Clinical trial NCT04668274
Conditions: Pharmacokinetics Safety Food-drug Interaction
Sponsor: Jupiter Orphan Therapeutics Inc.
Start date: 2021-01-21; Completion date: 2021-05-31
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Type of Study: Single Ascending Doses (SAD) Study

Objectives:

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 1,000 mg, in healthy subjects.

To evaluate the safety and tolerability of JOTROL To evaluate the effect of food on the PK profile of JOTROL. Study Design: Phase I, randomized, open-label, sequential SAD study with a food effect evaluation. Blood plasma and urine samples will be assessed for resveratrol and key metabolite content.

Type of Control: No control Test Product: JOTROL (resveratrol) 100 mg resveratrol in 1000 mg softgel capsule for oral administration Dosage Regimen: Planned dose levels of resveratrol: 200 mg, 500 mg, and 1,000 mg. Following completion of each dose level, PK, safety, and tolerability data will be evaluated; dose levels may be adjusted.

Route of Administration: Oral gelcaps with water Number of Subjects: 24 subjects will be included in Part 1; only 16 subjects, who completed Part 1, will be included in Part 2.

Subjects: Healthy, non-smoker, adult males or females, ≥ 18 and ≤ 75 years of age Study Duration: Participation of each subject in this study should last approximately 1 to 1.5 months (for subjects participating in study Part 1 only) and 1.5 to 2 months (for subjects participating in both study parts).

Detailed description:

Arms: arm 1: Participants received JOTROL (resveratrol) 200 (2\*100) milligram (mg) (Treatment A), gelatin capsule (gelcap), orally, once on Day 1 in fasted conditions in Study Period 1. arm 2: Participants who completed Study Period 1 received JOTROL (resveratrol) 500 (5\*100) mg (Treatment B), gelcap, orally, once on Day 1 in fasted conditions in Study Period 2. A 14 days washout period was maintained in study period 1 and 2. arm 3: Participants who completed Study Period 2 received JOTROL (resveratrol) 700 (7\*100) mg (Treatment C), gelcap, orally, once on Day 1 in fasted conditions in Study Period 3. A 14 days washout period was maintained in study period 2 and 3. arm 4: Participants who completed Study Period 3 (Part 1) received JOTROL (resveratrol) 500 (5\*100) mg (Treatment D), gelcap, orally, once on Day 1 in fed conditions in Study Period 4. A 14 days washout period was maintained in study period 3 and 4.
Interventions: intervention 1: 200 mg resveratrol as JOTROL intervention 2: 500 mg resveratrol as JOTROL intervention 3: 700 mg resveratrol as JOTROL intervention 4: 500 mg resveratrol as JOTROL administered to assess influence of food
Intervention descriptions: intervention 1: Low (first) dose of single ascending dose study intervention 2: Second (intermediate) dose of single ascending dose study intervention 3: Third (highest) dose of single ascending dose study intervention 4: 500 mg resveratrol as JOTROL administered to assess influence of food

Protocol documents:
ICF_002.pdf: 
 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 1 of 23 
 
 
 
 
 
INFORMATION AND CONSENT FORM 
AND 
AUTHORIZATION TO USE AND DISCLOSE PERSONAL AND HEALTH 
INFORMATION 
 
 
Sponsor: 
Jupiter Orphan Therapeutics 
Study Title: 
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 
Protocol Number: 
202016 
Principal Investigator:  
(Study Doctor) 
David J. Wyatt, M.D. 
 
Telephone: 
1-305-547-5800 
24-hour Telephone:  
1-305-205-6341 
Address: 
inVentiv Health Clinical Research Services LLC 
 a Syneos Health company (herein referred to as “Syneos 
Health”), 
1951 NW 7th Avenue, Suites 180 and 450 
Miami, FL 33136, USA 
Subject No.: ________________ 
 
Completed by / Date: 
_______________________ 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 2 of 23 
 
PART 1 
INTRODUCTION, DESCRIPTION, STUDY DURATION 
(1) Introduction 
You are invited to participate as a subject in a clinical research study. Your participation in this 
study is voluntary. You have the right to decide not to participate in it or to withdraw at any time 
without penalty or loss of benefits. During the study, you will be informed as soon as possible of 
any new information on the study drug that might affect whether you want to continue 
participating in the study. The study doctor or a designated study staff member can decide to 
withdraw you from the study, without your consent, if they judge that it would be better for your 
health, if you do not follow the instructions given to you, or for other reasons. If you are 
withdrawn from the study by the study doctor or study staff, the reason for your withdrawal will 
be explained to you. At the time of your withdrawal from the study, you will be asked to undergo 
additional tests for your safety; one last blood sample may also be collected to measure the 
amount of study drug in your body.  
In total, there will be approximately 24 healthy non-smoking adult subjects participating in this 
study. This Information and Consent Form is intended to give you an overview of this clinical 
research study and what it involves. It may contain words that you do not understand. Please ask 
the study doctor or a member of the study staff to explain any words or information that you do 
not understand.  
If you decide to participate in this study, you will be asked to sign and date this Information and 
Consent Form. This will confirm that you have been informed of the nature of the study and 
what it involves but does not take away any of your legal rights. 
The Sponsor, Jupiter Orphan Therapeutics, is paying Syneos Health to cover the costs of 
conducting this study. 
(2) General description of the study  
This study involves a drug called resveratrol, which is being developed as a gelcap called 
JOTROL for the treatment of Mucopolysaccharidosis type I (MPS1), Friedreich’s ataxia (FA) 
and or Alzheimer’s Disease. MPS1 is an inherited disease-causing damage to multiple organs, 
and which can lead to short stature, severe abnormalities in the development of bones and 
cartilage, impaired vision and hearing, swelling of liver and spleen, and intellectual disability. 
FA is an inherited disease-causing progressive damage to the nervous system. Initially 
characterized by impaired muscle coordination such as gait disturbance that worsens over time, 
FA can lead to gradual loss of strength and sensation in the arms and legs, muscle stiffness, 
impaired speech, hearing, vision, heart diseases, and diabetes. Alzheimer’s disease is a form of 
dementia (mental disorder characterized by a loss of memory, judgment and capacity to think, 
and changes in personality) that primarily afflicts older patients.   
The JOTROL gelcap contains trans-resveratrol (common name: resveratrol) as active ingredient. 
Resveratrol is naturally found in an abundant amount in red wine, grape berry skins, seeds and, 
particularly in dried roots of some plants. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 3 of 23 
 
Although resveratrol has been evaluated in human studies before, JOTROL has never been given 
to humans in any standardized clinical trial. In this study, it will be the first time ever that 
JOTROL is being given to humans. The safety and tolerability of the study drug in humans is 
unknown at this time. JOTROL is an “investigational” drug product, which means that JOTROL 
has not been approved for use by the United States Food and Drug Administration (FDA) outside 
of research studies. JOTROL is therefore considered experimental. 
The JOTROL gelcap contains 100 mg of resveratrol. 
The purposes of this study in healthy volunteers are to: 
• Evaluate how much and how quickly the study drug is taken up, and eliminated by the 
body when JOTROL is administered as a single dose at different dose levels ranging from 
200 mg resveratrol to a resveratrol dose currently estimated at 1000 mg.  
• Evaluate how much and how quickly the study drug is taken up and eliminated by the body 
when administered as gelcaps under fasting conditions and after a meal. 
The study will be divided into 2 parts (4 periods in total). All eligible subjects will participate in 
Study Part 1. You may not be invited to participate in the second part of the study. 
Study Part 1: 
This study part involves the administration of single doses of JOTROL under fasting conditions. 
It will be divided in 3 periods in which the study drug will be administered at increasing dose 
levels. Dose levels will be administered one after the other, beginning with the lowest dose level 
(200 mg resveratrol). The following JOTROL doses are planned to be administered: 
Periods 
Planned JOTROL doses 
Period 1 
Total JOTROL dose: 2 × 100 mg gelcaps (200 mg of resveratrol)  
Period 2 
Total JOTROL dose: 5 × 100 mg gelcaps (500 mg of resveratrol)  
Period 3 
Total JOTROL dose: 10 × 100 mg gelcaps (1000 mg of resveratrol) 
 
