Study of Angelica Gigas Dietary Supplements (Cogni.Q) and Potential Effects on Human Immune Cells
Phase: NA
Conditions: Innate Immune Cells
Sponsor: Milton S. Hershey Medical Center

Page 1 of 26 (V.7/18/2018) 
 
 
 
HRP-592 - Protocol for Human Subject  
Research with Use of Test Article(s) 
 
Protocol Title: 
Study of Angelica gigas dietary supplement (Cogni.Q) potential effects on human immune cells 
 
Principal Investigator: 
Name: Junxuan Lu, Ph.D. 
Department:  Pharmacology 
Telephone: 717-531-8964 
E-mail Address: junxuanlu@pennstatehealth.psu.edu 
 
Version Date: 7/18/2018 (version 4) 
 
Clinicaltrials.gov Registration #: Pending 
 
Important Instructions for Using This Protocol Template: 
1. 
Add this completed protocol template to your study in CATS IRB (http://irb.psu.edu) on the “Basic Information” 
page, item 7.  
2. 
This template is provided to help investigators prepare a protocol that includes the necessary information needed 
by the IRB to determine whether a study meets all applicable criteria for approval.  
3. 
Type your protocol responses below the gray instructional boxes of guidance language.  If the section or item is 
not applicable, indicate not applicable. 
4. 
For research being conducted at Penn State Hershey or by Penn State Hershey researchers only, delete the 
instructional boxes from the final version of the protocol prior to upload to CATS IRB (http://irb.psu.edu).  For all 
other research, do not delete the instructional boxes from the final version of the protocol. 
5. 
When making revisions to this protocol as requested by the IRB, please follow the instructions outlined in the Study 
Submission Guide available in the Help Center in CATS IRB (http://irb.psu.edu) for using track changes.  
 
If you need help… 
University Park and other campuses: 
Office for Research Protections Human Research Protection Program 
The 330 Building, Suite 205 
University Park, PA 16802-7014 
Phone: 814-865-1775 
Fax: 814-863-8699 
Email: irb-orp@psu.edu 
College of Medicine and Hershey Medical Center: 
Human Subjects Protection Office 
90 Hope Drive, Mail Code A115, P.O. Box 855 
Hershey, PA 17033 
(Physical Office Location: Academic Support Building Room 1140) 
Phone: 717-531-5687 
Fax number: 717-531-3937 
Email: irb-hspo@psu.edu 
 
 
 
 
 

Page 2 of 26 (V.7/18/2018) 
Table of Contents 
1.0 
Objectives 
2.0 
Background 
3.0 
Inclusion and Exclusion Criteria 
4.0 
Recruitment Methods 
5.0 
Consent Process and Documentation 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
7.0 
Study Design and Procedures 
8.0 
Subject Numbers and Statistical Plan 
9.0 
Confidentiality, Privacy and Data Management 
10.0 
Data and Safety Monitoring Plan 
11.0 
Risks 
12.0 
Potential Benefits to Subjects and Others 
13.0 
Sharing Results with Subjects 
14.0 
Subject Stipend (Compensation) and/or Travel Reimbursements 
15.0 
Economic Burden to Subjects 
16.0 
Resources Available 
17.0 
Other Approvals 
18.0 
Multi-Site Research 
19.0 
Adverse Event Reporting 
20.0 
Study Monitoring, Auditing and Inspecting 
21.0 
Future Undetermined Research: Data and Specimen Banking 
22.0 
References 
 
 

Page 3 of 26 (V.7/18/2018) 
1.0 
Objectives 
 
1.1 
Study Objectives 
The purpose of this pilot clinical trial is to test that daily intake of Korean Angelica gigas Nakai (AGN) dietary 
supplement (Cogni.Q, Quality of Life Laboratories, Purchase, NY) may boost human innate immune functions.  
Cogni. Q is a dietary supplement which is commercially available for anyone to purchase without a prescription 
for memory improvement.  
The hypothesis to be tested is that daily consumption of Cogni. Q supplement leads to increased 
number and/or activation of neutrophils and Natural Killer (NK) cells in healthy men. 
To test the hypothesis, we propose a double-blinded, placebo-controlled trial design (See scheme). 
 
 
 
1.2 
Primary Study Endpoints 
The primary endpoints/Aims are: 
Primary Aim 1 (Tube 1). whole blood for CBC diff.  
Primary Aim 2 (Tube 1). Flow analyses for NK cell counts.   
 
1.3 
 Secondary Study Endpoints 
Secondary objectives are: 
Aim 3 (Tube 1): Flow analyses for T cell counts. 
Aim 4 (Tube 1): To determine plasma concentration of pyranocoumarins (as compliance to 
Cogni.Q/placebo exposure); plasma protein profiling for androgens, and inflammatory/anti-
inflammatory cytokines.  
Aim 5 (tube 2): To profile the NK mRNA signature by RNA-seq transcriptomics using RNA 
prepared from Pax Gene tube-preserved whole blood collected on each visit.  
  
 
 
Tube 1. 10 ml blood EDTA vacutainer (purple): Primary Aim 1. whole blood for CBC 
diff,  Primary Aim 2. Flow analyses for NK cells
Secondary aim 3. Flow analyses for T cells 
Secondary aim 4. bank plasma for  measurements of pyranocoumarins, androgens 
and inflammatory and anti-inflammatory cytokines.
Tube 2. 2.5 ml blood in PAXgene® Blood RNA Tube (BD Biosciences). Secondary 
aim 5.  for PBMC RNA NK signatures 
CognI.Q
N= 20 men
Twice daily 
(800 mg per 
day)
Informed Consent
Screening check up and 
fasting blood workups
5 ml blood SST vacutainer 
(yellow): serum CMP eGFR
If the subject fits the 
inclusion and exclusion 
criteria listed in section 3.1 
and 3.2 they will be 
enrolled and randomized
Day  0      1                21 
Placebo
N= 20 men
Twice daily
35   36                56                                                
70
CognI.Q vs. 
Placebo for 
21 days   
Cross 
over for 
21 days   
Washout  for 
14 days 
Washout  for 
14 days 

Page 4 of 26 (V.7/18/2018) 
Fig. 1 Chemical structures of 
pyranocoumarins from AGN   
Fig. 2  Human plasma (a) D,DA& (b) DOH concentration (nM) 
vs. time. Insets are data presented on log scale. Mean + sem 
2.0 
Background 
 
2.1 
Scientific Background and Gaps 
 
Korean Angelica gigas Nakai (AGN)-containing products (e.g., Cogni.Q to be 
studied in the current protocol, AcheAction, Decursinol-50, Fast-Acting Joint 
Formula, EstroG-100/Profemin) are marketed as dietary supplements for memory 
improvement, pain relief and women’s health especially for menopausal symptom 
management. Except for the 3-herbal EstroG-100/Profemin (AGN, Cynanchum 
wilfordii, Phlomis umbrosa) [1], these dietary supplements have not been tested 
in Americans in rigorously controlled human trials. Their benefit to US consumers 
is an open question.  Because of the differences between Koreans and US 
residents in genetic background, life styles, food patterns and preferences, etc., 
human studies in the US are needed to ensure health benefits are translatable to 
American consumers. 
 
