A Pilot Randomized, Double-blind, Placebo-controlled Trial to Investigate the Anti-inflammatory Effects of Frondanol in Adults With Inflammatory Bowel Disease
Phase: PHASE2
Conditions: Ulcerative Colitis Chronic Mild, Ulcerative Colitis Chronic Moderate, Crohn Colitis
Sponsor: Mohammed Bin Rashid University of Medicine and Health Sciences

 
 
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Research Protocol  
 
Full title: A pilot randomized, double-blind, placebo-controlled trial to 
investigate the anti-inflammatory effects of Frondanol in adults with 
inflammatory bowel disease 
 
 
Short title: Frondanol in IBD                          
 
 
Protocol Number: 1  
 
Protocol Date: 04 December 2021 
 
 
 
Version Number: 3.2 
 
 
Version Control Table: 
Version 
Date 
Author 
Rationale 
1.0 
14/03/21 
Reem Jan 
First Protocol Version submitted to MOHAP 
2.0 
28/06/21 
Reem Jan 
Resubmission to MOHAP following initial 
review and requested changes – approved 
01/09/21 
3.0 
19/10/21 
Reem Jan 
Resubmission to MOHAP to correct typing 
error in Frodnanol strength and with other 
amendments such as minor changes in 
inclusion/exclusion criteria and in placebo 
content from cellulose to corn starch and 
addition of post-doctoral fellow 
3.1 
30/11/21 
Reem Jan 
Addition of coinvestigator Dr Mazin Aljabiri  
3.2 
04/12/21 
Reem Jan 
Addition of coinvestigators Dr Usama 
Warshow and Dr Hossam Al-Hilou  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement:  
The information provided in this document is the property of Mohammed Bin Rashid University 
of Medicine and Health Sciences (MBRU) and Mediclinic City Hospital (MCH), Dubai, UAE. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of MBRU and MCH, except to the extent 
necessary to ensure adequate conduct of the study. 
 
 
Ethics Statement:  
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
 
 

 
 
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KEY STUDY CONTACT DETAILS 
STUDY INVESTIGATORS 
Principal Investigator: 
Name: Dr. Reem Jan 
Title: Assistant Professor - Pharmacology 
Institution: MBRU 
Tel: 04 383 8733 
Email: reem.jan@mbru.ac.ae 
 
Role: Principal Investigator Involved in all aspects of the project, including 
securing funding, study design, hypothesis formation, experimental 
methods, data analysis and dissemination of findings 
 
Co-Investigator: 
 
Name: Prof. Thomas Adrian 
Title: Professor – Physiology  
Institution: MBRU 
Tel:  
Email: thomas.adrian@mbru.ac.ae 
 
Role: Involved in all aspects of the project, including study design, hypothesis 
formation, experimental methods, data analysis and dissemination of findings 
Co-Investigator: 
 
Name: Dr. Jamil Akhras 
Title: Consultant Gastroenterlogist 
Institution: Mediclinic City Hospital  
Tel:  
Email: jamil.akhras@mediclinic.ae 
 
Role: Clinical lead - Recruitment, clinical assessment and follow-up of 
patients, performing colonoscopies and obtaining tissue biopsies and blood 
samples, input into study design, hypothesis formation and dissemination of 
findings 
Co-Investigator: 
 
Name: Prof. Samuel Ho 
Title: Professor – Medicine, Consultant Gastroenterlogist 
Institution:MBRU and Mediclinic City Hospital  
Tel: 04 383 8749 
Email: smauel.ho@mbru.ac.ae 
 
Role: Clinical lead - Recruitment, clinical assessment and follow-up of 
patients, performing colonoscopies and obtaining tissue biopsies and blood 
samples, input into study design, hypothesis formation and dissemination of 
findings 
 
Co-Investigator: 
 
Name: Dr. Aida Azar 
Title: Associate Professor – Epidemiology  
Institution: MBRU 
Tel: 04 383 8712 
Email: aida.azar@mbru.ac.ae 
 
Role: Input into study design, hypothesis formation, data analysis and 
dissemination of findings 
 

 
 
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Co-Investigator: 
 
Name: Dr. Fahad Ali 
Title: Assistant Professor – Molecular Biology  
Institution: MBRU 
Tel: 04 383 8740 
Email: fahad.ali@mbru.ac.ae 
 
Role: Provision of organoids for in vitro research, input into experimental 
design, data analysis and dissemination of findings 
Co-Investigator: 
 
Name: Dr. Hardik Ghelani 
Title: Postdoctoral Research Fellow  
Institution: MBRU 
Tel: 04 383 8694 
Email: hardik.ghelani@mbru.ac.ae 
 
