Evaluation of the Impact of the HLNatural, Inc. Upset Stomach Relief Product on the Reduction of Symptoms in Adults Who Suffer From Mild to Moderate Indigestion and Heartburn
Phase: NA
Conditions: Indigestion, Heartburn
Sponsor: Hawthorne Effect Inc.

1 
 
 
 
 
 
 
 
 
 
 
Evaluation of the impact of the HLNatural, Inc. Upset Stomach 
Relief product on the reduction of symptoms in adults who 
suffer from mild to moderate indigestion and heartburn 
 
NCT04153552 
 
Day Month Year 
July, 17th 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
Evaluation of the impact of the HLNatural, Inc. Upset Stomach 
Relief product on the reduction of symptoms in adults who 
suffer from mild to moderate indigestion and heartburn 
 
 
 
 
Sponsored by: 
HLNatural, Inc. 
 
 
Principal Investigator: 
Soyona Rafatjah, MD 
 
 
 
Version Number 
Version 1.1 
 
Day Month Year 
July, 17th 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

3 
 
 
 
Statement of Compliance 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
● U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
● ICH GCP E6 
● Completion of Human Subjects Protection Training 
● NIH Clinical Terms of Award 
Refer to: 
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/faq/45-cfr-46/index.html 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_
_Step_4_2016_1109.pdf 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html  
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIGNATURE PAGE 

4 
 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Principal Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
Project Manager: 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
Sponsor: 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
 
Statistician 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
 
 
 
 
 
 
Title: 
Evaluation of the impact of the HLNatural, Inc. Upset Stomach Relief 
product on the reduction of symptoms in adults who suffer from mild to 
moderate indigestion and heartburn  
 
Population: 
The study will consist of at least 200 participants who self-identify as 
satisfying the inclusion criteria. The geography of participant enrollment 
will be spread across the United States. 

5 
 
 
Number of Sites: 
This is a single (virtual) site study. 
 
Study Type 
Single site, prospective, one arm observational study of Minimal Risk. 
 
Study Duration: 
The duration of the study is expected to be 6 months depending on the 
speed of enrollment. 
 
Participant Duration: The duration of participation for each participant is expected to be 60 
days. 
 
Objectives: 
The purpose of this study is to demonstrate whether this plant-based 
remedy will reduce the severity of symptoms of occasional indigestion 
and heartburn. This trial will gather data on performance of the test 
product. These data will be used to describe the performance currently, 
and potentially to design a two-arm trial in the future 
 
 
Primary Endpoints: 
• The primary endpoint is reduction in indigestion severity and 
reduction in heartburn severity. There is no control group for 
the primary analysis. 
 
Secondary Endpoints: 
● 
The time to other intervention will be analyzed. 
● 
A longitudinal analysis will be performed for participants who 
report on more than one incident of heartburn or indigestion.  
● 
Adverse events will be summarized. 
● 
An additional data presentation will consist of results from 
both Treatment and Control in similar studies appearing in the 
literature. There will be no formal statistical comparison of 
results from this study and historical studies. 
● 
The Net Promoter Score will be summarized and compared 
against outcomes.  
● 
Comparison against normal behavior will use the paired 
sample t-test 
Table OF Contents 
1. 
KEY ROLES ...................................................................................................................... 7 
2. 
Background Information and Scientific Rationale ............................................................ 8 
2.1. 
Background Information ....................................................................................................8 
2.2. 
Scientific Rationale .......................................................................................................... 10 
2.2.1. 
Potential Risk ........................................................................................................................................ 10 
2.2.2. 
Known Potential Benefits ..................................................................................................................... 11 

6 
 
2.2.3. 
Minimization of Risks ........................................................................................................................... 11 
3. 
Study Objectives ........................................................................................................... 12 
4. 
Study Design ................................................................................................................ 13 
4.1. 
Test Product .................................................................................................................... 13 
4.2. 
Required Behavior ........................................................................................................... 13 
4.3. 
Participation Period ......................................................................................................... 14 
4.4. 
Data Collection ................................................................................................................ 14 
5. 
Study Population .......................................................................................................... 14 
5.1. 
Selection of the Study Population ..................................................................................... 14 
5.2. 
Inclusion/Exclusion Criteria .............................................................................................. 15 
6. 
Study Evaluation .......................................................................................................... 16 
6.1. 
Study Procedures ............................................................................................................. 16 
6.2. 
Study Schedule of Activities ............................................................................................. 18 
6.3. 
Participant Enrollment and Follow-Up .............................................................................. 20 
6.4. 
Adverse Event and Safety Monitoring ............................................................................... 20 
6.4.1. 
Anticipated Adverse Events ................................................................................................................. 20 
6.4.2. 
Adverse Event Relationship ................................................................................................................. 21 
6.4.3. 
Serious Adverse Events ........................................................................................................................ 21 
6.5. 
Lost to Follow-Up ............................................................................................................. 21 
6.6. 
Test Product Packaging/Handling/Storage/Accountability ................................................ 21 
6.7. 
Study Management .......................................................................................................... 21 
7. 
Statistical Considerations ............................................................................................. 22 
7.1. 
Study Outcomes Measures ............................................................................................... 22 
7.2. 
Sample Size Considerations .............................................................................................. 23 
7.3. 
Analysis Plan .................................................................................................................... 23 
8. 
Informed Consent Process ............................................................................................ 24 
9. 
Subject Confidentiality ................................................................................................. 25 
10. 
Publication ............................................................................................................... 25 
11. 
Limitations ............................................................................................................... 25 
12. 
Bibliography ............................................................................................................. 25 
13. 
Supplement and Appendix ........................................................................................ 27 
13.1. 
13.1 Appendices .............................................................................................................. 27 
13.1.1. 
Appendix A Drug Interactions ......................................................................................................... 27 
13.1.2. 
Appendix B Instructions for Use ...................................................................................................... 37 
13.1.3. 
Appendix C Screening Form ............................................................................................................ 38 

7 
 
13.1.4. 
Appendix D Baseline Form .............................................................................................................. 38 
13.1.5. 
Appendix E Symptom Diary ............................................................................................................. 42 
13.1.6. 
Appendix F Study Exit Form ............................................................................................................ 48 
13.1.7. 
Appendix G Adverse Event Form..................................................................................................... 49 
13.1.8. 
Appendix H Test Product Insert ...................................................................................................... 50 
13.1.9. 
Appendix I Informed Consent ......................................................................................................... 52 
 
1. KEY ROLES 
For questions regarding this protocol, please contact: 
 
 
Principal Investigator: 
 
Soyona Rafatjah, MD 
1600 Broadway, Suite 1618 
Denver, CO 80216 
Tel: (303) 335-9092 
Email: soyona@primehealthdenver.com 
 
 
 
Sponsor:  
 
 
 
 
HLNatural, Inc.  
Nina Mullen, MBA, Co-CEO 
335 Madison Avenue, 3rd Floor 
New York, NY 10017  
Tel: (203) 249-3581.  
Email: nina@hilma.co  
 
 
 
Study Management Organization: 
 
 
 
 
Hawthorne Effect, Inc. 
 
 
3595 Mount Diablo Boulevard, Suite 320 
 
 
Lafayette, CA 94549 
 
 
 
Project Manager/Clinical Study Manager: 
Jerome Tonog, MD 
 
 
Email: jerome.tonog@hawthorne-effect.com 
 
 
 
 
 
 
 
Statistician:  
William N. Anderson, PhD 
 
 
 
Institutional Review Board: 
 
 
 

8 
 
 
 
Advarra 
 
 
6940 Columbia Gateway Dr., Suite 110 
 
 
Columbia, Maryland 21046 
 
 
Tel: (410) 884-2900 Fax: (410) 884-9190 
 
 
 
2. Background Information and Scientific Rationale 
 
2.1. 
Background Information 
The primary hypothesis of the present study is that supplementation with the Upset 
Stomach Relief test product will reduce the severity of the symptoms of occasional 
indigestion and heartburn. 
 
Dyspepsia, also known as indigestion, is a common symptom with an extensive differential 
diagnosis and a heterogeneous pathophysiology. It occurs in approximately 25 percent of 
the population each year, but most affected people do not seek medical care. 
Approximately 25 percent of patients with dyspepsia have an underlying organic cause. 
However, up to 75 percent of patients have functional (idiopathic or non-ulcer) dyspepsia 
with no underlying cause on diagnostic evaluation. Patients with functional dyspepsia 
usually describe postprandial fullness, early satiety, and/or epigastric pain/burning. 
Symptoms may be severe enough to limit usual activities. Some patients may have nausea, 
vomiting, or heartburn; however, these symptoms are usually infrequent. [28] The most 
common approach to treat occasional indigestion and heartburn is to use antacids to 
neutralize what is often believed to be an overproduction of stomach acid. This acid-
blocking approach can perpetuate the problem when used over a long period of time. Acid 
blocking also has the drawback of causing deficiencies in certain vitamins and minerals over 
time, such as calcium. By interfering with the digestive process, an overgrowth of bacteria 
and imbalances in gut health can also worsen health states. The Upset Stomach Relief test 
product is an herbal solution with ingredients that may ease occasional indigestion and 
heartburn, while helping to strengthen the digestive tract over time. [4] 
 
There are several causes of indigestion. Acid accumulation and improper gastrointestinal 
emptying can both prompt dyspepsia. Additionally, stomach or intestinal ulcers formed by 
bacteria named Helicobacter pylori can result in infection that ultimately will cause 
indigestion. Other potential causes can be from the intake of over-the-counter medications, 
like ibuprofen, overeating, fatty, greasy, or spicy food, alcohol, and caffeine. [5] 
 
While dietary and lifestyle changes can ease the symptoms of indigestion and heartburn, 
HLNatural, Inc. created the test product to reduce occasional indigestion and heartburn. The 
test product is a plant-based remedy formulated with ingredients that have demonstrated 

9 
 
efficacy reducing symptoms associated with occasional indigestion and heartburn. The 
product combines ingredients into an easy to consume capsule designed to be consumed at 
the onset of symptoms or before each meal, up to three times per day. The test product is 1) 
DGL Extract, 2) Artichoke Leaf Extract, 3) Ginger Root Extract (6% gingerols), 4) Chamomile 
(1% Apigenin), 5) Marshmallow Root Extract,  6) Capsule (Hydroxypropyl Methyl Cellulose, 
Purified Water, Carrageenan, Potassium Chloride), , 7) Rice Hull Concentrate. Below, the 7 
ingredients of the test product are listed. All ingredients are Generally Recognized as Safe 
(GRAS) by the FDA. 
 
Upset Stomach Relief 
Active Ingredients: Licorice Extract, Artichoke Leaf Extract, Chamomile, Marshmallow 
Root, Ginger. 
 
Inactive Ingredients:Capsule (Hydroxypropyl Methyl Cellulose, Purified Water, 
Carrageenan, Potassium Chloride), Rice Hull Concentrate.  
 