Decursin (D) and its isomer decursinol angelate (DA) (Fig. 1) are the major 
marker compounds in the ethanol extract of AGN root [2]. In rodent models, we 
and others have shown that D/DA are rapidly converted to decursinol (DOH) after 
gavage or i.p. injection [2-4].  Our “omic” analyses of the TRAMP (the transgenic 
adenocarcinoma of the mouse prostate model) neuroendocrine carcinomas 
suggest immune enhancement by AGN [5]. 
However, a crucial gap in translating our rodent 
mechanistic studies to human benefits is whether 
humans metabolize AGN and D/DA to DOH as in 
these rodent models.    
To fill in that gap, we completed a 20-
subject single dose-PK study in Adult Men and 
Women with normal liver and kidney function (per 
CMP eGFR) in  Amarillo, TX residents (age 21-58 
years, 65% Caucasian, 20% Hispanic, 15% Asian 
Indian) with AGN dietary supplement Cogni.Q 
(purchased from Quality of Life Laboratories, 
Purchase, NY) [6]. For dosage, each person 
swallowed 4 vegicaps (800 mg AGN) at time 0, the 
recommended daily dose by manufacturer.  Cogni.Q 
is marketed for promoting cognitive agility and 
healthy brain function.   Fig. 2 shows plasma D/DA 
and DOH vs. time curves. The human AUC0-48h for 
DOH (27579 h.nmol/L) is much higher than for DA 
(335 h.nmol/L) and D (37 h.nmol/L), supporting 
extensive conversion from D/DADOH.  The human 
PK parameters recapitulate patterns in rodent 
models ([2, 3], substantiating their biological 
relevance for mechanistic insights.   
Significantly, as secondary endpoint 
parameters, the neutrophil counts in these human 
subjects were increased by 71% at 24h post-dose vs. pre-dose and the natural killer cell (NK) mRNA signature (+60~90%) 
in their peripheral blood mononuclear cells (PBMC) (See 2.2 previous data). Neutrophils and NK cells belong to two 
lineages of immune cells that make up our innate immune defense. Neutrophils (myeloid lineage) fight against bacterial 
infection  whereas NK cells (lymphoid lineage) not only kill virus-infected cells but also recognize and kill cancer cells, 
serving as a crucial immune surveillance against malignancy in our body.   

Page 5 of 26 (V.7/18/2018) 
We hypothesize that daily intake of AGN dietary supplement (Cogni.Q) increases the number and/or activities of 
neutrophils and NK cells, and in turn may boost human innate immune function against bacterial and viral infections as 
well as cancer risk.  As an initial effort to test our hypothesis, the goal of this pilot clinical trial is to delineate the Cogni.Q 
supplement specific innate immune enhancement activity in healthy men in the Hershey-Harrisburg area using a 
double-blinded, placebo-controlled trial design conducted through Penn State Clinical Translational Science Institute’s 
Clinical Research Center (CTSI CRC) and College of Medicine laboratory facilities (See scheme Fig. 1).   
                            
2.2 
Previous Data 
 
Neutrophils and Natural killer (NK) cells are first line immune cells that defend against viral and bacterial infections as 
well as cancer.   
These two cell lineages of the innate immune system mount acute defense against invading microorganisms and 
regulate inflammation.  Neutrophils phagocytose and kill engulfed bacteria by enzymatic (e.g., lysozymes to degrade 
bacterial wall, proteases to degrade cellular proteins) and chemical means (hypochlorite, ROS) [7, 8].  Neutrophils are 
abundant at sites of infection and inflammation and are critical for resolving inflammation [8].  NK cells search out and 
kill virus-infected cells and cancer cells that have stress-induced dysregulation of cell surface markers [9]. Cell killing by 
NK cells is mediated by granzyme serine-proteases released from cytoplasmic granules that enter target cells [10] 
through a multimeric complex made up of Granzyme B, Perforin, and Granulysin to trigger apoptosis through caspases. 
Therefore, enhancing the number and/or activities of these two innate immune cells through herbal supplements would 
be non-invasive and practical for fending off bacterial and viral infections and may shorten the time to resolve infection-
driven illnesses.  As chronic inflammation is causally linked to cancer the above benefits as well as NK cancer killing 
action could translate into cancer risk reduction and control.  
 
 
 
 
 
 
Measurable changes of human neutrophil counts after a single Cogni.Q supplement   As part of our published PK study 
[6], we collected complete blood cell (CBC diff, Quest Diagnostics) panel data on fasting blood at baseline and 24 h. To 
our surprise, total white blood cell (WBC) counts were 21% higher at 24 h (Table 1) and neutrophils were much higher 
(Table 1, individual ratio +71%; Table 2, group mean counts +42%).  
 
Importantly, 7/20 subjects had absolute neutrophil counts below 1500 (low normal reference value) at baseline (S1, 
232; S4, 598; S5, 673; S13, 821; S15, 1280; S18, 833; S20, 1485). At 24 h post-dose, 2 subjects remained below this cut 
off value (S1, 232  800; S13, 821 1468), the other 5 subjects all improved above 1500 (S4, 1847; S5, 1665; S15, 1783; 
S18, 1721; S20, 1998).  These data suggest that a substantial proportion (~35%) of “healthy” subjects may have had 
neutropenia of varying degree, including severe neutropenia (<500). Thus, the potential use of Cogni.Q dietary 
Men 
(n=10)
Women 
(n=9)
Mean
SD
Mean
Mean
t-test, p
R2**
R2**
Baseline
2065
1183
2027
2167
0.738
0.0438
<0.0001
24 h post 
Cogni.Q
2930
1396
3012
2952
0.952
0.0226
0.0151
Table 2 Neutrophil count (per microliter) in men vs. women
*Missing value from 1 female.  **R2-coefficient of determination for linear regression 
paired t-
test, p
0.0004
0.0108
0.0262
All Subjects 
(n=19)*
Neutrophil count per/µL
Men vs. 
Women
Correlation 
with age
Correlation 
with 
weight
CBC parameter
Ratio 24h/0h
ALBUMIN 
NO CHANGE
GLOBULIN 
NO CHANGE
white blood cells 
1.21 X
red blood cells
NO CHANGE
hemoglobin
NO CHANGE
hematocrit 
NO CHANGE
MCV 
NO CHANGE
MCH 
NO CHANGE
MCHC 
NO CHANGE
RDW 
NO CHANGE
Platelet 
1.13 X
Absolute neutrophils 
1.71 X
Absolute lymphocytes 
NO CHANGE
Absolute monocytes 
NO PATTERN
Absolute eosinophils 
NO PATTERN
Absolute basophils 
NO PATTERN
Table 1. CBC panel (24h/0h ratio) 
All fold changes p<0.05 

Page 6 of 26 (V.7/18/2018) 
supplementation to correct neutropenia affordably and non-invasively is implicated vs. the case of injection of 
granulocyte colony-stimulating factors (G-CSFs). 
 
Neither baseline nor 24 h counts correlated with age (range 21-58 yr) and body weight (range 115-200 lb) of the subjects 
(Table 2, R2-coefficient of determination indicates no contribution to neutrophil variance). Furthermore, gender did not 
affect the baseline or 24 h count (Table 2).  
 
NK-transcriptome changes in human peripheral blood mononuclear cells (PBMC) after Cogni.Q  We isolated RNA from 
PBMC using QIAamp® RNA Blood Mini kit (QIAGEN) and profiled mRNA expression from 6 subjects using Illumina Human 
HT-12 BeadChip array. All RNA labeling and hybridization were performed as before [5]. Table 3 highlights that NK-
related and immune signature genes were prominently affected.  We used real-time RT-PCR as before [5] to verify 
select genes, normalized to housekeeping gene ß-actin (Fig. 2). NK mRNA expression markers were +60~90% higher for 
24h post-dose vs. baseline (n = 6, p<0.01) (Fig. 2A). However, not all genes changed in the same direction (i.e., unlikely 
systematically biased). The inflammatory cytokine gene IL-8 in PBMC was reduced  (Fig. 2A). By 48 h, granulysin (GNLY) 
returned to baseline whereas KLRF1 was still elevated (Fig. 2B), suggesting temporal response differences among NK 
molecules.  We will use placebo and a week of daily supplement to rigorously test and validate the Cogni.Q-specific 
enhancement of the NK-signature at both cellular and molecular levels. 
 