Role: Data collection, data analysis and dissemination of findings 
 
 
Co-Investigator: 
Name: Dr. Mazin Aljabiri 
Title: Consultant Gastroenterlogist 
Institution: Mediclinic Parkview Hospital  
Tel: +971558841362 
Email: mazin.aljabiri@mediclinic.ae 
 
Role: Consultant gastroenterologist - Recruitment, clinical assessment and 
follow-up of patients, performing colonoscopies and obtaining tissue biopsies 
and blood samples, dissemination of findings 
Co-Investigator: 
Name: Dr. Usama Warshow 
Title: Consultant Gastroenterlogist 
Institution: Mediclinic Parkview Hospital  
Tel: +971563937628 
Email: usama.warshow@mediclinic.ae 
 
Role: Consultant gastroenterologist - Recruitment, clinical assessment and 
follow-up of patients, performing colonoscopies and obtaining tissue biopsies 
and blood samples, dissemination of findings 
Co-Investigator: 
Name: Dr. Hossam Al-Hilou 
Title: Consultant Gastroenterlogist 
Institution: Mediclinic City Hospital  
Tel:  
Email: hal-hilou@doctors.org.uk 
 
Role: Consultant gastroenterologist - Recruitment, clinical assessment and 
follow-up of patients, performing colonoscopies and obtaining tissue biopsies 
and blood samples, dissemination of findings 
STUDY FUNDER (S) 
 
Institution: MBRU 
City, Country: Dubai, UAE 
Tel: 800-MBRU (6278) 
Email: research.com@mbru.ac.ae 
 
Role: MBRU Internal Grant and MBRU Post-doctoral Fellowship salary 
provision  
 

 
 
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Principal Investigator Agreement  
I, the undersigned, have reviewed this protocol, and I agree to conduct this 
study in accordance with the International Conference on Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP), the ethical principles set forth in 
the Declaration of Helsinki and other applicable local regulatory requirements.  
The protocol may not be modified without written approval of the Sponsor/ 
Funder. All changes to the protocol must be submitted to the applicable 
regulatory authorities and Research Ethics Committee (REC) and must be 
approved by the REC prior to their implementation, except where necessary 
to prevent immediate danger to the subject.  
 
Principal Investigator  
   
 
 
_28/06/2021___ 
Signature:   
 
 
 
 
 
Date: DD/MM/YY 
 
 
The signatory agrees to the content of the final study protocol as presented. 
 
The signatory agrees to the content of the final study protocol as presented. 
 
 

 
 
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TABLE OF CONTENTS 
 
1. Protocol summary………………………………………………………………….. 
2. Abbreviations……………………………………………………………………….. 
3. Background………………………………………………………………………..... 
4. Rationale………………………………………………………………………….... 
5. Research objectives……………………………………………………………….. 
6. Study design/methodology……………………………………………………….. 
7. Safety considerations………………………………....................................… 
8. Study outcome evaluations/statistical analysis………………………………... 
9. Data management……………………………...…………………..................... 
10. Ethical and regulatory considerations…………………………………............. 
11. Clinical study report and publications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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1. PROTOCOL SUMMARY  
 
Study Title 
A pilot randomized, double-blind, placebo-controlled trial 
to investigate the anti-inflammatory effects of Frondanol 
in adults with inflammatory bowel disease 
Internal ref. no. (or short title) 
Frondanol in IBD 
Study Design 
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 IBD who are in 
remission and on standard of care treatment. 
Study Participants 
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 
diarrhoea 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 (Pabla and 
Schwartz, 2020). 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 
(Pabla and Schwartz, 2020), with active symptoms) will 
not be eligible to participate in the study. 
 
Reference: 

 
 
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Pabla BS, Schwartz DA. Assessing Severity of Disease 
in Patients with Ulcerative Colitis. Gastroenterol Clin 
North Am. 2020; 49(4):671–688 
Planned Size of Sample (if 
applicable) 
100 patients (50 per arm) with stable IBD will be 
recruited into this pilot study. 
Follow up duration (if 
applicable) 
Six months 
Planned Study Period 
Two years 
Research Question/Aim(s) 
 
1) To compare plasma levels, biopsy mRNA (using low 
density expression arrays) and protein (using either 
Luminex or Western blotting) levels of the following 
parameters between IBD patients treated with Frondanol 
and those treated with placebo at baseline and after six 
months of treatment:  
a) Cytokines: TNFα, IL1β, IL6, IL17A, IL21, IL22, IL23, 
IFNγ, IFNα, as well as vascular endothelial growth factor 
(VEGF-A), MIP-1, MIP-2;  
b) 
Markers 
of 
inflammation: 
Myeloperoxidase, 
calprotectin, S100A12, β2-microglobulin, amyloid A (A-
SAA), intercellular adhesion molecule 1 (ICAM-1), 
vascular cell adhesion molecule 1 (VCAM-1), MIP-2α 
(CXCL2), MCP-1 (CCL2). Leukotriene B4 (LTB4), 5-
hydroxyeicosatetraenoic acid (5-HETE) and prostaglandin 
E2 (PGE2) will be measured by specific ELISA assays. 
2) To compare the following routine clinical parameters 
between IBD patients treated with Frondanol and those 
treated with placebo at baseline and after six months of 
treatment:  
a) Patient symptoms;  
b) Blood: Complete blood count (CBC), erythrocyte 
sedimentation rate (ESR), C-reactive protein (CRP), 
albumin;  
c) Stool: Fecal calprotectin level;  
d) Endoscopic and histologic features.  
 