The ingredients in the test product have been included because they have demonstrated 
benefit for digestive health. The justifications for their inclusion are briefly described here: 
 
Licorice has a long history of traditional use in promoting digestive health. DGL is a type of 
extract of licorice in which the glycyrrhizin has been removed, which helps prevent side 
effects that can occur in some people from regular Licorice use. Scientific investigation into 
the mechanism of activity of DGL for providing digestive support shows that it helps in 
maintaining digestive comfort by maintaining the integrity of the protective mucosal lining 
in the stomach and intestine. It is also an anti-spasmolytic, which helps to relax the 
intestinal wall and aid in digestive comfort. [10, 16, 17, 18] 
 
Artichoke Leaf Extract helps stimulate and aid the digestive process. Artichoke Leaf extract 
is a traditional herbal digestive bitter known to stimulate the digestive process. Artichoke 
Leaf extract has been shown in studies to relieve occasional heartburn. [9] 
 
Marshmallow Root has a long history of traditional use for soothing mucosal membranes. 
The mucilage-rich roots of Marshmallow are thought to be responsible for many of the 
pharmacological activities of Marshmallow. Preclinical research shows that the 
mucilaginous nature can help form a protective coating on the mucosal lining, which acts as 
a shield from irritants and exerting spasmolytic and antisecretory properties. [11, 19, 20, 21, 
22] 
  
Ginger is a spice that has long history of traditional use for digestive discomfort. Clinical 
research shows that Ginger supports health through its benefits to the immune, respiratory 

10 
 
systems, aiding digestion, and promoting normal cytokine balance. Ginger works on the gut-
brain axis by supporting neurotransmission which supports gastric emptying, upper GI 
digestive comfort and intestinal motility. It exerts a gastroprotective effect and relief of 
occasional heartburn. [7, 8, 23, 24] 
 
Chamomile is one of the most world-renowned herbs for promoting healthy digestion. It 
contains a phytochemical called apigenin which has a number of health-promoting benefits, 
including promoting healthy cytokine balance. Chamomile is also antispasmodic, affecting 
the muscles of the intestine and promoting digestive comfort. Additionally, stress and mood 
have been proven to affect indigestion and in clinical studies, Chamomile has shown 
support for relaxation and healthy mood. [3, 6, 25, 26, 27] 
 
2.2. 
Scientific Rationale 
The test product’s formulation is based on the most promising clinical research on natural 
ingredients that safely impact digestive health and relieve symptoms of occasional 
indigestion and heartburn. While the evidence to support the use of these individual active 
ingredients is growing, well-designed human clinical trials showing benefit are necessary to 
demonstrate efficacy of the test product’s unique formulation.  
The present study will include a minimum of 200 participants who suffer from the 
symptoms of mild to moderate indigestion and/or heartburn and is designed to observe the 
level of symptom reduction in this population after consuming the test product.   
 
2.2.1. Potential Risk 
Minimal risk is foreseen for participants through their participation in the study. All the 
ingredients composing the test product are Generally Recognized as Safe (GRAS) by the 
FDA for daily consumption at their present concentrations. 
The ingredients in the test product have been shown to have some theoretical drug 
interactions which have been listed in the appendix. (Appendix A) 
Potential side-effects have been observed in high doses which are significantly greater 
than the dose of the capsules as recommended in the instructions for use: 
• 
Headache 
• 
Amenorrhea 
• 
Upset Stomach 
• 
Diarrhea 
• 
Hives 
• 
Difficulty breathing 
• 
Facial swelling 

11 
 
• 
Drowsiness 
• 
Tiredness 
• 
Vomiting 
 
This study is determined by Sponsor and Principal Investigator to be a Minimal Risk 
Study. 
Minimal risk is defined by 45 U.S. Code of Federal Regulations (CFR) 46.102 (i) as follows: 
“Minimal risk means that the probability and magnitude of harm or discomfort 
anticipated in the research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical or psychological 
examinations or tests.” 
Refer to: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.102 
 
 
2.2.2. Known Potential Benefits 
Over-the-counter and prescription remedies for occasional indigestion and heartburn 
have known undesirable side effects. Additionally, these products often contain 
additives, dyes, fillers and other unnatural or synthetic ingredients that consumers are 
looking to avoid. As such, these consumers are seeking natural, plant-based alternatives 
for symptom relief. Research participants may benefit from the intervention by 
eliminating such unwanted side effects when treating their symptoms of occasional 
indigestion and heartburn while achieving symptom relief.  If the intervention is shown 
to be efficacious, this would provide a viable solution for those people who want to 
decrease their use of drugs that contain undesired ingredients. Other benefits include 
detailed surveillance of symptoms and documentation of activities, routine medications 
and supplements that may provide participant and their regular physician or other 
healthcare provider with useful information for diagnosis and treatment of symptoms 
should they occur. 
 
2.2.3. Minimization of Risks 
 
Research participants will be carefully screened to meet enrollment criteria. Participants 
meeting exclusion criteria will not be enrolled. The study participant informed consent 
will be presented with clear description of the study requirements and opportunity to 
have questions answered before enrollment. Once an event occurs, review of symptoms 
will be ascertained at onset, 15, 30, and 60 minutes. Reporting of adverse events will be 
reviewed routinely and in accordance with regulatory guidelines (21CFR, GCP) by the 
Principal Investigator. Participants with occurrence of worsening symptoms or adverse 

12 
 
events will be advised to stop taking the test product, may seek medical attention, and 
exit the study. 
 
3. Study Objectives 
The purpose of the present study is to evaluate 1) the impact of the test product on 
symptoms of occasional  indigestion and heartburn in 200 adult participants who suffer 
from occasional indigestion and heartburn and 2) the subjective experience of these 
participants related to general health, indigestion and heartburn symptoms, and personal 
experience with the test product.  
This will be evaluated based on the primary and secondary endpoints. These endpoints, the 
analysis populations, and their respective measures are described below. Further details on 
the methods for measuring the outcomes can be found in the Study Outcome Measures 
and Analysis Plan sections. 
 
 
Primary Endpoint: 
 
The primary endpoint has two components, reduction in indigestion severity and reduction 
in heartburn severity. Participants will be asked to rate each symptom (bloating, early 
fullness during a meal, pain or discomfort in the upper abdomen, burning in the upper 
abdomen, pain/burning in the center of your chest, nausea, vomiting, and burping) on a 4-
point scale at 4 time points: prior to taking the test product, 15, 30 , and 60 minutes after 
taking the test product. The improvement in symptoms from baseline will be evaluated on a 
pairwise basis separately for each component and each time point. P-values will be 
computed for the improvement. Given that indigestion can impact an individual’s quality of 
life, the primary endpoint was chosen to see the test product’s effects on symptoms. [1, 9, 
12] 
 
 
Secondary Endpoint: 
 
Secondary endpoints will be analyzed to evaluate safety and patient satisfaction with relief of 
symptoms. These include: 
 
● 
The time to other intervention will be analyzed. 
● 
A longitudinal analysis will be performed for participants who report on more than one 
incident of heartburn or indigestion.  
● 
Adverse events will be summarized. 
● 
An additional data presentation will consist of results from both Treatment and Control 
in similar studies appearing in the literature. There will be no formal statistical 
comparison of results from this study and historical studies. 
● 
The Net Promoter Score will be summarized and compared against outcomes.  
● 
Comparison against normal behavior will use the paired sample t-test. 

13 
 
 
4. Study Design 
 
The present study will be a single site, prospective, one arm observational study of minimal risk 
consisting of at least 200 participants who suffer from symptoms of occasional indigestion and 
heartburn. The participants must meet additional inclusion/exclusion criteria (see 
Inclusion/Exclusion Criteria). Participants will begin taking the capsules at the onset of indigestion 
and heartburn symptoms. Onset is defined as the point in time the participant takes the test 
product for relief of symptoms. When the participant decides to take the test product, they will 
report and rate their symptoms on a 4-point Likert scale in the symptom diary prior to taking the 
test product. After consuming the test product, the participant will complete a 4-point Likert scale 
for each symptom at  15 minutes, 30 minutes, and 1 hour after taking the test product. If needed 
the participant will be allowed to take an alternative medication an hour after taking the test 
product. If medication is taken, the participant will record this in their symptom diary.  
 
Study enrollment and management will be decentralized, where participants do not visit an 
investigator or a clinic for clinical assessment. The participants will participate in the study at home.  
All data collected from during this study will be reported by the participant via eCRFs, eDiary, and 
other electronic data entries.  If a visit is required, it will be conducted via remote contact by 
telephone.  
 
4.1. 
Test Product 
 
Below is the description of the test product and its ingredients. 
 
Upset Stomach Relief Product 
Description: Combining Deglycyrrhizinated licorice (DGL), Artichoke Leaf, Marshmallow 
Root, Ginger, and Chamomile for comprehensive, yet gentle plant-based support for 
occasional indigestion and heartburn relief. This formula is designed to promote digestion 
and feelings of digestive comfort. 
Active Ingredients: Licorice Extract, Artichoke Leaf Extract, Chamomile, Marshmallow 
Root, Ginger. 
 
Inactive Ingredients:Capsule (Hydroxypropyl Methyl Cellulose, Purified Water, 
Carrageenan, Potassium Chloride), Rice Hull Concentrate.  
 
4.2. 
Required Behavior  
 
During the hour directly following consumption of the test product, no medication or 
supplementation (including all CBD products) other than the test product should be taken 

14 
 
for relief of indigestion and heartburn symptoms.  Once the 1-hour report has been recorded 
the participant may take other medications or supplements. If medication is taken, the 
participant will record this in their symptom diary. 
 
Participants are asked to limit the consumption of alcohol beverages to less than or equal to 
two drinks per day.  
 
4.3. 
Participation Period 
Participants are expected to participate in the study for 60 days after study start. The 
product may be used after each onset of indigestion and heartburn episode, but not 
exceeding three times per day. Participants will be discontinued from the study 60 days 
after Study Start or after three recorded episodes of indigestion and heartburn. Study start is 
defined as the day the participant recorded received receipt of the test product on the start 
form in the platform. 
 
 
4.4. 
Data Collection 
All data in the present study will be self-reported by the participant and collected via their 
online portal (Hawthorne Effect Study Visit Management System (HE VMS)). Participants 
will be asked to take the test product according to the instructions for use, complete study 
surveys and respond to study reminders during the course of the study. The instructions for 
use and study forms can be found in the appendix. (Appendices B, D, E, F, G) 
 
5. Study Population 
 
5.1. 
Selection of the Study Population 
The study population will consist of at least 200 participants who suffer from symptoms of 
indigestion and heartburn. The participants will otherwise be in good health.  
The target sample size for this study is initially 200 participants, with a desired sample of 97 treated 
participants. This is described in detail in the Statistical Considerations section. 
At such time as 180 participants have been enrolled, the available data will be analyzed 
using a constant hazard model to determine if it seems realistic that the desired number of 
97 treated participants will be met by the end of follow-up. If the expected number of 
treated participants is less than 97, the target sample size will be increased as needed, 
considering both the desire for 97treated participants and the timelines of the trial sponsor. 
The actual outcomes of treated 

15 
 
participants will not be considered in this analysis, merely whether or not enrolled 
participants have reported starting using the test product. 
Enrollment will be stopped once the target number of participants has been enrolled, no further 
participants will be offered a place in the trial once the target sample size criteria has been met.  All 
participants who have already been offered places, but who have not yet consented, will be allowed 
to participate as long as they have signed the study consent within 15 days and the total number of 
participants does not exceed 125% of the target (either 200 or the recomputed target if 
recomputation has been performed.)  
In order to ensure an age and sex distribution that is reasonably representative of the US 
population, enrollment may be stopped early in some age and sex groups. 
Target population for this study are candidates who suffer from symptoms of occasional indigestion 
and heartburn.  
Participants will be enrolled from across the United States. No participants will be enrolled 
outside of the United States. It is expected that the geographical distribution of the 
participants enrolled in the study will correlate with the geographical distribution of the 
general population across the United States. 
Participants will be recruited via digital advertisements and social media.   
 
After clicking on an advertisement, potential participants will then be directed to a website where 
they will complete a screening questionnaire (See Appendix C). The screening questionnaire will 
automatically qualify or disqualify them for study participation. If the participant qualifies, they will 
be provided an informed consent. Upon completion of the informed consent they will be deemed 
enrolled in the study. 
 
