Effect of Sea Weed (Ecklonia Cava Extract) on Postprandial Blood Glucose and Insulin Level on Pre-diabetic Patients: A Double-blind Randomized-controlled Trial
Phase: PHASE4
Conditions: PreDiabetes
Sponsor: King Saud University

 
 
 
 
 
 
 
 
Effect of seaweed (Ecklonia cava extract) on Postprandial blood 
glucose and insulin level on pre-diabetic patients: A double-blind 
randomized-controlled trial  
(SW2020) 
 
 
Date: 25/09/2020 
 
IRB Approval No: 
E-24-4249 
 
 

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Clinical Research Protocol 
SEAWEED STUDY 
Protocol Number: 
SW2020 
Version Date: 
    25 / 09 / 2020 
Investigational Product: 
  Brown Seaweed (Ecklonia cava) 
IND Number: 
 
Development Phase: 
Phase 3 
Sponsor: 
Name: Malak Almutairi  
Address: 22 King Abdullah st, Alrayan, Almethnab 56526, 
Qassim, KSA 
City, State Almethnab, Qassim, KSA  
Funding Organization: 
King Saud University 
Principal Investigator: 
Name: Malak Almutairi  
 
Telephone: +966544479135  
Fax: 
 
 
E-mail: malak.rog@gmail.com 
 
Medical Monitor: 
Name:  
 
Telephone: 
 
Fax: 
 
 
E-mail: 
 
Coordinating Center: 
Clinical trial Unit at King Khalid University Hospital 
 
Approval: 
 
 
 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Malak Almutairi the PI with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide 
by the terms of this protocol. 
 
Protocol Number:  SW2020 
 
Protocol Title: SEAWEED STUDY 
 
Protocol Date:  25/09/2020 
 
 
 
25 / 09 / 2020 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 

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TABLE OF CONTENTS 
 
1 
BACKGROUND .............................................................................................................12 
       1.1 
Overview of Non-Clinical Studies ...........................................................................12 
1.2 
Overview of Clinical Studies ...................................................................................13 
2 
STUDY RATIONALE ....................................................................................................14 
2.1 
Risk / Benefit Assessment .......................................................................................15 
3 
STUDY OBJECTIVES ...................................................................................................16 
3.1 
Primary Objective....................................................................................................16 
3.2 
Secondary Objectives ..............................................................................................16 
4 
STUDY DESIGN ............................................................................................................16 
4.1 
Study Overview .......................................................................................................15 
5 
CRITERIA FOR EVALUATION ..................................................................................16 
5.1 
Primary Efficacy Endpoint ......................................................................................16 
5.2 
Secondary Efficacy Endpoints .................................................................................17 
5.3 
Safety Evaluations ...................................................................................................17 
6 
SUBJECT SELECTION .................................................................................................17 
6.1 
Study Population .....................................................................................................17 
6.2 
Inclusion Criteria .....................................................................................................17 
6.3 
Exclusion Criteria ....................................................................................................17 
7 
CONCURRENT MEDICATIONS .................................................................................18 
7.1 
Allowed ..................................................................................................................18 
7.2 
Prohibited ................................................................................................................18 
8 
STUDY TREATMENTS ................................................................................................18 
8.1 
Method of Assigning Subjects to Treatment Groups ................................................18 
8.2 
Blinding ..................................................................................................................18 
8.3 
Test and Control Formulation ..................................................................................19 
           8.3.1   Formulation of Test Product 
                                                                        19 
           8.3.2   Formulation of Control Product 
                                                                        20 
           8.3.3   Formulation of Control Product 
                                                                        20 
8.4 
Supply of Study Medication at the Site ....................................................................20 
           8.4.1   Dosage/Dosage regimen                                                                                       20 
           8.4.2   Dispensing                                
                                                                        20 
           8.4.3   Administration Instruction        
                                                                        20 
8.5 
Study Medication Accountability .............................................................................21 
           8.5.1   Storage                                      
                                                                        21 
8.6 
Measures of Treatment Compliance .........................................................................21 
9 
STUDY PROCEDURES AND GUIDELINES ...............................................................21 
9.1 
Clinical Assessments ...............................................................................................21 
           9.1.1   Concomitant Medication                                                                                        21 
           9.1.2   Demographics                           
                                                                        21 

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           9.1.3   Medical History                         
                                                                        21 
           9.1.4   Physical Examination  
                                                                                     22 
    9.1.1 Vital Signs............................................................................................................22 
9.2 
Pharmacokinetic Measurements ...............................................................................22 
9.3 
Research Laboratory Measurements ........................................................................22 
10 EVALUATIONS BY VISIT ...........................................................................................22 
10.1 Visit 1 (Day/Week/Month #) ...................................................................................22 
10.2 Visit 2 (Day/Week/Month # include visit window) ..................................................23 
10.3 Early Withdrawal Visit ............................................................................................23 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION .......................23 
11.1 Adverse Events........................................................................................................23 
    11.1.1 AE Sevirty ..........................................................................................................24 
    11.1.2 AE Relationship to Study Drug ...........................................................................24 
11.2 Serious Adverse Experiences (SAE) ........................................................................25 
11.3 Medical Monitoring .................................................................................................25 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ..................................25 
12.1 Early of Discuntinuation of Study Drug ...................................................................25 
12.2 Withdrowal of Subjects from the Study ...................................................................26 
12.3 Replacement of Subjects ..........................................................................................26 
13 PROTOCOL VIOLATIONS ..........................................................................................26 
14 STATISTICAL METHODS AND CONSIDERATIONS ..............................................27 
14.1 Data Sets Analyzed..................................................................................................27 
14.2 Demographic and Baseline Characteristics ...............................................................27 
14.3 Analysis of Primary Endpoint ..................................................................................27 
14.4 Analysis of Secondary Endpoints .............................................................................27 
14.5 Interim Analysis ......................................................................................................28 
14.6 Sample Size and Randomization ..............................................................................28 
15 DATA COLLECTION, RETENTION AND MONITORING ......................................28 
15.1 Data Collection Instruments.....................................................................................28 
15.2 Data Management Procedures ..................................................................................29 
15.3 Data Quality Control and Reporting .........................................................................29 
15.4 Archival of Data ......................................................................................................29 
15.5 Availability and Retention of Investigational Records ..............................................29 
15.6 Monitoring ..............................................................................................................29 
15.7 Subject Confidentiality ............................................................................................30 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ..................30 
16.1 Protocol Amendments .............................................................................................30 
16.2 Institutional Review Boards and Independent Ethics Committees.............................30 
16.3 Informed Consent Form ...........................................................................................31 
16.4 Publications .............................................................................................................31 
16.5 Investigator Responsibilities ....................................................................................31 

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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FBG 
Fasting Blood Glucose  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
PPBG 
Postprandial Blood Glucose  
PPIL 
Postprandial Insulin Level  
SAE 
serious adverse experience 

