, dexamethasone, fluidcortisone, hydrocortisone or prednisone. Major mental illness, which does not allow informed consent. Previous cardiovascular event in the last 12 months. Liver, gastrointestinal, renal or severe previous endocrine or decompensated disease in the last 12 months. Presence of significant vesical lithiasis. Type I diabetic patients Type II diabetic patients in treatment with sulfonylureas and sodium-glucose cotransport inhibitors, as well as in patients with insulin therapy. Loss of patient follow-up Non-compliance with protocol procedures.

Ages Eligible for Study
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Minimum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open Randomized Clinical Trials
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Patients in the control group will be assigned to a free diet (ad libitum), according to the Spanish Association of Urology lifestyle recommendations for patients with LUTS | Behavioral: Control<br>* Subjects will receive diet and lifestyle recommendations from the Spanish Association of Urology, for symptoms secondary to HBP, without restriction in the meal schedule.<br>|
| Experimental: Caloric Restriction<br>Patients in the experimental group will be assigned to intermittent caloric restriction, based on an early time restricted eating, with a 16/8 fasting/feeding scheme. The patients in this group will have a RC progressive scheme until achieve a maximum of 5 days a week of fasting. | Behavioral: Caloric Restriction<br>* Subjects will be trained to perform intermittent caloric restriction, based on an early time restricted feeding, with a 16/8 hour fasting / feeding schedule, respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the International Prostatic Symptoms Score (IPPS) | IPSS is a 7 items questionnaire (0-35 points) with 5 answers each, which analyzes the lower urinary tract symptoms. Higher scores indicate greater symptomatology. It is classified as mild up to 7 points, moderate 8-19 and severe greater than 20 points. | Change from Baseline IPPS at 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Prostatic volumen | To evaluate prostatic volumen reduction, trough transrectal sonography | Change from Baseline Prostatic Volumen at 36 months | 
| Change in Insulin Resistance | To evaluate variations on insuline resistance through the HOMA-IR formula. | Change from Baseline Insulin Resistance at 36 months | 
| Prostatic Specific Antigen (PSA) | To evaluate PSA variation | Before and after 36 months | 
| Testosterone | To evaluate Testosterone variation | Before and after 36 months | 
| IIEF5 | To evaluate the International Index of Erectile Function variation | Before and after 36 months | 
| Prostate Cancer | To evaluate prostate cancer incidence | 36 months | 
| Change in SF36 score | To evaluate quality of life through SF36 questionnaire. | Change from Baseline SF36 questionnaire at 36 months | 
| Tamsulosin prescription | To assess the incidence of the prescription of Tamsulosin for symptoms relief. It will be analyzed as a percentage of patients with Tamsulosin prescription. | Before and after 36 months | 
| Dutasteride/Finasteride prescription percentage | To assess the incidence of the prescription of Dutasteride or Finasteride for symptoms relief . It will be analyzed as a percentage of patients with Dutasteride or Finasteride prescription. | Before and after 36 months | 
| Surgery for BPH | To assess the surgical treatment needs for BPH. It will be analyzed as a percentage of patients who are operated on by TURP or simple prostatectomy. | Before and after 36 months | 
| Change in Body Mass Index (BMI) variation | To evaluate variations on body mass index, measured as weight (kilograms) divided by height (cm) square. | Change from Baseline BMI at 36 months | 
| Change in Abdominal perimeter variation | To evaluate variations on abdominal perimeter, measured as centimeters. | Change from Baseline abdominal perimeter variation at 36 months | 
| Diastolic pressure variation | To evaluate variations on diastolic pressure variation, measured as mmHg. | Before and after 36 months | 
| Sistolic pressure variation | To evaluate variations on sistolic pressure variation, measured as mmHg. | Before and after 36 months | 
| Heart rate variation | To evaluate variations on heart rate, measured as beats per minute. | Before and after 36 months | 
| Total cholesterol variation | To evaluate variations on total cholesterol, measured as mg/dL. | Before and after 36 months | 
| High Density Lipoprotein cholesterol variation | To evaluate variations on HDL cholesterol, measured as mg/dL. | Before and after 36 months | 
| LDL cholesterol variation | To evaluate variations on LDL cholesterol, measured as mg/dL. | Before and after 36 months | 
| Triglyceride variation | To evaluate variations on triglyceride, measured as mg/dL. | Before and after 36 months | 
| Alanine transaminase (ALT) variation | To evaluate variations on alanine transaminase, measured as IU. | Before and after 36 months | 
| Aspartate transaminase (AST) variation | To evaluate variations on aspartate transaminase, measured as IU. | Before and after 36 months | 
| HRV parameter - Parasympathetic Nervous System Index (PNS index) | To evaluate variations on PNS index, measured by heart rate variability, through Kubios software version 3.1. PNS index includes the following measures: Mean RR, RMSSD and high frequency (HF) power | Before and after 36 months | 
| HRV parameter - Sympathetic Nervous System Index (SNS index) | To evaluate variations on SNS index, measured by heart rate variability, through Kubios software version 3.1. The SNS index includes the following measures: Mean HR, Stress index and low frequency (LF) power. | Before and after 36 months | 
| HRV parameter - Low frequency / High Frequency Ratio (LF/HF ratio) | To evaluate variations on LF/HF ratio, measured by heart rate variability, through Kubios software version 3.1. Values upper 1.6 indicates SNS predominance. | Before and after 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic Syndrome, Prostate, Caloric Restriction, Heart Rate Variability