 
5.2. 
Inclusion/Exclusion Criteria 
Prior to being enrolled, participants will fill out a screening questionnaire. The screening 
questionnaire will automatically qualify or disqualify them for study participation. The full 
screening questionnaire can be found in the Appendix (Appendix C). If the participant 
qualifies, they will be provided an informed consent. Upon completion of the informed 
consent they will be deemed enrolled in the study. 
Inclusion Criteria: 
Adult candidates who are in overall good health but who suffer from the symptoms of 
indigestion. 

16 
 
Participants will be deemed to be in good health if they do not report any of the existing 
medical conditions asked about in the screening questionnaire. 
Exclusion Criteria: 
● Age <18 years old. 
● Unwilling to take test product for their symptoms. 
● Are able to swallow pills.  
● Allergy to any of the following: Licorice, Artichoke Leaf, Marshmallow Root, Ginger, 
Chamomile, Cellulose Capsule, Rice Hull Concentrate, Carrageenan.  
● Participants who have been prescribed any medication by their physician for any GI 
disorder or medication that can affect the GI system.  
● Participants with previous diagnosis of cancer or with previous surgery of the upper 
gastrointestinal tract or of the biliopancreatic system (except for cholecystectomy) 
● Pregnant women or breastfeeding. 
● Alcohol consumption more than 10 drinks per week  
● Participants who are currently using anticoagulation medications daily. (Aspirin, 
Coumadin, Heparin etc.) 
 
6. Study Evaluation 
 
6.1. 
Study Procedures 
• 
Candidates will review information about the study and complete a screening form. 
• 
During the screening process, the candidate will be asked questions regarding their symptoms 
and medical history to ensure that they meet the requirements to participate in this study. 
Potential participants will also be asked questions to ensure that they do not meet any of the 
exclusion criteria and meet all of the inclusion criteria.  
• 
After successful screening (participant does not meet any exclusion criteria), participants will 
review and sign study informed consent form.  
• 
Upon verification of signed informed consent, participant will be enrolled into the study.  
• 
At time of enrollment, participant will be given access to the HIPAA compliant study portal.  
○ 
The study portal provides access to study information, signed informed consent form, 
instructions for test product use, frequently asked questions, study surveys, symptom diary, 
and data collection tools. 
• 
Participant shall complete baseline assessments upon access to the portal.  
○ 
Baseline assessment will include questions regarding the participants’ demographics, 
medications, detailed information regarding their indigestion/heartburn including 
treatment.  
• 
To ensure that baseline assessments are completed before test product is used by the 
participant, study materials and study welcome package will be shipped to the participant once 
the clinical study manager/clinical ops coordinator confirms that the baseline assessment has 
been completed. 
• 
The welcome package will include an information sheet that will outline instructions for their 
participation in the trial, the test product, and paper forms of the documents (paper form of 

17 
 
study documents will be provided for real time data collection, in the event that the participant 
cannot log into the study portal to input data).   
• 
Once the participant receives the test product, the participant will log into the study portal to 
acknowledge the receipt of the test product. 
• 
Study start date will be the reported date of receipt of test product. 
• 
Participant will be sent weekly email reminders that remind them of their participation in the 
study. 
• 
At the onset of the indigestion and heartburn episode, the participant will start a Symptom 
Diary and complete a 4-point Likert scale for each of the symptoms they are experiencing. 
○ 
Onset is defined as the point in time the participant takes the test product for relief of 
symptoms. 
• 
After completing the surveys, the participant will take the test product. The participant will take 
2 capsules per indigestion and heartburn episode. With a max of 6 capsules per day. (If 
participant takes 6 capsules in 1 day this will be defined as 3 indigestion and heartburn episodes 
and the participant will be exited from the study).   
• 
After taking the test product, the participant will complete a 4-point Likert scale assessment for 
each symptom at 15 minutes, 30 minutes, and 1 hour after taking the test product. 
• 
When the participants symptoms have resolved , the participant will complete the symptom 
diary.  
• 
If the participant takes any other medication outside of the test product, the participant will 
record this on the symptom diary.  
○ 
The participant is allowed to take alternative medications or supplements AFTER 1 hour from 
taking the test product. 
• 
After taking the test product, the participant will be instructed to fill out an Adverse Event form 
for any side-effects experienced.  
• 
After the first episode of indigestion and heartburn, the participant will be asked to complete 
the same process for another 2 episodes within the 60-day study time frame; however, these 
are not required. 
• 
If the participant completes the required assessments for a total of 3 episodes of indigestion and 
heartburn, they will be prompted, by email, to exit the study.   
• 
If the participant only completes the required assessments for the required 1 episode of 
indigestion and heartburn, the participant will be prompted, by email, to complete the study 
exit form and will be exited from the study on day 60 (60 days from the day of receipt of the test 
product).  
• 
Neither the sponsor nor Hawthorne Effect Inc. will not collect any unused test product.  
• 
Upon receipt of study exit survey and review of completed study forms, participant will receive 
an Amazon gift card of $25 via email.

18 
 
 
6.2. 
Study Schedule of Activities 
 
Assessments 
Screening 
Consent 
Before Receipt of 
Test Product  
Test Product 
Received 
Event 1 
15 Minutes 
After Event 
Start 
30 Minutes 
After Event 
Start 
60 Minutes 
After Event 
Start 
Study Window 
 
 
 
 
 
 
 
 
Screening Survey 
X 
 
 
 
 
 
 
 
Consent 
 
X 
 
 
 
 
 
 
Baseline Survey 
 
 
X 
 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
 
Acknowledgement of receipt of 
test product  
 
 
 
X 
 
 
 
 
Symptom Diary 
 
 
 
 
X 
 
 
X 
4-point Likert Scale 
 
 
 
 
X 
X 
X 
X 
Test Product Consumed 
 
 
 
 
X 
 
 
 
Medications & Supplements 
 
 
X 
 
 
 
 
 
AE Assessment 
 
 
 
 
X 
X 
X 
X 
Study Exit Survey 
 
 
 
 
 
 
 
 
 
 

19 
 
Assessments 
Event 2 
15 Minutes After 
Event Start 
30 Minutes 
After Event 
Start 
60 Minutes 
After Event 
Start 
Event 3 
15 Minutes 
After Event 
Start 
30 Minutes 
After Event 
Start 
60 Minutes 
After Event 
Start 
Study Exit 
Study Window 
 
 
 
 
 
 
 
 
 
Screening Survey 
 
 
 
 
 
 
 
 
 
Consent 
 
 
 
 
 
 
 
 
 
Baseline Survey 
 
 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
Acknowledgement of Receipt 
of Test Product  
 
 
 
 
 
 
 
 
 
Symptom Diary 
X 
 
 
X 
X 
 
 
X 
 
4-point Likert Scale 
X 
X 
X 
X 
X 
X 
X 
X 
 
Test Product Consumed 
X 
 
 
 
X 
 
 
 
 
Medications & Supplements 
 
 
 
 
 
 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Exit Survey 
 
 
 
 
 
 
 
 
X 

20 
 
 
6.3. 
Participant Enrollment and Follow-Up 
 
Participants suffering from mild to moderate symptoms of indigestion and heartburn will complete a 
cloud-based, HIPAA-secured screening survey to determine eligibility. All eligibility criteria must be 
met for participants to be approved for enrollment in the study. Participants will be provided 
informed consent and the opportunity to ask questions related to the study procedures, risks and 
benefits, and rights related to participation in the study. Participants who sign the study informed 
consent will be prospectively enrolled in the study and provided a link to a patient portal, which 
provides study resources. Participants will take the study formula at the onset of symptoms and 
provide information related to symptoms of indigestion/heartburn during the follow-up period. A 
remote study coordinator may prompt participants to provide study information to ensure that the 
study forms are completed. Efforts will be taken to ensure minimal withdrawals and loss to follow-
up.  
 
6.4. 
Adverse Event and Safety Monitoring 
 
Adverse Events (AEs) are defined as any untoward medical occurrences described by the study 
participant.  All AEs will be self-reported and documented on the platform. The AEs will be reviewed 
by the study team including the remote trial coordinator and study principal investigator and 
reported according to the IRB requirements. Participants who experience adverse events will be 
advised to seek medical attention.  
 
In the event that a participant experiences an adverse event, the clinical study manager or clinical 
ops coordinator will notify both the PI and Sponsor. The Sponsor will take appropriate action 
according to their standard operating procedures for any adverse events that warrant action by the 
sponsor.  
 
6.4.1. Anticipated Adverse Events 
 
Anticipated Adverse Events are complications that are known to be associated with the test 
product (in high doses exceeding recommended use):  
• 
Headache 
• 
Amenorrhea 
• 
Upset Stomach 
• 
Diarrhea 
• 
Hives 
• 
Difficulty breathing 
• 
Facial swelling 
• 
Drowsiness 
• 
Tiredness 

21 
 
• 
Vomiting 
6.4.2. Adverse Event Relationship 
 
Each reported AE will be assessed by the Investigator for relatedness, severity and causality.  
 
6.4.3. Serious Adverse Events 
 
A Serious Adverse Event is an Adverse Event that leads to death or to serious deterioration in 
the health of the participant that either resulted in a life-threatening illness or injury, or a 
permanent impairment of a body structure or body function.  
 
6.5. 
Lost to Follow-Up 
 
If a participant fails to provide event information via the study/patient portal 30 days after the start 
of the trial, the remote coordinator will attempt to contact the participant to ascertain whether or 
not the participant has had an episode of indigestion or heartburn or not and if the participant 
wishes to and/or should continue in the study.   
 
Before a participant is deemed lost to follow up, the investigator or designee must make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s study record. 
 
Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study and the study exit form will be completed. 
 
6.6. 
Test Product Packaging/Handling/Storage/Accountability  
 
• 
The 3-episode supply of test product will be packaged and labeled with ingredients and a study 
ID number. 
• 
Participants will receive guidance on how to report receipt, store, and use the test product. 
• 
Hawthorne Effect Inc. will support storage and shipment of test product, documentation of test 
product assignment, and completion of test product accountability. 
 
6.7. 
Study Management 
 
This study uses a decentralized clinical trial format to foster inclusivity, diversity and accessibility for 
a broad study population and to ensure efficiencies for enrollment and study data collection. The 
study will be managed using an end to end virtual clinical trial platform called Hawthorne Effect 
Study Visit Management Platform which is designed to make patient participation in clinical trials 
more accessible and as least burdensome as possible. The Hawthorne Effect platform 
(www.hawthorne-effect.com) is GCP/ICH/21CFR and HIPAA compliant. Hawthorne Effect uses a 
network of specialty vetted and trained healthcare professionals, or HEROs who are study 

22 
 
investigators, screeners and conduct personalized patient visits for screening and follow-up. For this 
trial, the Hawthorne Effect study visits will be virtual, and the platform will be used to collect patient 
reported outcomes and to track screening, enrollment and study compliance. 
 
7. Statistical Considerations 
 
7.1. 
Study Outcomes Measures 
Analysis populations: 
The intent to treat (ITT) population consists of all participants who are consented, report 
the onset of indigestion and heartburn, and have taken the study medication at least once. 
The primary analysis will be in the ITT population. 
 
 
Primary Endpoint: 
 
The primary endpoint has two components, reduction in indigestion severity and reduction 
in heartburn severity. Participants will be asked to rate each symptom (bloating, early 
fullness during a meal, pain or discomfort in the upper abdomen, burning in the upper 
abdomen, pain/burning in the center of your chest, nausea, vomiting, burping) on a 4-point 
Likert scale at 4 time points: prior to taking the test product, 15, 30, and 60 minutes after 
taking the test product. The improvement in symptoms from baseline will be evaluated on a 
pairwise basis separately for each component and each time point. P-values will be 
computed for the improvement.  
 
 
There is no control group for the primary analysis. 
 