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PROTOCOL SYNOPSIS 
TITLE 
Effect of sea weed (Ecklonia cava extract) on blood glucose and insulin 
level on pre-diabetic patients: A double-blind randomized-controlled 
trial (SEAWEED STUDY) 
SPONSOR 
Malak Almutairi  
FUNDING 
ORGANIZATION 
King Saud University  
NUMBER OF SITES 
One site  
RATIONALE 
There is a noticeable interest and enthusiasm toward brown seaweed 
anti-diabetic effects. Many vivo studies have shown strong inhibition 
activity of polyphenolic-rich brown seaweed on a-amylase and a-
glucosidase enzymes (12-15). For example, Heo et al. have displayed a 
significant inhibitory activity of a new phlorotannin, diphlorethohydrox-
ycarmalol (DPHC) isolated from brown seaweed called Ishige okamurae 
on a-glucosidase and a-amylase significantly as well as showed 
suppression of postprandial blood glucose level in diabetic and normal 
mice (14). This inhibitory activity on a-amylase and a-glucosidase were 
similar to an anti-diabetic commercial drug called acarbose (7). 
similarly, Lee et al, have claimed in their study that the IC50 value for 
phlorotannin derivatives extracted from brown algae, E. cava, against a-
glucosidase were higher than the IC50 value for the drug acarbose (15). 
In regard to human trials, investigation of polyphenolic-rich brown 
seaweed effect on glycemic control did not yield consistent   evidence, 
yet (4,5,8,9).. However, desirable effects have been shown in some 
clinical studies (11, 12, 13). Lee et al, have conducted a randomized 
clinical trial on 73 male and female participants with fasting blood 
glucose (FBG) between 100 to 180 mg dL−1 (11). Participants were 
randomly divided into two groups given 500 mg of AG-dieckol three 
times a day for 12 weeks. The result shows acute significant reduction in 
postprandial blood glucose (PPBG) ( p < 0.05) after 12 weeks 
intervention. However, non-significant postprandial insulin level (PPIL) 
reduction was seen in group who consumed AG-dieckol compared to 
placebo group. Nonetheless, within group reduction was significantly 
observed in terms of insulin level compared to baseline (11). Moreover, 
a study has investigated the acute effects of brown algae extracts 
(Ascophyllum nodosum and Fucus vesiculosus) on postprandial glucose 
and insulin concentration (12). participants were given 508 mg brown 
algae extract 30 minutes prior to 110 g carbohydrates consumption. 
Despite of healthy individuals and different seaweed source, containing 
only 10% polyphenols, used in this study, acute inulin concentration was 
significantly decreased (p < 0.05) in brown algae groups compared to 
placebo group (12). Also, non-significant postprandial glucose 
concentration was found to be decreased in brown algae extract (p > 

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0.05). In contrast, non-significant result was reported in a clinical study 
examining high dose (2000 mg), low dose (500 mg) of polyphenolic-rich 
brown algae (Fucus vesiculosus) compared to placebo in healthy people. 
The study concludes non-significant result in terms of acute PPBG and 
PPIL (14). As pointed out by Margaret et al, in their systematic review 
that the source of seaweed extract and its polyphenolic content is very 
important in triggering antidiabetic effect (15). Thus, they strongly 
suggest that more clinical studies are required to determine consistent 
pattern of dose-response and to identify the effectiveness dose in a high-
risk population (15). According to side effect, no study has reported any 
significant differences between brown seaweed and placebo in terms of 
measuring adverse effect (9-14). Lee et al, have reported similar 
incidence of adverse event between groups (22.2 vs 16.2) for brown 
algae group compared to placebo, respectively (11). Similarly, paradis et 
al, find that 13 subjects in each group have reported adverse effect with 
minimal intensity (1 in a scale of 0 to 3 where 0 absent and 3 means 
sever intensity) being the most reported for most of measured symptoms 
(12). Despite many promising results in vitro and vivo studies (animal 
studies), the effects of polyphenol-rich brown seaweed on blood glucose 
and insulin level in human have not been effectively investigated. Thus, 
more investigational studies are needed particularly on the interaction of 
brown seaweed and its polyphenols with human cellular systems which 
may provide better understanding on parameters such as bioavailability, 
mechanisms of actions of in glucose homeostasis in humans. This can be 
translated into long-term health benefits. Further research would widen 
the likelihood of screening more biologically proficient polyphenols and 
its derivatives. Results of such studies could provide us with resourceful 
drug substitute to reduce or regulate diet-linked chronic malfunctions 
such as diabetes. In terms of the type of seaweed intended to be used, 
Kunihisa, et al have claimed that "this type of brown seaweed (E. cava) 
polyphenolic-rich extract is an important functional food component that 
could be used in reducing diabetes related symptoms" (16). Also, 
Margert et al, on their systematic review investigating the effect of algal 
polyphenols on antidiabetic, anti-hyperlipidaemia or anti-inflammatory 
effects in humans, have stated that " E. cava is currently the most 
extensively investigated source of marine polyphenols for anti-
hyperglycaemic effects and has shown the most promise in this area" 
(8). Indeed, they have concluded that " Marine polyphenols, particularly 
from E. cava, show potential as natural functional ingredients for the 
prevention and management of type 2 diabetes and CVD. However 
further high quality RCTs are required to determine the most effective 
dose, treatment schedule and macroalgal source to produce consistent 
effects on glycaemia and dyslipidaemia in humans" (8). Moreover, 
Previous human studies have mainly performed on healthy individuals 
using different types of seaweed (4,5). Therefore, this proposal is meant 
to address the gap in this scientific area, using Ecklonia cave on 

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prediabetes patient which hypothesized to have beneficial result 
regarding blood glucose and insulin level (8). Although, the 
methodology in this study focuses on the acute effect of E. cava on 
glycaemic control, it can be a promising result for future studies 
including long-term studies. Result in this study would give indications 
for future research regarding type of seaweed, dose and targeted 
population. More research in this area may benefits us in different aspect 
including prevention and clinical use of seaweed extract, diabetic 
patients' compliance, and cost spent in health care systems as seaweed is 
an abundant and sustainable naturally existing source of active biologic 
compounds, which makes it one of the best proposed choices for 
tackling diabetes. 
STUDY DESIGN 
randomized, double-blind, placebo-controlled phase 3 study. 
PRIMARY 
OBJECTIVE 
Investigate the effectiveness of seaweed (E. cava) in reducing 
postprandial blood glucose and plasma. 
insulin level (to determine insulin sensitivity) in pre-diabetic patients, 
compared to placebo. 
SECONDARY 
OBJECTIVES 
Investigate the safeness and potential adverse effect of applying sea 
weed (E. cava) as a therapeutic diet composition on patient with pre-
diabetes, compared to placebo. 
NUMBER OF 
SUBJECTS 
30 subjects  
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: Participants will be eligible to participate in this study 
if they are: 
 diagnosed in their medical history as pre-diabetic patient with 
fasting plasma glucose (FPG) between 100 and 125 mg dL−1. 
  aged between 18 and 65 years. 
 blood pressure within the normal range (systolic blood pressure ≤ 
140 mmHg, diastolic blood pressure ≤ 90 mmHg). 
 having no other health complications. 
 
Exclusion Criteria: Participants will be excluded if they are: 
 taking any treatment with either insulin or anti-diabetic drugs. 
  any other natural health products known to impact blood sugar, 
or polyphenol absorption (e.g. fish oil). 
 Smoker. 
 pregnant or lactation 

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 having liver, thyroid, or significant gastrointestinal disorders.  
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Product brown seaweed (ecklonia cava) will be given at 580 mg dose 
Product will be administered only one time at the only one visit to 
investigate the acute effect of the investigational product.  administration 
will be orally. 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Product plain dextrin as a placebo at 500 mg dose 
Product will be administered only one time at the only one visit to 
investigate the acute effect of the investigational product.  administration 
will be orally.  
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for only one time for only 3 hours 
Screening:  one visit 
Treatment:  one time at the only one visit.  
Follow-up:  one day 
The total duration of the study is expected to be 4 months.  2 months for 
subject recruitment and 2 months for final subject follow-up as they will 
visit in different days. 
CONCOMMITANT 
MEDICATIONS 
 Allowed:  
- 
any medication that are not listed in prohibited list.  
 