 
           
 
 
 
 
 
 
 
                  
  
  
 
 
 
 
 
Pathway # 
source
genes
Natural killer cell mediated cytotoxicity KEGG
5 KLRD1;GZMB;KIR2DL3;KIR2DL4;PRF1
1.06E-05
Graft-versus-host disease
KEGG
4 KLRD1;GZMB;KIR2DL3;PRF1
1.95E-06
IL12-mediated signaling events (NK)
PID
4 EOMES;CCL4L2;GZMB;GZMA
1.18E-05
P values
Table 3.  Enriched pathways 24h post-Cogni.Q vs. baseline in PBMC mRNA by microarray profiling 
Pathway name
Overlapping genes
Fig. 2. (A) PBMC mRNA changes 24h post-dose/baseline (n=6). (B) Time course of selected genes 

Page 7 of 26 (V.7/18/2018) 
 
2.3 
Study Rationale 
Based on the literature with AGN animal studies and our single dose PK study which showed, as secondary readouts, an 
enhancement of immune cells (neutrophil cells) and NK mRNA signatures, the current study was designed to rigorously 
establish the impact of Cogni.Q on 2 types of human innate immune cells by placebo-controlled and crossover design.  
The research is novel because the immune promotion activity has not been reported in any human population before.  
Positive data from our proposed trial will be the first of its kind to support acute enhancement in healthy US residents of 
these innate immune cells by an AGN dietary supplement.  Both public health and clinical therapeutic applications could 
be developed.  Clinical applications for treating human neutropenia of various causes including many cancer 
therapeutics should be of great further research interest.  
 
3.0 
Inclusion and Exclusion Criteria 
 
Note: Our pilot clinical trial will be only focused on men due to three main reasons: i) our ongoing focus on male-only 
prostate cancer prevention and therapy by AGN, ii) the preliminary data with a single dose of AGN supplement had 
suggested that both men and women responded to the same extent for boosting up neutrophils (Table 2); and iii) 
menstrual cycle variations and potential pregnancy in women over a two-month study may complicate acquisition of 
data to address our hypothesis in our pilot trial of a small study population. The information gained from this pilot study 
will be used for the future trials with more study subjects and will include both genders.  
 
 
3.1 
Inclusion Criteria 
 
o Male subjects 21 to 65 years of age  
o Subjects weighing between 100 to 240 pounds; their body mass index (BMI) should be in the range 
of 19 to 30 
o Subjects having normal hepatic, renal function as assessed by history, physical and clinical chemistry 
analysis (CMP eGFR, see supporting document for normal reference ranges). 
o Subjects with normal blood pressure (systolic below 120 mm Hg and diastolic below 80 mm Hg) 
  
3.2 
Exclusion Criteria 
 
o Subjects positive for HIV, HBV and HCV (self-reported)  
o Subjects taking any kind of prescription medications regularly or within 10 days of the study will be 
excluded. Therefore, subjects with diabetes, major cardiovascular diseases, cancer, severe 
hypertension, severe hepatic cirrhosis or cirrhosis of the liver, and kidney disease (self-reported) will 
be excluded. 
o Subjects using tobacco products, nicotine patches and excessive alcohol 
o Subjects taking dietary or herbal supplements that contain AGN (e.g. Cogni.Q, Decursinol-50, Ache 
Action, Fast-Acting Joint Formula, EstroG-100/Profemin) within 10 days of the study. 
o Non-English-speaking subjects 
  
3.3 
Early Withdrawal of Subjects 
 
3.3.1 
Criteria for removal from study 
Although we expect Cogni.Q supplement-caused adverse event (AE) or serious adverse event 
(SAE) to be extremely unlikely, nevertheless, the clinical research staff and study physician will 
be responsible for detecting and documenting events that meet protocol defined criteria as an 
adverse event (AE) or a serious adverse event (SAE) and assist the PI in reporting.  
An AE is defined as an untoward medical occurrence in a subject temporally associated 
with the use of a medicinal study product whether or not it is considered related to the 
medicinal product 

Page 8 of 26 (V.7/18/2018) 
An AE can be any unfavorable and unintended symptom or sign (abnormal laboratory 
finding) or disease temporally related to the use of a medicinal product.  This can include the 
following: 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or grade of the condition 
 
New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study 
 
Signs, symptoms or the clinical sequelae of a suspected interaction  
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication.  
 
An SAE is defined as the following: 
 
Results in death 
 
Is life-threatening  
 
Requires hospitalization 
 
Results in disability/incapacity 
 
Any subject who experiences an adverse event may be withdrawn from the supplement 
(either arm) and/or the study at any time and for any reason.   
 
 
3.3.2 
Follow-up for withdrawn subjects 
 
A subject can withdraw from trial at any time of the study. Withdrawn subjects will be followed 
up by study staff with phone calls or electronic media within 2 weeks.   
 
4.0 
Recruitment Methods 
 
4.1 
Identification of subjects 
 
CTSI CRC healthy volunteer database will be used to solicit study subjects plus multiple advertising 
venues of trial participation opportunity will be made in the Hershey and Harrisburg metro area, 
including CTSI website and CTSI community engagement outreach networks, Penn State STUDYfinder, 
local civic institutions and grocery supermarkets. 
 
4.2 
Recruitment process 
 
After a “scripted” phone screening containing the verbal consent (see supporting documents for phone 
script), eligible male subjects will be invited to an initial visit to CRC for informed consent.  Once the 
written informed consent has been obtained, the subject’s eligibility will be verified as per the 
procedure described in section 7.2. If the subject fits all the inclusion and exclusion requirements listed 
in section 3.1 and 3.2, he will be contacted by the research staff to see whether he wants to participate 
in the trial.  
 
4.3 
Recruitment materials 
For recruitment material the Office of Marketing and Communications has prepared a draft flyer for the 
committee review (see supporting documents). Moreover, flyer will be also displayed on the television 
throughout the campus and social media advertisement. Furthermore, STUDYfinder will be used for 
recruitment purposes.  
 

Page 9 of 26 (V.7/18/2018) 
4.4 
Eligibility/screening of subjects 
Verbal informed consent will be obtained before asking potential subjects with eligibility questions on 
phone.  
 
5.0 
Consent Process and Documentation 
 
5.1 
Consent Process  
  
5.1.1 
Obtaining Informed Consent 
 
5.1.1.1 
Timing and Location of Consent 
After verbal consent during phone screening, a written Informed consent will be 
obtained when the subjects come for their initial (screening) visit at CRC.  
 
5.1.1.2 
Coercion or Undue Influence during Consent 
In order to minimize the possibility of coercion or undue influence in the 
consent process, a member of the study team will explain the details about the 
trial during their initial screening visit. Potential subjects will then be given time 
to read and sign the consent in a private setting at CRC.   
 
5.1.2 
Waiver or alteration of the informed consent requirement 
 
Not applicable 
 
5.2 
Consent Documentation 
 
5.2.1 
Written Documentation of Consent 
See attached supporting documents 
 
5.2.2 
Waiver of Documentation of Consent (Implied consent, Verbal consent, etc.) 
 We request a waiver of documentation of consent for phone screen procedure. 
 
 
5.3 
Consent – Other Considerations  
5.3.1 
Non-English Speaking Subjects 
NOT APPLICABLE 
5.3.2 
Cognitively Impaired Adults 
NOT APPLICABLE 
5.3.2.1 Capability of Providing Consent 
NOT APPLICABLE 
5.3.2.2 
Adults Unable To Consent 
 
 
 
 
         NOT APPLICABLE 
5.3.2.3 Assent of Adults Unable to Consent 
NOT APPLICABLE 
5.3.3 
Subjects who are not yet adults (infants, children, teenagers)  
5.3.3.1 Parental Permission 
NOT APPLICABLE 
5.3.3.2 Assent of subjects who are not yet adults 
NOT APPLICABLE 
 
 

Page 10 of 26 (V.7/18/2018) 
 
6.0 
HIPAA Research Authorization and/or Waiver or Alteration of Authorization 
 
6.1 
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
 
Check all that apply: 
  
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable] 
 
X 
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable] 
 
 
Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3] 
 
 
Full waiver is requested for entire research study (e.g., medical record review studies). 
[Complete all parts of sections 6.2 and 6.3] 
 
 
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3] 
 
6.2 
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI 
NOT APPLICABLE 
6.2.1 
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual 
 
6.2.1.1 Plan to protect PHI from improper use or disclosure 
Not applicable 
6.2.1.2 Plan to destroy identifiers or a justification for retaining identifiers  
Not applicable 
6.2.2 
Explanation for why the research could not practicably be conducted without access to and 
use of PHI 
Not applicable 
 
6.2.3 
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization 
 Not applicable 
 
6.3 
Waiver or alteration of authorization statements of agreement 
Not applicable  
 

Page 11 of 26 (V.7/18/2018) 
 
7.0 
Study Design and Procedures 
 
7.1 
Study Design 
We plan on conducting a double-blinded, placebo-controlled, crossover trial design for testing our 
hypothesis.   
                  