 
Secondary Endpoints: 
Secondary endpoints will be gathered on the subjective experience of these participants 
related to general health, personal experience with the test product. The secondary 
endpoints will be self-reported by the participant on their online portal. There will be a 
questionnaire related to general health and the subjective experience of the participant 
administered at baseline and at study exit.  
 
The purpose of the secondary analyses is to investigate the association between various 
baseline and other measurements and outcomes. These secondary analyses are considered 
hypothesis generating, and the descriptions are somewhat informal.  The trial data may 
suggest secondary analyses not described here. 
 
Secondary endpoints: 
 

23 
 
● 
The time to other intervention will be analyzed. 
● 
A longitudinal analysis will be performed for participants who report on more than one 
incident of heartburn or indigestion.  
● 
Adverse events will be summarized. 
● 
An additional data presentation will consist of results from both Treatment and Control 
in similar studies appearing in the literature. There will be no formal statistical 
comparison of results from this study and historical studies. 
● 
The Net Promoter Score will be summarized and compared against outcomes.  
● 
Comparison against normal behavior will use the paired sample t-test. 
 
 
 
7.2. 
Sample Size Considerations 
Based on information from a variety of studies a highly pessimistic assumption is that there 
would be a mean improvement of 0.5 with a standard deviation of 1.5. (These values refer 
to the 4-point scale.) Based on these assumptions, a sample size of 97 participants would 
result in a 90% power to detect an improvement using the paired-sample t-test. If data from 
multiple incidents per participant are useful, the power to detect an improvement would 
increase. The final sample size of 200 participants has been chosen to allow for various 
contingencies, including uncertainties about compliance in this self-reported trial, and the 
fact that some participants may not experience heartburn or indigestion during the trial 
period.   
It should be emphasized that these assumptions are for sample size purposes only. Trial 
analysis will use the data as collected.  
As discussed above, the number 200 may be increased based on observed data concerning the 
number of participants with indigestion and heartburn. The actual outcomes of treated participants 
will not be considered in this analysis, merely whether or not enrolled participants have reported 
starting using the test product. The method of reevaluating the sample size will be described in the 
Statistical Analysis Plan. 
7.3. 
Analysis Plan 
 
Separate tables will be presented showing the changes from baseline for each component 
and each time point. The changes will be evaluated by the paired sample t-test. A 
longitudinal analysis will be performed for participants who report on more than one 
incident of heartburn or indigestion.  
 
General statistical methods: 
 

24 
 
Data will be analyzed using standard statistical methods, as further specified in a statistical 
analysis plan (SAP), which will be prepared in detail later. 
• 
Data analysis will largely consist of summary statistics and graphs. The only formal group 
comparisons will be in covariate analyses.  
• 
For continuous variables data presentation will consist of means, confidence intervals computed 
using the t-statistic, medians, and interquartile ranges. Group comparisons will use t-tests or 
ANOVA. 
• 
For discrete variables confidence intervals will use the exact intervals, where available. Group 
comparisons will use Fisher’s exact test, with the Monte Carlo version used where 
computationally necessary.  
• 
For time to event variables analysis will use the Kaplan-Meier algorithm, and group comparisons 
will use the log-rank or proportional hazards methods, depending on the data type.   
• 
Visual analog scale values will be treated as continuous variables. Frequency counts will also be 
provided for scales with 10 or fewer distinct response levels. 
• 
Covariate analyses will investigate the relation between baseline and outcome variables, using 
methods appropriate to the data types involved. Age, gender, and baseline medications will be 
included in these analyses where appropriate data are available. 
• 
Present intention is that the analysis will be performed in R, and the precise form of algorithms 
will be the default of R. Kaplan-Meier, log-rank, and proportional hazards algorithms will be the 
defaults of the survival package. 
• 
The exact items to be compared depend on what is reported in each historical control study. 
When possible, the items will include symptom relief at each time measured, including within-
participant p-values, and time to the lowest level on a 4-point scale and to the lowest 2 levels on 
a 10-point scale. as well as reported baseline characteristics. When two-arm studies are 
compared, both arms will be reported in this comparison. In some studies, only indigestion or 
heartburn will be reported; when both are reported they will be separated for the 
comparison. Specific studies to be considered will be identified prior to the analysis of actual 
trial data. 
 
8. Informed Consent Process 
 
The study protocol and informed consent will be reviewed and approved by Advarra Institutional 
Review Board prior to study start. 
 
Study candidates will learn about the study via digital advertisements. If interested in learning more, 
they will be referred to a website “landing page” that will provide detailed information about the 
study. They may opt to complete a screening survey ascertaining study eligibility through patient 
reported outcomes. If successfully completed (no exclusion criteria are selected), candidate will be 
invited to review the study consent form tutorial which includes the opportunity to ask questions 
related to the study from the Principal Investigator or delegated authority of the investigator. 
Candidate will be provided with contact information to reach investigator or study manager as 
desired. 

25 
 
 
Candidate may sign the informed consent via electronic signature as provided by 
Hawthorne Effect. The study manager will verify candidate signature prior to enrollment as 
a study participant. 
 
 
 
9. Subject Confidentiality 
All participants’ data and personal information will be kept confidential. Only those involved with 
the study will have access to participant information. The data will be stored by Hawthorne Effect on 
a HIPAA compliant platform. The platform, which the data is stored on, will require a personalized 
username and password to gain access.  
 
10. Publication 
 
This study will be registered on clinicaltrials.gov prior to commencement of enrollment the results 
will be analyzed and submitted for publication. 
 
 
11. Limitations 
 
The study described in this protocol has some limitations. There is no concurrent control, as 
seems appropriate for the first study on this combination test product. The study relies 
solely on participants' subjective information and self-reporting; there is no medical review 
of symptoms, and no independent check on participant compliance.  Some participant 
groups are not studied, including those under 18 years of age and pregnant women. 
 
 
12. Bibliography  
1. 15 Pain Scales (And How to Find The Best Pain Scale For You). (2018, January 05). Retrieved 
from https://paindoctor.com/pain-scales/ 
2. Artichoke: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved from 
https://www.webmd.com/vitamins/ai/ingredientmono-842/artichoke 
3. Chamomile Plant, Tea, and Oils: Health Benefits and Uses. (n.d.). Retrieved from 
https://www.webmd.com/diet/supplement-guide-chamomile#1 
4. Duncanson, K. R., Talley, N. J., Walker, M. M., & Burrows, T. L. (2017). Food and functional 
dyspepsia: A systematic review. Journal of Human Nutrition and Dietetics, 31(3), 390-407. 
doi:10.1111/jhn.12506 
5. Dyspepsia (Indigestion). (2011, March 01). Retrieved from 
https://www.aafp.org/afp/2011/0301/p554.html 
6. Friedman, L. M., Furberg, C., DeMets, D. L., Reboussin, D., & Granger, C. B. (2015). 
Fundamentals of clinical trials. Cham: Springer. 

26 
 
7. Giacosa, A., Guido, D., Grassi, M., Riva, A., Morazzoni, P., Bombardelli, E., . . . Rondanelli, M. 
(2015). The Effect of Ginger (Zingiber officinalis) and Artichoke (Cynara cardunculus) Extract 
Supplementation on Functional Dyspepsia: A Randomised, Double-Blind, and Placebo-
Controlled Clinical Trial. Evidence-Based Complementary and Alternative Medicine, 2015, 1-9. 
doi:10.1155/2015/915087 
8. Ginger Uses, Benefits & Dosage (n.d.). Retrieved from 
https://www.drugs.com/npp/ginger.html 
9. Holtmann, G., Adam, B., Haag, S., Collet, W., Grunewald, E., & Windeck, T. (2003). Efficacy of 
artichoke leaf extract in the treatment of patients with functional dyspepsia: A six-week 
placebo-controlled, double-blind, multicentre trial. Alimentary Pharmacology and Therapeutics, 
18(11-12), 1099-1105. doi:10.1046/j.1365-2036.2003.01767.x 
10. Licorice: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved from 
https://www.webmd.com/vitamins/ai/ingredientmono-881/licorice 
11. Marshmallow: Uses, Side Effects, Interactions, Dosage, and Warning. (n.d.). Retrieved from 
https://www.webmd.com/vitamins/ai/ingredientmono-774/marshmallow 
12. McMahon, G. (2019). Comparison of a Numeric and a Descriptive Pain Scale in the 
Occupational Medicine Setting. Retrieved from 
https://scholarworks.sjsu.edu/etd_doctoral/98/ 
13. The R Project for Statistical Computing. (n.d.). Retrieved from https://www.R-project.org/. 
14. Vitamin C. (2017, October 18). Retrieved from https://www.mayoclinic.org/drugs-
supplements-vitamin-c/art-20363932 
15. Leidy NK, Farup C, Rentz AM, Ganoczy D, Koch KL. Patient- based assessment in dyspepsia: 
Development and validation of dyspepsia symptom severity index (DSSI). Dig Dis Sci. 
2000;45:1172–1179.  
16. Evaluation of the genotoxic potential of standardized extract of Glycyrrhiza glabra 
(GutGard™). Chandrasekaran CV, Sundarajan K, Gupta A, Srikanth HS, Edwin J, Agarwal 
A. Regul Toxicol Pharmacol. 2011 Dec;61(3):373-80. doi: 10.1016/j.yrtph.2011.10.002. 
Epub 2011 Oct 13. 
17. Deglycyrrhizinized liquorice in the treatment of chronic duodenal ulcer. A retrospective 
endoscopic survey of 32 patients. Larkworthy W et al. Practitioner. 1975 
Dec;215(1290):787-92. 
18. An Extract of Glycyrrhiza glabra (GutGard) Alleviates Symptoms of Functional 
Dyspepsia: A Randomized, Double-Blind, Placebo-Controlled Study. Raveendra KR, 
Jayachandra, Srinivasa V, Sushma KR, Allan JJ, Goudar KS, Shivaprasad HN, 
Venkateshwarlu K, Geetharani P, Sushma G, Agarwal A. Evid Based Complement 
Alternat Med. 2012;2012:216970. doi: 10.1155/2012/216970. Epub 2011 Jun 16. 
19. Rational Phytotherapy: A Physician's Guide to Herbal Medicine. Schulz V, Hansel R, 
Tyler VE.  Terry C. Telger, transl. 3rd ed. Berlin, GER: Springer, 1998. 
20. Marshmallow soothes cough. Bone K.  Br J Phytother 1993;3(2):93. 
21. Antitussive Activity of a Rhamnogalacturonan Isolated from the Roots of Althaea 
Officinalis L., Var. Robusta. Gabriela Nosáľvá DMartin, Slovakia , Anna Strapková , 
Alžbeta Kardošová & Peter Capek Journal of Carbohydrate Chemistry Volume 12, 1993 - 
Issue 4-5 

27 
 
22. Marshmallow (Althaea officinalis L.) Monograph. Catherine Ulbricht, Ethan Basch, 
Catherine Ulbricht, Paul Hammerness & Mamta Vora Journal of Herbal 
Pharmacotherapy Volume 3, 2003 - Issue 3 
23. A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe).Haniadka 
R et al. Food Funct. (2013) 
24. Effect of ginger on gastric motility and symptoms of functional dyspepsia.Hu ML et al. 
World J Gastroenterol. (2011) 
25.  [Dyspeptic pain and phytotherapy--a review of traditional and modern herbal drugs]. 
Saller R, Iten F, Reichling J. Forsch Komplementarmed Klass Naturheilkd. 2001 
Oct;8(5):263-73. Review. 
26. Acute metabolic actions of the major polyphenols in chamomile: an in vitro mechanistic 
study on their potential to attenuate postprandial hyperglycaemia. Villa-Rodriguez JA, 
Kerimi A, Abranko L, Tumova S, Ford L, Blackburn RS, Rayner C, Williamson G. Sci Rep. 
2018 Apr 3;8(1):5471. doi: 10.1038/s41598-018-23736-1. 
27. A randomized, double-blind, placebo-controlled trial of oral Matricaria recutita 
(chamomile) extract therapy for generalized anxiety disorder. Amsterdam JD, Li Y, 
Soeller I, et al. J Clin Psychopharmacol. 2009;29(4):378-382 
28. Functional dyspepsia in adults retreieved from  
https://www.uptodate.com/contents/functional-dyspepsia-in-adults#H4244969612 
 