Each dose level (or period) will be separated from the previous by at least 14 days. After the 
procedures are completed for a given period, a Safety Review Committee (composed of at least 
the Study Doctor, an independent third party physician, and a Sponsor’s medical representative) will 
review all information collected for this dose level to decide if it is safe to continue the study 
with the next planned dose level. If the Safety Review Committee judges that it is not safe to 
proceed with the next planned dose level, the next dose level may be decreased, the previous 
dose level may be repeated, or the part of the study that you are participating in may be stopped. 
If that part of the study is stopped, your participation may be cancelled. 
Study Part 2: 
Even if you have participated in study Part 1, you may not be offered to participate in Part 2. 
Only 16 subjects who have completed study Part 1 will be invited to participate in this study part 
during which they will be administered JOTROL at the highest dose level used during study Part 
1 after eating a breakfast high in calories and fat. This is referred to as Period 4. Administration 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 4 of 23 
 
of the study drug in Period 4 (study Part 2) will be separated from the one of Period 3 (study Part 
1) by at least 14 days. 
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. Each of the 4 study periods involves a 
stay of approximately 3 days at Syneos Health (including 2 nights), during which you will not be 
allowed to leave the site or receive visitors. The first 3 periods form the study Part 1 while study 
Part 2 consists of Period 4 only. You will be sharing the clinical facilities, including bedrooms, 
with other subjects, which could reduce your privacy. Each study drug administration will be 
separated from the previous by at least 14 days to ensure that the study drug you took during one 
period is no longer in your body when you begin the next period. 
PART 2 
RISKS OF SIDE EFFECTS 
(1) Risks of side effects 
Participation in a clinical research study involves some unforeseeable risks of side effects that 
could occur. The frequencies listed below are not predictive of what could happen during the 
study. They result from a limited number of studies, usually performed in subjects receiving 
multiple doses of the study drug. Please be aware that the side effects mentioned below could 
occur at a frequency higher or lower than indicated, and some side effects not indicated below 
could also occur. Unless otherwise stated, the side effects listed below are anticipated to be 
temporary, and it is anticipated that they will disappear by the end of the study. 
(2) Risks associated with the study drug formulations 
Following the administration of oral (by mouth) resveratrol during clinical studies, resveratrol 
was well-tolerated. Side effects possibly related to resveratrol are gastrointestinal symptoms such 
as nausea and diarrhea, when resveratrol was given at repeated doses above those planned to be 
administered in this study. 
The following side effects were seen in 2% to 15% (except if otherwise stated) of the 64 subjects 
with mild to moderate Alzheimer’s disease and in equal or greater frequency than in the placebo 
(dummy pill that looks similar to resveratrol but does not contain the active ingredient) group are 
listed below. These subjects were taking resveratrol 500 mg once daily for 52 weeks, with a 500-
mg increments every 13 weeks, ending with 1000 mg twice daily (total daily dose of resveratrol: 
2000 mg). 
Gastrointestinal disorders (42%) 
• Diarrhea (41%) 
• Nausea 
 
General disorders 
• Weight loss (17%) 
• Fall (34%) 
 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 5 of 23 
 
Nervous system disorders (39%) 
• Headache 
 
 
The following side effects were seen in 2% to 15% (except if otherwise stated) of the 13 subjects 
with Friedreich’s ataxia taking resveratrol 500 mg twice daily (total daily dose: 1000 mg) for 12 
weeks and of the 14 subjects with Friedreich’s ataxia taking total daily dose of 5 gm of 
resveratrol for 12 weeks. 
 
Cardiac disorders 
• Rapid and irregular heartbeat 
• Increase in the level of substances 
(called enzymes) in blood that 
may indicate heart problems 
Gastrointestinal disorders 
• Loose stools 
• Abdominal pain/cramps 
• Bloating 
• Flatulence 
• Diarrhea 
• Nausea 
• Indigestion/upset stomach 
• Constipation 
 
Infections 
• Urinary tract infection (23%) 
• Tonsillitis (inflammation of tonsil) 
• Inflammation of the sinus 
(sinusitis) 
 
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 
 
 
Nervous system disorders 
• Headache (31%) 
• Fatigue (23%) 
 
Respiratory disorders 
• Upper respiratory tract infection 
(31%) 
 
 
Skin disorders 
• Skin rash 
• Swelling of the lower limbs 
 
Please note that these side effects were reported in subjects with mild to moderate Alzheimer’s 
disease or with Friedreich’s ataxia and receiving daily doses of resveratrol that are a multiple of 
the planned doses in the present study. In addition, during this study, you will receive JOTROL 
only 3 to 4 times at least 14 days apart. 
 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 6 of 23 
 
The following AEs were more frequently reported by subjects in the 5 g/day resveratrol group: 
loose stools, diarrhea, and abdominal pain/cramps. In another study conducted in subjects with 
hepatic metastasis given 5 g/day, the most commonly reported side effects were episodes of light 
diarrhea, nausea, anal pruritus (itching), and symptoms of hypersensitivity (allergic reactions). 
Other side effects have been reported. Any side effect, rare or not, may worsen and be 
life-threatening. 
(3) Allergic reaction risks 
With any medication, there is a small but real risk of allergic reactions that can be fatal. These 
reactions usually start shortly after taking the study drug. If you have a very serious allergic 
reaction, you may be at risk of death. Some symptoms of allergic reactions are: 
• Skin itching, redness, rash 
• Difficulty breathing 
• Dizziness and fainting 
• Swelling around the mouth, throat 
or eyes 
• A fast pulse 
• Sweating 
 
If you experience any of the reactions mentioned above, you must immediately inform the 
Syneos Health study staff or proceed to the nearest hospital emergency department. 
(4) Risks associated with study procedures 
Blood collections 
Among other known risks of side effects in a clinical research study, there are those related to the 
use of needles for blood collection and catheter (intravenous – IV) insertion: pain, bruising and 
swelling at the site of blood collection, fainting for a short period, and, very rarely, nerve damage 
or infection at the needle insertion site. 
Electrocardiograms 
Electrocardiogram(s) (recording of the electrical activity of the heart or “ECG”) will be done 
during this study. Electrodes (small sticky patches) will be placed on your body. There is no pain 
or risks related to an ECG. However, removing the electrodes may cause skin irritation. In some 
areas, it may be necessary to shave a small spot of body hair so the adhesive patches can be 
properly placed on your body. 
Contagious diseases 
Finally, although we try to make sure that all subjects are healthy upon participation in the study, 
the risk of contagious infection is increased because you will be in contact with a number of 
people during your stay at the site. 
 
 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 7 of 23 
 
(5) Risks associated with pregnancy 
Women: 
If neither you nor your male partner is surgically sterile (male partner vasectomized since at least 
6 months) and if you are not post-menopausal (absence of menses for at least 12 months), you are 
required to avoid becoming pregnant while you are participating in this study since there may be 
risks to you or the fetus associated with the use of resveratrol during pregnancy.  
You are therefore required to use one of the following methods of contraception for the time 
specified prior to taking the study drug, throughout the study and until 30 days following the last 
study drug intake:  
• Male condom with spermicide applied intravaginally, for at least 21 days before taking 
the study drug. 
• Intrauterine contraceptive device without hormone release system placed at least 4 weeks 
before taking the study drug. 
 
Except abstinence, no method of contraception is 100% effective. If you think you may have 
become pregnant even though you used required contraception while in the study, you should 
contact the study doctor or the study staff immediately (see telephone number at the first page of 
this form). Follow-up information about the pregnancy and the outcome will be collected and 
documented. 
PART 3 
SUBJECT’S SCREENING SESSION 
In order to participate in a clinical research study at Syneos Health, you must first (1) undergo a 
general medical examination, (2) provide a blood sample, (3) provide a urine sample, and (4) 
possibly undergo other tests and exams to determine your eligibility. This screening session is 
expected to last 1 to 3 hours. Some results of the tests and exams performed during this screening 
session could be used by Syneos Health as the screening tests and exams required for another 
study. 
(1) Medical examination 
The medical examination involves: 
1. A complete medical questionnaire (for example, past surgery, current condition, 
medication intake), 
2. 
A general physical examination, 
3. 
Recording of your demographic data (for example, height, weight, etc.), 
4. Measurement of your vital signs (for example, blood pressure, heart rate, respiration rate, 
oral temperature), 
5. 
Recording of the electrical activity of your heart (an ECG). 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 8 of 23 
 
The physical examination will involve, among other things, an examination of the armpit areas, 
groin, and the lower legs and ankles to check for swelling of the lymph glands and/or circulation. 
(2) Blood draw 
A blood sample is necessary to verify your general health status and to detect a possible HIV, 
Hepatitis B or Hepatitis C infection. A positive result for any of these tests must be reported to 
the Public Health authorities, as required by law. The total amount of blood collected during the 
screening session will not exceed 25 mL (about 2 tablespoons).  
(3) Urine sample 
A urine sample is necessary to verify your health status and to screen for drugs or medications of 
abuse. It will also be used to verify if you have smoked. 
(4) Other tests, exams, samples 
a) If you are a woman, you will undergo a urine pregnancy test. 
b) Additional samples may be required to repeat analyses or to measure other blood 
components. You will be informed if new, additional blood measurements are required. 
c) You could be asked to come back again to Syneos Health to repeat a test. 
 