Prohibited: 
- 
any treatment with either insulin or anti-diabetic drugs. 
- 
any other natural health products known to impact blood 
sugar, or polyphenol absorption (e.g. fish oil). 
- 
Any liver, thyroid, or gastrointestinal disorders medications.  
EFFICACY 
EVALUATIONS 
NA 
PRIMARY ENDPOINT 
 
Plasma glucose concentration will be determined immediately by 
blood finger-prick sample following standard procedure using Accu-
Chek® aviva (Roche Diagnostics, Rotkreuz, Switzerland), Whereas, 
plasma insulin will be measured at the laboratory department at 
KKUH using enzyme-linked immunosorbent assay (ELISA) 
SECONDARY 
ENDPOINTS 
 
Participant\s will be asked to indicate whether side effects are absent, 
mild, moderate or severe by giving scores as 0,1,2,3, respectively. 
The side effect questionnaire, will be required to be completed 
within 24 hours after intervention or placebo ingestion. 
OTHER 
EVALUATIONS 
NA 
SAFETY 
Change in blood glucose level from baseline to more than 240 mg /dl or 

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EVALUATIONS 
less than 70 mg /dl  
Adverse events such as: Headach, Bloating or Minor abdominal pain  
PLANNED INTERIM 
ANALYSES  
When approximately 50% of patients have completed the study through 
Visit 2, an interim analysis for safety will be conducted by an 
independent data monitoring committee. Serious adverse events will be 
monitored by the committee on an ongoing basis throughout the study. 
STATISTICS 
Primary Analysis Plan 
Mean (standard deviation) will be reported for normally distributed data, 
whereas median (interquartile range) will be reported for not normally 
distributed data. Either independent t-test or Mann-Whitney test, based 
on normality of data, will be used to determine the difference between 
the two groups for both PPBG and PPIL at a significant level of p < 
0.05. Mann-Whitney test will be used to determine differences for 
symptoms of intolerance between groups. Incremental area under the 
curve (iAUC), time to peak and peak blood concentration assessment 
will be used to assess postprandial responses of plasma glucose and 
insulin level. 
Rationale for Number 
of Subjects 
Sample size was calculated based in similar study (24) using sample size 
determination equation  
 
n =  2(32)2(1.96+0.84)2 / 382 
 =  2(1024)(2.8)2 / 1444   =    2048∗7.84 / 1444 
 = 16056.32 / 1444 
 = 11.11 ≈ 12 subjects/group 
whereas:  
- Za/2 = standard normal variate for level of significant, at 5% type 1 
error, (if p < 0.05 = 1.96). 
- ZB = Standard normal variate for power (for 80% power = 0.84, for 
90% power = 1.28). 
- SD= Standard Deviation (determined from the literature). 
- d= effect size –glucosidases, thus improving diabetic related response 
(8). In general, Seaweeds, also called difference between mean values 
(determined from the literature). 
 

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1 
BACKGROUND 
In general, Seaweeds, also called marine algae, is considered high-quality healthy food as 
it contains diversified bioactive compound which exhibits various beneficial biological 
effects (5). Seaweed, particularly brown seaweed, is excellent source of polyphenolic 
antioxidants such as catechines, flavonoids which are well-known as functional foods 
components (9). In addition, the only seaweed that contain phlorotannins is the brown 
colored seaweed, thus it is the most studied type of seaweed. Phlorotannins is a subgroup 
of tannins that produced completely by polymerization of phloroglucinol. Ecklonia cava 
species is expected to have high content of phlorotannins. The most studied seaweed 
polyphenols-rich extracted from Ecklonia cava (E. cava) are phloroglucinol, 
phloroglucinol tetramer, eckol, phlorofucofuroeckol A, dieckol, and 8,80-bieckol, 
dioxinodehydroeckol. Recent evidence found that phlorotannins has exhibited various 
biological activities in vivo and vitro. E. cava polyphenolic-rich extract is an important 
functional food component that could be used in reducing diabetes related symptoms 
1.1 
Overview of Non-Clinical Studies 
The effect of different types of phloroglucinol oligomers from E. bicyclis, a brown 
seaweed, on the activity of different types of glucosidase has been studied in a vitro study 
using the viscera of turan shell (Turbo cornutus). As resu lt, phlorofucofuroeckol A, 
dieckol, and 8,80-biecko have shown strong inhibition effect on α-fucosidase, α-
galactosidase, and α-mannosidase (1). Phloroglucinol derivatives from E. bicyclis namely 
2-phloroeckol, eckol and dieckol have also showed high anti-diabetic activity by the 
inhibition of α-amylase as well as glycation (2).  Okada et al, have reported the percentage 
of a-amylase inhibition as 89.5%, 87.5% and 97.5% by 2-phloroeckol, eckol and dieckol, 
respectively (3). Zhang et al, have found that ethanolic extract of Ascophyllum nodosum 
reduced liver glycogen levels in diabetic mice by inhibition of intestinal α-glucosidase 
with IC50 (half maximal inhibitory concentration) value of 77 mg/ml. ecklonia stolonifera 
is a brown alga species that contain high amount of polyphenols (estimated to be 
phlorotannins) (4). The ethanolic extract E. stolonifera (MEE) shows a reduction in 
plasma glucose peroxidation level in non-insulin dependent diabetic mice model KK-Ay 
model (4). Also, dieckol extracted from E. cava demonstrated significant activity for with 
IC50 value of 10.8mmol/l a-amylase and a-glucosidase and 124.9mmol/l (5). Also, 
phlorofucofuroeckol A from Ecklonia stolonifera showed similar anti-diabetic result when 
applied on diabetic-complication such asangiotensin converting enzyme (ACE), advanced 
glycation end products (AGE), rat lens aldose reductase (RLAR), reactive oxygen species 
(ROS) in vitro study (6). Heo et al. also have displayed a significant inhibitory activity of 
a new phlorotannin, diphlorethohydrox-ycarmalol (DPHC) isolated from Ishige okamurae 
on a-glucosidase and a-amylase significantly as well as showed suppression of 
postprandial blood glucose level indiabetic and normal mice (7). This inhibitory activity 
on a-amylase and a-glucosidase were similar to an anti-diabetic commercial drug called 
acarbose (5). similarly, Lee et al, have claimed in their study that the IC50 value for 
phlorotannin derivatives extracted from brown algae, E. cava, against a-glucosidase were 
higher than the IC50 value for the therapeutic drug acarbose (8). They found that dieckol 
high inhibitory activity against α- glucosidase and α-amylase, with IC50 values at 10.97 