 
  
7.2 
Study Procedures 
After phone screening and if they meet the criteria of the study inclusion and exclusion, they will be asked to come 
to CRC facility for a screening visit. Screening visit procedure is described below:    
 
Screening Visit:  
 
Subjects will be asked to read and sign a consent document before any study-specific tests or procedures are 
performed. Subjects will be given a signed and dated copy of the consent form for their records.   
 
They will complete a health history questionnaire (See Supporting Material) regarding their medical history past 
and present, any prescription and/or non-prescription medications they are taking including herbal 
preparations, multivitamins, supplements. They will also be asked about any underlying medical issues, prior 
surgeries which might affect the absorption of Cogni.Q such as gastric bypass/sleeve/banding surgery, alcohol 
and smoking histories.  
 
They will be required to undergo a physical examination which will include recording their height, weight, blood 
pressure, heart rate, as well as an examination of their head/neck area, lungs, heart, abdomen, extremities, 
neurological status.   
 
Blood will be collected from a vein in their arm (approximately 1 teaspoon or 5 mL) for common blood tests to 
test their health status. 
 
This screening visit will take approximately 1 hour.   
 
Based on data collected during the screening visit and lab report, study physicians will certify participation eligibility 
as per the inclusion and exclusion criteria described in section 3.1 and 3.2. A study coordinator will contact the 
eligible subjects to schedule their study visits. A subject number will be assigned to each subject after they have 
scheduled their study visits.  
 
The study team will fax a prescription [that has been signed by a study physician on the protocol] to the 
Investigational Drug Service Pharmacy (IDS).  The IDS Pharmacy will refer to the randomization table (provided in 
advance by the study biostatistician) and dispense the investigational product (IP)(Cogni.Q 200mg/ Placebo 
Capsules) that corresponds with the subject’s assigned subject number.  The IDS Pharmacy will call the CRC to relay 
the message that the IP is available for pick up.  A member of the study team will deliver the hardcopy of the 
prescription to the IDS Pharmacy when the IP is picked up. 
  
 
 
Tube 1. 10 ml blood EDTA vacutainer (purple): Primary Aim 1. whole blood for CBC 
diff,  Primary Aim 2. Flow analyses for NK cells
Secondary aim 3. Flow analyses for T cells 
Secondary aim 4. bank plasma for  measurements of pyranocoumarins, androgens 
and inflammatory and anti-inflammatory cytokines.
Tube 2. 2.5 ml blood in PAXgene® Blood RNA Tube (BD Biosciences). Secondary 
aim 5.  for PBMC RNA NK signatures 
CognI.Q
N= 20 men
Twice daily 
(800 mg per 
day)
Informed Consent
Screening check up and 
fasting blood workups
5 ml blood SST vacutainer 
(yellow): serum CMP eGFR
If the subject fits the 
inclusion and exclusion 
criteria listed in section 3.1 
and 3.2 they will be 
enrolled and randomized
Day  0      1                21 
Placebo
N= 20 men
Twice daily
35   36                56                                                  
70
CognI.Q vs. 
Placebo for 
21 days   
Cross 
over for 
21 days   
Washout  for 
14 days 
Washout  for 
14 days 

Page 12 of 26 (V.7/18/2018) 
 
Example of prescription temple wording that will be used for this study is: 
Cogni.Q 200mg or Placebo Capsules 
Take 2 capsules by mouth in the morning (before breakfast) and 2 capsules by mouth in the evening (before 
dinner) as directed by the study team. 
Dispense Quantity: 84 capsules 
Refills: 1 
 
Eligible subjects will be asked to fast for at least 8 hours before all of the study visits. 
 
The following describes the study procedures:  
Study visit #1: (Day 0) Subjects will come to Hershey Medical Center Clinical Research Center (CRC) prior to 
breakfast (fasting for 8 hours before blood draw).  
 
Their vitals will be taken. 
 
Approximately 12.5 ml (2.5 teaspoons) of blood will be collected.   
 
We will give subjects assigned IP for Day 0 until Day 20.  
o IDS will be responsible for dispensing IP based on a randomization table provided by study 
biostatistician. Therefore, subjects will be randomized (assigned by chance, like the flip of a coin) to 
group 1 or group 2 as defined below. They will have an equal chance to be assigned to either group. 
Neither the subjects nor the study staff will know which group they are in but this information is 
available in case of an emergency.  
 
Group 1: Subjects will receive Cogni.Q for the first 21 days (day 0 to day 20). From day 21 to 34 
they will take no IP (washout period). At day 35 they will start taking the placebo through day 
55. From day 56 until the end of the study (day 70) they will not take any IP. 
 
Group 2:  Subjects will receive placebo for the first 21 days (day 0 to day 20). For days 21 to 34 
they will take no IP (washout period). At day 35 they will start taking the placebo through day 
55. From day 56 until the end of the study (day 70) they will not take any more IP.   
 
Subjects will take 2 IP capsules with water before going home at CRC and 2 more in the evening time (before 
dinner) for Day 0.  
o Subjects will be asked to keep a medication diary (See Supporting Materials) in which they will write the 
time of IP capsules taken throughout the study, and anything they experience different than normal day. 
 
Study visit #2: (Day 1) Subjects will need to come back to CRC the next morning for fasting blood draw (12.5 ml, 
2.5 teaspoons). Their vital signs (blood pressure and heart rate) will be evaluated, and subjects will report any 
side effects/issues experienced with IP. They will swallow that day’s assigned IP capsules in CRC for the morning 
and be discharged. They will continue with the rest of the dosing regimen, that is, subjects will be taking 2 IP 
capsules in the evening for that day before dinner.  
 
After Study visit #2 (Day 1), subjects will continue taking the IP capsules, that is 2 IP capsules before breakfast 
and 2 IP capsules before dinner, until the morning of day 21 which is study visit #3.  
 
Study visit #3:  On Day 21, subjects will return to CRC, fasted, without taking any IP capsules.  Subjects will 
return any unused IP capsules at this visit. Their vitals will be assessed and recorded, and will be asked questions 
regarding any missed doses, reason for missed dose(s), and any side effects experienced.  2.5 teaspoons of 
blood will be drawn (12.5 ml). 
o From Day 21 through Day 34, they will not take any IP capsules.  This is the “washout” period.  
 
Study visit #4: On Day 35, subjects will return to CRC, fasted (before breakfast). Their vitals will be assessed and 
recorded, and will be asked questions regarding any side effects experienced during the washout period. 2.5 
teaspoons of blood will be drawn (12.5 ml). Subjects will be given a refill of IP capsules. i.e. if in Group 1, a refill 
for placebo and if in Group 2, a refill for Cogni.Q. They will then take 2 of the assigned IP capsules and depart the 
clinic. They will take the other two IP capsules in the evening before dinner. 
 
Study visit #5: Day 36, subjects will return to CRC, fasted, without taking any medication.  Their vitals will be 
assessed and recorded, and will be asked questions regarding the IP capsules, and any side effects experienced.  
2.5 teaspoons of blood will be drawn (12.5 ml). They will continue to take assigned IP capsules twice (morning 
and evening daily) until the morning of Day 56 which is study visit #6. 