(5) Abnormal results 
Any abnormal result in the exams, tests, and analyses mentioned above may affect your 
eligibility to participate in a study. You will be informed of any significantly abnormal result 
obtained during the screening session or during the study and, if necessary, you will be referred 
to a health professional. 
PART 4 
STUDY CONDUCT 
(1) Study Procedures 
For each period, you will have to show up at Syneos Health on Day -1 at a time specified by the 
clinic staff. 
The following tests will be done upon admission: 
• Urine analysis to screen for drugs or medications of abuse; 
• Urine cotinine test to confirm that you have not smoked; 
• Alcohol breath test; 
• Blood pregnancy test 
 
A positive result for one of these tests will automatically result in withdrawal from the study. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 9 of 23 
 
In addition to the above tests, blood sample will be collected to verify your general health status 
upon admission in Period 4 only. 
Study Part 1: 
The next morning in each of the first 3 study periods, after you have fasted for at least 10 hours, 
you will be asked to swallow JOTROL gelcaps containing 100 mg of resveratrol, at doses 
ranging from 200 mg to 1000 mg. The following doses are planned to be administered: 
• 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 
 
Doses in Period 2 and 3 may be modified upon decision of the Safety Committee. 
Study Part 2 (Period 4): 
Sixteen (16) subjects who complete Part 1 of the study may be invited to participate in Part 2 of 
the study, if deemed eligible by the study doctor. 
The next morning, after you have fasted for at least 11 hours, you will have 30 minutes to eat a 
breakfast in its entirety and then you will be asked to swallow JOTROL gelcaps containing 
100 mg of resveratrol, at a maximum dose of 1000 mg (10 x 100 mg JOTROL oral gelcaps, total 
resveratrol dose 1000 mg). The exact dose to be administered will be selected following 
collection and analysis of data from study Part 1. The clinical staff will advise you on the exact 
dose to be administered before dosing. The breakfast will consist of 2 eggs fried in butter, 
2 slices of toast with butter, 2 strips of bacon, hash brown potatoes, and about 1 cup of whole 
milk.  
Throughout the study, the study drug will be administered with 240 mL (about 1 cup) of water 
and a hand and mouth check will be performed to ensure consumption of the study drug. You 
must not crush or chew the gelcaps, they must be swallowed as a whole.  
In each of the 4 periods: 
A total of 17 blood samples will be collected to measure the amount of study drug in your body, 
over a period of 32 hours. In the hours following study drug administration, blood draws could 
be done close to one another. There will be 1 blood samples taken at night, which will interrupt 
your sleep, so you will not get a full night's rest. Blood draws will be done using needle puncture 
or a catheter (for the first 14 blood collections). A catheter (IV) is a flexible tube inserted into the 
vein that allows taking several blood samples without repeated needle insertion into the skin. The 
total volume of blood collected should not exceed 733 mL (about three cups) for the whole 
study and 605 mL (about 2 and half cups) for subjects participating in Part 1 only. In 
comparison, a blood donation generally represents approximately 450 mL (2 cups or 1 pint) of 
blood, and it is done in 1 day.  
Five (5) blood samples over a period of 24 hours will be collected for potential RNA analysis, 
iduronidase activity (how your body breaks down certain molecules), frataxin mRNA, and other 
possible investigational tests. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 10 of 23 
 
Genes are made up of deoxyribonucleic acid (DNA), the genetic material that is found in all cells 
of your body and containing instructions that your body reads to understand how it should be 
built and work. In order to send its instructions, DNA needs to be transcribed into ribonucleic 
acid (RNA). RNA is a molecule implicated in various biological processes, including protein 
synthesis. There are proteins involved in absorption, breaking down, and elimination of ingested 
substances. Studying RNA may help understand differences among individuals in the way they 
respond to the study drug, as well as helping in the development of new drugs or improvement of 
existing drugs. Therefore, this study includes collecting blood samples for RNA analysis. The 
blood samples will also be used for iduronidase activity measurement, and other possible 
investigational tests. Iduronidase is a protein involved in many processes in the body. A 
deficiency in this protein activity leads to the accumulation of some substances in the body cells 
that may result in diseases that might be severe. 
You have the right to decide not to participate in the RNA analysis and other investigational 
tests. However, because these analyses are part of the study, if you do not agree to participate in 
these tests, you cannot participate in this clinical research study. Blood samples will be sent to an 
external laboratory where your RNA will be analyzed, and the other tests will be done. These 
samples will be labeled with a code that will be kept by the investigator, so that you can not be 
identified.  Procedures will be done for the long-term preservation of these samples until planned 
tests have been done. Therefore, samples will be retained for up to 2 years, until exhausted or 
until the Sponsor requests destruction. If you withdraw consent, your banked specimens will be 
promptly disposed of. However, the data will not be discarded if analyses have been completed 
before you withdraw consent. 
For study Part 1 only, 3 additional blood samples (approximately 2 tablespoons per sample) in each 
period will be collected, from at most (maximum) 10 subjects, for the evaluation of immune cells in 
your blood. 
For Part 1 (Periods 1, 2, and 3), urine samples will be collected at 6 different time intervals from 
2 hours before dosing until 32 hours after dosing.   
A study doctor will be reachable at all times during the study. If deemed necessary by the study 
staff, additional tests or blood draws could be performed to ensure your safety. 
(2) Post-study procedures 
The following procedures will be performed on the last study day to check your overall health: 
• 
Blood and urine tests; 
• 
Vital signs; 
• 
ECG; 
• 
Urine pregnancy test for female subjects 
 
We recommend that you stay on our premises for 5 minutes following a blood draw. Please 
mention to the study staff if you feel sick or believe you are having side effects of any kind. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 11 of 23 
 
Even after the study is completed, Syneos Health may contact you within a few weeks after the 
last study day to clarify information or to ask you to come back for additional tests for your 
safety. 
PART 5 
STUDY RESTRICTIONS  
(1) Food and fluids 
You will have to follow a standard diet during your stay at Syneos Health: 
• Study Part 1 (Periods 1, 2, and 3): No food will be allowed from at least 10 hours before to 
at least 4 hours after taking the study drug, for a total of at least 14 hours. 
• Study Part 2 (Period 4): No food will be allowed at least 11 hours before receiving a 
breakfast high in fat and calories. You will also be fasting for 4 hours after the 
administration of study drug. 
• Except for fluids provided with the critical breakfast (study Part 2 only) and water given 
with the study drug, no fluids will be allowed from at least 1 hour before to at least 1 hour 
after taking the study drug. 
 (2) Physical activity 
You will be free to engage in normal activities after administration of study drug. Lying down or 
sleeping will be prohibited for the first 2 hours (study Part 1) and 4 hours (study Part 2) after 
taking the study drug, unless it is required for your health or by study procedures. Performing 
vigorous physical activity will be prohibited during your stay.  
 (3) Other restrictions to prevent possible interactions with the study drug 
It is important that you follow all the restrictions listed in the table below. Not following these 
restrictions could have consequences on your health or on the study results. 
Prohibited product 
Restriction before 
the study 
Restriction during 
the study 
Prescription medication*  
14 days before the 
first study drug 
administration 
Throughout the 
study 
Over-the-counter products* (other than the 
occasional use of acetaminophen [up to 2 g 
daily]) 
14 days before the 
first study drug 
administration 
Throughout the 
study 
Hard drugs (for example, cocaine, PCP, 
crack, heroin, amphetamines) 
1 year before the 
screening visit 
Throughout the 
study 
Soft drugs (for example, marijuana) 
3 months before the 
screening visit 
Throughout the 
study 
Food containing poppy seeds (muffins, bagels 
and cakes) 
24 hours before the 
admission  
None 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
Resveratrol (JOTROL) Gelcaps 
 
David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
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Natural health products (including herbal 
remedies, homeopathic products, traditional 
medicines, probiotics, food supplements such 
as vitamins, minerals, amino acids, essential 
fatty acids, and protein supplements used in 
sports) 
14 days before the 
first study drug 
administration  
Until after the last 
blood draw of each 
period 
Drugs known to induce or inhibit liver drug 
metabolism, including St. John’s wort 
30 days before the 
first study drug 
administration 
Until after the last 
blood draw of the 
study 
Depot injection or an implant of any drug 
3 months before the 
first study drug 
administration 
Throughout the 
study 
Grapefruit, starfruit, pomegranate, pineapple,  
or pomelo products (fresh, canned or frozen) 
7 days before study 
drug administration 
in each period 
Until after the last 
blood draw of each 
period 
Alcohol-based products  
24 hours before the 
admission in each 
period  
Until after the last 
blood draw of each 
period 
Food or beverages containing caffeine (for 
example, coffee, tea, chocolate, cola 
beverages or decaffeinated products) or 
energy drink  
48 hours before 
study drug 
administration in 
each period 
Until after the last 
blood draw of each 
period 
Tobacco products 
3 months before the 
screening visit 
Throughout the 
study 
Foods rich in resveratrol (for example grapes, 
peanuts and their derived-products including 
wines and juices) 
7 days before 
administration of 
study drug in each 
period 
Until after the last 
blood draw of each 
period 
* For certain drugs, the restriction period may be longer than indicated in the table. A study doctor will evaluate all 
medications you took before the beginning of the study to make sure that the restriction periods are appropriate. 
PART 6 
SAFETY INSTRUCTIONS, COMPENSATION, CONFIDENTIALITY, AND SUBJECT’S 
RIGHTS 
(1) Safety instructions 
If you do not follow the study restrictions, you should tell the study staff as soon as possible. 
 
Before taking any medication (prescription or over the counter), you need to check first with the 
study doctor or study staff if this medication is safe for you to take. In case a healthcare 
professional (for example, a doctor, pharmacist or dentist) recommends you to take medication 
for a health problem or if you need to have a medical procedure (for example, a surgery) while 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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Subject’s Initials: __________ 
Page 13 of 23 
 
participating in this study, you should inform the healthcare professional that you are taking part 
in a clinical research study on a study drug called JOTROL (resveratrol). 
Upon leaving the Syneos Health facility, if you feel dizzy or drowsy, you should not 
perform activities requiring mental alertness, judgment and physical coordination such as 
driving or operating machinery until you feel secure and safe to do so. 
(2) Study-related injury 
In case of injury or disease because of your participation in this study, you will receive 
appropriate medical care. The sponsor is committed to cover all necessary and related medical 
costs not covered by your private medical insurance (if any). 
To pay medical expenses, the sponsor will need to know some information about you like your 
name, date of birth, and Medicare Beneficiary Identifier (MBI). This is because the sponsor has 
to check to see if you receive Medicare and if you do, report the payment it makes to Medicare. 
If you suffer a serious or lasting injury as a result of participation in this study, it may affect your 
ability to obtain private health insurance, your employability, and/or quality of life. No 
compensation other than that mentioned in this Information and Consent Form is planned. 
In no way does signing and dating this consent form waive your legal rights nor does it relieve 
Syneos Health, the study staff, sponsor or others involved in the study from their legal and 
professional responsibilities. 
(3) Benefits 
 
No direct benefits can be anticipated from participating in this clinical research study. The tests 
provided may help you learn about your general health. This study may help doctors and 
scientists learn things about the study drug that will help others. 
(4) Alternatives to being in the study  
You are being asked to take part in this study because you are healthy. The only option is not to 
take part in this study. 
 (5) Compensation 
You will not receive compensation for your participation in the screening visit. 
You will receive compensation for the time and inconveniences related to your participation in 
this study. Details about the amount of compensation and the payment schedule specifying the 
specific amounts and timing of payments are outlined in Appendix 1 provided with this 
Information and Consent Form. 
If you do not complete the entire study, the amount you receive will depend on the portion of the 
study you completed, even if the study is cancelled or stopped by the sponsor or Syneos Health. 
There are no costs for you: any expenses and costs associated with the study are covered by the 
sponsor. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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Subject’s Initials: __________ 
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(6) Voluntary participation / Withdrawal 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. Your participation in this study is voluntary. You have the right to 
decide not to participate in it or to withdraw at any time without penalty or loss of benefits. The 
study doctor will inform you of any new significant information, when it becomes available, 
which may affect your willingness to continue to participate in this study. This new information 
may mean that you can no longer participate in this study. It could also mean that the sponsor 
may suspend or prematurely end the study. If this occurs, the study staff supervising the study 
will stop your participation.  
(7) Data retention 
If you decide to withdraw from the study, or if the study doctor or a study staff decides to 
withdraw you from the study for safety reasons, for not following the requirements of the study, 
or for any other reason, the data collected up to the time of your withdrawal from the study 
remains part of the study database and may not be removed. 
(8) Confidentiality 
Syneos Health takes necessary steps to protect the privacy of your personal information. The use 
and disclosure of your study records will be done in accordance with the Authorization to Use 
and Disclose your Personal and Health Information presented in Appendix 2 of this Information 
and Consent Form or when disclosure is required by law. You will be asked to sign and date this 
authorization before taking part in the study. 
Outside of Syneos Health, you will be identified at all times by a number and your initials, unless 
there is an emergency situation and/or a representative of Syneos Health has to communicate 
with your primary doctor. If the results of the study are published, your identity will remain 
confidential.  
As part of this clinical research study, the study doctor will collect personal information about 
you and your health. You have the right to check your study records and request changes if the 
information is not correct.  
The above-mentioned study data will be available for confidential consultation and may be 
accessed by representatives of Syneos Health in the United States and outside of United States, 
by representatives of the study sponsor, various regulatory agencies such as the U.S. Food and 
Drug Administration (FDA), as well as the Institutional Review Board, Advarra.  
While every effort will be made to protect the privacy of your information, absolute 
confidentiality cannot be guaranteed. This does not limit the duty of the study doctor and the 
study staff to protect your privacy. 
In addition, should you require medical care or hospitalization during the course of the study, 
Syneos Health’s representative may contact the treating physician with your consent, except that 
consent may not be requested if there is an emergency situation. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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Subject’s Initials: __________ 
Page 15 of 23 
 
(9) Monitoring 
As part of your participation in this study you will be monitored by closed-circuit television 
(CCTV) during screening, any stay and follow-up visits including exit visit. CCTV cameras are 
located throughout the screening center, the clinical unit and the eating area/recreation room. 
CCTV cameras are not placed in the restrooms/washrooms or showers. The purpose of CCTV is 
to maintain close watch of your health condition while participating in the study to make certain 
you are safe. By signing and dating this Information and Consent Form you agree to be 
monitored by closed-circuit television. 
(10) Whom to contact about the study 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor or study 
staff at the telephone number listed on the first page of this consent document. If you seek 
emergency care, or hospitalization is required, alert the treating physician that you are 
participating in this research study. 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
• By mail: 
Study Subject Adviser 
Advarra 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free: 877-992-4724 
• or by email: adviser@advarra.com 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00046245. 
Please note that for matters regarding payment or routine compensation issues, questions should 
be directed to Syneos Health. 
PART 7 
ATTESTATION, AUTHORIZATION, COMMITMENT, AND CONSENT 
(1) Attestation 
I acknowledge I have been given sufficient time to read this Information and Consent Form, ask 
any question I might have about the information presented and decide whether or not I want to 
participate in this study. 
I acknowledge having received satisfactory answers to questions I have asked.  


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 16 of 23 
 
(2) Authorization 
I authorize the confidential consultation of the study data including data collected about me by 
the organizations described in Part 6. 
For my safety, I authorize Syneos Health to contact other clinical research organizations to 
verify my past or current participation in clinical research studies and in blood donation 
sessions. I also authorize Syneos Health to disclose to these organizations information 
relative to my past or current participation in studies conducted by Syneos Health. The 
exchange of information with other organizations regarding my participation in other 
clinical research studies may be done with a system that uses my fingerprint. 
(3) Commitment 
• I will not donate blood or plasma from the screening session, during my participation in this 
study and for at least 56 days after the end of the study; 
• I will attend all scheduled visits on time; 
• I will give true information about my medical history; 
• I will not participate in another clinical research study during this study and for at least 
56 days after the end of the study;  
• I will respect all study restrictions and follow all instructions given to me by the study staff; 
• For women: I will use adequate contraceptive methods for at least 30 days following the last 
study drug administration; 
• I will advise the study staff of any change in my medical condition, minor or major, during 
the study and for 4 days following the last study drug administration;  
• I will comply with Syneos Health rules and requirements. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 17 of 23 
 
(4) Consent 
The study doctor has my permission to contact my doctor about my participation in this study:  
YES _________ 
NO _________ 
Initials 
Initials 
 
First and last name of the doctor to contact: _______________________________ 
 
I consent to taking part in the procedures described in this document and confirm that I will be 
given a signed and dated copy of this form for my records. 
______________________                                          _________________________ 
Print first name                                                                 Print last name 
 
__________________________ 
Date: 
 
 
-  
 
 
-  
 
 
 
Signature 
 
D D  M M M  Y Y Y Y 
 
By signing and dating this document you do not waive any of your legal rights, nor release 
the study doctor or sponsor from their legal and professional obligations. Signature of this 
document confirms you have been informed about the nature of the study you are 
participating in. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 18 of 23 
 
PART 8 
STUDY DOCTOR’S OR STUDY DESIGNEE’S DECLARATION 
I confirm that the subject was given an opportunity to ask any questions about the study. I 
have answered the subject's questions about study participation and the associated risks and 
benefits. I have also encouraged the subject to ask additional questions at any time during the 
course of the study. I confirm that the subject was given a signed and dated copy of the 
Information and Consent Form. 
 
 
_________________________________ 
 
_____________________________ 
Print first name 
 
 
 
            Print last name 
 
 
 
__________________________ 
Date: 
 
 
-  
 
 
-  
 
 
 
Signature 
 
D D  M M M  Y Y Y Y 
 
 
Time of signature if not recorded electronically: _____________ 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 19 of 23 
 
APPENDIX 1 – COMPENSATION 
As a compensation for the time and inconveniences related to your participation in this study, 
you could receive up to $2430 for the Part 1 of the study and up to an additional 700$ for Part 2.  
Compensation will be allocated at the completion of each event as follows: 
Compensation schedule Part 1 
Periods 1 and 2 
Each onsite stay* 
$500 
Period 3 
Onsite stay* 
$500 
Amount for the duration of the study 
(including washout duration in case you 
would be selected to participate in Part 2) 
$600** 
Amount allowed for completing Part 1*** 
$330 
Total 
$2430 
*If you don’t complete the entire stay, you will receive a prorated amount based on the reason 
you leave the study ($100 / 12 hrs).  Please ask your study doctor for more information. 
 
** This amount for the duration of the study will be given at the last period completed. 
 
*** This amount will be allocated only to subjects completing the whole study Part 1. 
Completing the whole study means completing all 3 Part 1 study periods.  
 
**** Subjects having extra blood collected for immune cells evaluation will get an 
additional $100 per period. 
You may be selected as a stand-by subject for Part 1 and should be ready to fully participate in 
the study as a replacement. If you are selected as a stand-by subject, you will receive $150 if you 
are asked to stay onsite until study drug administration is completed. If you are not called upon 
to spend the night at Syneos Health, you will receive $75. You will be paid at the time of leaving 
the site if you are not called upon to participate in the study. 
 
 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 20 of 23 
 
If you have completed Part 1, you may be selected as a subject for Part 2. If you are dosed in 
Part 2, you will receive: 
Compensation schedule Part 2 
Period 4 
Onsite stay* 
$500 
Amount allowed for completing Part 2** 
$200 
Total 
$700 
*If you don’t complete the entire stay, you will receive a prorated amount based on the reason 
you leave the study ($100 / 12 hrs).  Please ask your study doctor for more information. 
**This amount will be allocated only to subjects completing the Part 2 study period. 
You may be selected as a stand-by subject for Part 2 and should be ready to fully participate in the 
period as a replacement.  If you are selected as a stand-by subject, you will receive $150 as you 
will be asked to stay onsite until study drug administration is completed. 
The amounts mentioned above may be subject to tax withholding and reporting as per Federal and 
State laws. 
 
 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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David J. Wyatt, M.D. 
Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 21 of 23 
 
APPENDIX 2 – AUTHORIZATION TO USE AND DISCLOSE PERSONAL AND 
HEALTH INFORMATION 
As part of this clinical research study, the study doctor will collect personal information about 
you and your health. This personal and health information may include your date of birth, 
gender, ethnicity, information obtained via access to your personal medical records (for example, 
past medical history and test results), and the results of the study-related tests and procedures 
described in this Information and Consent Form (for example, laboratory test results, physical 
exam data, electrocardiogram, etc.). This personal and health information will be kept in the 
study records. 
Syneos Health requires that all study subjects provide authorization for the use and disclosure 
(release) of personal and health information collected by Syneos Health or otherwise as part of 
your potential participation in a clinical research study. You do not have to sign and date this 
authorization to use and disclose your personal and health information, but if you do not, you 
may not participate in this study. 
Your personal and health information may be used by and/or disclosed as follows: 
• Outside of Syneos Health, you will be identified at all times by a number and your 
initials, unless there is an emergency situation and/or Syneos Health is communicating 
with your primary doctor. 
• The study records will be available for confidential consultation by representatives of the 
study sponsor, various regulatory agencies such as the U.S. FDA, as well as the 
Institutional Review Board, Advarra. This consultation is done to verify study procedures 
and/or data, without violating confidentiality of the subjects except to the extent 
permitted by applicable laws and regulations. 
• In the context of this study, study data may also be sent to these persons/organizations 
upon their request. Some of the persons/organizations that will have access to your 
personal and health information may be based outside the United States. While every 
effort will be made to protect the privacy of your information, absolute confidentiality 
cannot be guaranteed. This does not limit the duty of the study doctor and the study staff 
to protect your privacy. 
• You have the right to check your study records and request changes if the information is 
not correct.  
• If the results of the study are published, your identity will remain confidential. 
• Your personal information, including your health information, will be kept by Syneos 
Health in a database with limited access for a period of at least 2 years after the marketing 
application for the study drug is approved, or if the application for the study drug is not 
approved, until at least 2 years after the study is over. 
The sponsor and those working for the sponsor may use the data and information sent to them: 
• To see if the study drug works and is safe. 
• To compare the study drug to other drugs. 
• For other research activities related to the study drug. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 22 of 23 
 
This authorization does not have an expiration date. You may change your mind and revoke 
(cancel) this authorization at any time. Even if you revoke this authorization, Syneos Health and 
the sponsor of the study may still use or disclose your personal and health information they have 
already obtained as necessary to maintain the integrity or reliability of the current study. To 
revoke this authorization, you must write to the study doctor at the address listed on the first page 
of this Information and Consent Form, stating that you are revoking your Authorization to Use 
and Disclosure your Personal and Health Information. If you revoke your authorization before 
the study is completed, you will not be allowed to continue your participation in the study. Other 
than in connection with any testing procedures to be performed in connection with your 
withdrawal from the study, no new personal or health information that identifies you will be 
gathered after your written request is received. However, your personal and health information 
that has already been gathered may still be used and given to others as described in this form. 
Your right to access your personal and health information in the study records will be suspended 
during the study to keep from changing the study results. When the study is over, you can access 
your study personal and health information. 


 
Jupiter Orphan Therapeutics / Protocol Number 202016 
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Final 2.0 
Advarra IRB Approved Version 17 Nov 2020 
Subject’s Initials: __________ 
Page 23 of 23 
 
Authorization 
I give permission to Syneos Health and representatives of the study sponsor to use or disclose my 
personal and health information that may identify me for the clinical research study, as described 
in this Information and Consent Form. I will receive a signed and dated copy of this form for my 
records. 
Name of the subject: 
 
_________________________________ 
 
_____________________________ 
Print first name 
 
 
 
 
Print last name 
 
__________________________ 
Date: 
 
 
-  
 
 
-  
 
 
 
Signature 
 
D D  M M M  Y Y Y Y 
 
Name of the person obtaining the authorization: 
 
_________________________________ 
 
_____________________________ 
Print first name 
 
 
 
 
Print last name 
 
__________________________ 
Date: 
 
 
-  
 
 
-  
 
 
 
Signature 
 
D D  M M M  Y Y Y Y 
 

SAP_004.pdf: 
 
Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 1 of 30 
 
 
 
Statistical Analysis Plan 
 
 
 
 
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 
 
Syneos Health Clinique Inc. Project No. 202016 
IND number:  132145 
 
 
Final Version: 1.0 
Date: 19-NOV-2020 
 
 
Contract Research Organization:  
inVentiv Health Clinical Research  
Services LLC, a Syneos Health  
company (« Syneos Health »)  
1951 NW 7th Avenue,  
Suite 450 Miami, FL 33136,  
 
 
 Sponsor:  
 Jupiter Orphan Therapeutics  
 601 Heritage Drive Jupiter,  
 Florida 33458  
 
 
 
 
CONFIDENTIAL 
This document contains confidential information of Jupiter Orphan Therapeutics. Any viewing or 
disclosure of such information that is not authorized in writing by Jupiter Orphan Therapeutics is strictly 
prohibited. Such information may be used solely for the purpose of reviewing or performing this study. 
DocuSign Envelope ID: CB3431CE-2439-4B1D-AED3-356FC3CC7B85


P P D
P P D
P P D
P P D
P P D
P P D


 
Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 3 of 30 
 
REVISION HISTORY 
 
Version 
Date 
Summary of Revisions 
Revised By 
1.0 
10-Nov-2020 
NA – Original version 
 
 
DocuSign Envelope ID: CB3431CE-2439-4B1D-AED3-356FC3CC7B85


 
Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 4 of 30 
 
TABLE OF CONTENTS 
 
SIGNATURES ....................................................................................................................... 2 
REVISION HISTORY........................................................................................................... 3 
TABLE OF CONTENTS ....................................................................................................... 4 
LIST OF ABBREVIATIONS ................................................................................................ 6 
1. 
Introduction ................................................................................................................. 8 
2. 
Study Objectives .......................................................................................................... 9 
3. 
Study Design ............................................................................................................. 10 
3.1 
General Design ...................................................................................................... 10 
3.2 
Study Procedures ................................................................................................... 10 
3.3 
Treatment Description ........................................................................................... 10 
3.4 
Confinement and Washout .................................................................................... 11 
3.5 
Sample Size ........................................................................................................... 11 
3.6 
Randomization and Blinding ................................................................................. 11 
3.7 
Subject Withdrawal and Replacement ................................................................... 11 
4. 
Change From the Protocol ......................................................................................... 13 
5. 
Primary and Secondary Parameters ........................................................................... 14 
6. 
Analysis Populations ................................................................................................. 15 
6.1 
Safety Population ................................................................................................... 15 
6.2 
Pharmacokinetic Concentration Population .......................................................... 15 
6.3 
Pharmacokinetic Parameter Population ................................................................. 15 
7. 
Interim Analyses ........................................................................................................ 16 
8. 
Study Population and Exposure ................................................................................ 17 
8.1 
Subject Disposition ................................................................................................ 17 
8.2 
Protocol Deviations ............................................................................................... 17 
8.3 
Demographics and Baseline Characteristics .......................................................... 17 
8.4 
Medical History ..................................................................................................... 17 
8.5 
Prior and Concomitant Medications ...................................................................... 17 
8.6 
Study Drug Administration ................................................................................... 17 
9. 
Safety Analyses ......................................................................................................... 18 
9.1 
Physical Examination Findings ............................................................................. 18 
9.2 
Adverse Events ...................................................................................................... 18 
9.3 
Laboratory Parameters ........................................................................................... 19 
9.4 
Vital Signs ............................................................................................................. 20 
9.5 
Safety ECG ............................................................................................................ 20 
10. 
Pharmacokinetic Analyses......................................................................................... 21 
10.1 Handling of the Below the Lower Limit of Quantification (BLQ) and the No 
Reportable Concentration ...................................................................................... 21 
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Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 5 of 30 
 
10.2 Handling of the Difference between the Scheduled and the Actual Sampling 
Times ..................................................................................................................... 21 
10.3 Pharmacokinetic Parameters .................................................................................. 21 
10.4 PK Parameters Calculated With Urine Concentrations ......................................... 22 
10.5 Statistical Analyses ................................................................................................ 23 
10.5.1 
PK Parameters in Plasma ............................................................................... 23 
10.5.2 
Assessment of Dose Proportionality .............................................................. 23 
10.5.3 
Criteria for Determination of Dose-Proportionality ...................................... 24 
10.5.4 
Food-Effect assessment ................................................................................. 24 
10.5.5 
Urine PK analysis .......................................................................................... 25 
11. 
Percentages and Decimal Places ............................................................................... 26 
12. 
Handling of Missing Data ......................................................................................... 27 
13. 
Data Handling ............................................................................................................ 28 
14. 
Software to be Used .................................................................................................. 29 
15. 
Reference List ............................................................................................................ 30 
 
 
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Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 6 of 30 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
aPTT 
activated partial thromboplastin time 
Ae0-t 
Cumulative amount excreted into urinary  from time zero to time t 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-t 
Area under the concentration-time curve from time zero to the last 
measurable concentration. 
AUC0-inf 
Area under the concentration-time curve from time zero to infinity 
(extrapolated) 
BLQ 
Below Limit Of Quantitation 
BP 
Blood Pressure 
bpm 
Beats per minute 
CI 
Confidence Interval 
CLsys/F 
Apparent systemic clearance 
CLr 
Renal Clearance 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HEENT 
Head, Eyes, Ears, Nose, and Throat 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
INR 
International Normalized Ratio 
IV 
Intravenous 
Kel 
Elimination rate constant 
kg 
Kilogram 
L 
Liter 
LDL 
Low-density lipoprotein 
LS 
Least squares 
Max 
Maximum 
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Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 7 of 30 
 
MedDRA 
Medical dictionary for regulatory activities 
MDMA 
3,4-methylenedioxymethamphetamine 
mg 
Milligram 
Min 
Minimum 
min 
Minute 
mmHg 
Millimeters of Mercury 
ms 
Millisecond 
OT 
Oral temperature 
PCP 
Phencyclidine 
PK 
Pharmacokinetic(s) 
PR 
PR Interval of the ECG 
PTT 
Partial Thromboplastin Time 
PT 
Prothrombin Time 
Rmax 
Maximum Rate of Urinary Excretion 
RR 
RR interval of the ECG 
Rsq 
r-squared 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
TEAE 
Treatment-Emergent Adverse Event 
T½ el 
Elimination Half-Life 
Tmax 
Time of Maximum Concentration 
TRmax 
Time of Maximal Urinary Excretion 
WHO DD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan 
 
 
 
 
 
 
         Jupiter Orphan Therapeutics 
Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 8 of 30 
 
1. 
Introduction 
This statistical analysis plan (SAP) is intended to give a detailed description of the summaries 
and the analyses that will be generated for the present study by Syneos Health or a designee. 
Analyses specified in this plan are based on Jupiter Orphan Therapeutics, Study Protocol No. 
202016 (Final version) dated August 20, 2020. Safety, tolerability, and pharmacokinetic (PK) 
analyses will all be described. 
 
This document defines the populations to be analyzed and provides full details of the statistical 
analyses, data displays, and algorithms to be used for data derivations to aid in the production of 
the statistical output. Relevant subject characteristics that will be evaluated are described along 
with the specific statistical methods. 
The plan may change due to unforeseen circumstances and any changes made after the plan has 
been finalized will be documented. If additional analyses are required to supplement the planned 
analyses described in the SAP, the changes and justification for the changes will be outlined in a 
SAP amendment and in the clinical study report (CSR). No change will be made without prior 
approval of the study sponsor. No revision to the SAP is required for changes that do not affect 
the statistical analysis methods, definitions, or rules defined in this document.  
When applicable, all methodology and related processes will be conducted according to Syneos' 
standard operating procedures (SOPs) as appropriate. Protocol deviations occurring during the 
study will be listed. 
Shells for all statistical tables, figures and listings referred to in this SAP will be displayed in a 
separate document. 
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2. 
Study Objectives 
 
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.  
 
 
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3. 
Study Design 
3.1 
General 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 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.  
 
In order to minimize potential variability, elder subjects will not be included in the food effect 
part (Part 2). 
This study is intended for submision under FDA regulations. 
3.2 
Study Procedures 
The overall schedule of procedures and assessments is provided in the protocol. 
3.3 
Treatment Description 
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. 
 
 
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3.4 
Confinement 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). 
3.5 
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. 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.  
 
An effort will be made to include to the extent possible, subjects of the following age groups: 
 
• ≥ 65 and ≤ 70 years of age;  
• ≥ 70 and ≤ 75 years of age.  
3.6 
Randomization and Blinding 
Subjects will be administered 200 mg, 500 mg and 1000 mg gelcaps sequentially in ascending 
order. As this is an open-label study no blinding will be applied. 
3.7 
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 a 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’s SOP: 
 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, or drug test will be definitively withdrawn 
from the study. Hematology results will be reviewed by the Investigator or designee prior to 
dosing in study Part 2 (Period 4). Subjects will be withdrawn from the study if it is deemed that 
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Page 12 of 30 
 
the subject’s safety may be at risk on the basis of these test results. 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 in order to assure initiating 
study Part 2 with 16 subjects. Such replacement resulting in dosing more subjects than planned 
in this protocol would be documented in a protocol amendment.  
 
Subjects who withdraw or are withdrawn will be asked to remain at the clinic until the 
Investigator or a designee agrees that the subject is fine and can be discharged. As soon as 
subject withdrawal is confirmed, blood sampling will be stopped. A PK blood draw may be 
collected at the time of withdrawal if deemed required by the Investigator. Study exit procedures 
will be performed at the time of withdrawal from the study or as soon as possible thereafter.   
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19-NOV-2020 (Final 1.0) 
 
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4. 
Change From the Protocol 
No changes in planned analyses were done compared to the protocol. 
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5. 
Primary and Secondary Parameters 
AUC0-inf, AUC0-t and Cmax derived from resveratrol, resveratrol-3-glucuronide, resveratrol-4'-
glucuronide, and resveratrol-3-sulfate plasma concentrations will be the primary PK parameters. 
Other PK parameters derived from plasma concentrations (Residual area, Tmax, T½ el, CLsys/F 
(resveratrol only) and Kel) will be secondary PK parameters (refer to Section 10.3).   
For urine PK analyses, Ae0-t, Rmax and TRmax parameters will be calculated using urine 
concentrations (refer to Section 10.4). 
Treatment-emergent AEs (TEAEs) will be tabulated by treatment phase. Safety and tolerability 
data will be reported using descriptive statistics. (refer to Section 9.2). 
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19-NOV-2020 (Final 1.0) 
 
Page 15 of 30 
 
6. 
Analysis Populations 
The analysis of safety and tolerability parameters will be based on the study population detailed 
in Section 6.1. The analysis of PK concentration will be based on the study population detailed in 
Section 6.2. The analysis of PK parameters will be based on the study population detailed in 
Section 6.3.  
6.1 
Safety Population 
The safety population is defined as all subjects who received at least one dose of the study 
medication. 
6.2 
Pharmacokinetic Concentration Population 
The PK Concentrations (PC) Population will comprise all subjects who received at least one dose 
of either study drug and have at least one quantifiable PK concentration.  
In addition, if a subject has an episode of emesis within 2 hours of study drug administration, 
their inclusion in the PK Concentration Population will be determined at the discretion of the 
pharmacokineticist. The PK Concentration Population will be used for the summaries of all PK 
concentration data. 
6.3 
Pharmacokinetic Parameter 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 3.7 may be evaluated after completion of the 
PK analysis. Any subject who experienced emesis within 3h post-dose 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. 
 
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Project No. 202016 
19-NOV-2020 (Final 1.0) 
 
Page 16 of 30 
 
7. 
Interim Analyses 
Interim PK analyses will be performed between each dose level and will inform selection of the 
subsequent dose. The Interim Analyses using PK concentration data will be done after the 
bioanalytical phase is completed and will include data from subjects who have finalized their 
study visits at the time of the interim database availability. 
 
PK parameters will be calculated using scheduled sampling times as actual sampling times will 
not be available for these interim analyses. Only descriptive statistics will be calculated and 
provided. Interim descriptive analyses of the PK variables will be conducted for each period 
(Number of observations [N], arithmetic mean, standard deviation [SD], coefficient of variation 
[%CV], median, minimum [Min], maximum [Max], geometric mean, and %CV geom.mean). 
 
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19-NOV-2020 (Final 1.0) 
 
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8. 
Study Population and Exposure 
No inferential analysis will be done. Only observed data will be used. 
8.1 
Subject Disposition 
Subject disposition will be summarized by treatment and overall (frequency and the percentage 
of subjects). Subject completion and discontinuation information will be listed. In addition, 
subjects who were dismissed from a period or who did not complete a dosing period will also be 
presented in this listing, including absence/early discontinuation reason, date and time of 
discontinuation. 
8.2 
Protocol Deviations 
The protocol deviations will be categorized and listed by subject. 
8.3 
Demographics and Baseline Characteristics 
The descriptive statistics (mean, median, standard deviation [SD], minimum [Min], maximum 
[Max], and sample size) will be calculated for continuous variables (age, body weight, height 
and body mass index [BMI]) considering last results (scheduled or unscheduled) obtained at 
screening. Frequency counts and percentages will be tabulated for categorical variables (age 
group, sex, ethnicity, and race). Results will be presented summarized by treatment and overall 
for the safety population and for PK population. All demographic characteristics will be listed by 
subject. 
8.4 
Medical History 
Medical history at screening will be listed by subject. The Medical Dictionary for Regulatory 
Activities (MedDRA®), Version 23.1 will be used to classify all medical history findings by 
System Organ Class (SOC) and Preferred Term (PT). 
8.5 
Prior and Concomitant Medications 
The use of prior and/or concomitant medication will be monitored throughout the study and 
listed by subject. The World Health Organization Drug Dictionary (WHO DD), Version 
Sep2020, format B3 will be used to classify all medication reported as from screening through 
study exit/early termination.  
8.6 
Study Drug Administration 
The study drug administration details (including period, total dose administered, start and end 
date/time of administration) will be listed by subject for the safety population.  
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9. 
Safety Analyses 
Safety data will be evaluated for the safety population through the assessment of AEs, laboratory 
parameters (hematology, biochemistry, serology, coagulation, urinalysis,), 12-lead 
electrocardiogram (ECG), physical examination, and vital signs assessments. AEs, laboratory 
values, and vital signs and ECG will be summarized overall as appropriate. Safety data will be 
summarized, but will not be subjected to inferential analysis.  
Details of the additional laboratory work (RNA-Seq Analysis, Iduronidase, mRNA Frataxin, and 
Other Possible Tests) will be available in a separate protocol. 
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 the Investigator or designee’s request. 
9.1 
Physical Examination Findings 
A complete physical examination will be performed at screening. Any abnormal finding prior 
dosing will be presented in Medical History (MH) and a finding happening after 1st dosing will 
be categorized as an Adverse Event(AE). 
9.2 
Adverse Events 
AEs will be recorded and evaluated for their seriousness, severity, and relationship to the study 
medication. AEs will be collected and documented during the course of the study and until 4 
days following the last study drug administration, if reported. AEs will be followed-up until 
complete resolution, or until the Investigator judges it to be safe to discontinue follow-up. The 
relationship to the study medication will be classified according to the clinical site SOPs.   
Treatment-emergent AEs and non-TEAEs (those occurring prior to administration of study 
medication or that first occurred prior to study drug administration and did not worsen in 
frequency or severity) will be listed. TEAEs will be defined as AEs that occur on or after the 
date and time of study drug administration, or those that first occur pre-dose but worsen by 
increase in occurrence or severity after study drug administration. AEs will also be documented 
if reported.  
The incidence of TEAEs will be summarized using the safety population. The MedDRA® 
dictionary Version 23.1 will be used to classify all AEs reported during the study by SOC and 
PT. 
Incidence of subjects who experienced TEAEs will be presented by treatment and overall, SOC, 
PT, by Investigator-assessed relationship and also by severity. Each subject may only contribute 
once to each of the incidence rates, for a TEAE following a given treatment, regardless of the 
number of occurrences; the highest severity or highest relationship will be presented, as 
appropriate. In each table, SOC will be presented in descending order of overall incidence rate in 
terms of frequency of subjects and then in frequency of events (alphabetical order will be used in 
case of equal rates). For each SOC, PT will be presented the same way.  
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Incidence of TEAEs (number of events) will also be presented by period(dose) and overall, by 
SOC, and PT, by Investigator-assessed relationship and severity. 
Frequency of subjects experiencing Serious Treatment Emergent Adverse Events and Suspected 
Unexpected Serious Adverse Drug Reactions; and the number of events would be also 
summarized per treatment and overall. Also, these events and Serious Adverse Events (SAEs) 
will be listed per subject. 
The assessment of the relationship of an adverse event with the administration of study drug will 
be classified according to the clinical site SOPs. The relationship of TEAEs will be classified as 
probably related, possibly related, remotely related and unrelated (not related) to JOTROL. 
9.3 
Laboratory Parameters 
Biochemistry will be performed at screening and study exit. The following will be assessed: 
albumin, alkaline phosphatase (ALP), Aspartate Aminotransferase (AST), Alanine 
Aminotransferase (ALT), urea, calcium, chloride, glucose, phosphorus, potassium, creatinine, 
sodium, total bilirubin, and total protein. 
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. 
Hematology will be performed at screening, at check-in of study Part 2 (Period 4), and at study 
exit. The following will be assessed: complete blood count with differential, hemoglobin, and 
hematocrit.  
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). 
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.  
Hematology, biochemistry, urinalysis, urine pregnancy test, vital signs (blood pressure [BP], 
respiratory rate [RR], heart rate [HR], and oral temperature [OT]), 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. 
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. 
A urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, PCP, MDMA, methadone) and a urine cotinine test will 
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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. 
Listings of all clinical laboratory results will be provided with the abnormal values flagged with 
"L" (below normal) and "H" (above normal) for continuous parameters, and “A” (abnormal) for 
categorical parameters, including the evaluation of the abnormal result as clinically significant or 
not clinically significant. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size) for each clinical laboratory 
test (continuous variables) will be presented for overall. Change from screening for hematology, 
biochemistry, and urinalysis will be presented. The unscheduled results will not be included in 
the summary tables. For categorical variable (urinalysis test), the number of subjects (frequency 
and percentage) will be tabulated by results (e.g., negative, positive, trace …). A summary table 
of shifts from screening to study exit will be provided. Results from repeat tests will not be 
included in the summary statistics unless the repeat was required (and documented as such) due 
to technical reasons or an invalid initial result. 
For Serology and Coagulation only listing will be provided. 
9.4 
Vital Signs 
BP, HR, RR and OT will be measured in a sitting position (except for safety reasons) at 
screening and study exit.  
Descriptive statistics (mean, median, SD, Min, Max, and sample size) will be presented by 
overall for screening and study exit for each vital sign measurement. Descriptive statistics for 
change from screening to study exit will be presented. Unscheduled results will not be included 
in the summary tables. Results from post-dose repeat tests will not be included in the summary 
statistics unless the repeat was required (and documented as such) due to technical reasons or an 
invalid initial result.  
A listing of all vital signs results will be provided. 
9.5 
Safety ECG 
Supine 12-lead ECG will be performed at screening and study exit.  
Descriptive statistics (mean, median, SD, Min, Max, and sample size) will be presented for 
screening and study exit for ECG. Unscheduled results will not be included in the summary 
tables. Change from screening descriptive statistics for study exit will also be presented. Results 
from repeat tests will not be included in the summary statistics unless the repeat was required 
(and documented as such) due to technical reasons or an invalid initial result. 
A listing of all ECG results will be provided with the abnormal values flagged. 
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10. Pharmacokinetic Analyses 
10.1 Handling of the Below the Lower Limit of Quantification (BLQ) and the No 
Reportable Concentration 
All concentration values that are BLQ occurring prior to dosing  as well as samples with no 
reportable value (NRV) occurring prior to dosing will be replaced by “0.00”; otherwise they 
(BLQ and NRV) will be set to missing for tabulation, graphical representation and calculation 
purposes. 
10.2 Handling of the Difference between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each collection time for the PK 
samples will be recorded using electronic data capture. For all sampling times, the actual 
sampling times will be calculated as the difference between the sample collection actual clock 
time and the actual clock time of dosing. The actual post-dose sampling times expressed in hours 
and rounded off to three decimal digits will be used to calculate the PK parameters, except for 
pre-dose samples occurring prior to dosing, which will always be reported as zero (0.000), 
regardless of the time difference. Scheduled sampling times will be presented in concentration 
tables and mean graphs, while actual sampling times will be presented in the individual graphs in 
the PK section of the report. A listing of the actual times for PK sampling will be provided for 
PK samples. 
10.3 Pharmacokinetic Parameters 
PK analyses will be performed using Phoenix® WinNonlin® version 8.2, which is validated by 
Syneos Health. Inferential statistical analyses will be performed using Statistical Analysis 
System (SAS®) version 9.4 according to FDA guidelines. Bioanalysis of all samples should be 
completed prior to the initiation of the PK statistical analyses. 
A total of 17 blood samples will be collected in each period for PK analyses:  
pre-dose and 0.133, 0.250, 0.500, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.0, 12.0, 16.0, 
24.0, and 32.0 hours post- dose. 
Plasma PK Parameters 
The following PK parameters will be calculated by standard non-compartmental methods with  
JOTROL (resveratrol) plasma concentrations: 
 
Primary parameter: 
AUC0-inf: 
Area under the concentration-time curve from time zero to infinity 
(extrapolated), calculated as AUC0-t + Ct/Kel, where Ct is the last observed 
measurable concentration.  
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AUC0-t: 
Area under the concentration-time curve from time zero to the last 
measurable concentration. AUC0-t will be calculated using the linear 
trapezoidal-linear interpolation method.  
Cmax: 
Maximum observed concentration. 
Secondary parameters: 
Residual area: 
Residual area, calculated as 100*(1- AUC0-t / AUC0-inf). 
Tmax: 
Time of observed Cmax. 
T½ el: 
Elimination half-life, calculated as ln (2)/Kel.  
Kel: 
 
Elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed concentration 
versus time profile in the terminal elimination phase. Best fit method will be 
used to calculate the Kel from at least 3 concentration data points excluding 
the Cmax. Rsq adjusted, the goodness of fit statistic for the terminal 
elimination phase, adjusted for the number of points used in the estimation of 
Kel must be ≥ 0.8. No points below Tmax will be used. If the Kel cannot be 
measured (e.g.: fewer than 3 non-zero concentrations in the terminal 
elimination phase or Rsq adjusted < 0.8), the PK parameters derived from Kel 
will not be reported for that individual PK profile (AUC0-inf, Residual area, 
and T½ el). The timepoint where ln-linear Kel calculation begins (Kel Lower) and 
the actual sampling time of the last measurable concentration used to 
estimate the Kel (Kel Upper), as well as the Rsq adjusted for the ln-linear 
regression for the calculation of the elimination rate constant will be 
reported. 
Additional PK analyses may be performed. Upon Sponsor's request, PK repeats might be 
performed according to Syneos Health’s SOP. If re-assays are requested for PK reasons (not 
advised) , 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. The rationale for re-
assays for PK reasons must be provided. 
10.4 PK Parameters Calculated With Urine Concentrations 
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. 
Urine samples will be used to calculate the following parameters for resveratrol, resveratrol-3-
glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate: 
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. 
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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. 
Tmax: 
Time of Rmax, calculated as the midpoint of the collection interval during 
which Rmax occurred.  
  
CLr: 
Renal clearance, calculated as Ae0-t/AUC0-t (plasma) where t is Tlast 
 
10.5 Statistical Analyses 
10.5.1   PK Parameters in Plasma 
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales. Descriptive statistics (number of observations, arithmetic and geometric 
means, SD, coefficients of variation [CV%], Min, Max, and median) of the plasma 
concentrations versus time data will be presented by Treatment as well for the PK parameters. 
Summary statistics will be used to describe the PK profile for each treatment. 
10.5.2   Assessment of Dose Proportionality 
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). 
Power model will include the PK parameter as the response variable and dose (mg) as the 
explanatory variable. For this model, the variable dose will be treated as a continuous variable.  
 
The form of the model is as follows: 
 
PK Parameter = a × Doseb × eϵ,         where Dose ≥ 0, and eϵ represents the associated error. 
Thus, perfect dose proportionality is met when b=1 (ignoring error). This becomes a linear 
relationship following a natural-log transformation, The mixed effect statistical model will be the 
following:  
ij
i
ij
ij
s
Dose
b
a
P






)
ln(
)
ln(
)
ln(
, 
where 
ij
P  is the value in the j th period for the i th subject for the PK parameter analyzed, 
ij
Dose  
is the dose in the j th period for the i th subject, 
is  is the random effect associated to the i th 
subject, and 
ij
 is the random error in the j th period for the i th subject. The 
is and 
ij
 values are 
assumed to be mutually independent and normally distributed. 
The estimate of b together with a 90% confidence interval (CI) will be provided (for each PK 
parameter model), and this will be used to quantify dose proportionality. 
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Page 24 of 30 
 
proc mixed data=dataset; 
class subject; 
model ln_pk_parameter = ln_dose / solution; 
random subject; 
estimate 'Beta Estimate' ln_dose 1 / cl alpha=0.1; 
ods output estimates = estimates; 
run; 
 
The PK parameter values estimated from the power model will be plotted against dose. This plot 
will also include individual subject values ± SD (separately by dose level). 
10.5.3   Criteria for Determination of Dose-Proportionality 
PK dose proportionality will be concluded if the 90% C.I. of b for AUC0-inf, AUC0-t and Cmax are 
entirely contained within the following bounds that depend on the dose range ratio (Smith BP, 
2000) (i.e., ln (1000/200) = ln (5)): 
 Lower bound = 1+ln (0.80)/ln (5) = 0. 861353116 and 
 Upper bound = 1+ln (1.25)/ln (5) = 1.138646884 
10.5.4   Food-Effect assessment  
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. 
If 90% CI for AUC0-t, AUC0-inf and Cmax are within 80.00% to 125.00% then no food effect will 
be concluded. 
For all analytes, using GLM procedure in SAS, ANOVA will be performed on ln-transformed 
AUC0-t, AUC0-inf and Cmax at the alpha level of 0.05. The model will include Treatment as fixed 
effect and Subject as a random effect. Inter- and intra-subject coefficient of variation will be 
estimated. The ratio of geometric means and 90% confidence interval for the ratio of geometric 
means, based on least-squares means from the ANOVA of the ln-transformed data, will be 
calculated for AUC0-t, AUC0-inf, and Cmax. 
SAS® codes for ANOVA: fed vs. fasting 
PROC GLM data=basepk; 
CLASS TREATMENT SUBJECT; 
MODEL VAR = TREATMENT SUBJECT; 
RANDOM SUBJECT; 
LSMEANS TREATMENT / cl pdiff alpha=0.1;   
ESTIMATE 'fed - fasting' TRT 1 -1/cl alpha=0.1; 
run; 
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Additional statistical analysis may be performed. 
10.5.5  Urine PK analysis 
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.  
 
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11. Percentages and Decimal Places 
If not otherwise specified, the following rules will be applied, with the exception of PK tables 
and listings described below: 
Percentages will be presented to one decimal point. 
Percentages equal to 0 or 100 will be presented as such without a decimal point. 
Minimum and maximum will be presented with the same precision as the original values and, 
mean, standard deviation, and median will be presented with one more decimal place than the 
original values. 
All digits will be used for pharmacokinetic and statistical PK calculations. For PK tables and 
listings, the final reportable results or data will be presented by rounding off to two decimal 
digits, except for the following situations (this applies to individual data and descriptive 
statistics): 
Kel and Rsq adjusted data: rounded off to four decimal digits. 
PK parameter related to time such as Tmax, must be reported with the same precision as the actual 
sampling time: rounded off to 3 decimal digits. 
Concentration versus time data, as well as Cmax: reported as they appear in corresponding dataset. 
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12. Handling of Missing Data  
For safety,  
 If an AE is recorded with an onset date corresponding to a dosing day, but the time is 
missing, then the AE will be assigned to the treatment phase planned treatment with a 
dosing planned that day. 
 If an AE is recorded with an onset date that does not correspond to a dosing day, but the 
time is missing, then the AE will be assigned to the treatment phase planned treatment that 
covers the AE onset day. 
 If an AE is recorded with an onset date where day and time are both missing, then the AE 
allocation to a treatment phase planned treatment will be done on a case by case basis 
considering available information (e.g. AE onset date, AE end date, AE comments, subject 
disposition). 
For PK, only observed data will be used in the data analysis except for concentration values BLQ 
as described in Section 10.1. No attempt will be made to extrapolate or interpolate estimates for 
missing data. 
 
 
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13. Data Handling 
The PK plasma concentrations, safety, and tolerability data will be received as SAS® datasets 
from the Syneos Health data management facility. Screening failures and ineligible volunteer’s 
data (subject disposition) will be received from the clinical site as source data. 
 
 
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14. Software to be Used 
PK analysis will be performed using Phoenix WinNonlin® version 8.2 or higher, which is 
validated for bioequivalence/bioavailability studies by inVentiv. The safety data tables and 
listings, as well as PK tables and listings will be created using SAS®, release 9.2 or a higher 
version. PK figures will be created using R version 3.5 (or higher).  The CSR will be created 
using Microsoft® Office Word 2010, or a higher version. 
 
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15. Reference List 
 Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for 
assessment of dose proportionality. Pharmaceutical research 2000;17:1278-83. 
 
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Prot_003.pdf: 
 
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 
 
 


202016 Resveratrol (JOTROL) Gelcaps Phase I SAD Study 
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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.