 
13. Supplement and Appendix 
13.1. 
13.1 Appendices 
13.1.1. 
Appendix A Drug Interactions 
 
Drug Interactions for Test Product 
 
DGL EXTRACT 
There are no Serious Drug Interactions known for DGL Extract. Whereas Licorice contains a 
constituent glycyrrhizic acid, which can cause a syndrome of apparent mineralocorticoid excess 
when eaten in large amounts, DGL extract has the glycyrrhizic acid removed and so should not 
pose the same interactions as regular Licorice extract. Still, there are some potential Moderate 
Interactions, where DGL may interact in the metabolism of certain drugs (which utilize the same 
enzymes it inhibits), or other effects, such as estrogenic or diuretic effects. See Below for List.  
CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
In vitro research shows that licorice extract and glabridin, a constituent found in the licorice 
species G. glabra, inhibit cytochrome P450 2B6 (CYP2B6) isoenzymes (10300,94822). 
Licorice extract from the species G. uralensis seems to inhibit CYP2B6 isoenzymes to a greater 
degree than G. glabra extract in vitro (94822). Theoretically, these species of licorice might 

28 
 
increase levels of drugs metabolized by CYP2B6; however, these interactions have not yet been 
reported in humans. Some drugs that are metabolized by CYP2B6 include ketamine (Ketalar), 
phenobarbital, orphenadrine (Norflex), secobarbital (Seconal), rifampin (Rifadin), and 
dexamethasone (Decadron). Use licorice cautiously or avoid in patients taking these drugs. 
CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
Licorice extracts from the species G. glabra and G. uralensis inhibit cytochrome P450 2C19 
(CYP2C19) isoenzymes in vitro (94822). Theoretically, these species of licorice might increase 
levels of drugs metabolized by CYP2C19; however, this interaction has not yet been reported in 
humans. Some drugs metabolized by CYP2C19 include proton pump inhibitors including 
omeprazole (Prilosec), lansoprazole (Prevacid), and pantoprazole (Protonix); diazepam 
(Valium); carisoprodol (Soma); nelfinavir (Viracept); and others. 
CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
Licorice extract from the species G. glabra and G. uralensis inhibits cytochrome P450 2C8 
(CYP2C8) isoenzymes in vitro (94822). Theoretically, these species of licorice might increase 
levels of drugs metabolized by CYP2C8; however, this interaction has not yet been reported in 
humans. Some drugs metabolized by CYP2C8 include amiodarone (Cardarone), paclitaxel 
(Taxol); nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (Cataflam, 
Voltaren) and ibuprofen (Motrin); rosiglitazone (Avandia); and others. 
CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
There is conflicting evidence about the effect of licorice on CYP2C9 enzyme activity. In vitro 
research shows that extracts from the licorice species G. glabra and G. uralensis moderately 
inhibit cytochrome P450 2C9 (CYP2C9) isoenzymes (10300,94822). However, evidence from 
an animal model shows that licorice extract from the species G. uralensis can induce hepatic 
CYP2C9 activity (14441). Reasons for these discrepancies are not clear. Until more is known, 
licorice should be used cautiously in people taking CYP2C9 substrates. Some drugs 
metabolized by CYP2C9 include celecoxib (Celebrex), diclofenac (Voltaren), fluvastatin 
(Lescol), glipizide (Glucotrol), ibuprofen (Advil, Motrin), irbesartan (Avapro), losartan 
(Cozaar), phenytoin (Dilantin), piroxicam (Feldene), tamoxifen (Nolvadex), tolbutamide 
(Tolinase), torsemide (Demadex), and warfarin (Coumadin). 
CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  

29 
 
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B  
Pharmacokinetic research shows that the licorice constituent glycyrrhizin, taken in a dosage of 
150 mg orally twice daily for 14 days, modestly decreases the area under the concentration-time 
curve of midazolam by about 20%. Midazolam is a substrate of cytochrome P450 3A4 
(CYP3A4). This suggests that glycyrrhizin modestly induces CYP3A4 activity (59808). 
Evidence from animal research also shows that licorice extract from the species G. uralensis 
induces CYP3A4 activity (14441). However, licorice extract from G. glabra species appear to 
inhibit CYP3A4-induced metabolism of testosterone in vitro. It is thought that the G. glabra 
inhibits CYP3A4 due to its constituent glabridin, which is a moderate CYP3A4 inhibitor in vitro 
and not present in other licorice species (10300,94822). Until more is known, licorice should be 
used cautiously in people taking CYP3A4 substrates. Some drugs metabolized by CYP3A4 
include lovastatin (Mevacor), clarithromycin (Biaxin), cyclosporine (Neoral, Sandimmune), 
diltiazem (Cardizem), estrogens, indinavir (Crixivan), triazolam (Halcion), and numerous 
others. 
ESTROGENS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = D  
Theoretically, licorice might interfere with estrogen therapy due to estrogenic and anti-
estrogenic effects (7860,16058). 
MIDAZOLAM (Versed, others) 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B  
In humans, the licorice constituent glycyrrhizin appears to moderately induce the metabolism of 
midazolam (59808). This is likely due to induction of cytochrome P450 3A4 by licorice. Until 
more is known, licorice should be used cautiously in people taking midazolam. . 
WARFARIN (Coumadin) 
Interaction Rating = Major Do not take this combination.  
Severity = High •  Occurrence = Probable •  Level of Evidence = D  
Licorice seems to increase metabolism and decrease levels of warfarin in animal models. This is 
likely due to induction of cytochrome P450 2C9 (CYP2C9) metabolism by licorice (14441). 
Advise patients taking warfarin to avoid taking licorice. 
 
Interactions with Herbs & Supplements 
CARDIAC GLYCOSIDE-CONTAINING HERBS: Theoretically, the overuse or misuse of 
licorice can increase the risk of cardiotoxicity due to potassium depletion (10393). Cardioactive 
herbs include digitalis, lily-of-the-valley, pheasant's eye, and squill. 
 
STIMULANT LAXATIVE HERBS: Theoretically, concomitant overuse or misuse of licorice 

30 
 
with stimulant laxatives can increase the risk of potassium depletion (10393). Stimulant laxative 
herbs include aloe, alder buckthorn, black root, blue flag, butternut bark, colocynth, European 
buckthorn, fo ti, gamboge, gossypol, greater bindweed, jalap, manna, Mexican scammony root, 
rhubarb, senna, and yellow dock.  
 
 
 
 
ARTICHOKE LEAF EXTRACT 
There are no known Drug Interactions for Artichoke Leaf Extract.  
 
None known.  
 
Interactions with Herbs & Supplements 
None known.  
 
 
 
GINGER ROOT EXTRACT 
There are no Serious Drug Interactions known for Ginger. There are some potential Moderate 
Interactions, where Ginger may cause a blood thinning effect which could interact with certain 
drugs. See Below for List.  
 
 
ANTICOAGULANT/ANTIPLATELET DRUGS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = B  
Based on laboratory research, ginger is thought to inhibit thromboxane synthetase and decrease 
platelet aggregation (7622,12634,20321,20322,20323,96257). However, this has not been 
demonstrated unequivocally in humans, with mixed results from clinical trials (96257). 
Theoretically, excessive amounts of ginger might increase the risk of bleeding when used with 
anticoagulant/antiplatelet drugs. Some anticoagulant or antiplatelet drugs include aspirin, 
clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), 
warfarin (Coumadin), and others. 
ANTIDIABETES DRUGS 
Interaction Rating = Minor Be watchful with this combination.  
Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D  
Evidence from animal and human research suggests that ginger might increase insulin levels 
and/or decrease blood glucose levels (12636,20402,20403,20404,20405,89895,89896). 
Theoretically, ginger might have an additive effect with antidiabetes drugs and cause 
hypoglycemia. Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, 

31 
 
Glynase PresTab, Micronase), insulin, metformin (Glucophage), pioglitazone (Actos), 
rosiglitazone (Avandia), and others. 
CALCIUM CHANNEL BLOCKERS 
Interaction Rating = Minor Be watchful with this combination.  
Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D  
Preliminary research suggests ginger might have hypotensive and calcium channel-blocking 
effects (12633). Theoretically, ginger might have an additive effect with calcium channel 
blockers. Calcium channel blockers include nifedipine (Adalat, Procardia), verapamil (Calan, 
Isoptin, Verelan), diltiazem (Cardizem), isradipine (DynaCirc), felodipine (Plendil), amlodipine 
(Norvasc), and others. 
CYCLOSPORINE (Neoral, Sandimmune) 
Interaction Rating = Minor Be watchful with this combination.  
Severity = Mild •  Occurrence = Possible •  Level of Evidence = D  
In an animal model, ginger juice taken 2 hours prior to cyclosporine administration reduced the 
maximum concentration and area under the curve of cyclosporine by 51.4% and 40.3%, 
respectively. This effect was not observed when ginger juice and cyclosporine were 
administered at the same time (20401). 
METRONIDAZOLE (Flagyl) 
Interaction Rating = Minor Be watchful with this combination.  
Severity = Mild •  Occurrence = Possible •  Level of Evidence = D  
In an animal model, ginger increased the absorption and plasma half-life of metronidazole. In 
addition, the elimination rate and clearance of metronidazole was significantly reduced (20350). 
NIFEDIPINE 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B  
Clinical research shows that combined treatment with ginger 1 gram plus nifedipine 10 mg 
significantly inhibits platelet aggregation compared to nifedipine alone or ginger alone (20324). 
PHENPROCOUMON 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = D  
Phenprocoumon, a warfarin-related anticoagulant used in Europe, might increase the 
international normalized ratio (INR) when taken with ginger. There is one case report of a 76 

32 
 
year old woman with a stable INR on phenprocoumon that increased to greater than 10 when 
she began consuming dried ginger and ginger tea (12880). 
WARFARIN (Coumadin) 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = B  
Preliminary evidence suggests that ginger might inhibit thromboxane synthetase and decrease 
platelet aggregation (7622,12634,20321,20322,20323). In one case report, ginger increased the 
INR when taken with phenprocoumon, which has similar pharmacological effects as warfarin 
(12880). In another case report, ginger increased the INR when taken with a combination of 
warfarin, hydrochlorothiazide, and acetaminophen (20349). A longitudinal analysis suggests 
that taking ginger increases the risk of bleeding in patients taking warfarin for at least 4 months 
(20348). However, research in healthy people suggests that ginger has no effect on INR, or the 
pharmacokinetics or pharmacodynamics of warfarin (12881,15176). Until more is known, 
monitor INRs closely in patients taking significant amounts of ginger. 
 
Interactions with Herbs & Supplements 
ANTICOAGULANT/ANTIPLATELET HERBS AND SUPPLEMENTS: Based on 
laboratory research, ginger is thought to inhibit thromboxane synthetase and decrease platelet 
aggregation (7622,12634,20321,20322,20323). However, this has not been demonstrated 
unequivocally in humans with mixed results from clinical trials (96257). Concomitant use of 
ginger with other herbs that might affect platelet aggregation could theoretically increase the risk 
of bleeding in some people. These herbs include angelica, clove, danshen, garlic, ginkgo, Panax 
ginseng, red clover, turmeric, and others. 
 