3) 
To 
compare 
in-vitro 
concentration-dependent 
responses to Frondanol and placebo on inflamed 
organoids by measurement of cytokines and other 
inflammatory markers, in particular 5-HETE, LTB4 and 
PGE2. 
 
 
 

 
 
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2. ABBREVIATIONS  
 
5-HETE 
5-hydroxyeicosatetraenoic acid 
CBC 
Complete blood count 
CRP 
C-reactive protein  
DCF 
Data Collection Form 
DHCR 
Dubai Healthcare City Authority-Regulation 
ELISA 
Enzyme-linked immunosorbent assay 
ESR 
Erythrocyte sedimentation rate 
IBD 
Inflammatory bowel disease 
ICAM-1 
Intercellular adhesion molecule 1 
IFN 
Interferon  
IL 
Interleukin  
LOX 
Lipoxygenase  
LTB4 
Leukotriene B4 
MCH 
Mediclinic City Hospital 
MCME 
Mediclinic Middle East 
PGE2 
Prostaglandin E2 
REC 
Research & Ethics Committee 
TNF 
Tumor necrosis factor 
VCAM-1 
Vascular cell adhesion molecule 1 
 
 
 
 
 
 
 
 

 
 
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Introduction  
3. BACKGROUND  
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 (1). The prevalence of IBD has rapidly increased worldwide; it 
affects between one in 200 and one in 300 individuals in high-income 
countries, and despite its incidence being lower in low-middle income 
countries, this has also been rapidly increasing (2, 3). The highest reported 
prevalence in the Middle East is one in 1,800 for Crohn’s disease and one in 
1,000 for ulcerative colitis (3).  
 
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 (1). Although 
the exact mechanism underlying the chronic gut inflammation is not fully 
understood, several cytokine networks are thought to be involved (4-6). The 
cytokine networks underlying the progression of IBD are depicted below in 
Figure 1 (4). 
 

 
 
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Figure 1: Cytokine networks underlying the progression of IBD (4) 
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 (7). Moreover, up to 40% of patients still exhibit non-response to 
therapy, and these treatment-refractory patients would require alternative 
therapeutic approaches (8, 9).  
 
Sea cucumbers and their extracts have been reported to have high nutritional 
value and several potential health benefits including anti-inflammatory effects, 
and used for centuries as folk medicine or traditional foods in countries such 
as Japan, Indonesia, Korea and China (10, 11). Frondanol, a widely available 
neutraceutical extract of the edible sea cucumber, Cucumaria frondosa, has 
been reported to possess potent chemopreventive and anti-inflammatory 
effects in both animals and humans (12-15), whilst showing no signs of toxicity 
(12, 16). The potent anti-inflammatory effects of Frondanol in a mouse model 
of IBD provide encouragement for investigating its effects in human IBD 
patients (15).  
 
Over the past 25 years, it is estimated that more than three 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. 
 
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. In addition, we plan to develop a stem cell-derived gut organoid 
model to investigate the mechanism of action of Frondanol.  
 
4. RATIONALE  

 
 
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The overall aim of this project is to investigate the anti-inflammatory effects of 
Frondanol on bowel inflammation in patients with IBD. 
 
5. RESEARCH OBJECTIVES  
1) To compare plasma levels, biopsy mRNA (using low density expression 
arrays) and protein (using either Luminex or Western blotting) levels of the 
following parameters between IBD patients treated with Frondanol and those 
treated with placebo at baseline and after six months of treatment:  
a) Cytokines: TNFα, IL1β, IL6, IL17A, IL21, IL22, IL23, IFNγ, IFNα, as well as 
vascular endothelial growth factor (VEGF-A), MIP-1, MIP-2;  
b) Markers of inflammation: Myeloperoxidase, calprotectin, S100A12, β2-
microglobulin, amyloid A (A-SAA), intercellular adhesion molecule 1 (ICAM-
1), vascular cell adhesion molecule 1 (VCAM-1), MIP-2α (CXCL2), MCP-1 
(CCL2). Leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE) 
and prostaglandin E2 (PGE2) will be measured by specific ELISA assays. 
 