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and 124.98 µmol L−1, respectively. This suggest that E. cava polyphenolic extract is an 
important functional food component that could be used in reducing diabetes related 
symptoms (5). In different study, dieckol isolated from E. cava showed reduced α-
glucosidase and α- amylase activity alongside with postprandial hyperglycemia reduction 
in diabetic male mice (9). There was no cytotoxicity reported in this experiment (19). 
Another brown seaweed extract, Ishige okamurae, anti-diabetic effects on postprandial 
glucose and insulin level were investigated in male diabetic mice. The study showed that 
improvement in insulin resistance and fasting blood glucose reduced HbA1c level in the 
diabetic mice group treated with Ishige okamurae extract compared to diabetic control 
mice group (10). 
1.2 
Overview of Clinical Studies 
In general, human studies that investigated effect of marine algae (seaweed) on glycaemic 
control are limited. However, desirable effects have been shown in some clinical studies 
(11, 12, 13). Lee et al, have conducted a randomized clinical trial on 73 male and female 
participants with fasting blood glucose between 100 to 180 mg dL−1 (11). Participants 
were randomly divided into two groups given 500 mg of AG-dieckol three times a day for 
12 weeks. The result shows acute significant reduction in postprandial glucose ( p < 0.05) 
after 12 weeks intervention. However, non-significant postprandial insulin reduction was 
seen in group who consumed AG- dieckol compared to placebo group. Nonetheless, 
within group reduction was significantly observed in terms of insulin level compared to 
baseline (11). It worth to mention that Lee et al study was the only long-term study 
investigating the effect of marine algae on blood sugar and insulin level (11). However, 
randomization, bindingness, and participants' compliance measurement were not reported 
in this study, which may impact the quality of the study. Moreover, a study has 
investigated the acute effects of brown algae extracts (Ascophyllum nodosum and Fucus 
vesiculosus) on postprandial glucose and insulin concentration (12). participants were 
given 508 mg brown algae extract 30 minutes prior to 110 g carbohydrates consumption. 
Despite of healthy individuals and different seaweed source, containing only 10% 
polyphenols, used in this study, acute inulin concentration was significantly decreased (p 
< 0.05) in brown algae groups compared to placebo group (12). Also, non-significant 
postprandial glucose concentration was found to be decreased in brown algae extract (p > 
0.05). One of early studies on sea weed effect on acute FBG and PPBG was conducted in 
Mexico (13). They found that FBG and PPBG were significantly decreased among group 
who received seaweed extract (not specified) compared to placebo group (13). 
Researchers have referred the reduction of FBG and PPBG to the increase in fibres intake, 
which were found to be 2.5 times in sea weed group compared to placebo groups (13). 
This could be another important research point related to the benefits of seaweed needed 
further investigation in different clinical population. In addition, Non-consistent evidence 
was reported in a clinical study examining high dose (2000 mg), low dose (500 mg) of 
polyphenolic-rich brown algae (Fucus vesiculosus) compared to placebo in healthy 
people. The study concludes non-significant result in terms of acute PPBG and IL (14). As 
pointed out by Margaret et al, in their systematic review that the source of seaweed extract 
and its polyphenolic content is very important in triggering antidiabetic effect (15). Thus, 
they strongly suggest that more clinical studies are required to determine consistent 
pattern of dose-response and to identify the effectiveness dose in a high-risk population 

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(15). According to the knowledge of researcher, no study has reported any significant 
differences between brown algae and placebo in terms of measuring adverse effect (9-14). 
Lee et al, have reported similar incidence of adverse event between groups (22.2 vs 16.2) 
for brown algae group compared to placebo, respectively (11). Similarly, paradis et al, 
find that 13 subjects in each group have reported adverse effect with minimal intensity (1 
in a scale of 0 to 3) being the most reported for most of measured symptoms (12). 
2 
STUDY RATIONALE 
There is a noticeable interest and enthusiasm toward brown seaweed anti-diabetic effects. 
Many vivo studies have shown strong inhibition activity of polyphenolic-rich brown 
seaweed on a-amylase and a-glucosidase enzymes (12-15). For example, Heo et al. have 
displayed a significant inhibitory activity of a new phlorotannin, diphlorethohydrox-
ycarmalol (DPHC) isolated from brown seaweed called Ishige okamurae on a-glucosidase 
and a-amylase significantly as well as showed suppression of postprandial blood glucose 
level in diabetic and normal mice (14). This inhibitory activity on a-amylase and a-
glucosidase were similar to an anti-diabetic commercial drug called acarbose (7). 
similarly, Lee et al, have claimed in their study that the IC50 value for phlorotannin 
derivatives extracted from brown algae, E. cava, against a-glucosidase were higher than 
the IC50 value for the drug acarbose (15). In regard to human trials, investigation of 
polyphenolic-rich brown seaweed effect on glycemic control did not yield consistent   
evidence, yet (4,5,8,9).. However, desirable effects have been shown in some clinical 
studies (11, 12, 13). Lee et al, have conducted a randomized clinical trial on 73 male and 
female participants with fasting blood glucose (FBG) between 100 to 180 mg dL−1 (11). 
Participants were randomly divided into two groups given 500 mg of AG-dieckol three 
times a day for 12 weeks. The result shows acute significant reduction in postprandial 
blood glucose (PPBG) ( p < 0.05) after 12 weeks intervention. However, non-significant 
postprandial insulin level (PPIL) reduction was seen in group who consumed AG-dieckol 
compared to placebo group. Nonetheless, within group reduction was significantly 
observed in terms of insulin level compared to baseline (11). Moreover, a study has 
investigated the acute effects of brown algae extracts (Ascophyllum nodosum and Fucus 
vesiculosus) on postprandial glucose and insulin concentration (12). participants were 
given 508 mg brown algae extract 30 minutes prior to 110 g carbohydrates consumption. 
Despite of healthy individuals and different seaweed source, containing only 10% 
polyphenols, used in this study, acute inulin concentration was significantly decreased (p 
< 0.05) in brown algae groups compared to placebo group (12). Also, non-significant 
postprandial glucose concentration was found to be decreased in brown algae extract (p > 
0.05). In contrast, non-significant result was reported in a clinical study examining high 
dose (2000 mg), low dose (500 mg) of polyphenolic-rich brown algae (Fucus vesiculosus) 
compared to placebo in healthy people. The study concludes non-significant result in 
terms of acute PPBG and PPIL (14). As pointed out by Margaret et al, in their systematic 
review that the source of seaweed extract and its polyphenolic content is very important in 
triggering antidiabetic effect (15). Thus, they strongly suggest that more clinical studies 
are required to determine consistent pattern of dose-response and to identify the 
effectiveness dose in a high-risk population (15). According to side effect, no study has 
reported any significant differences between brown seaweed and placebo in terms of 
measuring adverse effect (9-14). Lee et al, have reported similar incidence of adverse 

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event between groups (22.2 vs 16.2) for brown algae group compared to placebo, 
respectively (11). Similarly, paradis et al, find that 13 subjects in each group have reported 
adverse effect with minimal intensity (1 in a scale of 0 to 3 where 0 absent and 3 means 
sever intensity) being the most reported for most of measured symptoms (12). Despite 
many promising results in vitro and vivo studies (animal studies), the effects of 
polyphenol-rich brown seaweed on blood glucose and insulin level in human have not 
been effectively investigated. Thus, more investigational studies are needed particularly 
on the interaction of brown seaweed and its polyphenols with human cellular systems 
which may provide better understanding on parameters such as bioavailability, 
mechanisms of actions of in glucose homeostasis in humans. This can be translated into 
long-term health benefits. Further research would widen the likelihood of screening more 
biologically proficient polyphenols and its derivatives. Results of such studies could 
provide us with resourceful drug substitute to reduce or regulate diet-linked chronic 
malfunctions such as diabetes. In terms of the type of seaweed intended to be used, 
Kunihisa, et al have claimed that "this type of brown seaweed (E. cava) polyphenolic-rich 
extract is an important functional food component that could be used in reducing diabetes 
related symptoms" (16). Also, Margert et al, on their systematic review investigating the 
effect of algal polyphenols on antidiabetic, anti-hyperlipidaemia or anti-inflammatory 
effects in humans, have stated that " E. cava is currently the most extensively investigated 
source of marine polyphenols for anti-hyperglycaemic effects and has shown the most 
promise in this area" (8). Indeed, they have concluded that " Marine polyphenols, 
particularly from E. cava, show potential as natural functional ingredients for the 
prevention and management of type 2 diabetes and CVD. However further high quality 
RCTs are required to determine the most effective dose, treatment schedule and 
macroalgal source to produce consistent effects on glycaemia and dyslipidaemia in 
humans" (8). Moreover, Previous human studies have mainly performed on healthy 
individuals using different types of seaweed (4,5). Therefore, this proposal is meant to 
address the gap in this scientific area, using Ecklonia cave on prediabetes patient which 
hypothesized to have beneficial result regarding blood glucose and insulin level (8). 
Although, the methodology in this study focuses on the acute effect of E. cava on 
glycaemic control, it can be a promising result for future studies including long-term 
studies. Result in this study would give indications for future research regarding type of 
seaweed, dose and targeted population. More research in this area may benefits us in 
different aspect including prevention and clinical use of seaweed extract, diabetic patients' 
compliance, and cost spent in health care systems as seaweed is an abundant and 
sustainable naturally existing source of active biologic compounds, which makes it one of 
the best proposed choices for tackling diabetes. 
2.1 
Risk / Benefit Assessment 
NA 

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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
To Investigate the effectiveness of seaweed (E. cava) in reducing postprandial blood 
glucose and plasma insulin level (to determine insulin sensitivity) in pre-diabetic patients, 
compared to placebo. 
3.2 
Secondary Objectives 
Investigate the safeness and potential adverse effect of applying sea weed (E. cava) as a 
therapeutic diet composition on patient with pre-diabetes, compared to placebo. 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a single center, double-blind, placebo-controlled, randomized study.  30 (number) 
of subjects are planned. Because the study only investigating the acute effect of the study 
interventional product, each subject will be administered a single dose of either study 
dietary supplement or placebo only one time.  Subjects will be assigned to the treatments 
in random order.  Evaluations will be taken at baseline and every 30 min following the 
ingestion of carbohydrates for the following 2 hours at the interval of 30, 60, 90, 120 min.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  
The following treatment regimens will be used: 
 
A dietary supplement E.cava extracted capsule (seaweed) - at dose of 580 mg.  
 
Placebo (dextrin) – at a dose of 500 mg.  
Total duration of subject participation will be six weeks.  Total duration of the study is 
expected to be 12 weeks. 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
Reduction in postprandial blood glucose and insulin level compare to baseline.  
As the dietary supplement (seaweed) is expected to have an effect on a-amylase and a-
glucosidase enzymes that are responsible for breaking down carbohydrates which. Thus, 
postprandial blood glucose level and postprandial insulin level are best available way to 
see the effect of the product as it is expected to directly affect blood sugar enzymes that 
may lead to glycemic index control. As it is mentioned previously, this study is 
investigating the acute effect of the investigational product which will only compare 
change in PPBG and PPIL to baseline which will last only for one 3 hours in only one 
visit.  

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5.2 
Secondary Efficacy Endpoints 
In order to assess side effects of study intervention, measurement of side effects will be 
obtained by using an arbitrary scale, similar to that used by Paradis et al (12), that allow 
participants to rate symptoms of intolerance by indicating whether each side effect was 
absent (0), of mild intensity (1), of moderate intensity (2), or of severe intensity (3). The 
side effect questionnaire, will be required to be completed within 24 hours after 
intervention or placebo ingestion. The side effect will include headache, energy levels, 
appetite, gastrointestinal symptoms, unusual pain or sensations, cardiac palpitations, 
balance disorders, and anxiety.  
5.3 
Safety Evaluations 
Change in blood glucose level from baseline to more than 240 mg /dl or less than 70 mg 
/dl. Adverse events such as: Headach, Bloating or Minor abdominal pain Other 
Evaluations. 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of pre-diabetic who meet the inclusion and exclusion criteria 
will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
1. Male or female ≥ 18 years of age at Visit 1. 
2. Documentation of a pre-diabetic diagnosis as evidenced by one or more clinical 
features consistent with and one of the following criteria: 
- fasting plasma glucose (FPG) between 100 and 125 mg dL−1 as a set criterion by 
American Diabetic Association (16),  
3. Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal representative and ability for subject to comply with the requirements 
of the study. 
4. blood pressure within the normal range (systolic blood pressure ≤ 140 mmHg, 
diastolic blood pressure ≤ 90 mmHg). 
5. having no other health complications. 
6.3 
Exclusion Criteria 
1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in 
the study. 
2. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
3. taking any treatment with either insulin or anti-diabetic drugs or any other natural 
health products known to impact blood sugar, or polyphenol absorption (e.g. fish oil). 

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4. Smoker. 
5. having liver, thyroid, or significant gastrointestinal disorders. 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Standard therapy for pre-diabetic is allowed except for treatments noted in the exclusion 
criteria described above and as noted in the prohibited medications section below.   
7.2 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be 
considered a protocol violation: 
 any treatment with either insulin or anti-diabetic drugs. 
  any other natural health products known to impact blood sugar, or polyphenol 
absorption (e.g. fish oil). 
 Any liver, thyroid, or gastrointestinal disorders medications.  
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
 Up to 30 eligible patients will be randomly assigned to the dietary supplement seaweed or 
placebo treatment groups in a 1:1 ratio using a SAS-based computer-generated 
randomization scheme developed by a study investigator who will not be involved in data 
collection and analysis. Participants and other investigators will be blinded to which 
supplement is consumed each testing occasion for each participant until data analysis 
completed. At screening visit investigators will complete patient required data as detailed 
in the Study Manual, and fax it to the investigator who is responsible for randomization. 
The investigator who responsible for randomization will send back participants data 
encoded with numbers and supplements (intervention & placebo) with letters (A, B). 
Study intervention or placebo will be encapsulated in identical capsules and will be 
labelled with the letter A and B to conceal which supplement is given to each participants. 
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or patients.  The following study procedures will be 
in place to ensure double-blind administration of study treatments.   
 
Access to the randomization code will be strictly controlled.   
 
Packaging and labeling of intervention and placebo treatments will be encapsulated 
identically to maintain the blindness.  

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The study blind will be broken on completion of the clinical study and after the study 
database has been locked. Investigators will be aware of their subjects' treatment 
assignment after study statistical analysis completed.  
During the study, the blind may be broken only in emergencies when knowledge of the 
patient’s treatment group is necessary for further patient management. When possible, the 
Investigator should discuss the emergency with the Medical Monitor prior to unbinding. 
The pharmacist who is dispensing the study treatment will be available during study 
conduction and in case of any emergency, the pharmacist will disclose the blindness to 
medical monitor as it will be written in dispensing log in the research pharmacy.  
8.3 
Formulation of Test and Control Products 
8.3.1 
Formulation of Test Product 
The intervention product used in this study is a dietary supplement extracted from 
seaweed called Ecklonia cava called "Seoul" that contain 13% pholoratannic polyphenol 
per capsule as stated by the manufacture company (Seanol inside, 4215 95th St SW 
Lakewood, WA 98499 USA). Other ingredients are dextrin, magnesium stearate and silica 
(in neglected percentage). The intervention supplement is encapsulated in vegetable 
cellulose that contains 500 Ecklonia cava extract (Seanol). This dose was selected to be 
similar to previous studies that shows no harm or sever adverse effect on participants (12, 
14). The encapsulated product is brown-colored powder that requires no reconstitution.  
 
Table X: Formulation and Measured pH of Dietary supplement (Seanol) and Placebo 
 
Dietary supplement (Seanol)  
Placebo 
Active Ingredient, mg/mL 
13% phlorotanninic polyphenol 
(include eckols, dieckol, 6,6'-
bieckol, 
8,8'-bieckol, 
phlorofucofuroeckol-A) 
Dextrin 
Other ingredient, mg/mL 
80 % Dextrin  
magnesium stearate and silica (in 
neglected amount)  
Non 
pH 
 
0.5 – 7.5 
 

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8.3.2 
Formulation of Control Product 
The placebo will be dextrin (BETA CYCLODEXTRIN, NF) will be ordered and provided 
by 
the 
study 
PI 
from 
a 
pharmaceutical 
company 
"MEDISCA" 
(https://www.medisca.co.uk/). Dextrin was selected to account for the similar complex 
carbohydrate content of the intervention supplement. Placebo will be encapsulated in 
vegetable cellulose capsules that is identical in size and coulure to the intervention 
capsules 
8.3.3 
Packaging and Labeling 
Packaging: Study drug is supplied in a bottle containing 60 single use capsules. The 
capsules will be packaged in enclosed within a laminated foil pouch bottle. 
Labeling: Each bottle of study drug will be labeled with the required FDA warning 
statement, the protocol number, a treatment number, the name of the principle 
investigator, and directions for patient use and storage.  direction for both study test and 
placebo will be the same as both has the same direction which will ensure blinding in the 
study.   
8.4 
Supply of Study Drug at the Site 
The principle investigator will ship Study Drug to the investigational sites.  The initial 
study drug shipment will be shipped after site activation. Subsequent study drug 
shipments will be made after site request for resupply. 
8.4.1 
Dosage/Dosage Regimen 
The study test is a dietary supplement called brown seaweed (Ecklonia cava) which will 
be given at 580 mg dose. Seaweed will be administered only one time at the only one visit 
to investigate the acute effect of the investigational product.  administration will be orally. 
The placebo is a plain dextrin will be given at 500 mg dose. Placebo will be administered 
only one time at the only one visit to investigate the acute effect of the investigational 
product. administration will be orally. 
8.4.2 
Dispensing 
The pharmacists at research pharmacy at KKUH will be the only pharmacist at hospital 
who are responsible for study treatment or placebo dispensing.   
8.4.3 
Administration Instructions  
The study dietary supplement (seaweed) or placebo will be administered to patient at the 
study site only one time at a supervision of study investigator and medical monitor where 
the patient will be instructed to administer the study capsules orally.  
8.5 
Supply of Study Drug at the Site 
Study dietary supplement will be supplied to the pharmacy of research at study site 
(KKUH) by the principle investigator of the study. If more participants needed as a 
replacement of withdrawn participants, study treatment will be stored at the pharmacy of 
research at KKUH which will be available for the new participants. 

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8.5.1 
Storage 
Study dietary supplement should be stored by the study site at controlled room 
temperature, 15 to 30ºC (59 to 86ºF). If the temperature of study drug storage in the 
pharmacy exceeds or falls below this range, this will be reported to the study PI or 
designee and captured as a deviation. the supplement will be stored in original packaging 
(foil pouch and protected from light) at room temperature according to the instructions 
outlined on the Drug Administration Instructions. 
8.6 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
8.7 
Measures of Treatment Compliance 
Not applicable due to that study dietary supplement (seaweed) or placebo will be 
administered to patient at the study site only one time at a supervision of study 
investigator.  
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject If appropriate, assent must also be obtained prior to conducting any 
study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening. Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 

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9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a 
subinvestigator who is a physician at screening. Qualified staff (MD, NP, RN, and PA) 
may complete the abbreviated physical exam at all other visits.  New abnormal physical 
exam findings must be documented and will be followed by a physician or other qualified 
staff at the next scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes at all Visits.  
9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity outcome, treatment and relation to study drug will 
be recorded on the case report form (CRF). 
9.2 
Pharmacokinetic Measurements 
 NA   
9.3 
Research Laboratory Measurements  
9.3.1 Blood profile  
Blood will be obtained and sent to the site’s clinical chemistry lab for determination of 
random glucose, fasting blood glucose and insulin level. 
 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Day1 /Week 1/Month 1) 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, including a history of pre-diabetic, diagnosis date. 
5. 
Perform a complete physical examination. 
6. 
Perform and record vital signs. 
7. 
Perform and record results of blood pressure testing. 
8. 
Collect blood for clinical laboratory tests (baseline of blood glucose level). 
9. 
Schedule subject for Visit 2 in different days. 
10. 
List all additional procedures, such as Randomize subject 

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10.2 Visit 2  
1. 
Perform abbreviated physical examination. 
2. 
Perform and record vital signs. 
3. 
Collect blood for clinical laboratory tests (baseline of blood glucose and insulin 
levels). 
4. 
Administer either study dietary supplement (seaweed) or placebo based on blinded 
randomization. 
5. 
Perform carbohydrates ingestion  
6. 
Collect blood for clinical laboratory tests (blood glucose and insulin levels 30 min 
after administration of study treatment). 
7. 
Collect blood for clinical laboratory tests (blood glucose and insulin levels 60 min 
after administration of study treatment). 
8. 
Collect blood for clinical laboratory tests (blood glucose and insulin levels 90 min 
after administration of study treatment). 
9. 
Collect blood for clinical laboratory tests (blood glucose and insulin levels 120 min 
after administration of study treatment). 
 
10.3 Early Withdrawal Visit 
1. 
Record any Adverse Experiences  
2. 
Perform complete physical examination. 
3. 
Perform and record vital signs. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 

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11.1.1 AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
11.1.2 AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 

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Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
11.3 Medical Monitoring 
Insert Medical Monitor Name should be contacted directly at these numbers to report 
medical concerns or questions regarding safety. 
Phone: (966)505682918 
E-mail: aalguwaihes@ksu.edu.sa 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation: 
 
Subject withdrawal of consent (or assent) 
 
Subject is not compliant with study procedures 
 
Adverse event that in the opinion of the investigator would be in the best interest of 
the subject to discontinue study treatment 

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 
Protocol violation requiring discontinuation of study treatment 
 
PI request for early termination of study 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures. 
12.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to 1) should have an early discontinuation visit. 
Refer to Section 10 for early termination procedures.  Subjects who withdraw after Visit 1 
but prior to Visit 2 should be encouraged to come in for a final visit (and the procedures to 
be followed would include those for their next scheduled visit).   
12.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
Subjects who withdraw from the study will not be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
 
Failure to meet inclusion/exclusion criteria 
 
Use of a prohibited concomitant medication 

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Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The PI will determine if a protocol violation will result in withdrawal 
of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
14.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive the only one dose of 
the study dietary supplement (the Safety Population) will be included in the safety 
analysis. 
14.2 Demographic and Baseline Characteristics 
- weight 
- height 
- BMI,  
- age  
- exercise level  
- Collect blood for clinical laboratory tests (baseline of blood glucose level). 
14.3 Analysis of Primary Endpoint 
Mean (standard deviation) will be reported for normally distributed data, whereas median 
(interquartile range) will be reported for not normally distributed data. Either independent 
t-test or Mann-Whitney test, based on normality of data, will be used to determine the 
difference between the two groups for both PPBG and PIL at a significant level of p < 
0.05. Incremental area under the curve (iAUC), time to peak and peak blood concentration 
assessment will be used to assess postprandial responses of for plasma glucose and insulin 
level. Safety and tolerability data will be summarized by treatment group.   
14.4 Analysis of Secondary Endpoints 
Mann-Whitney test will be used to determine differences for symptoms of intolerance 
between groups.  