HERBS AND SUPPLEMENTS WITH HYPOGLYCEMIC POTENTIAL: Ginger might 
increase insulin levels and/or decrease blood glucose levels 
(12636,20402,20403,20404,20405,89895,89896). Theoretically, ginger might have additive 
effects with herbs that decrease blood glucose levels. Herbs with hypoglycemic potential include 
devil's claw, fenugreek, guar gum, Panax ginseng, and Siberian ginseng.  
 
 
 
CHAMOMILE EXTRACT 
There are no Serious Drug Interactions known for Chamomile. There are some theoretical 
Moderate Interactions, where Chamomile may interact in the metabolism of certain drugs (which 
utilize the same enzymes it inhibits), Chamomile might also exhibit an estrogenic activity, blood 
thinning activity or sedative effects that could have Moderate Interactions with certain drugs. See 
Below for List.  
 
 
BENZODIAZEPINES 

33 
 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
German chamomile has mild sedative effects. Theoretically, concomitant use with 
benzodiazepines might cause additive effects and side effects (9765,12725,19719). Some 
benzodiazepines are alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), 
lorazepam (Ativan), midazolam (Versed), temazepam (Restoril), triazolam (Halcion), and 
others. 
CNS DEPRESSANTS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = D  
German chamomile has mild sedative effects. Theoretically, concomitant use with drugs with 
sedative properties can cause additive effects and side effects (9765,12725,19719). Some CNS 
depressants are benzodiazepines, pentobarbital (Nembutal), phenobarbital (Luminal), 
secobarbital (Seconal), fentanyl (Duragesic, Sublimaze), morphine, zolpidem (Ambien), and 
others. 
CONTRACEPTIVE DRUGS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = D  
Theoretically, concomitant use of large amounts of German chamomile might interfere with 
contraceptive drugs through competition for estrogen receptors (12728). 
CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES 
Interaction Rating = Minor Be watchful with this combination.  
Severity = Mild •  Occurrence = Possible •  Level of Evidence = D  
There is preliminary in vitro and in vivo evidence that German chamomile might inhibit 
cytochrome P450 1A2 (CYP1A2) (12734,19720). So far, this interaction has not been reported 
in humans. However, watch for an increase in the levels of drugs metabolized by CYP1A2 in 
patients taking German chamomile. Some drugs metabolized by CYP1A2 include amitriptyline 
(Elavil), haloperidol (Haldol), ondansetron (Zofran), propranolol (Inderal), theophylline (Theo-
Dur, others), verapamil (Calan, Isoptin, others), and others. Use German chamomile cautiously 
or avoid in patients taking these drugs. 
CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
There is preliminary in vitro evidence that German chamomile might inhibit cytochrome P450 
2C9 (CYP2C9) (19720). So far, this interaction has not been reported in animals or humans. 
However, watch for an increase in the levels of drugs metabolized by CYP2C9 in patients 

34 
 
taking German chamomile. Some drugs metabolized by CYP2C9 include nonsteroidal anti-
inflammatory drugs (NSAIDs) such as diclofenac (Cataflam, Voltaren), ibuprofen (Motrin), 
meloxicam (Mobic), and piroxicam (Feldene); celecoxib (Celebrex); amitriptyline (Elavil); 
warfarin (Coumadin); glipizide (Glucotrol); losartan (Cozaar); and others. Use German 
chamomile cautiously or avoid in patients taking these drugs. 
CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
There i's preliminary in vitro evidence that German chamomile might inhibit cytochrome P450 
2D6 (CYP2D6) (19720). So far, this interaction has not been reported in animals or humans. 
However, watch for an increase in the levels of drugs metabolized by CYP2D6 in patients 
taking German chamomile. Some drugs metabolized by CYP2D6 include tricyclic 
antidepressants such as imipramine (Tofranil) and amitriptyline (Elavil); antipsychotics such as 
haloperidol (Haldol), risperidone (Risperdal), and chlorpromazine (Thorazine); beta-blockers 
such as propranolol (Inderal), metoprolol (Lopressor, Toprol XL), and carvedilol (Coreg); 
tamoxifen (Nolvadex); and others. Use German chamomile cautiously or avoid in patients 
taking these drugs. 
CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
There is preliminary evidence that suggests that German chamomile might inhibit the 
cytochrome P450 3A4 (CYP3A4) isoenzymes (6450,19720). Theoretically, German chamomile 
might increase levels of drugs metabolized by CYP3A4. However, so far, this interaction has 
not been reported in humans. Some drugs metabolized by CYP3A4 include lovastatin 
(Mevacor), ketoconazole (Nizoral), itraconazole (Sporanox), fexofenadine (Allegra), triazolam 
(Halcion), and numerous others. Use German chamomile cautiously or avoid in patients taking 
these drugs. 
ESTROGENS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
Theoretically, concomitant use of large amounts of German chamomile might interfere with 
hormone replacement therapy through competition for estrogen receptors (12728). 
TAMOXIFEN (Nolvadex) 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = D  

35 
 
Theoretically, large doses of German chamomile might interfere with tamoxifen because of its 
potential estrogenic effects (12728). 
WARFARIN (Coumadin) 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = High •  Occurrence = Possible •  Level of Evidence = D  
Taking German chamomile and warfarin together might increase the effects of warfarin and 
increase the risk of bleeding. In one case, a 70-year-old woman taking warfarin developed 
retroperitoneal hematoma and bilateral recti muscle bleeding along with an INR of 7.9 
following ingestion of German chamomile tea 4-5 cups/day and use of a topical chamomile-
based lotion applied 4-5 times daily (14309). 
 
Interactions with Herbs & Supplements 
HERBS AND SUPPLEMENTS WITH SEDATIVE PROPERTIES: German chamomile has 
mild sedative effects. Theoretically, concomitant use with herbs that have sedative properties 
might enhance therapeutic and adverse effects (9765,12725,19719). Some of these supplements 
include 5-HTP, calamus, California poppy, catnip, hops, Jamaican dogwood, kava, St. John's 
wort, scullcap, valerian, yerba mansa, and others.  
 
 
 
 
MARSHMALLOW ROOT EXTRACT 
There are no Serious Drug Interactions known for Marshmallow Root Extract.  There are some 
theoretical Moderate Interactions, where Marshmallow Root may interact in the metabolism of 
certain drugs, have hypoglycemic, blood thinning, or diuretic effects which may also affect the 
activity of certain drugs. See Below for List.  
 
 
ANTICOAGULANT/ANTIPLATELET DRUGS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
Animal research suggests that marshmallow flower extract has antiplatelet effects (92846). 
Theoretically, concomitant use of marshmallow and anticoagulant/antiplatelet drugs might lead 
to additive anticoagulant/antiplatelet effects, potentially increasing the risk for bleeding in some 
patients. 
 
Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, 
Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others. 

36 
 
ANTIDIABETES DRUGS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
Animal research suggests that marshmallow can have hypoglycemic effects (62022). 
Theoretically, marshmallow might have additive effects with hypoglycemic therapy (4). 
Monitor blood glucose levels closely. Dose adjustments to antidiabetes drugs may be necessary. 
Some antidiabetes drugs include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, 
Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others. 
LITHIUM 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D  
Marshmallow is thought to have diuretic properties. Theoretically, due to these potential diuretic 
effects, marshmallow might reduce excretion and increase levels of lithium. The dose of lithium 
might need to be decreased. 
ORAL DRUGS 
Interaction Rating = Moderate Be cautious with this combination.  
Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D  
The mucilage in marshmallow might impair absorption of oral drugs (1,11,12,19). 
 
Interactions with Herbs & Supplements 
ANTICOAGULANT/ANTIPLATELET HERBS AND SUPPLEMENTS: Animal research 
suggests that marshmallow flower extract has antiplatelet effects (92846). Theoretically, 
concomitant use of marshmallow with herbs and supplements with anticoagulant/antiplatelet 
effects might increase the risk of bleeding in some people. These herbs include angelica, clove, 
danshen, garlic, ginger, ginkgo, Panax ginseng, red clover, turmeric, willow, and others. 
 
HERBS AND SUPPLEMENTS WITH HYPOGLYCEMIC POTENTIAL: Animal research 
suggests that marshmallow may have hypoglycemic effects (62022). Theoretically, marshmallow 
might have additive effects when used with other herbs and supplements with hypoglycemic 
potential. This might increase the risk of hypoglycemia in some patients. Some herbs and 
supplements with hypoglycemic potential include alpha-lipoic acid, bitter melon, chromium, 
devil's claw, fenugreek, garlic, guar gum, horse chestnut, Panax ginseng, psyllium, Siberian 
ginseng, and others.  
 
 
 
 
 

37 
 
 
13.1.2. 
Appendix B Instructions for Use 
 
Instructions for Use  
Upset Stomach Relief 
 
 
This test product was created for support with indigestion and heartburn, combining 
Deglycyrrhizinated licorice (DGL), Artichoke Leaf, Marshmallow Root, Ginger, and Chamomile 
for comprehensive, yet gentle plant-based support with indigestion. This formula is designed to 
promote digestion and feelings of digestive comfort, but also to help build long-term digestive 
wellness. 
 
Daily Dosage: 
 
2 capsules contain: 
 
Active Ingredients: Licorice Extract, Artichoke Leaf Extract, Chamomile, Marshmallow 
Root, Ginger. 
 
Inactive Ingredients:Capsule (Hydroxypropyl Methyl Cellulose, Purified Water, 
Carrageenan, Potassium Chloride), Rice Hull Concentrate. 
 
 
Directions: Take 2 capsules at the onset of symptoms up to three times daily for 
relief of your indigestion and heartburn symptoms. 
 
 
 
 
 
*These statements have not been evaluated by the Food and Drug Administration. This 
product is not intended to diagnose, treat, cure or prevent any disease.  
 
 
 

38 
 
 
13.1.3. 
Appendix C Screening Form 
 
Screening 
 
Please answer the following questions to the best of your abilities.  
 