2) To compare the following routine clinical parameters between IBD patients 
treated with Frondanol and those treated with placebo at baseline and after 
six months of treatment:  
a) Patient symptoms;  
b) Blood: Complete blood count (CBC), erythrocyte sedimentation rate 
(ESR), C-reactive protein (CRP), albumin;  
c) Stool: Fecal calprotectin level;  
d) Endoscopic and histologic features.  
 
3) To compare in-vitro concentration-dependent responses to Frondanol and 
placebo on inflamed organoids by measurement of cytokines and other 
inflammatory markers, in particular 5-HETE, LTB4 and PGE2. 
 
6. STUDY DESIGN/METHODOLOGY  
5.1 Design overview 
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 IBD who are in remission 
and on standard of care treatment. 
 
6.2 Study setting  
Patients will be seen in-person at the Gastroenterology Department of any of 
the study centres that will participate in patient recruitment (Mediclinic City 
Hospital, Mediclinic Parkview Hospital and Rashid hospital) by one of the 
coninvestigator consultant gastroenterologists at screening and randomization 
(T0), at a follow-up visit at 3 months (T1), and at a second follow-up visit at 6 
months (T2). Routine blood tests as well as an extra sample for research 

 
 
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purposes will be obtained at these timepoints. Colonoscopies will be 
performed as part of the routine clinical practice and these include acquisition 
of routine biopsies, typically 10-15 from each patient. A few additional biopsies 
(2-4) will be needed for our studies, to be snap frozen and analyzed in MBRU 
research laboratory facilities. IRB approval for these additional biopsies and 
serological testing is being sought from both Mediclinic City Hospital’s REC, 
MBRU-IRB and DHA-REC. It is hoped that the routine colonoscopies can be 
scheduled prior to starting the study treatment and 6 months later. 
 
6.3 Sample and recruitment  
All eligible IBD patients visiting Gastroenterology Department of any of the 
study centres that will participate in patient recruitment (Mediclinic City 
Hospital, Mediclinic Parkview Hospital and Rashid hospital) under the care of 
any of the coinvestigator consultant gastroenterologists during the period of 
recruitment (12 months from the start date of the study – to be decided 
following ethical approval) will be offered to take part in the study. 
 
Block randomization over four blocks of 25 patients will be used to ensure an 
equal number of patients in each treatment group, even if the trial was 
terminated early for any reason. Two blocks will be reserved for patients with 
quiescent/minimal disease and two blocks for patients with mild disease, in 
order to ensure an equal number of these patients in each treatment group. 
Patients will be randomised (1:1) to receive Frondanol (one 1000 mg capsule 
twice daily) or placebo (in a similar capsule) as an adjunct to their standard 
therapy using a randomization number sequence generator. This will be 
conducted by the study statistician using the Microsoft Excel random number 
generator and will only be shared with the study coordinator. 
 
All patients and investigators, excluding the study coordinator, will be blinded 
to treatment allocation. Frondanol and placebo capsules will be placed in 
identical-looking vials which will be labelled with the study name and number, 
and no identifying information. The labelling of the vials will be done with the 
open randomization sheet by the study coordinator. When a patient agrees to 
participate, and signs the informed consent form, the physician will assign to 
the patient the next available randomization number from the randomization 
sheet (supplied by the study coordinator) with the corresponding labelled 
medication vial. Patients will be instructed to take one capsule of their assigned 
medication twice daily. Hence, capsules will be given in a double-blind manner 
where patient and physician are not aware of treatment allocation as the 
treatment and placebo vials will only indicate the pilot study name. 
Investigators involved in the laboratory analysis of samples will also be blinded, 
they will only know if a patient belongs to group 1 or 2 but will not know which 
group is taking Frondanol and which is taking placebo. 
 

 
 
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6.4 Study population  
One hundred patients (50 per arm) with stable IBD (Crohn’s disease or 
ulcerative colitis, in remission) will be recruited in one of the participating study 
centres (Mediclinic City Hospital, Mediclinic Parkview Hospital, Rashid 
Hospital) by one of the coinvestigator consultant gastroenterologists. 
 
6.5 Eligibility criteria 
• 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 diarrhoea 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 (Pabla and Schwartz, 2020). 
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 (Pabla and Schwartz, 2020), with active 
symptoms) will not be eligible to participate in the study. 
 
Reference: 
Pabla BS, Schwartz DA. Assessing Severity of Disease in Patients with 
Ulcerative Colitis. Gastroenterol Clin North Am. 2020; 49(4):671–688 
 
6.6 Sampling technique and recruitment 
All eligible IBD patients visiting the Gastroenterology Department of any of the 
study centres that will participate in patient recruitment (Mediclinic City 
Hospital, Mediclinic Parkview Hospital and Rashid hospital) under the care of 
any of the coninvestigator consultant gastroenterologists during the period of 
recruitment (12 months from the start date of the study – to be decided 
following ethical approval) will be offered to take part in the study. 