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Adverse events will be tabulated by treatment group and will include the number of 
patients for whom the event occurred, the rate of occurrence, and the severity and 
relationship to study drug.   
14.5 Interim Analysis 
When approximately 50% of patients have completed the study through Visit 2, an interim 
analysis for safety will be conducted by an independent data monitoring committee. 
Serious adverse events will be monitored by the committee on an ongoing basis 
throughout the study. 
14.6 Sample Size and Randomization 
Sample size was calculated based in similar study (24) using sample size determination 
equation:  
 
n = 2(32)2(1.96+0.84)2 / 382 = 2(1024) (2.8)2 / 1444   =    2048∗7.84 / 1444 
 = 16056.32 / 1444 
 = 11.11 ≈ 12 subjects/group 
whereas:  
- Za/2 = standard normal variate for level of significant, at 5% type 1 error, (if p < 0.05 = 
1.96). 
- ZB = Standard normal variate for power (for 80% power = 0.84, for 90% power = 1.28). 
- SD= Standard Deviation (determined from the literature). 
- d= effect size – difference between mean values (determined from the literature). 
15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.   
Study personnel at the site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific paper CRF when the information corresponding to 
that visit is available.  Subjects will not be identified by name in the study database or on 
any study documents to be collected by the PI (or designee), but will be identified by a 
subject number  
If a correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.   

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15.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
15.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Query reports (Data Clarification Requests) pertaining to data omissions and 
discrepancies will be forwarded to the Investigators and study monitors for resolution.  
The study database will be updated in accordance with the resolved queries.  All changes 
to the study database will be documented. 
15.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
15.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason. 
15.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 

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15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation submitted 
to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
16.1 Protocol Amendments 
Any amendment to the protocol will be written by PI.  Protocol amendments cannot be 
implemented without prior written IRB/IEC approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRBs are notified within five working days. 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to PI prior to the shipment of study supplies to the site.  
This approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 

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the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects must be given ample opportunity to inquire about details of the study.  
If appropriate and required by the local IRB/IEC, assent from the subject will also be 
obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed 
consent form (and assent) will be given to the subject and the original will be maintained 
with the subject’s records. 
16.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
16.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 

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2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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REFERENCE: 
1. Sriplang K, Adisakwattana S, Rungsipipat A & Yibchok-anun S (2007). Effects of 
orthosiphon stamineus aqueous extract on plasma glucose concentration and lipid 
profile in normal and streptozotocin-induced diabetic rats. J Ethnopharmacol 
109:510- 514.  
2.  Diabetes Fact Sheet No312. Available online: https://www.who.int/en/news-
room/fact-sheets/detail/diabetes (accessed on 30 October 2018).  
3.  Grundy, S.M.; Cleeman, J.I.; Daniels, S.R.; Donato, K.A.; Eckel, R.H.; Franklin, 
B.A.; Gordon, D.J.; Krauss, R.M.; Savage, P.J.; Smith, S.C.; et al. Diagnosis and 
Management of the Metabolic Syndrome. Circulation 2005, 112, 2735–2752.  
4. Duckworth, W.C. Hyperglycemia and cardiovascular disease. Curr. Artheroscler. 
Rep. 2001, 3, 383–glucosidases, 391.  
5. Murugan, A. C., Karim, M. R., Yusoff, M. B. M., Tan, S. H., Asras, M. F. B. F., & 
Rashid, S. S. (2015). New insights into seaweed polyphenols on glucose homeostasis. 
Pharmaceutical biology, 53(8), 1087-1097.  
6. Berg, J., Tymoczko, J., & Stryer, L. (2002). Complex carbohydrates are formed by 
linkage of monosaccharides. Biochemistry.  
7. Lorenzati, B., Zucco, C., Miglietta, S., Lamberti, F., & Bruno, G. (2010). Oral 
hypoglycemic drugs: pathophysiological basis of their mechanism of action. 
Pharmaceuticals, 3(9), 3005-3020.  
8. Lee, S. H., Han, J. S., Heo, S. J., Hwang, J. Y., & Jeon, Y. J. (2010). Protective 
effects of dieckol isolated from Ecklonia cava against high glucose-induced oxidative 
stress in human umbilical vein endothelial cells. Toxicology in Vitro, 24(2), 375-381.  
9. Cofrades, S., López-Lopez, I., Bravo, L., Ruiz-Capillas, C., Bastida, S., Larrea, M. T., 
& Jiménez-Colmenero, F. (2010). Nutritional and antioxidant properties of different 
brown and red Spanish edible seaweeds. Food science and technology international, 
16(5), 361-370.  
10. Johnston, K., Sharp, P., Clifford, M., & Morgan, L. (2005). Dietary polyphenols 
decrease glucose uptake by human intestinal Caco‐2 cells. FEBS letters, 579(7), 
1653-1657.  
11. Towler, M. C., & Hardie, D. G. (2007). AMP-activated protein kinase in metabolic 
control and insulin signaling. Circulation research, 100(3), 328-341.  
12. Shibata T, Yamaguchi K, Nagayama K, et al. (2002). Inhibitory activity of brown 
algal phlorotannins against glycosidases from viscera of the turban shell Turbo 

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cornutus. Eur J Phycol 37:493–glucosidases, thus improving diabetic related response 
(8). In general, Seaweeds, also called500.  
13. Lee SH, Li Y, Karadeniz F, et al. (2009). a-Glucosidase and a-amylase inhibitory 
activities of phloroglucinol derivatives from edible marine brown alga, Ecklonia cava. 
J Sci Food Agric 89:1552–glucosidases, thus improving diabetic related response (8). 
In general, Seaweeds, also called8.  
14. Okada Y, Ishimaru A, Suzuki R, Okuyama T. (2004). A new phloroglucinol 
derivative from the brown alga Eisenia bicyclis: Potential for the effective treatment 
of diabetic complications. J Nat Prod 67:103–5.  
15.  Zhang J, Tiller C, Shen J, et al. (2007). Antidiabetic properties of polysaccharide- 
and polyphenol-enriched fractions from the brown seaweed Ascophyllum nodosum. 
Can J Physiol Pharmacol 85: 1116–23 
16. IWAI, Kunihisa. Antidiabetic and antioxidant effects of polyphenols in brown alga 
Ecklonia stolonifera in genetically diabetic KK-A y mice. Plant Foods for Human 
Nutrition, 2008, 63.4: 163.  
17. Heo SJ, Hwang JY, Choi JI, et al. (2009). Diphlorethohydroxycarmalol isolated from 
Ishige okamurae, a brown algae, a potent a-glucosidase and a-amylase inhibitor, 
alleviates postprandial hyperglycemia in diabetic mice. Eur J Pharmacol 615:252–6. 
18. LEE, Sang‐Hoon, et al. α‐Glucosidase and α‐amylase inhibitory activities of 
phloroglucinal derivatives from edible marine brown alga, Ecklonia cava. Journal of 
the Science of Food and Agriculture, 2009, 89.9: 1552-1558.  
19. Lee SH, Min KH, Han JS, et al. (2012). Effects of brown alga, Ecklonia cava on 
glucose and lipid metabolism in C57BL/KsJ-db/db mice, a model of type 2 diabetes 
mellitus. Food Chem Toxicol 50: 575–82.  
20. Min KH, Kim HJ, Jeon YJ, Han JS. (2011). Ishige okamurae ameliorates 
hyperglycemia and insulin resistance in C57BL/KsJ-db/db mice. Diabetes Res Clin Pr 
93:70–6.  
21. Lee, S. H., & Jeon, Y. J. (2015). Efficacy and safety of a dieckol-rich extract (AG-
dieckol) of brown algae, Ecklonia cava, in pre-diabetic individuals: A double-blind, 
randomized, placebo-controlled clinical trial. Food & function, 6(3), 853-858.  
22.  Paradis, M. E., Couture, P., & Lamarche, B. (2011). A randomised crossover 
placebo-controlled trial investigating the effect of brown seaweed (Ascophyllum 
nodosum and Fucus vesiculosus) on postchallenge plasma glucose and insulin levels 
in men and women. Applied Physiology, Nutrition, and Metabolism, 36(6), 913-919.  
23. Kim, M. S., Kim, J. Y., Choi, W. H., & Lee, S. S. (2008). Effects of seaweed 
supplementation on blood glucose concentration, lipid profile, and antioxidant 
enzyme activities in patients with type 2 diabetes mellitus. Nutrition research and 
practice, 2(2), 62-67.  
24. Murray, M., Dordevic, A. L., Bonham, M. P., & Ryan, L. (2018). Do marine algal 
polyphenols have antidiabetic, antihyperlipidemic or anti-inflammatory effects in 

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humans? A systematic review. Critical reviews in food science and nutrition, 58(12), 
2039-2054.  
25. Retrieved from https://professional.diabetes.org/ 
26. Phillips, P. J. (2012). Oral glucose tolerance testing. Australian family physician, 
41(6), 391. 