1. Are you at least 18 years old? (DOB?)  
2. Do you suffer from symptoms of indigestion and/or heartburn (see severity index 
below)? (Y/N) 
3. Have you ever been diagnosed with any chronic liver disease? (Y/N) 
4. Have you ever been diagnosed with any chronic renal disease? (Y/N) 
5. Are you pregnant or breastfeeding? (Y/N) 
6. Do you have any allergies to any of the following? (Y/N) 
a. Licorice 
b. Artichoke leaf 
c. Marshmallow Root 
d. Ginger 
e. Chamomile 
f. Rice Hull Concentrate 
g.  Carrageenan 
h. Cellulose Capsule 
7. Do you have more than 10 alcoholic beverages per week? (Y/N) 
8. Are you willing to try the test product for relief of your indigestion and heartburn 
symptoms? (Y/N) 
9. Have you been prescribed any medication by your doctor for any GI disorder or 
medication that can affect the GI system? (Y/N) 
10. Have you ever had surgery of the upper GI tract or abdominal surgery (with the 
exception of having your gallbladder or appendix removed)? (Y/N) 
11. Are you currently taking any anticoagulation, blood-thinning, medication daily (aspirin, 
warfarin, etc.)? (Y/N) 
12. Are you able to swallow pills? (Y/N) 
 
 
 
 
Severity index 

39 
 
 
 
 

40 
 
 
13.1.4. 
Appendix D Baseline Form 
 
Baseline 
1. Demographics 
a. Race/Ethnicity (Black or African American, White, Asian, American Indian or 
Alaska Native, Native Hawaiian or another pacific islander, other: ____, do not 
want to share) 
b. Sex (M, F, or Do not want to share) 
2. On average how often do you get Indigestion and Heartburn? (few times a year, once a 
month, A few times a month, once a week, 2-3 times a week, Everyday) 
3. How long does it usually take for your symptoms to reach maximum intensity? (0-30 
min, 31 min- 1 hour, +1 hour) 
4. How long do your symptoms usually last without medication? (0-30 min, 31 min- 1 
hour,, 1-2 hour, >2 hours, do not resolve) 
5. How long do your symptoms usually last with medication? (0-30 min, 31 min- 1 hour,, 1-
2 hour, >2 hours, Do not resolve) 
6. On average how bad are your symptoms without medication? (1-10) 
7. On average how bad are your symptoms with medication? (1-10) 
8. What symptoms do you experience when you are having an episode of 
Heartburn/Indigestion? (Check all that apply) 
a. bloating  
b. early fullness during a meal 
c. pain or discomfort in the upper abdomen 
d. burning in the upper abdomen 
e. pain/burning in the center of your chest 
f. nausea 
g. vomiting 
h. burping 
i. other: _________________ 
j. None of the above 
 
9. Do any of the following bring on or trigger your symptoms of indigestion or heartburn? 
(Check All That Apply) 
a. Overeating 
b. Eating too quickly 
c. Fatty/greasy foods 
d. Spicy foods 
e. Caffeine 
f. Alcohol 
g. Smoking 
h. Other: _______________________________ 
i. None of the above 

41 
 
10. Do you take medications to treat your symptoms?  (yes/no) 
a. What medication do you take? (free response) 
b. how long do you wait before taking medication? 
i. Right away 
ii. Within an hour 
iii. 1-2 hours  
iv. >2 hours  
 
 
 
 
 
 

42 
 
 
13.1.5. 
Appendix E Symptom Diary 
 
Please complete the following items during your first episode of 
Indigestion/Heartburn. We encourage you to complete the forms online in real 
time. However, if you cannot log into your patient portal at the time of your 
symptoms please complete these forms and log into your patient portal as soon as 
possible and complete the online forms.  
 
Reminder: Do not take any other medications or supplements within the first 
hour of taking the test product.  
 
 
 
 
 
 Date of Onset: ________________  
Time of Onset: ________________ 
 
 
Trigger (check all that apply):   Overeating   Eating too quickly  Fatty/Greasy Food   Spicy 
Food     Caffeine    Alcohol   
  Smoking    Other: _____________________  None of the above  I do not know 
 
 
 
 
 
Time test product taken: ________________ 
 
 
 
 
 
Please rate the following symptoms at the following time points. Circle one 
answer.  
 
Onset (Prior to take the test product) 
Bloating  
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 

43 
 
 
Early Fullness During a Meal 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain or Discomfort in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burning in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain/Burning in the center of your chest 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Nausea 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Vomiting 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burping 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Other 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
15 Minutes after taking the test product 
 
Bloating  
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 

44 
 
 
Early Fullness During a Meal 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain or Discomfort in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burning in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain/Burning in the center of your chest 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
Nausea 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Vomiting 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burping 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Other: 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
30 Minutes after taking the test product 
 
Bloating  
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 

45 
 
Early Fullness During a Meal 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain or Discomfort in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burning in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain/Burning in the center of your chest 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Nausea 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Vomiting 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burping 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Other: 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
60 Minutes after taking the test product 
 
Bloating  
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 

46 
 
 
Early Fullness During a Meal 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain or Discomfort in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burning in the Upper Abdomen 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Pain/Burning in the center of your chest 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Nausea 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Vomiting 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Burping 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
 
Other: 
0 
1 
2 
3 
No Symptom 
Slight 
Moderate 
Severe 
 
After  your symptoms resolveplease complete any of the following questions if 
applicable.  
Did your symptoms resolve completely with the test product?   Yes    No  Time of complete 
symptom resolution: _________ 

47 
 
 
 
Did you need to take another medication:            Yes             No 
 
 
Medication #1: ____________________ Dose: _______________ Time: _________________  
 
Medication #2: ____________________ Dose: _______________ Time: _________________ 
 
Medication #3: ____________________ Dose: _______________ Time: _________________  
 
 
Did your symptoms resolve completely with taking your alternative medication?   Yes    No  
 
 
After taking the alternative medication, time of complete resolution of symptoms: 
________________ 
 
 
Did you experience any side effects after taking the test product? (Y/N)  If yes, Please fill out 
the Adverse Event form.  
 
 

48 
 
 
 
13.1.6. 
Appendix F Study Exit Form 
 
Study Exit 
 
 
1. Please rate your overall experience with the test product. 
 
0      1 
   2 
3 
4          5 
     6 
7 
8 
9 
10 
 Poor  
 
                     Neutral  
 
 
        Excellent  
 
1a. Why? (free response) 
 
 
2. Do you feel that the test product helped with your indigestion and heartburn?  
 
0      1 
   2 
3 
4          5 
     6 
7 
8 
9 
10 
Not at all 
 
 
         Neutral  
 
 
        definitely 
 
 
3. How likely are you to recommend the test product to your friends or family members? 
 
0      1 
   2 
3 
4          5 
     6 
7 
8 
9 
10 
Not Likely 
 
 
         Neutral  
 
 
        Extremely Likely 
 
4. Do you feel that the test product helped your body cope with occasional heartburn, 
occasional acid indigestion, and upset stomach? 
 
0      1 
   2 
3 
4          5 
     6 
7 
8 
9 
10 
Not at all 
 
 
         Neutral  
 
 
        definitely 
 
 
5. Is there anything else that you would like to let us know about your experience with the 
product (taste, smell, consistency, or other)?  (y/n) 
 (free response) 
 
6. Did the test product help prevent you from having to take any alternative medication 
for your symptoms? (y/n) 
 
 

49 
 
 
 
13.1.7. 
Appendix G Adverse Event Form 
 
Upset Stomach AE document 
 
 
1. Did you experience any side effects after taking the test product? Y/N 
a. If so, did you experience any of the following 
o itching, rash, hives, throat/lip/tongue swelling, wheezing 
o low blood pressure, fainting, chest pain, shortness of breath, palpitations, irregular 
heart beat 
o severe, persistent nausea, vomiting, diarrhea, or abdominal pain 
o difficulty urinating, decreased urination 
o fatigue, appetite loss, yellowing skin/eyes, itching, dark urine 
o severe joint/muscle pain 
o slurred speech, one-sided weakness of face, arm, leg, vision  
o abnormal bleeding from nose or gums 
o blood in urine, stool, vomit,  
o marked mood, cognitive, or behavioral changes, thoughts of suicide 
o Other: 
2. Please give a description of the event  
3. How soon after taking the test product did you experience the side effect? 
4. What did you do to alleviate the side effect? 
5. Did you have to go to the hospital or see a doctor for this side effect? 
a. Please describe any diagnosis or treatment that they provided. 
b. If you were seen in the hospital, please upload any discharge paperwork or other 
documents from the hospital.  
 
 
 
 
 
 
 

50 
 
13.1.8. 
Appendix H Test Product Insert 
 
Welcome to the Upset Stomach Relief Trial! 
We appreciate you taking the time to participate in this trial. As you may already know, the aim 
of this study is to measure the impact the test product has on your symptoms of indigestion and 
heartburn. Please take the time to read the following information below to become acquainted 
with the trial instructions. 
 
Instructions upon Test Product Receipt: 
1. Please log onto the study portal and acknowledge the receipt by completing the ‘Start 
Form’ 
2. Enclosed in the study bag, please find a 3-episode supply of the test product.  
3. You will take the test product the next time you have an episode of indigestion and 
heartburn and need to take something to relieve the discomfort. 
Instructions Once Product Intake Begins: 
1. The next time you have symptoms of indigestion and heartburn and feel the need to 
take the test product, you will FIRST start the symptoms diary (paper forms included in 
this package). 
o You will complete the date of the episode, the time the episode began, what 
triggered the episode, and check all the symptoms you are experiencing. 
o REMINDER: DO NOT TAKE ANY OTHER MEDICATION/SUPPLEMENT DURING 
THE HOUR AFTER TAKE THE TEST PRODUCT. 
2. Next, you will rate all the severity of each symptom you are experiencing. 
3. Take the test product (2 capsules) and record the time you take the test product.  
4. Rate each of your symptoms again at 15, 30, and 60 minutes after taking the test 
product.  
5. After your symptoms resolve , you should complete the symptom diary.  
o Record whether your symptoms completely went away with the test product, if 
so, record the approximate time your symptoms resolved.  
o Record whether you needed to take alternative medication to help with your 
symptoms (remember you are only allowed to take alternative medication 1 
hour after taking test product).  
o Record the name, dose, and time you took the alternative medication.  
o Record whether your symptoms completely went away with the alternative 
medication you took and the approximate time this occurred. 
6. If at any point after taking the test product you experience any side effects from the test 
product, please log into the study portal and complete an Adverse Event form.  
7. After the first episode of indigestion and heartburn, you will be asked to complete the 
same process for another 2 episodes; although we encourage you to complete these 
steps for another 2 episodes, they are not required. 

51 
 
8. If you complete the required assessments for a total of 3 episodes of indigestion and 
heartburn, you will be prompted, by email, to exit the study and complete the study exit 
form.  
9. If you only complete the required assessments for the required 1 episode of indigestion 
and heartburn, you will be prompted, by email, to complete the study exit form on day 
60 (60 days from the day of receipt of the test product).  
10. Upon receipt of study exit survey and review of completed study forms, you will receive 
an Amazon gift card of $25 via email. 
 
 
Thank you again for participating in this trial! 
 
If you have any questions, please contact: 
Jerome Tonog, Clinical Study Manager 
Jerome.tonog@hawthorne-effect.com 
 
 
 

52 
 
 
13.1.9. 
Appendix I Informed Consent 
 
RESEARCH SUBJECT  
INFORMED CONSENT FORM & HIPAA AUTHORIZATION 
 
Sponsor / Study Title: 
  
HL Natural, Inc. / “Evaluation of the impact of the HL Natural, 
Inc. Upset Stomach Relief product on the reduction of 
symptoms in adults who suffer from mild to moderate 
indigestion and heartburn” 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
 
Experimental Subjects Bill of Rights 
 
The rights below are the rights of every person who is asked to be in a research study. As an 
experimental subject you have the following rights:  
 
1. To be told what the study is trying to find out. 
2. To be told what will happen to me and whether any of the procedures, drugs, or devices 
is different from what would be used in standard practice. 
3. To be told about the frequent and/or important risks, side effects, or discomforts of the 
things that will happen to me for research purposes. 
4. To be told if I can expect any benefit from participating, and, if so, what the benefit 
might be. 5. To be told of the other choices I have and how they may be better or worse 
than being in the study. 
5. To be allowed to ask any questions concerning the study both before agreeing to be 
involved and during the course of the study. 
6. To be told what sort of medical treatment is available if any complications arise.  
7. To refuse to participate at all or to change my mind about participation after the study is 
started. This decision will not affect my right to receive the care I would receive if I were 
not in the study.  
8. To receive a copy of the signed and dated consent form.  
9. To be free of pressure when considering whether I wish to agree to be in the study.  
 

53 
 
If you have other questions, you should ask the investigator or any one on the research team. In 
addition, I may contact the Institutional Review Board, which is concerned with protection of 
volunteers in research projects.  
 
WELCOME 
Introduction 
 
You are invited to participate in a research study that examines an investigational product for 
occasional indigestion and heartburn relief. The test product contains all-natural substances 
which have been combined and placed into a chewable tablet to be taken at the sign of 
indigestion. All participants will receive the test product as part of their participation in the 
study. 
 
An investigational product is one that is not approved by the United States Food and Drug 
Administration (FDA). 
 