Page 13 of 26 (V.7/18/2018) 
 
Study visit #6: Day 56, subjects will return to CRC, fasted.  They will return any unused IP capsules at this visit. 
Their vitals will be assessed and recorded, and will be asked questions regarding any side effects experienced 
during the washout period. 2.5 teaspoons of blood will be drawn (12.5 ml).  They will then enter the second 
washout phase.  
 
Study visit #7: Day 70, subjects will return to CRC, fasted, will have vitals/blood drawn (2.5 teaspoons, 12.5 ml); 
they will be asked about any side effects experienced during the washout period.  
 
A study team member will text or call weekly as a reminder to take the IP capsules. 
 
If subjects cannot come for a study visit on a particular day, subject needs to contact the study team so that the 
study team can make arrangements for the following visit. 2 days plus or minus is within acceptable study visit 
window, EXCEPT the 24 h visits (i.e., Day 1 and Day 36). 
 
Withdrawn subjects will be followed up by study staff with phone calls or electronic media within 2 weeks.   
 
The Table in section 7.2.1 shows the required visits, and blood draws and the lab tests. 
 
Fasting blood samples will be used as follows: 
o Tube 1:  
 
to analyze complete blood counts with differential (CBC w diff) to quantify neutrophils (primary 
Aim 1) 
 
to quantify NK cells using immune staining and flow cytometry (primary Aim 2) 
 
to quantify T cells using immune staining and flow cytometry (Secondary aim 3) 
 
Rest of the blood sample will be used to prepare plasma, which will be banked at -80oC to 
measure trough pyranocoumarins as compliance to AGN exposure and inflammatory and 
immune cytokine profile (secondary Aim 4).  
o Tube 2: 
 
We will assess NK mRNA signature by RNA-seq transcriptomics using RNA prepared from Pax 
Gene tube-preserved whole blood (secondary Aim 5). The tube will be stored at -80oC until 
analysis time.  
 
The durability of the Cogni.Q supplement-induced innate immune enhancement will be assessed in the 
following 14 days washout period.  
 
Blood handling 
o Right after the blood collection, blood will be taken to the lab by a study team member on ice and 
processed on the same day (i.e. the primary aim studies will be performed on the day of blood 
collection; while plasma and Pax gene (tube 2) tubes will be banked at -80oC for later use) 
 
7.2.1 
Study Schedule 
Required Visit to CRC and 
blood draw 
Time frame 
CBC 
diff 
Plasma 
DOH 
NK and T 
cell flow 
cytometry 
Pax 
geneRNA 
tube 
#1, study visit, blood draw 
Day 0 
X 
X 
X 
X 
#2, study visit, blood draw 
Day 1 
X 
X 
X 
X 
#3, study visit, blood draw 
Day 21 
X 
X 
X 
X 
#4, study visit, blood draw 
Day 35 
X 
X 
X 
X 
#5, study visit, blood draw 
Day 36 
X 
X 
X 
X 
#6, study visit, blood draw 
Day 56 
X 
X 
X 
X 
#7, study visit, blood draw 
Day 70 
X 
X 
X 
X 
 
7.3 
Duration of Participation 
Each subject will remain in study for the duration of 70 days / 10 weeks 
 
7.4 
Test Article(s) (Study Drug(s) and/or Study Device(s)) 
7.4.1 Description 
The commercially available dietary supplement Cogni.Q has been tested as in our completed PK 
study (See Appendix 1).  Cogni.Q is sold as dietary supplement to promote cognitive agility and 
support healthy brain function, which are consistent with the reported neuro-protective 

Page 14 of 26 (V.7/18/2018) 
activities of AGN extract [11]. Cogni.Q and placebo capsules are provided by Cogni.Q 
manufacturer Quality of Life Labs (Purchase, NY, USA) (See letter of support, Appendix 2).   
 
7.4.2 Treatment Regimen 
Each subject will be instructed to take two capsules of Cogni.Q 200mg/Placebo by mouth twice 
daily for 21 days (Day 0 through Day 20) followed by a 14-day washout (day 21 through Day 34) 
and crossover to a second, 21-day treatment regimen (Day 35 through day 56). If they are 
assigned to group 1, participants will receive Cogni.Q 200mg on days 0 through 20 and a 
crossover to receive placebo on Days 21 through 34. If assigned to group 2, participants will 
receive placebo on Day 0 through 20 and crossover to receive Cogni.Q on Day 21 through 34.  
 
7.4.3 Method for Assigning Subject to Treatment Groups 
The statistician will generate a randomization table and provide to IDS.  
 
7.4.4 Subject Compliance Monitoring 
Study team members will text or give a reminder call to each subject to take the capsules 
weekly. On Day 21 and Day 56, study team will do a pill count for each subject of remaining 
number of capsules (to ensure that treatment regime was followed). Furthermore, plasma 
concentration of pyranocoumarins will be determined as compliance to AGN exposure. 
 
7.4.5 Blinding of the Test Article 
Cogni.Q and Placebo will be supplied to IDS at Penn State Hershey. IDS will be responsible for 
the storage, blinding, and dispensing of study medications.  
 
7.4.6 
Receiving, Storage, Dispensing and Return  
 
7.4.6.1 
Receipt of Test Article  
Quality of Life will ship the Cogni.Q and Placebo capsules (cellulose) directly to 
IDS Pharmacy at Penn State Hershey Medical Center.  An IDS staff member will 
inventory the shipment using the shipping invoice, notating lot number, 
expiration date, breakage, and total quantities.  The shipment will be recorded 
on the study-specific drug accountability record. 
7.4.6.2 
Storage 
The IDS Pharmacy will store the investigational product in the drug storage 
room within the IDS Pharmacy under the manufacturer’s recommended storage 
conditions (room temperature). IDS Pharmacy utilizes a continuous, wireless, 
electronic temperature monitoring system.  Temperature readings are 
monitored continuously and as long as no excursions occur, a recording is made 
every hour. Room temperature set-points are 20-25oC and the system is 
programmed to pre-alarm if the temperature reaches 21oC or 24oC.  When 
temperatures reach a pre-alarm level, the system begins contacting the 
pharmacy personnel via phone and pager, 24 hours a day, 7 days a week.  If the 
area reaches an alarm level, temperatures are recorded every 5 minutes or until 
the area is back within the acceptable range, whichever occurs first.  The system 
continually calls and pages until someone acts on the alarm. 
STORAGE/SECURITY:  Access to the IDS Pharmacy (PG200) is limited to 
pharmacy personnel with badge swipe access and the drug storage 
room(PG200A) is locked with a key.  The investigational product will be stored in 
a bin within the drug storage room and the bin will be clearly labeled with the 
name of the investigational product, the PI’s name, and the IRB number to 
clearly differentiate the investigational product from other medications that are 
stored in the same area. 
 

Page 15 of 26 (V.7/18/2018) 
 
7.4.6.3 
Preparation and Dispensing 
IDS will maintain a bulk supply of Cogni.Q and a bulk supply of placebo for 
Cogni.Q capsules.  The inventory for each supply will be tracked on 
corresponding drug accountability records.  
IDS Pharmacy will receive a patient-specific prescription for the study 
material (i.e., Group 1 or Group 2, take 2 capsules by mouth twice daily as 
directed by the study team, Dispense Quantity: 84 capsules Refills: 1). NOTE: 
The IDS pharmacy will only dispense investigational products after receipt of the 
documents listed to ensure that the patient signed consent and is enrolled in 
the study.  
RANDOMIZATION:  A randomization list will be provided to IDS that 
includes subject numbers and a corresponding treatment regimen (Cogni.Q 1st 
/placebo 2nd or placebo 1st/Cogni.Q 2nd) so that they know what to dispense 
to each participant. 
To ensure that the blind is maintained, the investigational product name 
will appear as “IDS Cogni.Q 200 mg or Placebo Capsules” on the pharmacy label.  
After the IDS pharmacy receives the required documentation, the IDS 
pharmacy staff will prepare 84 capsules (21-day supply) of the product that a 
subject was randomized to.  A subject-specific pharmacy label will be generated 
and affixed to the prescription vial.  
A refill will be processed for the second dispensing after the washout 
period.  No new prescription is required at this time because a refill was added 
to the initial prescription.  The IDS Pharmacy staff will ensure that the 
randomization module is followed and the correct medication is dispensed for 
the second treatment period. 
 
