Akkermansia Muciniphilia and Metabolic Side Effects of ADT

Study Overview
=================
Brief Summary
-----------------
The overriding objectives of this study are: Primary outcomes: To confirm that administration of oral acetate increases the proportion of A. muciniphilia in the stool samples of patients with metastatic, castration-sensitive prostate cancer compared to placebo. To confirm tolerability and assess for side effects of delayed oral acetate supplementation. Secondary outcomes: To determine if increased counts of A. muciniphilia correlate with improved metabolic parameters and improved bone health.

Official Title
-----------------
The Role of Akkermansia Muciniphilia in Combating the Metabolic Effects of Androgen Deprivation Therapy in Men With Metastatic Prostate Cancer

Conditions
-----------------
Prostate Cancer, Metabolic Syndrome, Obesity, Cardiovascular Morbidity, Bone Diseases, Hyperlipidemias, Diabetes

Intervention / Treatment
-----------------
* Drug: Apple Cider Vinegar
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
For inclusion in this study, patients must fulfill all of the following criteria: Men ≥18 years of age with histologically-proven metastatic castration-sensitive prostate adenocarcinoma planned to receive ADT (TNM stage Tany, Nany, M1) (see Appendix I). Must have baseline conventional imaging with CT of the abdomen, and pelvis and bone scan. Exclusion Criteria: Patients fulfilling any of the following criteria are NOT eligible for participation in this study: Age less than 18 Primary neuroendocrine prostate cancer Treatment with ADT within the year leading up to enrolment Unable to provide informed consent or unable to understand or read the English language (unless accompanied by an interpreter) Inadequate liver function

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This will be a single-institution, randomized placebo-controlled trial involving men ≥18 years of age with metastatic castration-sensitive prostate cancer. This study will require histologic confirmation of prostate adenocarcinoma and radiographic evidence of metastatic disease on conventional imaging (CT or BS). Patients will be randomized 1:1 to receive acetate supplementation or placebo. Our institution sees approximately 200 new metastatic prostate cancer patients each year, therefore, the investigators do not anticipate encountering difficulties with recruitment into this study over a period of 2 years.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apple Cider Vinegar<br>Webbers Natural apple cider vinegar pills (NPN: 80021269), enteric coated. Each patient will be instructed to take 6 enteric slow-release acetate capsules (equivalent of 500 mg/ capsule containing 25 mg acetate x 6 capsules) per day for 3 months. | Drug: Apple Cider Vinegar<br>* Each patient will be instructed to take 6 enteric slow-release acetate capsules (equivalent of 500 mg/ capsule containing 25 mg acetate x 6 capsules) per day for 3 months https://www.webbernaturals.com/en-ca/apple-cider-vinegar-500-mg-capsules/<br>|
| Placebo Comparator: Placebo<br>Placebo pills will be provided by our hospital pharmacy, and patients will be given the same instructions as in the treatment arm. | Drug: Placebo<br>* Each patient will be instructed to take 6 placebo capsules per day for 3 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal Akkermansia muciniphilia counts | Counts of Akkermansia muciniphilia in participant stool samples at 1 week following the intervention will be compared to baseline counts. | 1 week | 
| Fecal Akkermansia muciniphilia counts | Counts of Akkermansia muciniphilia in participant stool samples at 1 month following the intervention will be compared to baseline counts. | 1 month | 
| Fecal Akkermansia muciniphilia counts | Counts of Akkermansia muciniphilia in participant stool samples at 3 months following the intervention will be compared to baseline counts. | 3 month | 
| Fecal Akkermansia muciniphilia counts | Counts of Akkermansia muciniphilia in participant stool samples at 4 months following the intervention will be compared to baseline counts. | 4 month | 
| Fecal Akkermansia muciniphilia counts | Counts of Akkermansia muciniphilia in participant stool samples at 6 months following the intervention will be compared to baseline counts. | 6 month | 
| Side effects and tolerability | We will record side effects reported by the participants and the rate of Discontinuation of the intervention. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic parameters: fasting plasma glucose | Fasting plasma glucose (mmol/L) | 3 months | 
| Metabolic parameters: fasting plasma glucose | Fasting plasma glucose (mmol/L) | 6 months | 
| Metabolic parameters: HbA1C | HbA1c (%) | 3 months | 
| Metabolic parameters: HbA1c | HbA1c (%) | 6 months | 
| Metabolic parameters: triglycerides | Triglycerides (mmol/L) | 3 months | 
| Metabolic parameters: triglycerides | Triglycerides (mmol/L) | 6 months | 
| Metabolic parameters: LDL cholesterol | LDL cholesterol (mmol/L) | 3 months | 
| Metabolic parameters: LDL cholesterol | LDL cholesterol (mmol/L) | 6 months | 
| Metabolic parameters: HDL cholesterol | HDL cholesterol (mmol/L) | 3 months | 
| Metabolic parameters: HDL cholesterol | HDL cholesterol (mmol/L) | 6 months | 
| Metabolic parameters: total cholesterol | Total cholesterol (mmol/L) | 3 months | 
| Metabolic parameters: total cholesterol | Total cholesterol (mmol/L) | 6 months | 
| Metabolic parameters: PSA | PSA (ng/mL) | 6 months | 
| Metabolic parameters: PSA | PSA (ng/mL) | 3 months | 
| Metabolic parameters: hemoglobin | Hemoglobin (g/L) | 3 months | 
| Metabolic parameters: hemoglobin | Hemoglobin (g/L) | 6 months | 
| Metabolic parameters: serum creatinine | Serum creatinine (µmol/L) | 3 months | 
| Metabolic parameters: serum calcium | Serum calcium (µmol/L) | 3 months | 
| Metabolic parameters: serum calcium | Serum calcium (µmol/L) | 6 months | 
| Metabolic parameters: alanine transferase | Alanine transferase (U/L) | 3 months | 
| Metabolic parameters: alanine transferase | Alanine transferase (U/L) | 6 months | 
| Metabolic parameters: aspartate aminotransferase | Aspartate aminotransferase (U/L) | 3 months | 
| Metabolic parameters: aspartate aminotransferase | Aspartate aminotransferase (U/L) | 6 months | 
| Metabolic parameters: Insulin resistance index (HOMA IR) | Insulin resistance index (HOMA IR) | 3 months | 
| Metabolic parameters: HOMA IR | Insulin resistance index (HOMA IR) | 6 months | 
| Bone health: dp-ucMGP levels | Circulating plasma dp-ucMGP levels (surrogate for vitamin K2 levels) from baseline | 3 months | 
| Bone health: dp-ucMGP levels | Circulating plasma dp-ucMGP levels (surrogate for vitamin K2 levels) from baseline | 6 months | 
| Bone health: Vitamin K2 | Vitamin K2 levels | 3 months | 
| Bone health: Vitamin K2 | Vitamin K2 levels | 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
prostate cancer, metabolic syndrome, androgen deprivation therapy, microbiome, Akkermansias muciniphilia, cardiovascular disease