 
 
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Patients will be randomised (1:1) to receive Frondanol (one 1000 mg capsule 
twice daily) or placebo (in a similar capsule) as an adjunct to their standard 
therapy using a randomization number sequence generator. This will be 
conducted by the study statistician using the Microsoft Excel random number 
generator and will only be shared with the study coordinator. 
All patients and investigators, excluding the study coordinator, will be blinded 
to treatment allocation. 
 
6.7 Intervention  
Patients will be randomized (1:1) to receive Frondanol (one 1000 mg capsule 
twice daily) or placebo (in a similar capsule) as an adjunct to their standard 
therapy by a designated study coordinator. Both Frondanol and placebo 
capsules will be supplied by Coastside Bio Resources, Stonington, ME, USA. 
The placebo capsules will be red/brown-coloured gelatin capsules (similar in 
texture and colour to the Frondanol capsules), but will contain an inert (inactive) 
substance called food-grade corn starch, which will not interact with the immune 
system. Patients will be instructed to take one capsule of their assigned 
medication twice daily. 
 
6.8 Consent 
Informed consent will be obtained following consultation with one of the 
coinvestigator consultant gastroenterologists to assess eligibility for the study. 
The study will be explained to the patient by the consultant gastroenterologist 
and informed consent will be obtained prior to treatment. Patients will be 
requested to inform the study coordinator or the consultant gastroenterologist 
of any adverse events following the start of treatment. A direct phone number 
will be given to patients so that they are able to call the study coordinator in 
case of any adverse events. The study coordinator, PI and co-investigator 
gastroenterologists will have thorough understanding of the protocol and 
patient population. Retention of patients will be encouraged through discussion 
at the time of consent and throughout the duration of the study regarding the 
importance of adherence with the study procedures. The study will be 
conducted in accordance with the IRB-approved protocol and with the 
guidelines of the Good Clinical Practices (GCP). Patients may withdraw from 
the study at any time, and no further data will be collected from him/her or 
analyzed for the purpose of this research. 
 
6.9 Voluntary participation  
The following paragraph is included in the consent form regarding voluntary 
participation: 
“Your participation in the study is entirely voluntary and you may refuse to 
participate or discontinue participation at any time without penalty or loss of 

 
 
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benefits to which you would normally be entitled.  Your decision about whether 
or not to participate in the study will not affect your relationship with MBRU or 
medical treatment at the hospital/clinic, if applicable.” 
 
6.10 Criteria for subject withdrawal  
Patients may withdraw from the study at any time, and no further data will be 
collected from him/her or analyzed for the purpose of this research. 
 
6.11 Withdrawal from the study  
The following paragraph is included in the consent form regarding withdrawal 
from the study: 
“You are at liberty to withdraw from the research study at any stage, without 
prejudice. Should any new information become available that may affect your 
willingness in participation, you will be informed in a timely manner. However, 
the principal investigator or designee may take you out of the study at any time 
with or without your agreement. This may happen for example if it is in your 
best medical interest to stop your participation, or if the study is canceled. If 
you wish to withdraw from the study, any collected data will be safely stored 
for a minimum of three years following the completion of the study then 
discarded in a confidential manner that does not risk identifying your personal 
information.” 
 
6.12 Premature discontinuation of the study  
The whole study may be discontinued prematurely in the event of the following:  
• Mediclinic decision that continuation of the study is unjustifiable for medical 
or ethical reasons  
• Poor enrolment of subjects making completion of the study within an 
acceptable time frame unlikely  
DHCR and the MBRU-IRB and MCME-REC will be informed about the 
discontinuation of the study in accordance with applicable regulations. The 
whole study may be terminated or suspended upon the request of DHCR.  
 
6.13 Subject Identification  
All patient data and specimen will be de-identified and coded with the unique 
study number of the patient. The code linking the study number with the patient 
will be accessed by the study coordinator only and maintained at MBRU in a 
database and will not be provided to the PI or her research team. Patient data 
will be collected using protocol-specific case report forms (CRFs), which will 
be used to create electronic CRFs (e-CRFs). Clinical records for all patients, 
including CRFs, will be retained by the PI in a secure storage facility for ten 
years after the completion of the study. Paper data will be stored in a locked 

 
 
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cabinet and electronic data will be stored on a password-protected computer 
in the custody of the PI. The data linking patient identifying information and 
their de-identified data will be in the custody of the study coordinator who will 
be unblinded. All patients will complete the following study visits: Screening 
(medical history, physical examination, vital signs and standard of care tests 
including blood and stool tests), baseline endoscopy (day 1 of treatment, date 
to be agreed between the gastroenterologist and patient), 3 months (routine 
monitoring with standard of care tests including blood and stool tests), 6 
months (second endoscopy and standard of care tests including blood and 
stool tests). 
 