7.4.6.4 
Return or Destruction of the Test Article 
The participant will return their medication vial at the visits following their 21-
day treatment periods. The participant return will be documented on the 
corresponding drug accountability record and the empty vial and any remaining 
capsules will be destroyed on-site as per the IDS Pharmacy’s destruction policy. 
 
7.4.6.5 
Prior and Concomitant Therapy 
During the course of the study, prescription medicine and any medicine 
containing AGN are not permitted. At any point if a subject has to take 
prescription medication then they will be off the study.  
 
8.0 
Subject Numbers and Statistical Plan 
 
8.1 
Number of Subjects 
40 healthy men 
  
8.2 
Sample size determination 
We believe 20 participants in each group per arm in this 2 X 2 crossover design will allow us to detect an 
effect size of 0.75 (which is approximately equal to a difference of 920 in neutrophil mean count, 
assuming within-group common standard deviation is 1200, Table 2) between the two treatment arms 
with at least 81% power.  
 
8.3 
Statistical methods 
 
Descriptive statistics and bivariate tests will be used to compare distributional properties of all 
measured variables within and between the Cogni.Q and placebo arms. The main outcome variables are 

Page 16 of 26 (V.7/18/2018) 
the neutrophil and NK count, which will be measured repeatedly. Linear mixed models will be used to 
analyze the study outcomes. More specifically, we will evaluate overall difference between the Cogni.Q 
and placebo arms (group effect), linear/nonlinear change over time (time effect), and group difference 
in this change (group-by-time interaction), separately for the pre- and post-crossover periods. We will 
then estimate the same model parameters but for the two crossover periods combined while controlling 
for potential carryover effect (i.e., group-by-period interaction). Our two-period crossover models will 
include the pre-crossover’s baseline value (on Day 0) as a covariate common to the subsequent 
observations in both periods, thereby controlling for any carryover effect as well as bias due to 
difference at the first baseline. The outcome variables may be transformed to make sure the underlying 
statistical assumptions are satisfied. Other outcome variables including NK and neutrophil function 
assays will be analyzed in a similar statistical fashion. NK and neutrophil parameters will be examined for 
association for possible interaction/crosstalk. All analyses will be done using SAS version 9.4 or higher. 
The statistical significance level to be used is 0.05.  
 
 

Page 17 of 26 (V.7/18/2018) 
 
9.0 
Confidentiality, Privacy and Data Management  
 
9.1 
Confidentiality 
See the Research Data Plan Review Form 
9.1.1 
Identifiers associated with data and/or specimens 
See the Research Data Plan Review Form  
9.1.1.1 Use of Codes, Master List 
See the Research Data Plan Review Form  
9.1.2 
Storage of Data and/or Specimens 
See the Research Data Plan Review Form 
9.1.3 
Access to Data and/or Specimens 
See the Research Data Plan Review Form  
9.1.4 
Transferring Data and/or Specimens 
See the Research Data Plan Review Form  
9.2 
Subject Privacy 
See the Research Data Plan Review Form  
10.0 Data and Safety Monitoring Plan 
 
10.1 
Periodic evaluation of data 
The frequency of data review for this study differs according to the type of data and can be summarized 
in the following table (Table 10.1.1) 
 
Table 10.1.1 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including compliance with 
protocol enrollment criteria) 
Quarterly 
PI, Independent Monitor  
Status of all enrolled subjects, as of date of 
reporting  
Quarterly 
PI, Independent Monitor  
Adherence data regarding study visits and 
intervention 
Quarterly  
PI, Independent Monitor  
AEs and rates (including out-of-range lab 
values) 
Quarterly 
Study physicians, PI, 
Independent Monitor 
SAEs 
Per occurrence 
Study Physicians, PI, 
Independent Monitor, IRB 
 
 Independent Monitor: Andrea Manni, MD 
 Study Physicians: Diane M. Hershock, MD, Ph. D, Joseph Drabick, MD and Rebecca Phaeton, MD 
 
10.2 
Data that are reviewed 
Refer to Table 10.1.1 regarding who will be reviewing the data.  
 
10.3 
Method of collection of safety information 
Subjects will be called weekly during the period when Cogni.Q or Placebo is given (Day 1 to Day 21 and 
Day 35 to 56) and reminded to take their capsules. They will be asked if they have experienced any of 
the expected AE (Anorexia, Nausea and Dyspepsia) or any unexpected AE that they have recorded in the 
medication diary.  
If yes, study team personnel will inform the study physician(s) of the AE report. Study physician will 
contact the subject to assess the severity of AE and its relatedness to the intervention and record the 
data in Table 10.3.1. The physician(s) will take appropriate action of the care of the subject and make a 
decision in consultation with PI to whether keep the subject on the trial or withdraw.  
  

Page 18 of 26 (V.7/18/2018) 
Following table will be used to report and track any specific symptoms: 
 
Table 10.3.1 AE reporting and tracking 
Pt 
Identifier 
AE Onset 
AE End 
Severity 
SAE? 
(Y/N) 
Related-
ness 
Action 
Taken 
Outcome 
Comments 
Subj001 
05/01/2019 
   
1 
   
2 
1 
4 
Subject injured broke his hand 
Subj002 
06/26/2019 
   
2 
   
2 
1 
1 
   
Subj003 
03/04/2019 
   
3 
   
0 
4 
4 
Subj broke leg while skiing; 
withdrew from study 
   
   
   
   
   
   
   
   
   
 
Severity of AE: 
 
 
Relatedness to Intervention: 
 
1 = Mild  
 
 
0 = Definitely unrelated 
 
2 = Moderate 
 
 
1 = Unlikely 
 
3 = Severe 
 
 
2 = Possibly related 
 
4 = Life threatening or disabling 
3 = Probably related 
 
 
 
 
4 = Definitely related 
Action Taken: 
 
0 = None 
 
 
Outcome: 
 
1 = Medical intervention   
1 = Resolved 
 
(specify in comments) 
 
2 = Recovered with minor sequelae 
 
 
 
 
 
3 = Recovered with major sequelae 
 
2 = Hospitalization 
 
4 = Continuing treatment 
 
3 = Intervention discontinued 
5 = Condition worsening 
 
4 = Other 
 
 
6 = Patient death 
 
Following table will be used to track subject status: 
Table 10.3.2 Subject status 
Pt 
Identifier 
Date Enrolled 
Date 
Completed 
Study 
Study Status 
Reason for Withdrawal 
Subj001 
03/02/2019 
N/A 
A 
   
Subj002 
04/26/2019 
9/20/2019 
C 
   
Subj003 
08/04/2019 
N/A 
W 
Injury unrelated to 
intervention 
   
   
   
   
   
 
Status: 
 
 
A = Active 
 
 
C = Completed 
 
 
W = Withdrew 
 
 
L = Lost to follow up   
 
Following table will be used to keep track of the Frequency of specific symptom: 
 
 
 
Table 10.3.3 Frequency of specific Symptoms 
Symptoms 
N% 
Anorexia 
   
Nausea 
   
Dyspepsia 
   
Other  
   
 
10.4 
Frequency of data collection 
Data related to subject’s safety will begin the day they are enrolled in the trial. Safety related 
information will be collect during the reminder calls, and by going over the medication diary maintained 
by the subject during their visit. Hence, the data related to subject’s safety will be collected weekly and 
during their study visits to CRC.  
 

Page 19 of 26 (V.7/18/2018) 
10.5 
Individuals reviewing the data 
Refer to 10.1.1 
 
10.6 
Frequency of review of cumulative data 
The PI, study biostatistician, study physicians and co-investigators will review the cumulative data. 
Cumulative data analysis will be done at the end of the trial (after the last subject has successfully 
completed the trial), since this the study subject number is less hence an interim analysis is not required.  
 
10.7 
Statistical tests 
Study biostatistician will perform tests as described in 8.3. We do not see a need to perform statistics to 
determine safety because any occurrence will be evaluated immediately on a case-by-case basis.   
 
10.8 
Suspension of research 
If any unexpected serious adverse events (SAE) occur, the research will be suspended and reports will be 
submitted to IRB for review and other regulatory office (FDA) as appropriate.  
 
 

Page 20 of 26 (V.7/18/2018) 
 
11.0 Risks 
Physical health Risk assessment:   
 
Risk related to fasting: 
o Fasting for up to 8 hours could cause dizziness, headache, stomach discomfort, or 
fainting. 
 
Risk related to blood draw: 
o Blood draw needle pricks will inflict temporary superficial pain.  Venipuncture might 
occasionally lead to localized hemorrhage and bruises at site of needle insertion. 
Our CRC experienced research nurses are highly trained and experienced which 
greatly reduces these risks. Occasionally, a subject may experience fainting spell 
during the blood draw.  The CRC nurses are trained to respond to such situations. 
Subjects will be placed in a head-down position until consciousness is regained. 
Subjects will be monitored and given juice and/or light snacks until they are able to 
maintain blood pressure upon assuming an upright posture. 
 
Consumption of placebo vs Cogni.Q capsules:  
o As for the consumption of placebo vs. Cogni.Q capsules, we do not anticipate any 
more frequent or greater risks to the subject than the risks ordinarily encountered 
in daily life by taking a dietary supplement.  Reported side effects for Cogni. Q 
include anorexia (lack of appetite), nausea and indigestion [12]. 
 
Psychological, financial, legal risk assessment:   
o We do not anticipate any increased risk in these categories by participating in this 
study.  Psychological reward might be a positive factor of participating in our study 
as most people derive pleasure by knowing study results may benefit themselves 
and many others. Financial loss due to missed work is partially mitigated by our 
subject remuneration plan ($25 per visit). 
o Loss of confidentiality is a potential risk when conducting human subject research 
and hence, all efforts will be made by the study team to ensure that loss of 
confidentiality does not occur.  
  
  
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
Since we use a crossover design, each subject will consume placebo (no risk) and Cogni.Q (being tested 
for acute enhancement of two types of innate immune cells) capsules.  Therefore, all subjects will be 
participating in both groups, and hence no subject is at a disadvantage. Furthermore, there are no 
known benefits to the subject from participating in this study. 
 
12.2 
Potential Benefits to Others 
If the efficacy results are positive for the dietary supplement (net over placebo), the public health 
benefit to millions, and even billions of adults in this country and globally is self-evident.   Additional 
studies can be designed for children and special populations (e.g., therapy-induced neutropenia 
patients) to assess health promotional benefit and clinical therapeutic indications.   

Page 21 of 26 (V.7/18/2018) 
 
13.0 Sharing Results with Subjects 
The data of the study will not be shared with the subjects.  
 
14.0 Subject Stipend (Compensation) and/or Travel Reimbursements 
Each subject will be compensated $25 per visit completed.  ($200 per subject if completed; total 8 visits, 1 
screening visit and 7 study visits). 
 
15.0 Economic Burden to Subjects 
 
15.1 
Costs  
The cost of the comprehensive metabolic panel that is required for determination of eligibility will be 
paid by the study budget. These tests are being done for research purpose only and will not be billed to 
the subjects or their insurance company. 
 
15.2 
Compensation for research-related injury 
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.  
 
16.0 Resources Available 
 
16.1 
Facilities and locations 
The study visits will be at the CTSI CRC at Hershey Medical Center, Hershey PA. 
 
16.2 
Feasibility of recruiting the required number of subjects 
CTSI CRC healthy volunteer database will be used to solicit study subjects plus multiple advertising 
venues of trial participation opportunity will be made in Hershey and Harrisburg metro area, including 
CTSI website and CTSI community engagement outreach networks, Penn State STUDYfinder, local civic 
institutions and grocery supermarkets. 
 
16.3 
PI Time devoted to conducting the research 
PI will devote 20% time. PI and study physicians will be discussing about the study progress and 
frequency of AE occurrences quarterly and on a need basis in between.  PI will interact and coordinate 
with study team members through monthly meetings and on a need basis in between.  PI will 
participate in data analyses and interpretations along with biostatistician, CO-PI and study team 
personnel. Study physician(s) will perform physical exam for subjects at screening, review their lab 
report and determine their eligibility for participation.  They will be on call to answer subject’s query on 
study related AE issues, and review AE-related entries from medication diaries.   
 
16.4 
Availability of medical or psychological resources 
Medical or psychological resources at Penn State College of Medicine are available if subject needs to 
use them. However, subjects will be financially responsible for utilization of any resources.  
 
16.5 
Process for informing Study Team 
Monthly in person meetings will be conducted.  Weekly email updates will be sent to ensure the team 
stays well informed.  
 
17.0 Other Approvals 
 
17.1 
Other Approvals from External Entities 

Page 22 of 26 (V.7/18/2018) 
Not applicable 
 
17.2 
Internal PSU Committee Approvals 
 
Check all that apply: 
  Anatomic Pathology – Hershey only – Research involves the collection of tissues or use of pathologic 
specimens. Upload a copy of HRP-902 - Human Tissue For Research Form on the “Supporting 
Documents” page in CATS IRB. This form is available in the CATS IRB Library. 
 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals 
 
X  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens in 
a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA or gene 
therapy).  
 
X   Clinical Laboratories – Hershey only – Collection, processing and/or storage of extra tubes of body 
fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids that had 
been collected for clinical purposes, but are no longer needed for clinical use. Upload a copy of HRP-901 
- Human Body Fluids for Research Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library. 
 
X  Clinical Research Center (CRC) Advisory Committee– All campuses – Research involves the use of CRC 
services in any way.   
 
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest. 
 
  Radiation Safety – Hershey only – Research involves research-related radiation procedures. All 
research involving radiation procedures (standard of care and/or research-related) must upload a copy 
of HRP-903 - Radiation Review Form on the “Supporting Documents” page in CATS IRB. This form is 
available in the CATS IRB Library. 
 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE. 
 
X Scientific Review – Hershey only – All investigator-written research studies requiring review by the 
convened IRB must provide documentation of scientific review with the IRB submission. The scientific 
review requirement may be fulfilled by one of the following: (1) external peer-review process; (2) 
department/institute scientific review committee; or (3) scientific review by the Clinical Research Center 
Advisory committee.  NOTE: Review by the Penn State Hershey Cancer Institute Scientific Review 
Committee is required if the study involves cancer prevention studies or cancer patients, records and/or 
tissues. For more information about this requirement see the IRB website at: 
http://www.pennstatehershey.org/web/irb/home/resources/investigator  
 
18.0 Multi-Site Research 
Not applicable 
18.1 
Communication Plans 
Not applicable 
18.2 
Data Submission and Security Plan 
Not applicable 
 

Page 23 of 26 (V.7/18/2018) 
18.3 
Subject Enrollment 
Not applicable 
 
18.4 
Reporting of Adverse Events and New Information 
Not applicable 
 
18.5 
Audit and Monitoring Plans 
Not applicable 
 
19.0 Adverse Event Reporting 
 
19.1 
Adverse Event Definitions 
 
For drug studies, incorporate the following definitions into the below responses, as written: 
Adverse event 
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related 
Adverse reaction 
Any adverse event caused by a drug 
Suspected adverse 
reaction 
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than “adverse reaction”. 
 
Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. 
Serious adverse 
event or Serious 
suspected adverse 
reaction 
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction 
An adverse event or suspected adverse reaction is considered “life-threatening” 
if, in the view of either the Investigator (i.e., the study site principal investigator) 
or Sponsor, its occurrence places the patient or research subject at immediate 
risk of death.  It does not include an adverse event or suspected adverse reaction 
that had it occurred in a more severe form, might have caused death. 
Unexpected 
adverse event or 
Unexpected 
suspected adverse 
reaction.   
An adverse event or suspected adverse reaction is considered “unexpected” if it 
is not listed in the investigator brochure, general investigational plan, clinical 
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified. 
 
 
 
For device studies, incorporate the following definitions into the below responses, as written: 
Unanticipated 
adverse device 
effect 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or IDE application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a 

Page 24 of 26 (V.7/18/2018) 
device that relates to the rights, safety, or welfare of subjects. 
 
19.2 
Recording of Adverse Events 
 
Research subjects will be routinely questioned about adverse events at study visits and during reminder 
calls for taking their capsules.  
All adverse events (serious or non-serious) and abnormal test findings observed or reported to study 
team believed to be associated with the study capsules will be followed until the event (or its sequelae) 
or the abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
Based on our prior clinical study experience (PK study) and the discussion about potential risks 
above (not higher than that of average life), we believe the monitoring plan involving PI/Study 
Physicians, independent monitor and Institutional Review Board (IRB) will be sufficient. Study physicians 
will be on-call and consulted to delineate whether an adverse event is study-related.  Any reportable 
adverse effect will be timely reported to IRB-Hershey and other authorities including FDA (if warranted).    
To minimize the possibility of minor and reversible side effects, presumably due to psychological 
anxiety, we will only recruit healthy participants (normal liver and kidney functions) and exclude 
subjects with cancer, and major cardiovascular diseases. In addition, we will closely monitor any possible 
side effect during the whole study section.  
If emergency care is necessary during the study, our Study physician will be consulted. If the 
Study physician(s) determines emergency care is required, the subject will be referred/admitted to 
Hershey Medical Center where our Study Physicians has admitting privileges.  The subject may be 
required to remain in the hospital for a period until the symptoms clear. Study physicians and PI will 
determine whether or not the event was related to the study.  Study personnel will also document and 
report the adverse effects including but not limited to the following symptoms during the study to the 
IRB: 
 
anorexia (lack of appetite), nausea and indigestion [12]. 
 
 
 
19.3 
Causality and Severity Assessments 
The study physician will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event. 
 
If the final determination of causality is “unknown and of questionable relationship to the study drug(s) 
or device(s)”, the adverse event will be classified as associated with the use of the study drug(s) or 
device(s) for reporting purposes.  If the final determination of causality is “unknown but not related to 
the study drug(s) or device(s)”, this determination and the rationale for the determination will be 
documented in the respective subject’s case history. 
 
19.4 
Reporting of Adverse Reactions and Unanticipated Problems to the FDA   
 
19.4.1 Written IND/IDE Safety Reports 
 Not applicable 
 
19.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions 
 Not applicable 
 
19.5 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 

Page 25 of 26 (V.7/18/2018) 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
 
19.6 
Unblinding Procedures 
Unblinding will occur at the end of the trial, upon PI’s written request to IDS. In an event of AE, PI will 
have to give a written request to IDS for unblinding the subject, in order to figure out the treatment 
regime. AE will be reported to IRB. Anytime a person is unblinded and the cause will be reported to IRB 
by the PI. 
 
19.7 
Stopping Rules 
Stopping Criteria: 
 
Any SAE that is considered life threatening, requires hospitalization or results in a 
disability/incapacitation.  
 
Any sickness that requires prescription medication. 
 
CBC:  WBC counts over normal upper limit by 2 fold (i.e., 21,000 cells/µL) and for 2 
consecutive weeks without obvious source of infection or inflammation (3,500 to 10,500 
cells/µL).    
 
20.0 Study Monitoring, Auditing and Inspecting 
 
20.1 
Study Monitoring Plan  
 
 
20.1.1 Quality Assurance and Quality Control 
 Not applicable 
 
20.1.2 Safety Monitoring 
Not applicable  
21.0 Future Undetermined Research: Data and Specimen Banking 
 
21.1 
Data and/or specimens being stored 
RedCap will be used for data storage. PaxGene tubes and plasma will be stored for future use.  
 
21.2 
Location of storage 
Plasma, and blood in PAX gene tubes and the extracted RNA will be stored at -80 C freezers, and the 
isolated PBMC will be stored in liquid nitrogen tanks at C6813 of the BMR (Immune Correlatives Lab) 
under lock and key with authorized access only. 
 
21.3 
Duration of storage 
Data and specimen will be stored for maximum up to 10 years from the completion of the trial.   
 
21.4 
Access to data and/or specimens 
Access to the data on file will be limited to PI and trial coordinator. Anyone other than PI and trial 
coordinator will have to notify PI and get his written permission for accessing the data.  
 
21.5 
Procedures to release data or specimens 
In order to request release of any data, a written permission for data release must be obtained from the 
PI. 
 
21.6 
Process for returning results 
Any data or results obtained from the study finding must be sent to PI, by hand delivery or secure mail. 
 

Page 26 of 26 (V.7/18/2018) 
 
22.0 References 
1. 
Chang, A., et al., The effect of herbal extract (EstroG-100) on pre-, peri- and post-menopausal women: a 
randomized double-blind, placebo-controlled study. Phytother Res, 2012. 26(4): p. 510-6. 
2. 
Li, L., et al., Quantitative Determination of Decursin, Decursinol Angelate, and Decursinol in Mouse Plasma and 
Tumor Tissue Using Liquid-Liquid Extraction and HPLC. Planta Medica, 2012. 78(3): p. 252-259. 
3. 
Li, L., et al., Single Oral Dose Pharmacokinetics of Decursin, Decursinol Angelate, and Decursinol in Rats. Planta 
Medica, 2013. 79(3-4): p. 275-280. 
4. 
Park, H.S., et al., First-pass Metabolism of Decursin, a Bioactive Compound of Angelica gigas, in Rats. Planta 
Medica, 2012. 78(9): p. 909-913. 
5. 
Zhang, J., et al., Chemopreventive effect of Korean Angelica root extract on TRAMP carcinogenesis and 
integrative "omic" profiling of affected neuroendocrine carcinomas. Mol Carcinog, 2015. 54(12): p. 1567-83. 
6. 
Zhang, J., et al., Single oral dose pharmacokinetics of decursin and decursinol angelate in healthy adult men and 
women. PLoS One, 2015. 10(2): p. e0114992. 
7. 
Winterbourn, C.C. and A.J. Kettle, Redox reactions and microbial killing in the neutrophil phagosome. Antioxid 
Redox Signal, 2013. 18(6): p. 642-60. 
8. 
Pham, C.T., Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol, 2006. 6(7): p. 
541-50. 
9. 
Benson, D.M., Jr. and M.A. Caligiuri, Killer immunoglobulin-like receptors and tumor immunity. Cancer Immunol 
Res, 2014. 2(2): p. 99-104. 
10. 
Krzewski, K. and J.E. Coligan, Human NK cell lytic granules and regulation of their exocytosis. Front Immunol, 
2012. 3: p. 335. 
11. 
Kang, S.Y., et al., Decursin from Angelica gigas mitigates amnesia induced by scopolamine in mice. Neurobiology 
of Learning and Memory, 2003. 79(1): p. 11-18. 
12. 
Kim, J.H., et al., A three month placebo-controlled clinical trial of INM 176 in the old aged subjects with memory 
impairment. Journal of Korean Neuropsychiatric Association, 2003. 42(2): p. 254-262.