A Phase 1 Study to Assess the Pharmacokinetics and Safety of Ascending Doses of JOTROL Oral Gelcaps in Healthy Subjects, and to Determine the Influence of Food
Phase: PHASE1
Conditions: Pharmacokinetics, Safety, Food-drug Interaction
Sponsor: Jupiter Orphan Therapeutics Inc.

 
2 0 2 0 1 6 Res veratr ol (J O T R O L) Gelca ps P h ase I S A D St u d y 
J u pit er Or p h a n T hera p e utics 
2 5- N O V- 2 0 2 0 
 
 
C o nfi d e ntial 
 
P a ge 1 of 4 5 
A me n d me nt II 
 
 
 
 
P R O T O C O L 2 0 2 0 1 6 
I N D N u m ber: 1 3 2 1 4 5 
A me n d me nt II 
 
A P H A S E 1 S T U D Y T O A S S E S S T H E P H A R M A C O KI N E TI C S A N D S A F E T Y O F A S C E N DI N G 
D O S E S O F J O T R O L O R A L G E L C A P S I N H E A L T H Y S U B J E C T S, A N D T O D E T E R MI N E T H E 
I N F L U E N C E O F F O O D 
 
 
C o ntr act R ese a rc h Or g a niz ati o n:  
i n Ve nti v Healt h Cli nical Researc h 
Ser vices L L C, a S y ne os Healt h 
c o m pa n y ( « S y ne os Healt h ») 
1 9 5 1 N W 7 t h A ve n u e, S uite 4 5 0 
Mia mi, F L 3 3 1 3 6, U S A 
Tel.: 1- 3 0 5- 5 4 7- 5 8 0 0 
 
S p o ns or:  
J u piter Or p ha n T h era p e utics 
6 0 1 Herita ge Dri v e 
J u piter, Fl ori da 3 3 4 5 8  
Tel.: 
 
 
 
 
 
C O N FI D E N TI A L 
 
 
T his d o c u me nt is strictl y c o nfi de ntial. It was de vel o p e d f or J u piter O pr ha n T hera p e utics b y S y ne os Healt h a n d m ust 
n ot b e discl ose d t o a t hir d p art y, wit h t he e xce pti o n of re g ulat or y a ge ncies a n d st u d y a u dit pers o n nel wit h o ut t he 
c o nse nt of eit her S y ne os Healt h or t he S p o ns or. T his d o c u me nt is c o p yri g hte d i n fa v or of S y ne os Healt h a n d ca n n ot 
b e re pr o d uce d, m o difie d, or a d a pte d, i n p art or i n t otal, wit h o ut pri or writte n a p pr o val b y S y ne os Healt h.  
P P D

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Amendment II 
Protocol Historical File 
Version 
number 
Brief description/summary of changes 
Date 
Final 
Version submitted to the IEC. 
20-AUG-2020 
Amendment I 
Peripheral blood mononuclear cells will be isolated from 
additional blood samples in all periods of study Part 1, leading 
to a total blood volume exceeding 500 mL in Period 3. Hence, a 
hematology test is included before dosing in Period 3. A 
clarification to subjects to be included in Part 2 is also provided.
12-NOV-2020 
Amendment II See the description of changes below. 
25-NOV-2020 
 
Changes included in Amendment II: 
Based on the anticipated bioavailability profile of the JOTROL formulation, the U.S. National 
Institute of Aging (NIA) recommended to establish a formal Data and Safety Monitoring Board 
(DSMB) constituted by 3 qualified pharmacovigilance persons, totally independent of Syneos 
Health, JOT, and the associated investigators on the study. This independent group of experts 
will periodically review and evaluate the accumulated study data for participant safety, study 
conduct and progress, and make recommendations concerning the continuation, modification, or 
termination of the trial. Therefore, there are changes under: 
 Section 2. Synopsis of Protocol  Study Design / Subjects / Drug Administration 
 Section 6. Study Design 
 Section 7.5 Dose Escalation Criteria 
 Section 9.5 Drug Administration 
 Section 9.11 Subject Withdrawal and Replacement 
Two additional guidances are cited for the establishment of DSMB 
Brochure has been updated. Therefore, reference numbering is updated throughout the protocol 
and the section 15. References is also updated. 
 

2 0 2 0 1 6 Res veratr ol (J O T R O L) Gelca ps P h ase I S A D St u d y 
J u pit er O pr h a n T h era p e utics 
2 5- N O V- 2 0 2 0 
 
 
C o nfi d e ntial 
P a ge 3 of 4 5 
A me n d me nt II  
Si g n at ure P a g e 
S p o ns or  
J u piter O pr ha n T h era p e utics 
6 0 1 Herita ge Dri v e 
J u piter Fl ori da 3 3 4 5 8 
U S A 
Tel.: 
 
 
 
 
 
_
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
, P h. D 
Date 
 
P P D
P P D
P P D
P P D

2 0 2 0 1 6 Res veratr ol (J O T R O L) Gelca ps P h ase I S A D St u d y 
J u pit er O pr h a n T h era p e utics 
2 5- N O V- 2 0 2 0 
 
 
C o nfi d e ntial 
P a ge 4 of 4 5 
A me n d me nt II  
Si g n at ure P a g e 
C o ntr act R ese a rc h Or g a niz ati o n ( C R O) 
I n v esti g at or: 
I h a ve c aref ull y rea d t his st u d y pr ot o c ol a n d a gree t hat it c o ntai ns all necess ar y i nf or mati o n 
re q uire d t o c o n d u ct t his st u d y. I a gree t o c o n d uct t he st u d y acc or di n g t o t his pr ot oc ol (i ncl u di n g 
a n y a me n d m e nts) a n d i n acc or d a nce wit h t he cli nical site
( S O Ps), I C H G o o d Cli ni cal Practices ( G C P), all ot her a p pli ca ble r e g ulati o ns, a n d t he 
rec o m me n d ati o ns lai d d o w n i n t he m ost rece nt versi o n of t he Declarati o n of Helsi n ki. 
 
_ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
, M. D. 
Date 
   
 
P P D
P P D
P P D
P P D
P P D

2 0 2 0 1 6 Res veratr ol (J O T R O L) Gelca ps P h ase I S A D St u d y 
J u pit er O pr h a n T h era p e utics 
2 5- N O V- 2 0 2 0 
 
 
C o nfi d e ntial 
P a ge 5 of 4 5 
A me n d me nt II  
1.  
F acilities a n d Res p o nsi ble St aff 
1. 1  
Cli ni c al Res e arc h F acilities 
T his st u d y will be c o n d ucte d b y S y n e os Healt h at t he f oll o wi n g facilit y: 
1 9 5 1 N W 7 t h A ve n u e, S uites 1 8 0 a n d 4 5 0 
Mia mi, F L 3 3 1 3 6, U S A 
Tel.: 1- 3 0 5- 5 4 7- 5 8 0 0 
1. 2  
Bi o me di c al L a b or at or y F acilities 
Bi o me dical la b orat or y testi n g will be perf or me d b y t he f oll o wi n g l a b orat ories: 
Ecc ola b Gr o u p C o. 
8 3 7 0 W. Fla gler Street, S uit e 2 1 6 
Mia mi, F L 3 3 1 4 4, U S A 
Tel.: 1- 8 0 0- 6 1 6- 1 7 7 0 
S y ne os H ealt h 
1 9 5 1 N W 7t h A ve n ue, S uites 1 8 0 a n d 4 5 0 
Mia mi, F L 3 3 1 3 6, U S A 
Tel.: 1- 3 0 5- 5 4 7- 5 8 0 0 
If a n ot her bi o me di cal la b orat or y is use d, t his will be d oc u me nte d a n d a n ne x e d t o t he pr ot oc ol. 
1. 3  
Cli ni c al P h ar m ac ol o g y a n d R e g ul at or y Aff airs  
S y ne os H ealt h 
2 5 0 0, r ue Ei nstei n 
Q ué bec ( Q ué bec), Ca n a da, G 1 P 0 A 2 
Tel.: 
, P h. D. 
 
, P h. D. 
  
1. 4  
Bi o a n al ytic al F acilit y 
S y ne os H ealt h Cli nical Bi oa nal ytic al Facilit y 
3 0 1 D C olle ge R o a d E ast 
Pri ncet o n, NJ 0 8 5 4 0 
Tel: 
 
, P h. D. 
 
, B. S. 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

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Table of Contents 
1. 
FACILITIES AND RESPONSIBLE STAFF .................................................................... 5 
1.1 
CLINICAL RESEARCH FACILITIES ........................................................................................................................ 5 
1.2 
BIOMEDICAL LABORATORY FACILITIES .............................................................................................................. 5 
1.3 
CLINICAL PHARMACOLOGY AND REGULATORY AFFAIRS ................................................................................... 5 
1.4 
BIOANALYTICAL FACILITY .................................................................................................................................. 5 
2. 
SYNOPSIS OF PROTOCOL ............................................................................................. 8 
3. 
SCHEDULE OF EVENTS................................................................................................ 14 
4. 
INTRODUCTION ............................................................................................................. 16 
4.1 
BACKGROUND INFORMATION............................................................................................................................ 16 
4.2 
TOXICOLOGY .................................................................................................................................................... 17 
4.3 
CLINICAL .......................................................................................................................................................... 18 
4.4 
RATIONALE FOR STUDY CONDUCT .................................................................................................................... 21 
4.5 
RATIONALE FOR THE STUDY POPULATION ........................................................................................................ 21 
5. 
OBJECTIVES .................................................................................................................... 24 
6. 
STUDY DESIGN ............................................................................................................... 24 
7. 
RATIONALE FOR DOSE SELECTION ....................................................................... 24 
7.1 
STARTING DOSE ................................................................................................................................................ 24 
7.2 
MAXIMUM DOSE IN THIS STUDY ....................................................................................................................... 24 
7.3 
DOSE ESCALATION SCHEME (STUDY PART I) .................................................................................................... 25 
7.4 
DOSE LEVEL IN STUDY PART II ......................................................................................................................... 25 
7.5 
DOSE ESCALATION CRITERIA ............................................................................................................................ 25 
8. 
STUDY POPULATION .................................................................................................... 27 
8.1 
SAMPLE SIZE ..................................................................................................................................................... 27 
8.2 
INCLUSION CRITERIA ........................................................................................................................................ 27 
8.3 
EXCLUSION CRITERIA ....................................................................................................................................... 28 
9. 
CLINICAL PROCEDURES ............................................................................................ 29 
9.1 
SCREENING PROCEDURES .................................................................................................................................. 29 
9.2 
CONFINEMENTS, VISITS, AND WASHOUT .......................................................................................................... 29 
9.3 
STUDY MEDICATION ......................................................................................................................................... 30 
9.4 
DRUG SUPPLIES AND ACCOUNTABILITY ............................................................................................................ 30 
9.5 
DRUG ADMINISTRATION ................................................................................................................................... 30 
9.6 
STUDY RESTRICTIONS ....................................................................................................................................... 31 
9.7 
SAMPLE COLLECTION AND PROCESSING ........................................................................................................... 33 
9.8 
SUBJECT MONITORING ...................................................................................................................................... 34 
9.9 
STUDY EXIT PROCEDURES ................................................................................................................................ 36 
9.10 
DATA COLLECTION AND EVALUATION ............................................................................................................. 36 
9.11 
SUBJECT WITHDRAWAL AND REPLACEMENT .................................................................................................... 36 
9.12 
ADVERSE EVENTS ............................................................................................................................................. 37 
9.13 
PREGNANCY ...................................................................................................................................................... 38 
9.14 
REPORTABLE DISEASE ...................................................................................................................................... 38 
10. 
PREMATURE TERMINATION OF THE STUDY ...................................................... 38 
11. 
ANALYTICAL METHODOLOGY ................................................................................ 38 
12. 
PHARMACOKINETIC AND STATISTICAL ANALYSES ........................................ 39 
12.1 
PHARMACOKINETICS ......................................................................................................................................... 39 
12.2 
ANALYSIS POPULATIONS................................................................................................................................... 40 
12.3 
STATISTICAL ANALYSES ................................................................................................................................... 40 

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13. 
REGULATORY CONSIDERATIONS AND QUALITY ASSURANCE .................... 41 
13.1 
INDEPENDENT ETHICS COMMITTEE APPROVAL OF PROTOCOL AND OTHER STUDY DOCUMENTS ..................... 41 
13.2 
COMPLIANCE..................................................................................................................................................... 42 
13.3 
QUALITY ASSURANCE PROGRAM ...................................................................................................................... 42 
13.4 
AUDITS, INSPECTIONS AND MONITORING .......................................................................................................... 42 
14. 
CONFIDENTIALITY ....................................................................................................... 42 
15. 
REFERENCES .................................................................................................................. 44 
 
 

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2. 
Synopsis of Protocol 
Project No.: 
202016 
Title: 
Phase 1 Study, to Assess the Pharmacokinetics and Safety of Ascending 
Doses of JOTROL Oral Gelcaps in Healthy Subjects, and to Determine the 
Influence of Food. 
Study Phase and Type:  
Phase 1 - Single Ascending Doses (SAD) study 
Objectives: 
The objectives of this study are: 
 
To characterize the pharmacokinetic (PK) profile of JOTROL 
(resveratrol) following oral administration of SAD ranging from 200 mg 
up to a dose currently estimated at 1000 mg, in healthy adult subjects.  
 
To evaluate the effect of food on the PK profile of JOTROL. 
Study Design: 
Single center, Phase 1, open-label, sequential SAD study, with a food-effect 
arm. The study will be divided into two parts: 
 
Study Part 1 consists of 3 periods with SAD of JOTROL under fasting 
conditions. Periods 2 and 3 will be initiated with updated doses after 
safety, tolerability, and PK data are evaluated by the Safety Committee 
and the Data and Safety Monitoring Board (DSMB) and deemed 
acceptable for single doses for subsequent doses.  
 
Study Part 2 consists of a single JOTROL dose under fed conditions. 
JOTROL dose will derive from study Part 1 safety, tolerability, and PK 
data. 
Subjects: 
24 healthy adult males or females,  
 75 years of age, non-smokers 
will be included in the study Part 1. Only 16 subjects who completed study 
Part 1 will be included in study Part 2. In order to minimize potential PK 
variability, elderly (more than 65 years old subjects) will be not be included 
in study Part 2.These 16 subjects will be selected according to their order of 
enrolment in the study, provided their consent to continue the study, they 
follow the study restrictions and they still meet study criteria. 
Subjects who withdraw or are withdrawn from study Part 1 after dosing, for 
reasons other than safety and tolerability, may be replaced after consultation 
between the Safety Committee members and the DSMB members in order 
to assure initiating study Part 2 with 16 subjects.  
For study Part 1 only, an effort will be made to include to the extent possible, 
subjects of the following age groups: 
 
 
 70 years of age; 
 
 
 75 years of age. 
Inclusion Criteria: 
1) Normal healthy male or female volunteers, non-smokers (no use of 
tobacco products within 3 months prior to screening), 
 75 years of age, with BMI > 18.5 and < 30.0 kg/m2 and body weight 
 50.0 kg for 
 
2) Healthy as defined by: 
a) the absence of clinically significant illness and surgery within 
4 weeks prior to dosing. Subjects vomiting within 24 hours predose 
will be carefully evaluated for upcoming illness/disease. Inclusion 
pre-dosing is at the discretion of the Investigator. 

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b) the absence of clinically significant history of neurological, 
endocrine, cardiovascular, respiratory, hematological, 
immunological, psychiatric, gastrointestinal, renal, hepatic, and 
metabolic disease as determined by the Investigator. 
3) Females of childbearing potential who are sexually active with a male 
partner must be willing to use one of the following acceptable 
contraceptive methods throughout the study and for 30 days after the last 
study drug administration: 
a) intra-uterine contraceptive device without hormone release system 
placed at least 4 weeks prior to study drug administration; 
b) male condom with intravaginally applied spermicide starting at least 
21 days prior to study drug administration;  
c) sterile male partner (vasectomized since at least 6 months). 
4) Capable of consent 
Exclusion Criteria: 
1) Any clinically significant abnormality at physical examination, clinically 
significant abnormal laboratory test results or positive test for hepatitis B, 
hepatitis C, or HIV found during medical screening.  
2) Positive urine drug screen or urine cotinine test at screening. 
3) History of allergic reactions to resveratrol, polyphenols, other related 
drugs, or to any excipient in the formulation. 
4) Positive pregnancy test at screening. 
5) Breast-feeding subject. 
6) Clinically significant ECG abnormalities or vital sign abnormalities 
(systolic blood pressure lower than 90 or over 140 mmHg, diastolic 
blood pressure lower than 50 or over 90 mmHg, or heart rate less than 50 
or over 100 bpm) at screening. 
7) History of significant alcohol abuse within 1 year prior to screening or 
regular use of alcohol within 6 months prior to the screening visit (more 
than 14 units of alcohol per week [1 unit = 150 mL of wine, 360 mL of 
beer, or 45 mL of 40% alcohol]).  
8) History of significant drug abuse within 1 year prior to screening or use 
of soft drugs (such as marijuana) within 3 months prior to the screening 
visit or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid 
derivatives including heroin, and amphetamine derivatives) within 1 year 
prior to screening. 
9) Use of resveratrol for a medical condition or in the context of another 
clinical trial within a period of 30 days prior to the first dosing. 
10) Participation in a clinical research study involving the administration of 
an investigational or marketed drug or device within 30 days prior to the 
first dosing, administration of a biological product in the context of a 
clinical research study within 90 days prior to the first dosing, or 
concomitant participation in an investigational study involving no drug or 
device administration. 
11) Use of medications for the timeframes specified below, with the 
exception of medications exempted by the Investigator on a case-by-case 
basis because they are judged unlikely to affect the PK profile of the 
study drug or subject safety (e.g., topical drug products without 
significant systemic absorption):  
a) prescription medication within 14 days prior to the first dosing; 

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b) over-the-counter products and natural health products (including 
herbal remedies, homeopathic and traditional medicines, probiotics, 
food supplements such as vitamins, minerals, amino acids, essential 
fatty acids, and protein supplements used in sports) within 14 days 
prior to the first dosing, with the exception of the occasional use of 
acetaminophen (up to 2 g daily); 
c) use of any drugs known to induce or inhibit hepatic drug 
metabolism
 wort, within 30 days prior to the 
first study drug administration; 
d) depot injection or an implant of any drug within 3 months prior to 
the first dosing. 
12) Donation of plasma within 7 days prior to dosing. Donation or loss of 
blood (excluding volume drawn at screening) of 50 mL to 499 mL of 
blood within 30 days, or more than 499 mL within 56 days prior to the 
first dosing. 
13) Any reason which, in the opinion of the Investigator, would prevent the 
subject from participating in the study. 
Screening Procedures: 
Demographic data, medical and medication histories, physical examination, 
body measurements, electrocardiogram (ECG), vital signs (blood pressure, 
heart rate, respiratory rate, and oral temperature), hematology, biochemistry, 
coagulation, serology (human immunodeficiency virus [HIV], hepatitis B and 
C tests), urinalysis, urine cotinine test, urine pregnancy test, and urine drug 
screen.  
Confinements, Visits, and 
Washout: 
For each period, subjects will be confined from Day -1 until after the 32-hour 
post-dose blood draw. 
There will be a washout period of 14 days or more between each study drug 
administration. 
Drug Administration: 
Single oral dose: 
Study Part 1: 
Subject will be sequentially dosed in an ascending manner with at least 
14 days between the last dosing and the subsequent nominal dose level below, 
which will be calculated based on observed PK results: 
 
Period 1: 2 x 100 mg JOTROL oral gelcaps, total resveratrol dose 
200 mg 
 
Period 2: 5 x 100 mg JOTROL oral gelcaps, total resveratrol dose 
500 mg 
 
Period 3: 10 x 100 mg JOTROL oral gelcaps, total resveratrol dose 
1000 mg 
Targeted doses will be achieved with multiple JOTROL  gelcaps of 100 mg 
resveratrol strength. 
For Periods 2 and 3, JOTROL
reassessed 
when safety, tolerability, and PK data analysis are available. Adjustment to 
the currently outlined doses and/or dosing regimen may be necessary, but the 
dose to be administered in Period 2 or 3 will not exceed the one currently 
outlined in the protocol. 
No food will be allowed from at least 10 hours before dosing until at least 
4 hours after dosing in each period. 
Study Part 2: 

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In order to minimize potential PK variability, elderly (more than 65 years old 
subjects) will be not included in study Part 2. 
There will be at least 14 days between dosing of Periods 3 and 4. 
 
Period 4: one single dose of JOTROL oral gelcaps. Dose to be 
administered will be derived from study Part 1 PK and safety data. 
The same dose will be administered in Periods 3 and 4. However, if the 
exposure is higher than expected in Period 3, the dose to be administered in 
Period 4 could be lower, in order to keep AUC exposures lower than 
2.1 
7.2. 
After a supervised fast of at least 11 hours, subjects will be served a critical, 
high-fat, high-caloric meal. Drug administration will occur approximately 
30±1 minutes after the meal has been started. 
Except for water given with study medication and fluids provided with the 
critical breakfast (study Part 2 only), no fluids will be allowed from 1 hour 
before dosing until 1 hour post-dose. 
Following completion of each dose level, PK, safety, tolerability data will be 
evaluated by a Safety Committee and a DSMB before proceeding to the next 
dose. Depending on safety and tolerability as well as on available PK data, 
the escalation scheme may be modified such that intermediate dose levels are 
administered. The Safety Committee will be composed by at least the 
Investigator and one medically qualified Sponsor representative. A formal 
DSMB will be established and constituted by an independent group of 
experts (totally independent of Syneos Health, JOT, and the associated 
investigators on the study) that advises the NIA Director and the study 
investigator. The members of the DSMB serve in an individual capacity 
and provide their expertise and recommendations. The DSMB will be 
constituted and will act according to the FDA Guidance for Clinical Trial 
Sponsors - Establishment and Operation of Clinical Trial Data 
Monitoring Committees1 and the NIA Guidance on Clinical Trials.2 Some 
adjustments to the currently outlined doses and/or dosing regimen may be 
implemented by the Safety Committee or the DSMB as described in Section 
7. 
Study Restrictions: 
Subjects will be asked to refrain from using products that may potentially 
affect their safety and/or the PK profile of the study drug. Main study 
restrictions include: 
 
prescription medication from 14 days prior to the first dosing until after 
the last PK blood sample collection of the study ; 
 
over-the-counter products from 14 days prior to the first dosing until after 
the last PK blood sample collection of the study; 
 
any drugs known to be strong inducer or inhibitor of hepatic drug 
dosing until after the last PK blood sample collection of the study; 
 
natural health products from 14 days pre-dose until after the last 
pharmacokinetic blood sample collection of each period; 
 
food containing poppy seeds within 24 hours prior to admission; 
 
food or beverages containing xanthine derivatives or xanthine-related 
compounds or energy drinks from 48 hours pre-dose until after the last 
PK blood sample collection of each period; 

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food or beverages containing grapefruit, starfruit, pomegranate, 
pineapple, or pomelo from 7 days pre-dose until after the last PK blood 
sample collection of each period;  
 
foods rich in resveratrol (e.g. grapes, peanuts and their products including 
juices and wines) from 7 days pre-dose until after the last PK blood 
sample collection of each period; 
 
alcohol-based products from 24 hours prior to admission until after the 
last PK blood sample collection of each period. 
Subjects will be allowed to engage in normal activity but will avoid lying 
down or sleeping, unless medically necessary or procedurally required, for 2 
hours (study Part 1) and 4 hours (study Part 2) after study drug 
administration. 
Blood Sample Collection for 
PK/PD Biomarkers Analysis:
A total of 17 blood samples will be collected in each period for PK analyses: 
pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 
32 hours post-dose. 
A total of 5 additional blood samples will be collected in each period for 
potential RNA-Seq analysis: pre-dose, and 3, 6, 12, and 24 hours post-dose. 
For study Part 1 only, peripheral blood mononuclear cells (PBMC) will be 
isolated, from at most (maximum) 10 subjects at the following timepoints, in: 
 
Period 1 at pre-dose, 3, and 24 hours post-dose;  
 
Period 2 at 3, 6, and 24 hours post-dose; and in  
 
Period 3 at 3, 6, and 24 hours post-dose. 
Other investigations may be performed using remaining samples already 
collected. 
Urine Collection for PK 
Analysis:  
For study Part 1, urinary levels will be quantified for PK analysis. Urine 
samples will be collected at 6 times or time intervals: spot pre-dose (within 
2 hours before dosing), 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, and 
24-32 hours post-dose. 
Subject Safety: 
Urine drug screen, alcohol breath test, urine cotinine test, and serum 
pregnancy test: at check-in of each period. 
Hematology: at check-in of Period 3 (study Part 1) and study Part 2 
(Period 4). 
Medical surveillance: Subjects will be monitored throughout the study by the 
clinical staff for adverse events (AEs). In each period, the Investigator or 
designee will be on site for drug administration and until 2 hours (study 
Part 1) and 4 hours (study Part 2) post-dose, and available on call for the 
remainder of the study. 
Study Exit Procedures: 
Hematology, biochemistry, urinalysis, urine pregnancy test, vital signs (blood 
pressure, heart rate, respiratory rate, and oral temperature), ECG, and AEs 
monitoring. 
Analytical Method: 
Syneos Health Clinical Bioanalytical Facility will analyze resveratrol, 
resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and 
resveratrol-3-sulfate in plasma and urine samples using a validated method. 
RNA-Seq Analysis, 
Iduronidase, mRNA 
Frataxin, and Other Possible 
Tests 
Potential RNA-Seq analysis and other investigational tests such as 
iduronidase activity measurement and mRNA frataxin will be performed by 
an external laboratory. Details of this additional laboratory work will be 

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available in a separate protocol. Details of the laboratory will be outlined 
when available in an additional information form. 
Pharmacokinetics: 
Plasma PK Parameters: AUC0-t, AUC0-inf, Cmax, Residual area, Tmax, T½ el, and 
Kel. 
Urine PK parameters: Ae0-t, Rmax, and Tmax. 
Statistical Analyses: 
A Statistical Analysis Plan (SAP) will be prepared after completion of the 
final protocol. 
Safety and tolerability: 
Treatment-emergent AEs (TEAEs) will be tabulated by treatment. Changes 
from baseline values in vital signs, ECG, and clinical laboratory parameters 
will be evaluated. Safety and tolerability data will be reported using 
descriptive statistics. A listing of all TEAEs will be provided. Results of vital 
signs, ECG, and clinical laboratory parameters will be listed. 
PK: 
 
Plasma PK:  
For all analytes, summary statistics will be used to describe the PK profile for 
each dose level under fasting conditions (Periods 1, 2, and 3) and for 
administration under fed conditions (Period 4). 
Dose proportionality analysis for AUC0-t, AUC0-inf and Cmax will be performed 
(using the power model with mixed procedure from SAS®) considering data 
under fasting conditions (Periods 1, 2, and 3). 
For evaluation of the food-effect, PK data (ln-transformed AUC0 t, AUC0-inf, 
Cmax and untransformed Tmax) reported under fed conditions (Period 4) and 
under fasting conditions (for the same dose level) will be compared using 
ANOVA from SAS®. The ratio (fed/fasting) and 90% geometric confidence 
interval will also be calculated for AUC0-t, AUC0-inf, and Cmax. 
All inferential statistical analyses will be interpreted in an exploratory sense 
only at an alpha level of 5% for statistical significance.  
Interim PK analyses will be performed between each dose level and will 
inform selection of the subsequent dose. 
 
Urine PK:  
Summary statistics will be used to describe urinary excretion. 

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3. 
Schedule of Events 
 
PROCEDURE 
Screening
Part 1 
Part 21 
Study Exit2
Periods 1, 2 & 3 
Period 4 
D-1 
D1 
D2 
D-1 
D1 
D2 
Demographic Data 
X 
 
 
 
 
 
 
 
Medical and Medication 
Histories
X 
 
 
 
 
 
 
 
Review and Monitoring of 
AEs and Concomitant 
Medications 
 
X 
X 
X 
X 
 
X 
X 
Physical Exam. & Body 
Measurements 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
X 
Biochemistry 
X 
 
 
 
 
 
 
X 
Hematology 
X 
X3 
 
 
X 
 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
HIV and Hepatitis 
X 
 
 
 
 
 
 
 
Urinalysis  
X 
 
 
 
 
 
 
X 
Urine Drug Screen  
X 
X 
 
 
X 
 
 
 
Urine Cotinine Test  
X 
X 
 
 
X 
 
 
 
Alcohol breath test 
 
X 
 
 
X 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
X 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
X 
Confinement  
 
X 
X 
X 
X 
X 
X 
 
Drug Administration 
 
 
X 
 
 
X 
 
 
Blood PK Samples4 
 
 
X 
X 
 
X 
X 
 
Urine PK Samples5 
 
 
X 
X 
 
 
 
 
PBMC Isolation6 
 
 
X 
X 
 
 
 
 
Blood Samples for RNA-Seq 
Analysis, Iduronidase, 
mRNA Frataxin, and Other 
Investigational Tests7 
 
 
X 
X 
 
X 
X 
 
1. For 16 subjects who completed study Part 1 only. 
2. Study exit procedures for subjects who are not included in study Part 2 will be completed after the last blood 
draw of Period 3 (after 32 hours post-dose on Day 2) or within 14 days after the last participation of the 
subject in the study. Study exit procedures for subjects who are included in study Part 2 will be completed 
after the last blood draw of Period 4 (after 32 hours post-dose on Day 2) or within 14 days after the last 
participation of the subject in the study. 
3. For Period 3 only. 
4. Blood samples for PK analysis: pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 
32 hours post-dose.  
5. Urine samples for PK analysis: Urine samples will be collected at 6 times or time intervals: spot pre-dose 
(within 2 hours before dosing), 0-4 hours, 4-8 hours, 8-12 hours, 12-24 hours, and 24-32 hours post-dose. 

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6. PBMC will be isolated in: Period 1 at pre-dose, 3, and 24 hours post-dose; Period 2 at 3, 6, and 24 hours post-
dose; and in Period 3 at 3, 6, and 24 hours post-dose. 
7. Blood samples for potential RNA-seq analysis, iduronidase activity, and mRNA frataxin /other investigational 
tests: pre-dose and 3, 6, 12, and 24 hours post-dose. 

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4. 
Introduction 
4.1 
Background Information 
Resveratrol is a chemical compound (trans-
-trihydroxystilbene3) that is a member of a 
unique family of polyphenols called viniferins.4 It is a polyphenolic compound similar to 
diethylstilbestrol, a synthetic estrogen. Resveratrol presents itself in both trans- and cis- isomeric 
forms. It is found in an abundant amount in red wine, grape berry skins and seeds and, 
particularly in dried roots of the plant Polygonum cuspidatum. Content of resveratrol in grapes 
varies from 0.16 to 3.54 mg/g; dry grape skin contains about 24 mg/g of resveratrol. Resveratrol 
is also present in other berries and nuts. For example, cranberry raw juice contains about 
0.2 mg/L. In other natural foods, the concentration of resveratrol varies in the range of mg/g 
(peanuts, pistachios) to ng/g (bilberries, blue berries). It has been documented that red wine 
contains a much greater amount of polyphenolic compounds than white wine. The concentration 
of resveratrol ranges from 0.1 to 14.3 mg/L in various types of red wine, while white wines 
contain only about 0.1 2.1 mg/L of resveratrol.5 
Resveratrol is also a phytoalexin, a antimicrobial substance synthesized by plants and 
accumulating rapidly at areas of pathogen infection.6 Resveratrol is produced in plants usually in 
response to stress, injury or fungal infection but also in response to mechanical injury, UV 
irradiation and changes in climate.4,6,7  In plants, resveratrol exerts antioxidant function by 
protecting against sun damage. Food products contain both 
- and 
-isoforms of 
resveratrol, mostly in the glycosylated form. Glycosylation prevents enzymatic oxidation, 
thereby increasing stability and bioavailability of resveratrol.5 
Research has recognised the beneficial effects of resveratrol as an important component of the 
overall injury that occurs in various disorders such as oxidative stress, myocardial injury, 
anticancer activity, anti-diabetic activity, and antihypercholesterolemic effects.8 Resveratrol is 
both a free radical scavenger and a potent antioxidant that promotes the activities of a variety of 
antioxidant enzymes. Resveratrol is believed to exert its protective actions through the regulation 
of nitric oxide production and has been shown to have anti-inflammatory, anti-carcinogenic and 
anti-aging effects. The anti-inflammatory and anti-oxidant properties of resveratrol have been 
linked with the prevention of ocular diseases such as age-related macular degeneration (AMD), 
diabetic retinopathy, and glaucoma.4 
Multiplicity of resveratrol biological effects is mainly caused by the abundance and diversity of 
molecular targets of this compound like cyclooxygenases/lipooxygenases, a wide range of 
various kinases, sirtuins, transcription factors, cytokines, DNA polymerase, adenylyl cyclase, 
ribonucleotide reductase, aromatase and others. It is hypothesized that resveratrol provides a 
complex physiological action because of its capability to modulate different pathways in a 
micromolar range. Many studies have shown that resveratrol possesses cardiovascular protective, 
antiplatelet, antioxidant, anti-inflammatory, blood glucose-lowering, and anti-cancer activities. 
By increasing the production of nitric oxide, resveratrol inhibits platelet aggregation and 
stimulates vasodilation. Recently published data have shown that resveratrol protects against 
some neurodegenerative diseases, such as Alzheimer's disease and obesity as well as is effective 
in the management of osteoporosis in post-menopausal women without an increased risk of 
breast cancer.5 

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The trans-isoform is more common in plants. It has been reported that this compound has low 
toxicity as it was well tolerated in the short-term experiments performed in humans. Recent 
clinical trials proved that resveratrol is well-tolerated and pharmacologically safe at doses up to 
5 g/day. However, the data on toxicity of resveratrol in long term experiments are scarce.5 
However, it is reported that resveratrol treatment at a dose of 8 mg/day for one year significantly 
reduced a number of cardiac risk factors.9 
Thousands of basic science experiments in vitro and in animal models suggest low toxicity and 
many positive effects of resveratrol. 
4.2 
Toxicology 
There is ample published nonclinical oral toxicity data regarding the use of resveratrol in acute, 
subchronic, and chronic settings (Table 7 in the Investigator Brochure).10 In a 28-day study 
conducted in male and female CD rats (20/sex/group) where the animals were dosed once daily 
with 0, 300, 1000 or 3000 mg/kg body weight (bw)/day resveratrol by gavage, no observed 
adverse effects were observed in animals treated with 300 mg/kg bw/day resveratrol. Changes 
observed in animals treated with 1000 mg/kg bw/day resveratrol were mild reduced body weight 
in females, slight increase in white blood count and lymphocytes in males, and decreased adrenal 
gland weights in females. No histological changes were observed. Male and female rats treated 
with 3000 mg/kg bw/day of resveratrol showed reduced body weight and food consumption, 
elevated kidney weight, and increased incidences of kidney lesions.11 
The incidence and severity of nephropathy was similar to the animals who received placebo. It 
was concluded that the nephropathy seen in resveratrol groups was not treatment related; 
however, the kidney was identified as the target organ of toxicity in animals treated with 
3000 mg/kg bw/day resveratrol. The 300 mg/kg bw/day resveratrol body weight was identified 
as the no-observed-adverse-effect-level (NOAEL).11  
Three 28-day studies were conducted in rat, dog, and rabbit with daily oral doses ranging from 
250 mg/kg to 3 g/kg. The resveratrol used in these trials was a micronized formulation. In the rat 
study, the only finding was a slight hemolytic anemia in male rats at the 1,000 mg/kg body 
weight per day dose that was not associated with microscopic changes in bone marrow or spleen. 
Recovery animals were not anemic. The NOAEL for both male and female rats was considered 
to be 300 mg/kg/day. For the dog study, dosing up to 300 mg/kg/day did not show any 
cardiovascular effects and there were no changes in weight gain or food consumption. As in the 
rat study, the NOAEL for both male and female dogs was considered to be 300 mg/kg/day. In 
rabbits, the highest daily dose given was 750 mg/kg. At this dose, 5 of 8 males and 1 of 
8 females were euthanized because of body weight loss. Other clinical findings included 
discolored urine and stool abnormalities; and in females, increases in total bilirubin and urea 
nitrogen were seen. These clinical chemistries were not seen after recovery. In this study, the 
kidneys were identified as the target organs of toxicity in males treated with 750 mg/kg/day and 
in females treated with 500 mg/kg/day and 750 mg/kg/day. As with the clinical chemistries, all 
resveratrol-related histopathological findings in the kidneys were reversed following the 4-week 
recovery period. For male rabbits, the NOAEL was considered to be 500 mg/kg/day and 
250 mg/kg/day for females.12 

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4.2.1 
Subchronic Toxicity 
In two studies conducted in CD rats and beagle dogs, rats received daily gavage doses of 0, 200, 
400, or 1000 mg/kg bw of resveratrol for 90 days while dogs received daily orally doses of 0, 
200, 600, or 1200 mg/kg bw of resveratrol for 91 days. No mortality was seen in either study nor 
were there any clinical observations of treatment-related gross toxicities. Female rats in all dose 
groups experienced a reduction in body weight during weeks 10-13; however, females at the 
highest dose experienced statistically significant decrease in body weight. For both male and 
female dogs, there was a statistically significant decrease in body weight at the highest dose that 
started at week 5 in male dogs and at week 6 in female dogs. Other clinical findings for rats 
included a small, but statistically significant increase in mean total bilirubin levels in both sexes 
of rats in the high dose group at study termination. Additionally, a modest but statistically 
significant and dose-related hepatomegaly was seen in both male and female rats. There was no 
evidence of any neurotoxicity in either sex. For dogs, only minimal toxicity was seen. 
Treatment-related changes were limited to inflammatory infiltrates in the urinary bladder and 
kidneys of which the severity ranged from minimal to mild with most dogs demonstrating only 
changes of minimal severity. No other changes were noted in other organs or tissues. The 
NOAEL for rats was determined to be 200 mg/kg/day and 600 mg/kg/day for dogs. The NOAEL 
for both species was determined on the decreases in body weight.13 
4.2.2 
Chronic Toxicity  
A 6-month rat study was conducted using oral doses of resveratrol at 300, 1000, and 
2,000 mg/kg/day or placebo. Weight loss occurred in the 2,000 mg/kg group. Total bilirubin 
values were increased in the 1000 mg/kg group with the values returning to normal after the 
recovery period. The NOAEL was considered to be 300 mg/kg/day.12 Another 6-month study 
using oral daily doses of 100, 300, and 500 mg/kg or placebo was conducted in rabbits. No drug-
related mortality was observed during the study and there were no apparent drug-related clinical 
abnormalities. For animals in the 500 mg/kg dose group, modest increases were seen in clinical 
chemistry parameters of total protein, albumin, GGT, globulin, glucose, urea nitrogen, indirect 
bilirubin and calcium along with decreases in potassium, but these findings were not present in 
the recovery animals. The NOAEL was considered to be 500 mg/kg/day.12 
4.2.3 
Reproductive Toxicity 
A study was conducted in rats using oral daily doses of 300, 1000, and 3000 mg/kg or placebo 
administered on days 7 through 17 of presumed gestation. Five of the 25 animals in the 
3000 mg/kg dose group were sacrificed due to adverse clinical conditions. No effects on the fetus 
were noted. The maternal NOAEL was considered to be 300 mg/kg/day and the developmental 
NOAEL was considered to be 1000 mg/kg/day.12  
4.3 
Clinical 
4.3.1 
Safety 
In a 12-week clinical study 
27 participants who received 
the study drug, 24 completed the study. Thirteen patients received 1 g/day of resveratrol while 
the other 14 patients received 5 g/day of resveratrol. No serious adverse events were noted. 

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Gastrointestinal (GI) side effects were the most frequent occurring adverse effects and were 
deemed to be dose-related. 
The following side effects were seen in 2% to 15% (except if otherwise stated) of the 13 patients 
with Friedreich  ataxia taking resveratrol 500 mg twice daily (total daily dose: 1000 mg) for 
12 weeks: 
 
Infections 
 Urinary tract infection (23%) 
 Tonsilitis (inflammation of tonsil) 
 Inflammation of the sinus 
(sinusitis) 
 
Nervous system disorders 
 Headache (31%) 
 Fatigue (23%) 
 
Gastrointestinal disorders 
 Loose stools  
 Abdominal pain/cramps  
 Bloating 
 Diarrhea  
 Nausea 
 Indigestion/upset stomach 
 
Respiratory disorders 
 Upper respiratory tract 
infection (31%) 
 
 
Cardiac disorders 
 Rapid and irregular heartbeat  
 Increase in the level of substances 
(called enzymes) in blood that 
may indicate heart problems 
 
Kidney and urinary disorders 
 Proteins in urine 
 
 
Liver, gallbladder or pancreas disorders 
 Increase in the level of substances 
(called enzymes) in blood that may 
indicate liver problems  
 
 
Overall, 1,000 mg/day resveratrol was well tolerated.14 
Another randomized, placebo-controlled, double-blind, multicenter 52-week trial of resveratrol in 
subjects 
total of 119 individuals were randomized and 104 completed through to week 52. Fifty-five 
subjects received placebo. The starting dose was 500 mg/day of resveratrol or matching placebo. 
The dose was escalated at 500 mg increments every 13 weeks as follows: 500 mg/day am; 500 mg 
twice a day; 1000 mg am and 500 mg pm; and 1000 mg twice a day. No differences between the 
resveratrol and placebo groups were found on vital signs, physical examinations, or neurologic 
examinations.  

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The side effects that were seen in 2% to 15% (except if otherwise stated) of the 64 patients  with 
who received resveratrol and in equal or greater frequency 
than in the placebo group are listed below. These patients were taking resveratrol 500 mg/day 
ending with 1000 mg twice daily (total daily dose of resveratrol: 2000 mg).15 
 
Infections and infestations (42%) 
 
Nervous system disorders (39%) 
 Headache 
 
 
Gastrointestinal disorders (42%) 
 Diarrhea (41%) 
 Nausea 
 
Psychiatric disorders (36%) 
 
 
General disorders 
 Weight loss (17%) 
 Fall (34%) 
 
Respiratory problem (20%) 
 
Vascular disorders 
 
4.3.2 
Pharmacokinetics  
There are many published human studies dealing with the pharmacokinetics, metabolism, and 
disposition of resveratrol. Absorption, bioavailability, and metabolism of 14C-resveratrol after 
oral and intravenous (IV) doses was investigated in six human volunteers. The absorption of a 
dietary relevant 25-mg oral dose was at least 70%
6,16 Peak 
plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h following oral trans-
resveratrol administration at doses 25, 50, 100 or 150 mg, six times/day.17 A second peak of 
plasma concentration occurring at 6 hours after the oral dose (but not after the IV dose) may be 
due to enterohepatic recirculation of conjugated metabolites by reabsorption after intestinal 
hydrolysis.16 Absorption is reduced when resveratrol is given with a high fat meal with a delayed 
time of peak plasma concentrations.18 There was an increase in systemic exposure to trans-
resveratrol with increasing doses of 25-150 mg. Over this dose range, there was a more than 
dose-proportional increase in AUC0-t and Cmax. The dose proportionality factor was 2.8 for Cmax 
and 6.6 for AUC0-t following a single dose. With repeated doses, steady-state was reached at 
least by dose 7.17  
Resveratrol has poor water solubility and thus has to be bound to plasma proteins to assure its 
body distribution and bioavailability. The plasma protein binding of resveratrol in human plasma 
was 98%.19 
Following oral trans-resveratrol, three metabolic pathways were identified, i.e., sulfate and 
glucuronic acid conjugation of the phenolic groups and hydrogenation of the aliphatic double 
bond, the latter likely produced by the intestinal microflora. There was no evidence of enzymatic 

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oxidation of resveratrol. The rapid appearance of a sulfate conjugate pair in plasma at 2 hours 
after either IV or oral doses suggests that sulfation by the intestine/liver may indicate a rate-
may be important for the oral dose, iv doses also demonstrate highly efficient systemic 
metabolism. In humans, the major metabolites were the glucuronide- and sulfate-conjugates of 
resveratrol and of dihydro-resveratrol, with most of the dose (64 to 70%) recovered in the urine. 
The total recovery of glucuronic and sulfate conjugations in human urine and feces was about 
83 % after oral doses and 74 % after intravenous doses. Resveratrol was shown to inhibit the 
phenotypical index of CYP3A4, CYP2D6 and CYP2C9 and was able to induce the phenotypical 
index of CYP1A2. On the other hand, GST and UGT1A1 activity was minimally affected.20 
Most of the oral dose was recovered in urine. Plasma half-life is 9.2 ± 0.6 hours.16 An almost 
complete elimination of resveratrol and its metabolites from tissues is observed by 72 h after a 
single dose.21  
Additional PK parameters are shown in Table 1 and concentration versus time profiles in Figure 1.22 
Further detailed PK information can be found in the Investigator Brochure.10  
4.4 
Rationale for Study Conduct 
Absorption of micronized resveratrol is good (~70%) but the compound is almost totally 
eliminated by first pass metabolism, primarily to glucuronides and sulfates.10 One of the biggest 
challenges in translating the therapeutic effects of resveratrol is the poor bioavailability of the 
drug when it is administered orally. Resveratrol is eliminated from the body extremely quickly 
and maintaining a therapeutic level in the bloodstream is difficult.16,23 In an attempt to improve 
the oral bioavailability of resveratrol, various formulations and drug delivery systems have been 
tested but none have been forthcoming, with the exception of multiparticulate formulations, 
which have shown increased bioavailability.24 Results have shown that high doses of resveratrol 
are needed to affect disease state; however this causes serious side effects that limit treatment 
utilization. To bypass the first pass effect, a micellar formulation could allow access to lymphatic 
distribution. The structure of the product micelle, with a size of appr. 30 nm, is similar to the 
structure of the naturally formed physiological mixed micelles containing water-insoluble 
compounds in its core which is enclosed by ambiphilic molecules. The higher bioavailability, 
which is obtained by the product micellation, is based on the independence of this transport 
system from the limiting parameters in the formation of the physiological mixed micelle. It is 
important to appreciate the product micelle's character as an "encapsulation and transport 
medium". This must not be confused with "nanoparticles" which are often spoken about in 
nanotechnology. Jupiter Orphan Therapeutics (JOT) is developing a new formulation (called 
JOTROL) of trans-
-trihydroxy-trans stilbene) for the treatment of 
Mucopolysaccharidosis type I (MPS I) and Friedreich ataxia (FRDA). JOTROL is a micellar 
10% resveratrol solubilization formulation that is thought to increase the amount of resveratrol 
and metabolite concentrations in the blood via the lymphatic system.10  
4.5 
Rationale for the Study Population 
As above mentioned, published data have shown that resveratrol protects against some 
neurodegenerative diseases, such as Alzheimer's disease and obesity as well as is effective in the 
management of osteoporosis in post-menopausal women. In order to assess the potential clinical 

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use of resveratrol in usual populations with these medical conditions, the upper age limit of study 
participants will be 75 years. 
Since there have been no studies with pregnant women, it is uncertain whether there is human 
fetal risk associated with the use of resveratrol. Therefore, non-pregnant, non-lactating females 
will be included in the study. In addition, females of childbearing potential will be included if 
they use appropriate methods of contraception. 
Given the fact that smoking may alter the metabolism of resveratrol, smokers will not be 
included in this study. 
Table 1 Plasma PK of Resveratrol, Two Resveratrol Monoglucuronides and Resveratrol 3-
sulfate After Single Oral Doses of Drug  
 
 
 

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Figure 1 Mean Plasma Concentrations of Resveratrol (A), Two Resveratrol 
Monoglucuronides (B and C), and Resveratrol-3-sulfate (D) Versus Time in Healthy 
Volunteers Who Received a Single Dose of Resveratrol at 0.5, 1.0, 2.5, or 5.0 g Doses. 
 
 
 

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5. 
Objectives 
The objectives of this study are: 
 To characterize the PK profile of JOTROL (resveratrol) following oral administration of 
SAD ranging from 200 mg up to a dose currently estimated at 1000 mg, in healthy adult 
subjects; 
 To evaluate the effect of food on the PK profile of JOTROL. 
6. 
Study Design 
This will be a single center, Phase 1, open-label, sequential SAD study, with a food-effect arm. 
The study will be divided into two parts: 
 Study Part 1 consists of 3 periods with SAD of JOTROL under fasting conditions. Periods 2 
and 3 will be initiated with updated doses after safety, tolerability, and PK data are evaluated 
by the Safety Committee and the DSMB and deemed acceptable for single doses for 
subsequent doses. 
 Study Part 2 consists of a single oral JOTROL dose under fed conditions. JOTROL dose for 
this study part will derive from study Part 1 safety, tolerability, and PK data. 
This study is intended for filing under FDA regulations. 
7. 
Rationale for Dose Selection 
7.1 
Starting Dose 
Diarrhea or other gastrointestinal symptoms were reported in clinical studies in healthy 
volunteers at doses of 1,000 mg/day or higher of unmodified resveratrol. Studies do not indicate 
significant adverse effects below 1,000 mg.20,25 In addition, results of metabolic interactions with 
cytochrome P-450 complex enzymes at doses higher than 1,000 mg/day suggested that this dose 
of unmodified resveratrol is the upper limit for clinical studies.20 Considering different NOAEL 
values obtained with different animal species in subchronic and chronic toxicity studies (sections 
4.2.1, 4.2.2, and 4.2.3) that are within 200 mg/kg and 700 mg/kg25 it may be assumed that 
resveratrol shows a good safety profile within a certain range dose. In addition, a dose of 
50 mg/kg of study product JOTROL administered to rats produced an AUC (2.5 
) 
roughly equivalent to that seen after a 2,500 mg dose in humans.10 Applying a security factor of 
10, the entry dose might be 250 mg. Consequently, a starting dose of resveratrol 200 mg can be 
considered safe. 
7.2 
Maximum Dose in this Study 
The FDA preliminary review of the published data on resveratrol shows that the nonclinical data 
can only support daily oral doses of unmodified resveratrol (i.e. non-micronized drug with no 
absorption enhancers) of up to 3,000 mg/day for no more than 13 weeks. Published data from a 
26-week study in mice demonstrated renal toxicity at 1,000 mg/kg/day, for which the Human 
Equivalent Dose is approximately 5,000 mg. Based on published data in healthy volunteers, 
AUC exposures at a dose of 3,000 mg/day of unmodified resveratrol is estimated to be 

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2.1 
JOTROL formulation has been modified to enhance bioavailability, 
JOTROL doses to be used in this study should produce AUC exposures less 
26  
7.3 
Dose Escalation Scheme (Study Part I) 
The dose escalation scheme for this SAD study (Part 1) was established considering the 
following assumptions: 
 PK animal data (rat, with a dose of 50 mg/kg) suggest that resveratrol administered as 
JOTROL produce an AUC (2.5 
) roughly equivalent to that seen after a 
2,500 mg dose in humans; 
 AUC exposures at a dose of 3,000 mg/day of unmodified resveratrol is estimated to be 
2.1 
res during this study must not be higher than 2.1 
; 
 The bioavailability of resveratrol from JOTROL increases linearly with the dose. 
The nominal planned dose escalation scheme for Study Part I corresponds to a 2.5-fold 
increment between the two first doses, and 2 fold increment between the second and third dose 
levels. Both current second and third dose levels are nominal as JOTROL
administered in Periods 2 and 3 will be reassessed when safety, tolerability, and PK data analysis 
are available. These dose levels will be adjusted, lowered or increased, but in any case 
 
7.4 
Dose Level in Study Part II 
The same dose is planned to be administered in Periods 3 (Part I) and 4 (Part 2). However, if the 
exposure is higher than expected in Period 3, the dose to be administered in Period 4 could be 
 7.2. 
7.5 
Dose Escalation Criteria 
Each dose level will be dosed sequentially in an ascending fashion, with at least 14 days between 
dosing of consecutive dose levels. Following completion of each level, safety, tolerability, and 
PK data will be evaluated by a Safety Committee and a DSMB before proceeding to the next 
dose. The Safety Committee and the DSMB will review the whole safety and tolerability data, 
as well as PK data up to 32 hours post-dose, in order to make decisions regarding progression to 
the next prescribed dose level, decreasing the next dose level, repeating a dose level or not 
evaluating any additional dose level, based on consideration of the clinical significance of 
several safety and tolerability parameters, as well as PK data. The Safety Committee will be 
composed by at least the Investigator, one medically qualified Sponsor representative, and an 
independent third party physician. A formal DSMB will also be established and constituted by 
an independent group of experts (totally independent of Syneos Health, JOT, and the 
associated investigators on the study) that advises the NIA Director and the study 
investigator. The members of the DSMB serve in an individual capacity and provide their 
expertise and recommendations. The DSMB will be constituted and will act according to 
the FDA Guidance for Clinical Trial Sponsors - Establishment and Operation of Clinical 
Trial Data Monitoring Committees1 and the NIA Guidance on Clinical Trials.2 Dose 

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escalation may occur only following mutual agreement between the Safety Committee and the 
DSMB members.  
Minutes of the safety review committee meeting and the DSMB will be prepared and signed by 
all voting participants. Minutes will include the decision to escalate the dose, confirmation of the 
next dose level, confirmation of the safety monitoring and washout period, rationale for the 
decisions and supportive data. The minutes will be shared with the Independent ethics committee 
(IEC)/Institutional review board (IRB). 
Some adjustments to the currently outlined doses may be implemented by the Safety Committee, 
or the DSMB but the dose to be administered at a given dose level will not exceed the dose 
corresponding to AUC exposures of 2.1 
 
Stopping Rules for Dose Escalation 
Dose escalation will be halted if any of the events described below occur within one dose level: 
 
 2 subjects in the same study period suggesting that 
subjects receiving higher dose levels would be at risk for similar adverse drug reactions. 
 The occurrence of one serious adverse event (SAE) considered at least possibly related to 
the study drug. 
 The occurrence of severe AEs considered at least possibly related to the study drug in 
 2 subjects and independent of within or not within the same system organ class (SOC). 
 Clinically significant abnormalities of the same character, at least of moderate severity, 
 2 subjects 
Cumulative Study Events 
In addition to the events listed above, any of the events described below occurring at different 
dose levels administered throughout the study (i.e., cumulative events) will also result in a 
temporary halt of dose escalation: 
 The occurrence of severe AEs of the same character considered at least possibly related 
 2 subjects. 
 Clinically significant abnormalities of the same character, at least of moderate severity, 
 3 subjects 
 Determination by the SRC that a pattern of AEs precludes further dose escalation, even if 
no other stopping rules have been met. 
Study Stopping Rules 
The study will be terminated if any of the following criteria are met: 
 The occurrence SAEs considered at least possibly related 
 2 subjects 
and independent of within or not within the same SOC. 

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 Determination by the SRC that a pattern of AEs precludes any further dosing. 
8. 
Study Population 
8.1 
Sample Size 
A total of 24 healthy adult male or female volunteers will be included in study Part 1. Only 
16 subjects who completed study Part 1 will be included in study Part 2. In order to minimize 
potential PK variability, elderly (more than 65 years old subjects) will be not included in study 
Part 2. These 16 subjects will be selected according to their order of enrolment in the study, 
provided their consent to continue the study, they follow the study restrictions and they still meet 
study criteria. Subjects numbers are judged adequate to achieve the study objectives. 
For study Part 1 only, an effort will be made to include to the extent possible, subjects of the 
following age groups: 
 
 
 70 years of age; 
 
 
 75 years of age. 
8.2 
Inclusion Criteria 
Subjects enrolled in this study will be members of the community at large. The recruitment 
advertisements may use various media types (e.g., radio, newspaper, the clinical site Web site 
and volunteer database). Subjects must meet all of the following criteria to be included in the 
study: 
1) Normal healthy male or female volunteers, non-smokers (no use of tobacco products within 
3 months prior to screening),  
 75 years of age, with BMI > 18.5 and < 30.0 kg/m2 
and body weight 
 
. 
2) Healthy as defined by: 
a) the absence of clinically significant illness and surgery within 4 weeks prior to dosing. 
Subjects vomiting within 24 hours predose will be carefully evaluated for upcoming 
illness/disease. Inclusion pre-dosing is at the discretion of the Investigator. 
b) the absence of clinically significant history of neurological, endocrine, cardiovascular, 
respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, 
and metabolic disease as determined by the Investigator. 
3) Females of childbearing potential who are sexually active with a male partner must be 
willing to use one of the following acceptable contraceptive methods throughout the study 
and for 30 days after the last study drug administration: 
a) intra-uterine contraceptive device without hormone release system placed at least 
4 weeks prior to study drug administration; 
b) male condom with intravaginally applied spermicide starting at least 21 days prior to 
study drug administration;  
c) sterile male partner (vasectomized since at least 6 months). 
4) Capable of consent 

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8.3 
Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1) Any clinically significant abnormality at physical examination, clinically significant 
abnormal laboratory test results or positive test for hepatitis B, hepatitis C, or HIV found 
during medical screening.  
2) Positive urine drug screen or urine cotinine test at screening. 
3) History of allergic reactions to resveratrol, polyphenols, other related drugs, or to any 
excipient in the formulation. 
4) Positive pregnancy test at screening. 
5) Breast-feeding subject. 
6) Clinically significant ECG abnormalities or vital sign abnormalities (systolic blood pressure 
lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, 
or heart rate less than 50 or over 100 bpm) at screening. 
7) History of significant alcohol abuse within 1 year prior to screening or regular use of alcohol 
within 6 months prior to the screening visit (more than 14 units of alcohol per week 
[1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]).  
8) History of significant drug abuse within 1 year prior to screening or use of soft drugs (such as 
marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, 
phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine 
derivatives) within 1 year prior to screening. 
9) Use of resveratrol for a medical condition or in the context of another clinical trial within a 
period of 30 days prior to the first dosing. 
10) Participation in a clinical research study involving the administration of an investigational or 
marketed drug or device within 30 days prior to the first dosing, administration of a 
biological product in the context of a clinical research study within 90 days prior to the first 
dosing, or concomitant participation in an investigational study involving no drug or device 
administration. 
11) Use of medications for the timeframes specified below, with the exception of medications 
exempted by the Investigator on a case-by-case basis because they are judged unlikely to 
affect the PK profile of the study drug or subject safety (e.g., topical drug products without 
significant systemic absorption:  
a) prescription medication within 14 days prior to the first dosing; 
b) over-the-counter products and natural health products (including herbal remedies, 
homeopathic and traditional medicines, probiotics, food supplements such as vitamins, 
minerals, amino acids, essential fatty acids, and protein supplements used in sports) 
within 14 days prior to the first dosing, with the exception of the occasional use of 
acetaminophen (up to 2 g daily); 

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c) use of any drugs known to induce or inhibit hepatic drug metabolism, including 
St. 
 
d) depot injection or an implant of any drug within 3 months prior to the first dosing. 
12) Donation of plasma within 7 days prior to dosing. Donation or loss of blood (excluding 
volume drawn at screening) of 50 mL to 499 mL of blood within 30 days, or more than 
499 mL within 56 days prior to the first dosing. 
13) Any reason which, in the opinion of the Investigator, would prevent the subject from 
participating in the study. 
9. 
Clinical Procedures 
Unless otherwise specified, procedures, data collection and evaluation will be conducted as per 
the clinical site SOPs. 
9.1 
Screening Procedures 
Subject screening procedures will be performed within 28 days preceding administration of study 
medication. Subjects must provide written informed consent prior to initiation of any screening 
procedures. The consent to perform some general screening procedures may be obtained on a 
consent document other than the Informed Consent Form (ICF) specific to this study, and 
therefore, some screening test results could be obtained before signature of the ICF specific to 
this study. The study-specific ICF must be signed and dated by the subject before participation to 
study-specific procedures. 
Screening procedures will include: demographic data, medical and medication histories, physical 
examination, body measurements, ECG (12-lead), vital signs (blood pressure, heart rate, 
respiratory rate, and oral temperature), hematology, biochemistry, coagulation, serology (HIV, 
hepatitis B and C tests), urinalysis, urine cotinine test, urine pregnancy test, and urine drug 
screen. 
For eligibility purposes, abnormal laboratory or vital signs results may be repeated once if 
abnormal result is observed at the initial reading. Moreover, abnormalities found in the ECG may 
need to be confirmed by repeated measurements. In the event that the participation of a subject in 
the study is delayed and some screening procedures had been performed outside the prescribed 
screening window, outdated screening procedures can be repeated. 
9.2 
Confinements, Visits, and Washout 
For each period, subjects will be confined from Day -1 until after the 32-hour post-dose blood 
draw. 
There will be a washout of 14 days or more between doses. The washout period may be 
increased for logistical considerations. Participation of each subject in this study should last 
approximately 1 month (for subjects participating in study Part 1 only) and 1.5 months (for 
subjects participating in both study parts). 

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9.3 
Study Medication 
Treatment A (Period 1): 
JOTROL (resveratrol) 100 mg oral gelcap (Jupiter Oprhan 
Therapeutics, USA) given as 2 x 100 mg gelcaps under fasting 
conditions, total resveratrol dose: 200 mg 
Treatment B (Period 2): 
JOTROL (resveratrol) 100 mg oral gelcap (Jupiter Oprhan 
Therapeutics, USA) given as 5 x 100 mg gelcaps under fasting 
conditions, total resveratrol dose: 500 mg 
Treatment C (Period 3): 
JOTROL (resveratrol) 100 mg oral gelcap (Jupiter Oprhan 
Therapeutics, USA) given as 10 x 100 mg gelcaps under fasting 
conditions, total resveratrol dose: 1000 mg 
Treatment D (Period 4): 
JOTROL (resveratrol) 100 mg oral gelcap (Jupiter Oprhan 
Therapeutics, USA) given as 10 x 100 mg gelcaps under fed 
conditions, total resveratrol dose: 1000 mg 
Targeted doses will be achieved with multiple JOTROL
containing 100 mg of 
resveratrol. For Periods 2 and 3, JOTROL
hen 
safety, tolerability, and PK data analysis are available. The same dose is planned to be 
administered in Periods 3 and 4. However, if the exposure is higher than expected in Period 3, 
the dose administered could be lower in Period 4, in order to keep AUC exposures lower than 
2.1 
, as specified in section 7.2.  
9.4 
Drug Supplies and Accountability 
It is the responsibility of the Sponsor to ensure that study medication provided for this study are 
manufactured under Good Manufacturing Practices (GMP) and are suitable for human use. The 
Sponsor is responsible to ship a sufficient amount of dosage units to allow the clinical site to 
maintain an appropriate sampling for the study.  
Study medication will be stored at the clinical site as per applicable requirements. The 
medications will be stored in a locked, environmentally-controlled medication room with 
restricted access. Container(s) will bear a label containing at least the name of the study drug, lot 
and/or batch number, and manufacturing and/or expiry/retest date. 
Individual doses for each subject will be dispensed at the clinical site, as per appropriate SOP. 
Individual doses will be dispensed in appropriate envelopes/containers indicated with at least the 
project number and the subject number/spare number. 
All study drug received at the site will be inventoried and accounted for throughout the study and 
the result recorded in the drug accountability/retention record according to the clinical site 
appropriate SOP. 
9.5 
Drug Administration 
Study medication will be administered to each subject with approximately 240 mL of water and 
a hand and mouth check will be performed to ensure consumption of the medication. Additional 
water may be provided if needed. 

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Study Part 1 (Periods 1, 2, and 3): All subjects will be sequentially dosed in an ascending manner 
with at least 14 days between the last dosing and the subsequent nominal dose level which will 
be calculated based on observed safety, tolerability, and PK results. Subjects will receive a single 
oral dose of JOTROL gelcaps under fasting conditions using the following nominal dosage 
levels: 
Study period 
Planned dose levels of JOTROL 
1 
200 mg (given as 2 x 100 mg gelcaps), total dose of resveratrol: 200 mg  
2 
500 mg (given as 5 x 100 mg gelcaps), total dose of resveratrol: 500 mg 
3 
1000 mg (as 10 x 100 mg gelcaps), total dose of resveratrol: 1000 mg 
For Periods 2 and 3, JOTROL
to be administered will be reassessed when safety, 
tolerability, and PK data analysis are available. Adjustment to the currently outlined doses and/or 
dosing regimen may be necessary, but the dose to be administered in Period 2 or 3 will not 
exceed the one currently outlined in the protocol. 
Time of dosing will be set equal to the time when the first gelcap is administered to the subject. 
The complete dosing procedure must be completed within 3 minutes. 
Following completion of each dose level, PK, safety, tolerability data will be evaluated by a 
Safety Committee and a DSMB before proceeding to the next dose.  
The same JOTROL dose will be administered in Periods 3 and 4. 
Study Part 2 (Period 4): Only 16 subjects who completed study Part 1 will receive the highest 
dose of JOTROL tested during study Part 1, as a single oral dose of JOTROL gelcaps under fed 
conditions. In order to minimize potential PK variability, elderly (more than 65 years old 
subjects) will be not included in study Part 2. However, depending on safety and tolerability as 
well as on available PK data from Part 1 (in order to keep AUC exposures lower than 2.1 
7.2.), the dose to be used during study Part 2 may be reduced. 
9.6 
Study Restrictions 
9.6.1 
Food and Fluids 
Study Part 1 (Periods 1, 2, and 3): No food will be allowed from at least 10 hours before dosing 
until at least 4 hours after dosing. 
Study Part 2 (Period 4): After a supervised fast of at least 11 hours, subjects will be served a 
critical, high-fat, high-calorie meal of approximately 800 to 1000 calories (approximately 50% of 
total caloric content of the meal derived from fat). This test meal should derive approximately 
150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. The meal will 
consist of two eggs fried in butter, two slices of toast with butter, two strips of bacon, 120 g of 
hash brown potatoes, and 240 mL of whole milk. Subjects will be informed to start their meal as 
soon as it is served and to complete it in 30 minutes or less. Subjects will be informed that they 
should eat the entire meal. Drug administration will occur 30 ± 1 minutes after the meal has been 
started. Subjects will fast for not less than 4 hours after drug administration.  

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Meals will be standardized and similar in composition between periods. 
Except for fluids provided with the critical breakfast (study Part 2 only) and water given with 
study medication, no fluids will be allowed from 1 hour before dosing until 1 hour post-dose. 
Water will be provided ad libitum at all other times.  
In addition, subjects will be required to abstain from: 
 food containing poppy seeds within 24 hours prior to admission; 
 food or beverages containing xanthine derivatives or xanthine-related compounds or energy 
drinks from 48 hours prior to dosing until after the last PK blood sample collection of each 
period; 
 food or beverages containing grapefruit, starfruit, pomegranate, pineapple, or pomelo from 
7 days prior to dosing until after the last PK blood sample collection of each period; 
 foods rich in resveratrol (e.g. grapes, peanuts and their derived-products including wines and 
juices) from 7 days pre-dose until after the last PK blood sample collection of each period. 
9.6.2 
Tobacco, Alcohol, and Illicit Drugs 
Subjects will be required to abstain from using soft or hard drugs or any tobacco products from 
screening and throughout the study. 
Consumption of alcohol-based products will be prohibited from 24 hours prior to admission until 
after the last PK blood sample collection of each period. 
9.6.3 
Concomitant Medications 
Subjects will be required to avoid using prescription and over-the-counter medications for the 
period of time specified in exclusion criterion 11) and throughout the study. Subjects will be 
required to avoid using natural health products (including herbal remedies, homeopathic and 
traditional medicines, probiotics, food supplements such as vitamins, minerals, amino acids, 
essential fatty acids, and protein supplements used in sports) from 14 days prior to dosing until 
after the last PK blood sample collection of each period. 
No concomitant medications are allowed during the study, with the exception of one(s) required 
for the medical management of an adverse event, medications exempted by the Investigator on a 
case-by-case basis that are judged unlikely to affect the pharmacokinetic profile of the study drug 
or subject safety (e.g., topical drug products without significant systemic absorption) and 
occasional use of acetaminophen. 
All medications taken by subjects after screening until the last study day will be documented as 
concomitant medications. Any concomitant medication use, other than the allowed medications 
stated above, will be reviewed and evaluated on a case-by-case basis by the Investigator to 
potential impact on the study results.  

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9.6.4 
Posture and Physical Activity 
Subjects will be allowed to engage in normal activity but will avoid lying down or sleeping, 
unless medically necessary or procedurally required, for 2 hours (study Part 1) and 4 hours 
(study Part 2) after drug administration. Vigorous activity will be prohibited at all times during 
the confinement. 
9.7 
Sample Collection and Processing 
9.7.1 
Blood Sample Collection  
In each period : 
 a total of 17 blood samples will be drawn from each subject for PK analyses. Blood samples 
will be collected prior to drug administration and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 
12, 16, 24, and 32 hours post-dose (3 mL for each sampling time). The time tolerance 
window for blood sample collection during the confinement period will be ±1 minute for all 
samples collected before 8 hours post-dose and ±3 minutes for subsequent samples. Sample 
collections done outside the pre-defined time windows will not be considered as protocol 
deviations since actual post-dose sampling times will be used for PK and statistical analyses. 
Unless otherwise specified or for subject safety, when blood draws and other procedures 
coincide, blood draws will have precedence. A saline intravenous catheter will be used for 
blood collection to avoid multiple skin punctures, when appropriate. Otherwise, blood 
samples will be collected by direct venipuncture. 
 a total of 5 additional blood samples (for plasma and buffycoats) will be collected for 
potential RNA Seq analysis, iduronidase activity, and mRNA frataxin: pre-dose, and 3, 6, 12, 
and 24 hours post-dose (10 mL for each sampling time). 
For study Part 1 only, PBMC will be isolated, from at most (maximum) 10 subjects at the 
following timepoints (16 mL for each sampling time): 
 Period 1: pre-dose, 3, and 24 hours post dose; 
 Period 2: 3, 6, and 24 hours post dose; 
 Period 3: 3, 6, and 24 hours post dose. 
PBMC will be isolated as per the Project Specific Procedure (PSP).  
The total volume of blood including that collected for eligibility and safety purposes should not 
exceed 733 mL for the whole study (605 mL for subjects participating in study Part I only).  
9.7.2 
Urine Sample Collection for PK analysis 
In study Part 1, urine will be collected for quantitation for PK analysis. Urine samples will be 
collected at 6 times or time intervals: spot pre-dose (within 2 hours before dosing), 0-4 hours, 
4-8 hours, 8-12 hours, 12-24 hours, and 24-32 hours post-dose. 
If a subject cannot void his or her bladder within 30 minutes before dosing, a sample from earlier 
that morning may be used as the pre-dose sample. Voids that occur within the time interval will 

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be pooled, and subjects will be asked to void their bladder within 10 minutes before the end of 
each collection interval, so that each new interval will begin with an empty bladder. Any urine 
voided by subjects at the intersection (within 10* minutes) of two intervals will be included in 
the earlier sample. Any urine voided by subjects but not collected will be documented. 
**For Day 2 (24 hours post-dose) urine collection, subjects will be asked to void their bladder 
within 15 minutes before the end of the collection interval (12-24 hours). 
Plasma and urine samples will be collected and processed as per the Analytical Methodology 
Information Sheet. 
Since resveratrol is sensitive to light, blood and urine collection tubes will be protected from 
light, sample processing will be performed under sodium lamp, and urine and plasma samples 
will be transferred into amber vials. 
Other investigations may be performed using remaining samples already collected. 
9.8 
Subject Monitoring 
Subjects will be monitored throughout the study by the clinical staff for AEs. In each period, the 
Investigator or designee will be on site for drug administration and until 2 hours (study Part 1) 
and until 4 hours (study Part 2) post-dose, and available on call for the remainder of the study. If 
necessary, the Investigator or designee at the clinical site or a healthcare professional in a nearby 
hospital will administer treatment for any AE(s). A crash cart or emergency bag containing the 
necessary rescue material and appropriate medications will be available in the clinic to allow 
rapid intervention in case of emergency. 
Safety parameters, including laboratory results and ECG, will be assessed by the Investigator or 
designee, using 
s criteria for biomedical laboratory and ECG acceptance ranges 
as suggested guidelines in making the medical assessment. 
Scheduled safety measurements will be repeated according to the clinical site SOPs or upon 
request from the Investigator or designee. Any abnormal repeated measurement will be evaluated 
by the Investigator or designee and repeated if judged necessary. Further action may be taken 
upon 
s request. 
Subjects will be advised to notify their health care professional(s) (e.g. physician, dentist, and/or 
pharmacist) that they are participating in a clinical research study on a drug called resveratrol 
before taking any medicines or undergoing any medical procedure. 
9.8.1 
Vital Signs 
Blood pressure, respiratory rate, oral temperature, and heart rate will be measured in a sitting 
position (except for safety reasons) at screening and study exit. 
9.8.2 
ECG 
Supine ECG will be performed at screening and study exit. 

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9.8.3 
Physical Examination 
A physical examination will be performed at screening. 
9.8.4 
Cotinine, Drug, and Alcohol Screen 
A urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, PCP, MDMA, methadone) and a urine cotinine test will 
be performed at screening. A urine drug screen, a urine cotinine test, and an alcohol breath test 
will be performed before dosing at check-in of each period. 
9.8.5 
Pregnancy Test 
A urine pregnancy test will be performed at screening and at study exit, and a serum pregnancy 
test will be performed at check-in of each period. 
9.8.6 
Laboratory Assessments 
9.8.6.1 
RNA-Seq Analysis, Iduronidase, mRNA Frataxin, and Other Possible Tests 
Potential RNA-Seq analysis will be performed before dosing and 3, 6, 12, and 24 hours post-
dose in each period. Details for this analysis will be included in a separate protocol. Other 
investigational tests such as iduronidase activity measurement and mRNA frataxin may be 
performed by an external laboratory. Details of this additional laboratory work will be available 
in a separate protocol. 
9.8.6.2 
PBMC Isolation 
PBMC will be isolated, from at most (maximum) 10 subjects on Days 1-2 in study Part 1. 
9.8.6.3 
Biochemistry 
Biochemistry will be performed at screening and study exit. The following will be assessed: 
albumin, alkaline phosphatase, AST, ALT, urea, calcium, chloride, glucose, phosphorus, 
potassium, creatinine, sodium, total bilirubin, and total protein. 
9.8.6.4 
Serology 
Serology will be performed at screening. The following will be assessed: HIV antigen and 
antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibody. 
9.8.6.5 
Hematology 
Hematology will be performed at screening, at check-in of Period 3 (study Part 1) and of study 
Part 2 (Period 4), and at study exit. The following will be assessed: complete blood count with 
differential, hemoglobin, and hematocrit. 
9.8.6.6 
Coagulation 
Coagulation tests will be performed at screening. The following will be assessed: prothrombin 
time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT). 

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9.8.6.7 
Urinalysis 
Urinalysis will be performed at screening and at study exit. The following will be assessed: 
macroscopic examination, pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, 
nitrite, urobilinogen, and leukocytes. Unless otherwise specified, microscopic examination will 
be performed according to internal procedures. 
9.9 
Study Exit Procedures 
Hematology, biochemistry, urinalysis, urine pregnancy test, vital signs (blood pressure, 
respiratory rate, heart rate, and oral temperature), ECG, and AE monitoring will be performed on 
the last study day. For subjects who are not included in study Part 2, study exit procedures will 
be completed after the last blood draw of Period 3 (after 32 hours post-dose on Day 2). For 
subjects who are included in both study parts, study exit procedures will be completed after the 
last blood draw of Period 4 (after 32 hours post-dose on Day 2). If not possible, all efforts will be 
made to complete study exit procedures within 14 days after the last participation of the subject 
in the study. 
9.10 Data Collection and Evaluation 
Subjects' personal information will be stored in an electronic data capture (EDC) system 
Alphadas®). All clinical raw data will be recorded promptly, accurately, and 
legibly; either directly into the EDC system as e-source data or indelibly on paper (e.g., ECG 
readings or raw data sheets when electronic data capture is not possible). A detailed list of the 
type (electronic or paper) and location for all source data will be included in the Trial Master 
File. When recorded electronically, Case Report Forms will be electronically generated 
afterwards. All raw data will be conserved in order to maintain data integrity. The Investigator 
and/or the clinical staff have the responsibility of ensuring the completeness and accuracy of the 
® are validated and are Code of Federal Regulations (CFR) 
part 11 compliant applications. 
9.11 Subject Withdrawal and Replacement 
Subjects will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or designee may withdraw any subject from 
the study for one of the reasons described below; subject withdrawal will be done in accordance 
with the clinical site
 
 
safety reason; 
 
non-compliance with protocol requirements; 
 
significant protocol deviation; 
 
positive cotinine, alcohol, drug, or pregnancy test; 
 
vomiting within 3 hours (study Part 1) and 7 hours (study Part 2) after dosing.  
Subjects excluded from dosing in one period as per criteria listed above, may be invited to 
participate in subsequent periods of the study if deemed appropriate by the Investigator and 
appropriate from a statistical standpoint (i.e. would permit adequate statistical comparison). 
However, subjects with positive cotinine, alcohol, drug, or pregnancy test will be definitively 
withdrawn from the study. Hematology results will be reviewed by the Investigator or designee 
prior to dosing in Period 3 (study Part 1) and in Period 4 (study Part 2). Subjects will be 

2 0 2 0 1 6 Res veratr ol (J O T R O L) Gelca ps P h ase I S A D St u d y 
J u pit er O pr h a n T h era p e utics 
2 5- N O V- 2 0 2 0 
 
 
C o nfi d e ntial 
Pa ge 3 7 of 4 5 
A me n d me nt II  
t hese test res ults. S u bjects w h o wit h dra w or are wit h dra w n fr o m st u d y Part 1 after d osi n g, f or 
reas o ns ot her t h a n safet y a n d t olera bilit y, ma y b e re pla ce d after c o ns ultati o n bet wee n t he S afet y 
C o m mittee me m bers a n d t he D S M B me m be rs  i n or der t o ass ure i niti ati n g st u d y Part 2 wit h 
1 6 s u bjects. S uc h re place me nt res ulti n g i n d osi n g m ore s u bjects t h a n pla n n e d i n t his pr ot oc ol 
w o ul d be d oc u me nte d i n a pr ot oc ol a me n d me nt. 
S u bjects w h o wit h dra w or are wit h dra w n will be as k e d t o re m ai n at t he cli nic u ntil t h e 
I n v esti gat or or a d esi g n ee a grees t hat t he s u bject is fi n e a n d ca n be disc har ge d. As s o o n as 
s u bject wit h dra wal is c o nfir me d, bl o o d sa m pli n g will be st o p pe d. A P K bl o o d dra w ma y b e 
c ollecte d at t he ti me of wit h dra wal if dee me d re q uir e d b y t h e I n vesti gat or. St u d y e xit pr oce d ures 
will b e perf or me d at t he ti me of wit h dra w al fr o m t he st u d y or as s o o n as p ossi ble t h ereafter.  
9. 1 2  A d verse E ve nts 
9. 1 2. 1  Rec o r di n g of A d verse E ve nts 
A Es will be rec or de d a n d e val uate d f or t heir seri o us ness, se verit y, a n d relati o ns hi p t o t he st u d y 
me dicati o n. A Es will be c ollecte d a n d d oc u me nte d d uri n g t he c o urse of t he st u d y a n d u ntil 
4 da ys f oll o wi n g t he l ast st u d y dr u g a d mi nistrati o n, if re p orte d. A Es will be f oll o we d- u p u ntil 
c o m plete res ol uti o n, or u ntil t he I n vesti gat or j u d ges it t o be safe t o disc o nti n ue f oll o w- u p. T he 
relati o ns hi p t o t he st u d y me dicati o n will be classifie d acc or di n g t o t he cli ni cal site S O Ps. 
9. 1 2. 2  Seri o us A d verse E ve nts 
9. 1 2. 2. 1  
Seri o us A d verse E ve nt Re p orti n g t o t he S p o ns or 
A n y S A E will be re p orte d t o t he S p o ns or via tele p h o ne, fa x, e- mail or i n pers o n, wit hi n 2 4 h o urs 
of k n o wle d ge b y t he I n vesti gat or, a n d t h e n i n writi n g as s o o n as p ossi ble, b ut n o later t ha n 
7 cale n dar da ys after first k n o wle d g e of t he S A E. T he n otificati o n m ust be directe d t o: 
, P h. D. 
 
J u piter Or p ha n T h era p e utics 
6 0 1 Herita ge Dri v e 
J u piter, Fl ori da 3 3 4 5 8  
Tel.: 
9. 1 2. 2. 2  
Seri o us A d verse E ve nt Re p orti n g t o Re g ul at or y A ge nc y(ies) 
T he S p o ns or is res p o nsi ble f or n otif yi n g t h e F D A of s us pecte d, u n e x pecte d, seri o us a d verse dr u g 
reacti o ns o bser ve d d uri n g c o n d u ct of st u dies i n w hic h t he i n vesti gati o nal dr u g is a d mi nistere d.  
F D A n otificati o n of fatal or life-t hreate ni n g s us pecte d, u ne x p ecte d, seri o us a d vers e dr u g reacti o n 
m ust be ma de as s o o n as p ossi ble, b ut n o later t ha n 7 cale n dar da ys after bec o mi n g a ware of t h e 
i nf or mati o n. F D A n otificati o n of all ot her s us pect e d, u ne x pecte d, seri o us a d vers e dr u g reacti o ns 
t hat are n eit h er fat al n or life-t hreate ni n g m ust be ma de as s o o n as p ossi ble, b ut n o later t ha n 
1 5 cale n dar da ys after bec o mi n g a ware of t h e i nf or mati o n. 
P P D
P P D
P P D

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The Sponsor is responsible to comply with any other applicable regulatory requirement(s) related 
to the reporting of SAE to other regulatory authority(ies). 
9.12.2.3 
Serious Adverse Event Reporting to the Independent Ethics Committee 
It is the responsibility of Syneos to report as soon as possible, but no later than 7 calendar days 
after first knowledge by the Investigator, fatal or life-threatening suspected, unexpected, serious 
adverse drug reactions to the IEC responsible for the study. 
It is the responsibility of Syneos to report to the IEC all other suspected, unexpected, serious 
adverse drug reactions that are neither fatal nor life-threatening, as soon as possible, but no later 
than 14 calendar days after first knowledge by the Investigator. 
9.13 Pregnancy 
In the event a dosed female subject becomes pregnant during or shortly after participation in the 
study, this pregnancy will be reported to the Sponsor within 24 hours of first knowledge of the 
event. Any subject who becomes pregnant during the study will be immediately withdrawn. 
Follow-up information regarding the course and outcome of the pregnancy will be documented 
as an SAE, reporting of the event to the IEC and regulatory agency(ies) will be performed as per 
s
 
9.14 Reportable Disease 
In the case a subject has or manifested any clinical signs characteristic of a reportable disease or 
condition (e.g., HIV, tuberculosis, SARS, COVID-19), it is the responsibility of the Medical 
Director to notify the public health department of the State of Florida within 72 hours after 
becoming aware of the information. 
10. Premature Termination of the Study 
The study may be prematurely terminated by the Investigator following consultation with the 
Sponsor, by the Sponsor or by the regulatory authorities. Following a decision to discontinue the 
trial, the Investigator will promptly inform the active study subjects and the IEC responsible for 
this trial, stating the reasons for discontinuation of the study and, furthermore, advise them in 
responsibility to report the premature termination of the study to the regulatory authority(ies), 
when required by the applicable regulatory requirement(s).  
11. Analytical Methodology 
When applicable, samples will be transported to the bioanalytical facility in at least two separate 
shipments, with each set of aliquots in separate shipments. Once the bioanalytical laboratory 
confirms receipt of the first shipment, the second set of aliquots may be sent. The samples should 
be packed on sufficient dry ice to keep them frozen for at least 72 hours. 
Syneos Health Clinical Bioanalytical Facility will analyze resveratrol, resveratrol-3-glucuronide, 
resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma and urine samples using a 
validated method.  

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Samples for potential RNA-Seq analysis and for the other possible investigational tests 
(iduronidase activity measurement and mRNA frataxin) will be transported to the external 
laboratory, when identified. Details of this additional laboratory work will be available in a 
separate protocol. 
Analyst and Watson LIMS (Laboratory Information Management System) will be used at 
different steps of the analysis. 
The bioanalytical work in support of the study will be conducted in compliance with the GCP, 
using the SOPs in place by Syneos Health Clinical Bioanalytical Facility. These SOPs are in 
accordance with applicable regulations in the industry: Guidelines on Bioanalytical Method 
Validation, Good Laboratory Practice (GLP), and Guideline for GCP ICH E6 (R2). 
Samples from subjects included in the pharmacokinetic population (see section 12.2.2) and from 
subjects who were withdrawn from the study due to AEs or vomiting episodes will be analyzed. 
12. Pharmacokinetic and Statistical Analyses 
PK analysis will be performed using Phoenix® WinNonlin®. Inferential statistical analyses will 
be performed using SAS® according to FDA guidelines. 
12.1 Pharmacokinetics 
12.1.1 PK Parameters Calculated With Plasma Concentrations 
The following PK parameters will be calculated by standard non-compartmental methods for 
resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate:
1) 
AUC0-t: area under the concentration-time curve from time zero to the last non-zero 
concentration 
2) 
AUC0-inf: area under the concentration-time curve from time zero to infinity 
(extrapolated) 
3) 
Cmax: maximum observed concentration  
4) 
Residual area: calculated as 100*(1- AUC0-t / AUC0-inf) 
5) 
Tmax: time of observed Cmax 
6) 
T½ el: elimination half-life 
7) 
Kel: elimination rate constant 
12.1.2 PK Parameters Calculated With Urine Concentrations 
Urine samples will be used to calculate the following parameters for resveratrol, 
resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate: 
1) 
Ae0-t: cumulative urinary excretion from time zero to time t, calculated as the sum of the 
amounts excreted over each collection interval.  The amount excreted in urine for each 
time interval is calculated as the urine concentration multiplied by the urine volume. 
2) 
Rmax: maximum rate of urinary excretion, calculated by dividing the amount of drug 
excreted in each collection interval by the time over which it was collected. 
3) 
Tmax: time of Rmax, calculated as the midpoint of the collection interval during which Rmax 
occurred. 

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Additional PK analysis may be performed. Upon the Sponsor's request, PK repeats might be 
performed according to Syneos Health
-assays are requested for PK reasons, final 
results will include re-assay values, while results with original values will be presented in an 
appendix of the clinical study report as supportive data. 
12.2 Analysis Populations 
12.2.1 Safety Population 
The safety population is defined as all subjects who received at least one dose of the study 
medication. 
12.2.2 Pharmacokinetic Population 
The PK population will include all subjects completing at least one period and for whom the PK 
profile can be adequately characterized. 
Any subject with pre-dose concentrations will be excluded from the PK and statistical analysis 
for the respective analyte for the concerned period if the pre-dose concentration is greater than 
5% of the Cmax value of that period for that subject. 
Data from subjects who experienced emesis during the sampling interval and who were not 
withdrawn as per criterion established under section 9.11 may be evaluated after completion of 
the PK analysis. Any subject who experienced emesis within 2 times median Tmax of the current 
study (based on the reference product) will be excluded from the statistical analysis. Data 
(concentrations and PK parameters) from subjects excluded due to a pre-dose concentration 
greater than 5% of their Cmax or from subjects withdrawn due to AEs or vomiting episodes will 
be presented but excluded from descriptive statistics for the concerned period. 
12.3 Statistical Analyses 
Demographic parameters will be summarized descriptively. TEAEs will be summarized 
descriptively by treatment for all subjects who were dosed (safety population). No inferential 
statistical analysis of safety data is planned. 
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales. Descriptive statistics (arithmetic and geometric means, standard deviation 
[SD], coefficient of variation [CV%], minimum [Min], maximum [Max], and median) of the 
plasma concentrations versus time will be presented as well for the pharmacokinetic parameters. 
A Statistical Analysis Plan (SAP) will be prepared after completion of the final protocol. 
Safety and tolerability: 
TEAEs will be tabulated by treatment. Changes from screening to study exit values in vital signs, 
ECG, and clinical laboratory parameters will be evaluated. Safety and tolerability data will be 
reported using descriptive statistics. Results of vital signs, ECG, and clinical laboratory 
parameters, urine drug screens, clinical laboratory tests, pregnancy tests, alcohol breath test, and 
urine cotinine test will be listed. 

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PK 
 Plasma PK:  
For all analytes, summary statistics will be used to describe the PK profile for each dose level 
under fasting conditions (Periods 1, 2, and 3) and under fed conditions (Period 4).  
Dose proportionality analysis for AUC0-t, AUC0-inf and Cmax will be performed (using the power 
model with mixed procedure from SAS®) considering data under fasting conditions (Periods 1, 2, 
and 3).  
For evaluation of the food-effect, PK data (ln-transformed AUC0-t, AUC0-inf, Cmax and 
untransformed Tmax) reported under fed conditions (Period 4) and under fasting conditions (for 
the same dose level) will be compared using ANOVA from SAS®. The ratio (fed/fasting) and 
90% geometric confidence interval will also be calculated for AUC0-t, AUC0-inf and Cmax. 
All inferential statistical analyses will be interpreted in an exploratory sense only at an alpha 
level of 5% for statistical significance. 
Additional statistical analysis may be performed. 
 Urine PK:  
Summary statistics will be used to describe urinary excretion of resveratrol, 
resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate. 
Additional statistical analysis may be performed. 
13. Regulatory Considerations and Quality Assurance 
13.1 Independent Ethics Committee Approval of Protocol and Other Study Documents 
The Investigator(s) agree to provide the IEC with all appropriate documents, including a copy of 
the protocol/amendments, 
any other written information provided to study subjects. The trial will not begin until the 
Investigators have obtained the IEC favourable written approvals for the above-mentioned study 
documents. A properly executed written ICF shall be read, signed, and dated by each subject 
prior to entering the trial or prior to performing any study procedure. The original signed and 
dated ICF will be kept at Syneos Health and a copy will be given to the subject.  
In the event that the protocol is amended, the revised protocol must be approved by the IEC prior 
to its implementation, unless the changes involve only logistical or administrative aspects of the 
trial. If a revised ICF is introduced duri
obtained. The new version of the ICF must be approved by the IEC, prior to subsequently 
 
The 
amendments (if 
any) before initiating the study. 

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 submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary. 
13.2 Compliance 
This study will be conducted in compliance with the protocol, GCP, and all applicable 
regulations, including the Federal Food, Drug and Cosmetic Act, U.S. applicable Code of 
Federal Regulations (title 21), and any IEC requirements relative to clinical studies. The study 
will also be conducted in compliance with the recommendations laid down in the most recent 
version of the Declaration of Helsinki, with the exception that registration of such Phase 1 trials 
in a publicly accessible database is not mandatory.  
13.3 Quality Assurance Program 
Syneos Health has established Quality Control (QC) and Quality Assurance (QA) systems with 
written SOPs to ensure that the study will be conducted and data will be generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. A 
rigorous QC program is applied to ensure accuracy of all data and reports. QA oversees a 
complementary risk-based program of audits to assure compliance with applicable regulations 
and 
s prescriptive documentation. 
13.4 Audits, Inspections and Monitoring 
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor and Syneos Health. The Sponsor is entitled to access information about 
the status of the study and to review the original documents of the study. 
14. Confidentiality 
This document contains trade secrets and commercial information that is confidential and may 
not be disclosed to third parties. Persons to whom this study protocol is disclosed must be 
informed that all the information herein is confidential and may not be further divulged. These 
restrictions will apply as well to all future communications if deemed privileged or confidential. 
Publication of the study results may only be allowed with written permission from the Sponsor. 
All information on a subject obtained during the conduct of the study will be kept confidential. 
Subjects will be identified by an anonymized identifier on all samples and study records 
provided to the Sponsor or designee. In compliance with 
uthorized 
representatives, monitor(s), auditor(s), IEC, and regulatory authority(ies) will be granted direct 
-related records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations. Consent from the subject for disclosure of such information will 
be obtained in writing in the ICF. In addition, should a subject require medical care or 
hospitalization during the course of the study, the clinical site may contact the treating physician 
consent may not be requested if there is an emergency 
 will remain confidential. 
The clinical site will maintain adequate study records for 2 years after the marketing application 
is approved for the drug for the indication for which it is being investigated; or, if no application 

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is to be filed or if the application is not approved for the drug, until 2 years after the study is 
discontinued. The Sponsor will be notified prior to the destruction of study records. 
 
 

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15. References 
1 
U.S. Department of Health and Human Services, Food and Drug Administration. 
Guidance for Clinical Trial Sponsors - Establishment and Operation of Clinical 
Trial Data Monitoring Committees. March 2006. Available at: 
https://www.fda.gov/media/75398/download 
2 
National Institute on Aging. NIA Guidance on Clinical Trials. Available at: 
https://www.nia.nih.gov/research/grants-funding/nia-guidance-clinical-trials#studies 
3 
Resveratrol, Natural Health Product. Product Monograph. Version dated August 28, 
2018. Drugs and Health Products. Natural Health Products Ingredients Database, Health 
Canada. Available online at: http://webprod.hc-sc.gc.ca/nhpid-
bdipsn/atReq.do?atid=resveratrol&lang=eng 
4 
THEA. Resveratrol and eye health. Available online at: http://www.thea-
pharmaceuticals.co.uk/assets/products/Nutritional-PDFs/resveratrol-and-eye-health.pdf 
5 
, L. et al. Multiplicity of effects and health benefits of resveratrol. medicina 
52 (2016) 148-155 
6 
Sergides, C. et al. 2016. Bioavailability and Safety Study of Resveratrol 500 mg Tablets 
in healthy Male and Female Volunteers. Experimental and Therapeutic Medicine 11:164-
170, 2016. 
7 
Gambini, J. et al. 2015. Properties of Resveratrol: In Vitro and In Vivo Studies about 
Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans. 
Oxidative Medicine and Cellular Longevity Volume 2015. 
http://dx.doi.org/10.1155/2015/837042 
8 
Juhasz, B. et al. Resveratrol: a multifunctional cytoprotective molecule. Curr Pharm 
Biotechnol 2010; 11 (8): 810-8. 
9 
Tomé-Carneiro J, et al. One-year consumption of a grape nutraceutical containing 
resveratrol improves the inflammatory and fibrinolytic status of patients in primary 
prevention of cardiovascular disease. Am J Cardiol 2012;110(3):356 63. 
10 
Jupiter Orphan Therapeutics. 
JOTROL. Version 1.3 dated 
November 24, 2020. 
11 
Crowell, J. A., et al. 2004. Resveratrol-associated renal toxicity. Toxicol Sci, 82: 614-9. 
12 
Elliott, PJ et al. 2009. Resveratrol/SRT501. Monography. In Drugs of the Future 
34(4):291-295. 
13 
Johnson, W. D. et al., 2011. Subchronic oral toxicity and cardiovascular safety 
pharmacology studies of resveratrol, a naturally occurring polyphenol with cancer 
preventive activity. Food Chem Toxicol, 49: 3319-27. 
14 
Yiu, E. et al., 2015. An open-label trial in Friedreich ataxia suggests clinical benefit with 
high-dose resveratrol, without effect on frataxin levels. J Neurol, 262: 1344-53. 
15 
Turner, R. S., et al., 2015. A randomized, double-blind, placebo-controlled trial of 
resveratrol for Alzheimer disease. Neurology, 85: 1383-91. 
16 
Walle, T. 2011. Bioavailability of resveratrol, Ann N Y Acad Sci, 1215: 9-15. 
17 
Almeida, L, et al., 2009. Pharmacokinetic and safety profile of trans-resveratrol in a 
rising multiple-dose study in healthy volunteers. Molecular Nutrition & Food Research 
53(Suppl 1):S7-S15. 

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18 
La Porte, C. et al., 2010. Steady-State pharmacokinetics and tolerability of trans-
resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol) in healthy 
human subjects. Clinical Pharmacokinetics 49(7):449- 454. 
19 
Robinson, K. et al., 2015. Pre-formulation studies of resveratrol. Drug Dev Ind Pharm. 
41(9): 1464 1469. 
20 
Muñoz, O et al., 2015. Pharmacological Properties of Resveratrol. A Pre-Clinical and 
Clinical Review. Biochem Pharmacol (Los Angel)4:5 
21 
Williams, LD et al., 2009. Safety studies conducted on high-purity trans-resveratrol in 
experimental animals. Food Chem Toxicol. 47(9):2170-82. 
22 
Boocock, D. J., et al. 2007. Phase I dose escalation pharmacokinetic study in healthy 
volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol 
Biomarkers Prev, 16: 1246-52. 
23 
Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Molecular 
nutrition & food research. 2005; 49: 472-481 
24 
Amri A, Chaumeil JC, Sfar S, Charrueau C. Administration of resveratrol: What 
formulation solutions to bioavailability limitations? Journal of controlled release: official 
journal of the Controlled Release Society. 2012;158(2):182-193 
25 
Safety of synthetic trans-resveratrol as a novel food pursuant to Regulation (EC) No 
258/97. European Food Safety Authority, Journal 2016;14(10:4368. Scientific Opinion. 
Adopted: 11 December 2015 
26 
US FDA Meeting preliminary comments. Pre-IND meeting, November 15, 2016. PIND 
132145.