 

 
 
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6.14 Study schedule 
Table 1: Variables to be collected from participants 
Method of 
data collection 
Variables 
Questionnaires 
Mayo Score, IBDQ 
Medical record 
Symptoms 
Blood samples 
Routine blood tests as well as an extra sample (10 mL) for research 
purposes will be obtained at T0 (start of study), T1 (3 months) and T2 (6 
months). 
Stool samples 
Routine stool sample will be collected for measurement of fetal calprotectin 
levels at the recruiting hospital at T0, T1 and T2. 
Tissue samples 
Colonoscopies will be performed as part of the routine clinical practice and 
these include acquisition of routine biopsies, typically 10-15 from each 
patient. A few additional biopsies (2-4) will be collected for our studies 
during routine colonoscopies when these are performed, then they will be 
snap frozen and analyzed in MBRU research laboratory facilities. 
 
Table 2: Schedule of Activities  
Variable 
Visit # 1 (T0) 
Visit # 2 (T1 – 
3months) 
Visit # 3 (T2 – 6 
months) 
Questionnaires 
Mayo Score, IBDQ 
Mayo Score, IBDQ 
Mayo Score, IBDQ 
Medical record 
Symptoms 
Symptoms 
Symptoms 
Blood samples 
Routine blood tests as 
well as an extra sample 
(10 
mL) 
will 
be 
obtained, stored and 
analyzed 
in 
MBRU 
research 
laboratory 
facilities. 
Routine blood tests as 
well as an extra sample 
(10 
mL) 
will 
be 
obtained, stored and 
analyzed 
in 
MBRU 
research 
laboratory 
facilities. 
Routine blood tests as 
well as an extra sample 
(10 
mL) 
will 
be 
obtained, stored and 
analyzed 
in 
MBRU 
research 
laboratory 
facilities. 
Stool sample 
Routine stool sample 
will be collected for 
measurement of fetal 
calprotectin levels at 
MCH 
Routine stool sample 
will be collected for 
measurement of fetal 
calprotectin levels at 
MCH 
Routine stool sample 
will be collected for 
measurement of fetal 
calprotectin levels at 
MCH 
Tissue samples 
If 
colonoscopy 
is 
performed for routine 
clinical practice at the 
start of the study, a few 
additional biopsies (2-
4) will be collected for 
our 
studies, 
snap 
frozen and analyzed in 
No 
tissue 
samples 
collected 
If 
colonoscopy 
is 
performed for routine 
clinical practice at the 
end of the study, a few 
additional biopsies (2-
4) will be collected for 
our 
studies, 
snap 
frozen and analyzed in 

 
 
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MBRU 
research 
laboratory facilities. 
MBRU 
research 
laboratory facilities. 
 
6.15 Definition of End of Study  
The study ends after six months of treatment with either Frondanol or 
placebo. 
 
7. SAFETY CONSIDERATIONS 
The recommended dose on the marketed neutraceutical product of Frondanol 
is 1000 mg twice daily. Over the past 25 years more than 3 million 1000 mg 
capsules have been consumed in the human market, with no reported side 
effects. Hence, we based the dosing for our study on the marketed 
recommended dose, as we do not anticipate any side effects. We will be 
excluding patients with allergy to seafood or marine products to avoid the risk 
of allergic reactions. 
Colonoscopies performed in this study are considered part of routine care and 
not for research purposes. The overall expected rate of serious complications 
(bleeding or perforation) from routine colonoscopies is 2-3 per 1000 
procedures (Lee and Salzman, 2020). The only additional procedure that is 
done for the research is to take several additional biopsies after all routine 
biopsies are taken. The expected increase in risk from taking these several 
additional biopsies is considered to be very small and likely insignificant. The 
consent form will state that the “increased risk of taking additional biopsies, for 
the purposes of this research, after all routine biopsies are taken is considered 
to be very small.”    
In the unlikely event that side effects occur, patients will be requested to 
immediately inform the study coordinator/research nurse, PI or consultant 
gastroenterologist. A direct phone number will be given to patients so that they 
are able to call the study coordinator or assigned nurse in case of any adverse 
events. Depending on the severity of the event, the participant will be 
instructed whether to report to the Gastroenterology unit at the study site or to 
head to the emergency department of one of the hospitals covered by the trial’s 
liability insurance, for further investigation and possible treatment.  
Additional risks to the study subjects would be embarrassment or discomfort 
in answering items on questionnaires to be completed. Participants will be 
instructed not to answer any questions that they feel uncomfortable with.  
 
8. STUDY OUTCOME EVALUATIONS/STATISTICAL ANALYSIS 
 
8.1 Sample size/Power calculation 
All eligible IBD patients visiting the Gastroenterology Department of any of the 
study centres that will participate in patient recruitment (Mediclinic City 
Hospital, Mediclinic Parkview Hospital and Rashid hospital) under the care of 

 
 
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any of the coninvestigator consultant gastroenterologists during the period of 
recruitment (12 months from the start date of the study – to be decided 
following ethical approval) will be offered to take part in the study. 
Patients will be randomised (1:1) to receive Frondanol (one 1000 mg capsule 
twice daily) or placebo (in a similar capsule) as an adjunct to their standard 
therapy using a randomization number sequence generator. This will be 
conducted by the study statistician using the Microsoft Excel random number 
generator and will only be shared with the study coordinator. 
All patients and investigators, excluding the study coordinator, will be blinded 
to treatment allocation. 
 
8.2 Statistical methods 
All statistical analyses will be carried out using SPSS Software (Armonk, New 
York, USA). Potential confounders such as age and sex will be controlled for 
during the analysis phase. A per-protocol analysis including only participants 
who have a full data set will be used to assess the efficacy of Frondanol 
treatment in lowering inflammatory markers. An intention-to-treat analysis will 
also be conducted including patients who drop out before the study ends, for 
whom we will use last observation carried forward (LOCF) i.e. we will impute 
the last observed data for all subsequent (missing) observation points. For 
quantitative data, within-group and between-group comparisons will be 
analyzed using the General linear Repeated Model (MANOVA), which would 
allow for adjustment of potential confounders such as age and sex. Data will 
be plotted as mean ± SEM and p values ˂0.05 will be considered statistically 
significant. 
 
9.  DATA MANAGEMENT  
9.1 Subject Identification and Privacy  
A unique subject number will be assigned to each subject at inclusion, 
immediately after informed consent has been obtained. This number will 
serve as the subject’s identifier in the study.  
The subject’s data collected in the study will be stored under this number only. 
Only the study coordinator will be able to link the subject’s study data to the 
subject via an identification list kept at MBRU and/or MCH sites.  
Data protection and privacy regulations will be observed in capturing, 
forwarding, processing and storing subject data. Subjects will be informed 
accordingly, and will be requested to give their consent on data handling 
procedures in accordance with MCH and DHCR policies and guidelines.   
 
9.2 Data handling and record-keeping 
A data collection form (DCF) will be completed for each subject enrolled into 
the study.  The investigator will review, approve and sign/date each completed 

 
 
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DCF; the investigator’s signature serving as attestation of the investigator’s 
responsibility for ensuring that all data entered on the DCF are complete, 
accurate and authentic. All study data will be stored at MCH according to ICH-
GCP standard for a period of 10 years, or until all regulatory and funder 
requirements are met. 
 
9.3 Record maintenance and retention  
The investigator will maintain and retain the investigator site file (ISF). The file 
will contain all documents necessary for the conduct of the study and will be 
updated and completed throughout the study. The investigator will permit 
study-related monitoring, audits, REC review, and regulatory inspections, 
providing direct access to source data. 
 
9.4 Monitoring, QUALITY CONTROL AND QUALITY ASSURANCE 
This study will be monitored in accordance with the ICH Note for Guidance on 
Clinical Practice (ICH Topic E6, 1996). The assigned site monitor will monitor 
data collected at regular intervals. The quality control and quality assurance of 
the study will be performed by MCH.   
Representatives of DHCR will be permitted to inspect all study related 
documents and other materials at the site, including the ISF, completed DCFs 
and the subject’s medical records/files. 
 
10. ETHICAL and REGULATORY CONSIDERATIONS    
10.1 Responsibilities of the Investigator  
The Investigator is responsible for the conduct of the study and will ensure that the study is 
performed in accordance with the study protocol and with the ethical principles that have 
their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on Good 
Clinical Practice (ICH Topic E6, 1996) and applicable regulatory requirements. In particular, 
the Investigator must ensure that only subjects who have given their informed consent are 
included into the study. 
 
10.2 Benefits to participants 
Currently, treatment of IBD relies on minimizing symptoms and improving 
quality of life through the control of disease progression and complications. 
Treatments for IBD include aminosalicylates, high-dose oral steroids, 
azathioprine, cyclosporine or methotrexate. Alternatively for severe refractory 
disease, anti-TNF drugs such as infliximab, adalimumab and golimumab can 
be used. More recently, integrin antagonists such as vedolizumab and 
etrolizumab have shown some promising results. 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 is a widely available neutraceutical extract from the edible sea 
cucumber which has been shown to have potent anti-inflammatory (as well as 
anti-cancer) effects in rats, in particular in the colon and in humans. Therefore, 

 
 
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we decided to investigate the anti-inflammatory effects of Frondanol in human 
IBD patients. 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. LD50 for Frondanol has 
not be ascertained because no deaths were observed following the 
administration of large amounts to rats, to the point that no more could be given 
due to gastric distention (unpublished observations by our group). All patients 
in the proposed study will continue to receive standard therapy. 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. 
 
10.3 Costs and Payments 
Participants will not receive study incentives (compensation) nor will they 
incur costs for participating in this study. 
 
10.4 Safety Monitoring: 
In the unlikely event that side effects occur, patients will be requested to 
immediately inform the study coordinator/research nurse, PI or consultant 
gastroenterologist. A direct phone number will be given to patients so that they 
are able to call the study coordinator or assigned nurse in case of any adverse 
events. Depending on the severity of the event, the participant will be 
instructed whether to report to the Gastroenterology unit at the study site or to 
head to the emergency department of one of the hospitals covered by the trial’s 
liability insurance, for further investigation and possible treatment.  
 
Simultaneously, the PI, assisted by the clinical gastroenterologists on the 
team, and taking into account any other medical information available, will 
perform a causality assessment to ascertain whether the adverse event was 
related to participation in the trial. If the adverse event is deemed to be related 
to participation in the trial, the participant will be advised to immediately stop 
taking the study medication (whether Frondanol or placebo) and will be 
provided with the necessary medical care until the issue is resolved.  
 
In the unlikely event that the adverse event is deemed to be caused by 
Frondanol and if the assessment by the study team results in a doubt that 
further adverse events may occur with other participants, the trial will be 
immediately suspended, and all participants will be informed and required to 
stop taking their assigned study medication and await further instructions from 
the PI or trial coordinator.   
 
Any serious or unexpected adverse event will be reported by the PI to all 
ethical committees that have approved this study, no later than 24 hours for 

 
 
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life threatening events and no later than 10 working days for non-life-
threatening events. Reports to the involved ethical committees will include 
advice from PI as to whether in her opinion (supported by the opinions of the 
study team’s gastroenterologists): 
• The adverse event was related to the protocol or the study drug 
• The adverse event necessitates an amendment to the study protocol 
and/or patient information/consent form 
 
The PI will be obliged to conform with the course of action that the relevant 
ethical committees have deemed necessary to occur. In the unlikely event that 
the ethical committees recommend termination of the trial, participants will be 
contacted immediately and asked to stop taking their assigned medication and 
return it to the study centre at their earliest convenience. The entire process 
will be documented and safely stored electronically on the devices of the PI 
and trial coordinator. 
 
10.5 Conflicts of Interest: 
The Investigators and the research do not have a financial or commitment 
conflict of interest in relation to this study. Completed disclosure forms will be 
held at MCH. 
 
10.6 Clinical Study Insurance and Compensation to Subjects 
In the unlikely event that side effects occur, patients will be requested to 
immediately inform the study coordinator/research nurse, PI or consultant 
gastroenterologist. A direct phone number will be given to patients so that 
they are able to call the study coordinator or assigned nurse in case of any 
adverse events. Depending on the severity of the event, the participant will 
be instructed whether to report to the Gastroenterology unit at the study site 
or to head to the emergency department of one of the hospitals covered by 
the trial’s liability insurance, for further investigation and possible treatment. 
 
Subjects will not be offered compensation for their participation in the trial.  
 
10.7 Independent Research Ethics Committee 
Prior to commencement of the study the study protocol will be submitted 
together with its associated documents to the responsible REC for its 
favourable opinion/approval. The written favourable opinion/approval of the 
REC will be filed in the Investigator Site File.  
The study must not start before the obtaining written confirmation of 
favourable opinion/approval from the concerned REC.  
Amendments to the study will also be submitted to the concerned REC 
before implementation in case of substantial changes. Relevant safety 
information will be submitted to the REC during the course of the study in 
accordance with national regulations and requirements. 

 
 
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11.  CLINICAL STUDY REPORT AND PUBLICATIONS  
 
11.1 Study Report 
After completion of the study, a study report according to good clinical 
practice will be written by the Investigator.  
 
11.2 Publication and Dissemination of results  
The principle of research is to obtain data and results to benefit society and, 
in this context, research may be published. Due to the anonymizing nature of 
data collection, participants will not be personally identified in any publication. 
Research data may be kept indefinitely as use of such data is sometimes 
required by other researchers and occasionally by editors of publications. 
 
 
Principal Investigator  
   
 
 
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Signature:   
 
 
 
 
 
Date: DD/MM/YY 
 
 
 
Sponsor 
  
 
 
 
 
 
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Signature:   
  
 
Date: DD/MM/YY