Participation in this study is voluntary. Before you decide to participate please read this form 
carefully and ask the study staff for further information or clarification as necessary. Ask as 
many questions as required to fully understand what your participation will involve. Please do 
not sign and date this form unless you are fully satisfied with the answers you have received. 
 
This form is called an informed consent form and it contains information regarding the purpose 
of the study, participation requirements, potential risks, potential benefits and how your 
protected health information (PHI) will be managed.   
 
Please take as much time as you need to review the material and make an informed decision.  
 
ABOUT THE STUDY 
 
Background 
 
Dyspepsia, also known as indigestion, is a common symptom that can have many different 
causes. It occurs in about 25 percent of the population each year, but most affected people do 
not seek medical care. Approximately 25 percent of people with indigestion have do have a 
medical cause. However, up to 75 percent of people have functional dyspepsia, which means 
that there is no underlying cause on diagnostic evaluation. People with this type of dyspepsia 
usually describe feeling bloated, feeling full early during a meal, and/or upper middle stomach 
pain/burning. Symptoms may be bad enough to limit usual activities. Some people may have 
nausea, vomiting, or heartburn; however, these symptoms are usually infrequent. The most 
common approach to treat occasional indigestion and heartburn is to use antacids to neutralize 
what is often believed to be an overproduction of stomach acid. This acid-blocking approach 
can perpetuate the problem when used over a long period of time. Acid blocking also has the 

54 
 
drawback of causing deficiencies in certain vitamins and minerals over time, such as calcium, 
because it prevents absorption. 
 
Who can participate? 
 
Participants who are at least 18 years of age and who suffer from indigestion and heartburn 
and who are otherwise in good health will be invited to be screened for the study. There will be 
about 200 participants in this study. All potential participants in the study must meet the rules 
of the study. These are called the inclusion-exclusion criteria. You will be asked to complete a 
few screening questions before you can be enrolled in the study. If you meet all the rules you 
may choose to participate in the study.  
 
What is the purpose of the study? 
 
The purpose of the study is to evaluate the impact of the test product on the symptoms of 
occasional indigestion and heartburn in adult men and women who suffer from occasional 
indigestion and heartburn. 
 
How long is the study? 
 
The duration of participation for each participant is expected to be the shorter of two 
outcomes: 1) 60 days after the study start or 2) after the participant completes the protocol 
assessments for 3 episodes of indigestion or heartburn.   
 
 
Can I withdraw from the study? 
 
Your participation in the study is voluntary. You may choose not to participate without penalty 
or loss of benefits. If you decide to participate you may change your mind at any time 
throughout the study without any penalty or loss of benefits. If you withdraw from the study, 
any data collected from you prior to your withdrawal may be used for study purposes however 
no data will be collected or used after your withdrawal. You will not be asked to return the test 
product.  
 
The study doctor or the sponsor can stop your participation at any time, without your consent, 
for any reason. 
 
What’s in the test product capsule ? 
Active Ingredients: Licorice Extract, Artichoke Leaf Extract, Chamomile, Marshmallow Root, 
Ginger 
 
Inactive Ingredients: Capsule (Hydroxypropyl Methyl Cellulose, Purified Water, Carrageenan, 
Potasium Chloride), Rice Hull Concentrate.  
The ingredients in the test product have been included because they are potentially beneficial 
in promoting digestion and feelings of digestive comfort. 

55 
 
 
When will I take the test product? 
 
You will be asked to take the test product at the onset of your indigestion or heartburn episode. 
The onset is defined as the time you take the test product.   
 
Instructions for taking the product are: take 2 capsules per episode. The test product may be 
used after each onset of episode, but not more often than three times per day. 
 
What else will I be asked to do? 
 
1. Complete the screening survey. 
2. Sign and date the eConsent. 
3. Complete a baseline survey that includes demographic information as well as 
information on what medication and supplements you currently take.  
4. Receive test product, log into study portal and complete test product receipt form. This 
will mark the start of your participation in this study. 
5. 1st indigestion or heartburn event: start your symptom diary, complete the 4-point 
Likert Scale in order to rank the severity of your symptoms.  
6. Take test product after completing the scale and first part of the symptom diary. 
7. Continue to fill out the 4-point Likert Scale for each symptom you are experiencing at 15 
minutes, 30 minutes and 60 minutes after taking test product.  
8. Write down any adverse or ill effects after taking the test product any time after taking 
the test product. 
9. Once your symptoms resolve, complete the symptom diary.  
10. Repeat steps 5-9 for event 2 and event 3 (this is encouraged but not required). 
11. Note any final adverse events (side effects) and complete the exit form. 
12. During the 1 hour after taking the test product, no medication or supplementation 
(including all CBD products) other than the test product should be taken for relief of 
indigestion and heartburn symptoms.  Once the 1-hour report has been submitted you 
may take other medications if required and record that behavior as part of your diary 
entry. 
13. Participants are asked to limit the consumption of alcohol beverages to less than or 
equal to two drinks per day, and to abstain from the use of cannabis for the duration of 
the study.  
 
You will be exited from the study if you complete the required assessments for three episodes 
or 60 days after the study start date (the day you receive the test product). When you reach 
either of these milestones you will be prompted, by email, to exit the study. 
 

56 
 
Are there any potential risks? 
 
Minimal risk is foreseen for participants through their participation in the study. All the 
ingredients composing the test product are Generally Recognized as Safe (GRAS) by the FDA for 
daily consumption at their present concentrations. 
 
The potential risks seen with high doses (significantly higher than the dosage for the study) are: 
• 
Headache 
• 
Amenorrhea (not having a period) 
• 
Upset Stomach 
• 
Diarrhea 
• 
Hives 
• 
Difficulty breathing 
• 
Facial swelling 
• 
Drowsiness (excess sleepiness) 
• 
Tiredness 
• 
Vomiting 
 
There are some potential drug interactions that have only been noted in animal trials or 
preliminary/pre-clinical trials. There may be other risks that are unknown.  
 
What are the potential benefits? 
 
You may experience relief from your indigestion and heartburn symptoms faster than 
otherwise experienced by taking the study tablet as directed. However, there is no guarantee 
that you will benefit from your participation in this study. Information learned from the study 
may help other people in the future. 
 
New findings 
 
Any new important information that is discovered during the study that may influence your 
willingness to continue participation in the study will be provided to you. 
 
Alternatives 
 
This research study is for research purposes only. The only alternative is to not participate in 
this study. 
 
Compensation 
 
If you complete the study, which includes all of the surveys and study forms, you will receive an 
Amazon gift card of $25.00 sent to your email, at the end of your participation in the study. You 
will not receive any other compensation.  
 

57 
 
There will be no charge to you for your participation in this study. The test product will be sent 
to each participant without any cost. Any leftover test product will not need to be returned.  
 
Compensation for study related illness 
 
If you experience an adverse health outcome as a result of participation in this research, you 
should seek immediate medical attention. As soon as possible after the incident contact the 
study doctor or study staff at the phone number listed on the first page of this form.  
 
If your adverse health outcome is found to result from the product provided to you as part of 
this study, the study sponsor will compensate you for related medical care. By signing and 
dating this document, you will not lose any of your legal rights or release anyone involved in the 
research from responsibility for mistakes. 
 
To pay medical expenses, the sponsor will need to know some information about you like your 
name, date of birth, and Medicare Beneficiary Identifier (MBI).  This is because the sponsor has 
to check to see if you receive Medicare and if you do, report the payment it makes to Medicare. 
 
How will my information be protected? 
 
The Health Insurance Portability and Accountability Act (HIPAA) describes how 
your Protected Health Information (PHI) may be used, disclosed and made 
accessible to you. You will be asked to logon to a secured internet site using a 
login code and a password. The platform (internet site) used for the data 
collection is HIPAA compliant, meaning your private information is protected by 
law.   
 
In order to validate your identity, communicate with you, determine your 
eligibility and send you the test product, we will collect your name, address, 
phone number, email address, date of birth and some medical records. Through 
the surveys we will be collecting personal health information related to the study. 
 
The information we collect will be kept confidential and will be used only for the 
purpose of this study. Only study staff who are involved in this study will have 
access to your PHI. All reports and communications released from this study will 
identify participants by an identification number only and will not contain 
identifying information. The overall results of the study may be published 
however the identity of participants will not be included. 
 

58 
 
Your right to access your PHI in the study records will be suspended during the 
study to keep from changing the study results. When the study is over, you can 
access your study health data. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you. At most, the Web site will include a summary of the results. You can 
search this Web site at any time. 
You will be emailed a PDF copy of this signed and dated consent form. There may 
be risks of loss of privacy and confidentiality if the PDF copy of this consent form 
is viewed and/or stored on a personal electronic device (PED), especially if that 
PED is shared with other users or is lost, hacked, or subject to a search warrant or 
subpoena. Also, the PDF copy of the consent may not be able to be permanently 
removed from a PED. 
 
Medical Release 
 
By signing and dating this document, you authorize the study doctor, the research 
team, the FDA, Advarra Institutional Review Board, and/or other authorized 
members of the HL Natural, Inc. and Hawthorne Effect workforce to request, 
receive, use, and share all health information pertaining to your medical history, 
mental or physical condition and treatment received for the duration of your 
participation in this research study.  
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways 
other than those listed here. 
 
If you decide not to sign and date this form, you will not be able to take part in 
the study. 
 
You understand that the research team and other authorized member of the 
Hawthorne Effect workforce may use and share your information to ensure that 
the research meets legal, institutional or accreditation requirements.  
 
You understand that in all disclosures outside of Hawthorne Effect, you will not be 
identified by name, social security number, address, telephone number or any 

59 
 
other direct personal identifier unless disclosure of the direct identifier is required 
by law.  
 
Your authorization to use and share your study records does not expire; however, 
in California and any other state that does require an expiration date, the 
authorization will expire 50 years after you sign and date this authorization 
document. 
 
You understand that you may withdraw your permission for the use and 
disclosure of any of your protected information for research, but you must do so 
in writing to the study doctor at the address on the first page.  
 
You understand that even if you withdraw your permission, the study doctor for 
the research study may still use your protected information that was already 
collected if that information is necessary to complete the study.  
 
Your health information may still be used or shared after you withdraw your 
authorization if you should have an adverse event (a bad effect) from being in the 
study.  
 
If you withdraw your permission to use your protected health information for 
research that means you will also be withdrawn from the research study, but 
standard medical care and any other benefits to which you are entitled will not be 
affected. You can also tell us you want to withdraw from the research study at 
any time without cancelling the authorization to use your data.  
 
You will receive a signed and dated copy of this form for your records. 
 
__________________________________ 
Printed Name of Participant 
 
__________________________________ 
 
 
__________ 
Signature of Participant  
 
 
 
 
Date 
 
 

60 
 
 
Whom to contact about this study 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the Investigator at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study. 
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00037630.  
 
 

61 
 
 
Closing Statement 
 
I have read and understand the information in this informed consent form. My questions (if 
any) have been answered to my satisfaction and I do not have any further questions or doubts 
about partaking in this study. All written and oral communication regarding this study were in a 
language I fully comprehend. My decision to participate in this study is voluntary. I hereby 
consent to participate in this study under the conditions described above. 
 
An electronic copy of the signed and dated consent form will be sent to you as an email 
attachment. Be aware that electronic copies may not be readily removed from personal 
electronic devices. If the personal electronic device is shared with other users, lost or hacked 
the consent form may be revealed. 
 
If you would like to request a paper copy of your consent as an alternative to the electronic 
copy, please inform study staff before signing and dating the consent.  
 
 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DSMB 
Data and Safety Monitoring Board 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SMC 
Safety Monitoring Committee 

62 
 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization