Investigating the Anti-inflammatory Effects of Frondanol in Adults With Inflammatory Bowel Disease

Study Overview
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Brief Summary
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This is a pilot, prospective, double-blinded, two-arm, randomized controlled trial of the efficacy of Frondanol in comparison to placebo in decreasing bowel inflammation in patients with a clinical diagnosis of inflammatory bowel disease who are in remission and on standard of care treatment.

Detailed Description
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Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a debilitating condition, particularly during active periods (flares) of the disease and can sometimes lead to life-threatening complications. IBD is characterized by chronic gut inflammation resulting in symptoms such as severe diarrhea, abdominal pain, blood in stool, fatigue and unintended weight loss, which significantly affect the quality of life of patients. Although the exact mechanism underlying the chronic gut inflammation is not fully understood, several cytokine networks are thought to be involved. Currently, treatment of IBD relies on minimizing symptoms and improving quality of life through the control of disease progression and complications; however, these drugs have significant systemic side effects that reduce their tolerability. Moreover, up to 40% of patients still exhibit non-response to therapy, and these treatment-refractory patients would require alternative therapeutic approaches. Frondanol, a widely available nutraceutical extract of the edible sea cucumber, Cucumaria frondosa, has been reported to possess potent anti-inflammatory effects in both animals and humans, whilst showing no signs of toxicity. The potent anti-inflammatory effects of Frondanol in a mouse model of IBD provide encouragement for investigating its effects in human IBD patients. The proposed study is a pilot, double-blinded, placebo-controlled trial of Frondanol in patients with IBD (Crohn's disease or ulcerative colitis) who are currently in remission and are on standard therapy. One hundred patients will be randomized (1:1) to receive Frondanol or placebo as an adjunct to their standard therapy for the period of six months. Blood and tissue samples from colon biopsies obtained during routine visits and endoscopies at baseline and six months later will be collected. The levels of inflammatory markers such as myeloperoxidase, tumor necrosis factor (TNF)-α, interleukin (IL)1β, IL6, IL17A, IL22, interferon gamma (IFN-γ) and several other inflammatory markers will be compared between patients treated with Frondanol and those treated with placebo, and the findings will be correlated with clinical and histological parameters. Over the past 25 years, it is estimated that more than 3 million Frondanol capsules have been consumed on the human market with no reported side effects. An even larger amount has been consumed on the veterinary market without a single reported incident. If proven beneficial, Frondanol, will be a useful supplement in treating the underlying chronic gut inflammation in IBD patients, increasing the likelihood of patients remaining in remission and potentially providing an effective, natural and safe treatment for treatment naive patients in the future.

Official Title
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A Pilot Randomized, Double-blind, Placebo-controlled Trial to Investigate the Anti-inflammatory Effects of Frondanol in Adults With Inflammatory Bowel Disease

Conditions
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Ulcerative Colitis Chronic Mild, Ulcerative Colitis Chronic Moderate, Crohn Colitis

Intervention / Treatment
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* Drug: Frondanol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: A confirmed clinical diagnosis of IBD of any duration, age 18 years or older, with mild to moderate disease and on standard therapy. The diagnostic criteria for IBD include the presence of chronic diarrhea for more than four weeks, and evidence of active inflammation on endoscopy and chronic changes on biopsy. Patients with stable mild to moderate IBD will be eligible for the study. Stable IBD is defined as having stable symptoms over a period of several weeks, diagnostic evaluation has been completed and the patient has been on consistent medication. Mild to moderate IBD is indicated by a Partial Mayo score (Mayo Clinic Score/Disease Activity Index for Colitis) of between 1-6, and a total of Mayo score of 1-10. For patients with Crohn's disease, only those with Crohn's colitis will be included (patients with small bowel disease are eligible to enter the trial as long as they also have large bowel inflammation). Exclusion criteria: Pregnancy, breastfeeding, allergy to seafood or marine products Severe medical illness such as uncontrolled diabetes (HbA1C>10), significant or unstable cardiovascular or pulmonary disease, impaired renal function (Cr>2.0mg/dL), current or recent (<1 year) malignancy, or other significant medical illness that in the view of the investigators may impair participation in the study. Patients with severe IBD (defined by a Partial Mayo score of 7-9 and a total Mayo score of 11-12, with active symptoms) will not be eligible to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: This is a parallel group, randomized, double-blind, placebo-controlled pilot trial where participants will be randomized to receive either Frondanol 1000mg twice daily or placebo twice daily for 6 months.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental -Frondanol<br>Eligible participants will receive Frondanol capsule orally (1000 mg capsule twice daily) for 6 months | Drug: Frondanol<br>* Frondanol capsule (1000 mg) will be administered orally (Twice daily) in the double blind settings<br>|
| Placebo Comparator: Placebo<br>Eligible participants will receive placebo capsule (twice daily) for 6 months | Drug: Placebo<br>* Placebo (corn starch) capsule will be administered orally (Twice daily) in the double blind settings<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the change in plasma levels of cytokines between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | Cytokines will be measured in plasma samples. | Baseline and after 6 months | 
| To assess the change in plasma levels of marker of inflammation between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | Marker of inflammation will be measured in plasma samples. | Baseline and after 6 months | 
| To assess the change in biopsy mRNA levels between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | The mRNA levels of transcription factors involved in inflammation will be measured in tissue biopsy samples | Baseline and after 6 months | 
| To assess the change in the biopsy mRNA levels between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | The mRNA levels of cytokines involved in inflammation will be measured in tissue biopsy samples | Baseline and after 6 months | 
| To assess the change in the biopsy mRNA levels between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | The mRNA levels of markers involved in inflammation will be measured in tissue biopsy samples | Baseline and after 6 months | 
| To assess the change in the proteins expression between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | The proteins expression of transcription factors involved in inflammation will be measured in tissue biopsy samples | Baseline and after 6 months | 
| To assess the change in the proteins expression between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | The proteins expression cytokines involved in inflammation will be measured in tissue biopsy samples | Baseline and after 6 months | 
| To assess the change in the proteins expression between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment | The proteins expression of markers involved in inflammation will be measured in tissue biopsy samples | Baseline and after 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the change in routine clinical parameters between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment: | Mayo score, which are based on ratings of frequency and severity of clinical symptoms and endoscopic activity will be measured. | Baseline and after 2 months and after 4 months and after 6 months | 
| To assess the change in routine clinical parameters between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment: | Complete blood count will be measured | Baseline and after 2 months and after 4 months and after 6 months | 
| To assess the change in routine clinical parameters between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment: | Erythrocyte sedimentation rate will be measured | Baseline and after 2 months and after 4 months and after 6 months | 
| To assess the change in routine clinical parameters between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment: | Serum C-reactive protein will be measured | Baseline and after 2 months and after 4 months and after 6 months | 
| To assess the change in routine clinical parameters between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment: | Serum albumin will be measured | Baseline and after 2 months and after 4 months and after 6 months | 
| To assess the change in routine clinical parameters between IBD patients treated with Frondanol and those treated with placebo at baseline and after six months of treatment: | Fecal calprotectin will be measured | Baseline and after 2 months and after 4 months and after 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inflammatory bowel disease, Crohn disease, ulcerative colitis, frondanol, randomized controlled trial, placebo-controlled, chronic bowel inflammation