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APPENDIX 1.   
 
VISIT 1 
(Day/Week/Month #)a 
VISIT 2 
(Day/Week/Month #)a 
Informed Consent 
X 
 
Medical History 
X 
 
Complete Physical Exam 
X 
 
Height  
X 
X 
Weight  
X 
X 
Vital Signs  
X 
X 
Exercise Level  
X 
 
Baseline Fasting Blood glucose Level 
X 
X 
Postprandial Blood glucose Level 
 
X 
Baseline Insulin Level  
 
X 
Postprandial Insulin Level  
 
X 
ESR 
X 
 
Randomization 
X 
 
Dispensing or Administration of Study Drug 
 
X 

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Concomitant Medication Review 
 
X 
Adverse Experiences 
 
X 
a  
2 days

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Required Components of Informed Consent 
 
Informed consent is not a single event or just a form to be signed; it is an educational 
process that takes place between the investigator and the prospective subject. The basic 
elements of the consent process include:  
full disclosure of the nature of the research and the participant's involvement, 
adequate comprehension on the part of the potential participant, and 
the participant's voluntary choice to participate. 
 
It is the investigator’s responsibility to document that the informed consent process has 
taken place, and an informed consent form is the standard for documenting the process for 
research projects involving human participants.  
 
Consent forms must contain all the required components of informed consent as defined in 
SOP 9: Informed Consent Options, Processes, and Documentation and summarized below. 
The consent form must be written in language that is easy for a potential participant to 
understand and assures that individual’s comprehension. Therefore, avoiding technical 
terms and complex sentences, even for the educated layperson, is very important.  
 
When the participant population is not homogeneous, different consent documents may be 
required for different groups of people. If the research population will include participants 
under 18 years of age, then the IRB will expect investigators to use an assent form and a 
parental permission form instead (see SOP 11: Informed Consent, Enrollment, and Other 
Considerations for Research Involving Children). Similarly, research with cognitively or 
decisionally impaired individuals will require documented consent from another party—
namely that person’s legally authorized representative (see SOP 9, section 8 and/or SOP 
10: xxx).  
 
The IRB also recognizes that there are instances when documenting written informed 
consent is not appropriate to a research project. Alternatives to using a signed form for 
documenting informed consent are detailed in SOP 9.  
 
Regardless of the method of documenting informed consent, however, the process of 
obtaining informed consent should always contain the same required components.  
 
Helpful guidelines for constructing an effective consent form:  
Use common, ordinary language instead of technical, academic terms. Ideally we would 
like consent forms to be written an 8th grade reading level. A helpful gage is to consider if 
one’s 13 year-old cousin would be able to understand the research after reading the consent 
form. 
Try to keep the sentences as short and simple as possible. Write in the second person using 
you/your pronouns. For example: "You are being asked to participate in a research 

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project…," "If you have questions later, you may contact…," or "You will be given a copy 
of this form to keep for your records." 
Do not use assumptive statements such as "You understand that ..." or "You have been told 
that...." 
Use adequate white space so that the form is easy to read, and avoid using small fonts to 
squeeze all the text onto one page. 
Headings for paragraphs are helpful and make the form easier to read and understand. 
 
 
Required Elements of Informed Consent Forms:  
1. A clear, concise explanation of the purposes of the research, including the name of the 
study and prominent use of the term "research." (Note: the IRB can waive this element if 
the study requires deception. In such cases, a debriefing statement should also be used to 
inform participants at an appropriate time after their involvement in the study.)  
2. An explanation of what will be happening to the participant during the study, and an 
indication of the participant's time commitment for each component.  
3. Description of the risks, side effects or discomforts of the study procedures. For instance, 
even though it is not considered a risky procedure, a needle stick to draw blood may cause 
brief pain or discomfort. For social science and behavioral research, though risks usually do 
not extend beyond the possible loss of confidentiality and/or mild emotional distress, these 
should also be made clear to prospective participants.  
 
 If it appears that there are no real risks to participation, state, "We do not anticipate any 
risks to you participating other than those encountered in daily life." Please see our Sample 
Consent Form for an example of appropriate wording of a risk statement.  
4. Description of any potential benefits from participating.  
 
 For individual participants, these should be limited to direct benefits: information about 
better coping skills, awareness of available support or resources, or any other personal gain 
other than financial rewards. (Learning about how experiments are conducted, receiving a 
gift, or earning extra credit for being a research participant are NOT recognized as benefits. 
Gifts, extra credit for courses, and reimbursement for expenses are considered 
compensation.) If there are no direct benefits, simply indicate that there are none.  
 
 For indirect benefits to society or scientific knowledge, statements such as "…information 
from this study may benefit other people now or in the future…" or "…we hope to learn 
more about ________ …" are appropriate.  
5. A statement that the participant's involvement is voluntary, the participant may refuse to 
participate before the study begins, discontinue at any time, or skip any questions that may 
make him/her feel uncomfortable, with no penalty to him/her, and no effect on the 
compensation earned before withdrawing, or their academic standing, record, or 
relationship with the university.  

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6. A statement that the participant is allowed to ask questions concerning the study, both 
before agreeing to be involved and during the course of the study. See required contact 
information in #11 below.  
7. A description of how the participant's confidentiality will be protected.  
8. A description of what will be done with the data once the study is completed.  
9. An indication that recording devices, audio or visual, are being used (when applicable).  
 
 Be sure to describe what will be done with the any video or audio tapes upon the 
completion of the study (destroyed, erased, archived, etc.), and when (after transcription, 3 
years, 5 years, etc.).  
 
 Also, provide a separate signature line on the consent form for the participant to agree to 
be video/audio taped or photographed, if the recording is optional for participation. For 
example:  
 
 Please sign below if you are willing to have this interview recorded on tape (specify audio 
or video). You may still participate in this study if you are not willing to have the interview 
recorded.  
 
 I am willing to have this interview recorded on tape:  
 
 Signed: __________________________________________  
 
 Date: ____________________________________________  
10. An indication that the participant shall receive a copy of the signed and dated consent 
form.  
11. The name(s) of the investigator(s) and contact information.  
12. An indication that the participant may contact the Institutional Review Board for 
Human Participants (IRB) with any concerns or complaints. Additionally, a statement 
indicating that participants can report their concerns or complaints anonymously through.  
13. A "statement of consent" and the name and signature of the participant.  
14. The name signature of the person obtaining consent.  
15. At the bottom of the form the following statement: "This consent form will be kept by 
the researcher for at least three years beyond the end of the study and was approved by the 
IRB on [date]."