JOTROL PK, Safety, and Food Effect Assessment

• Sponsor: Jupiter Orphan Therapeutics Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04668274
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 24
• Location: 1
• Arms: 4
• Actual Duration (Months): 4.3
• Patients Per Site Per Month: 5.6

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Pharmacokinetics; Safety; Food-drug Interaction	Drug: 200 mg resveratrol as JOTROL; Drug: 500 mg resveratrol as JOTROL; Drug: 700 mg resveratrol as JOTROL; Drug: 500 mg resveratrol as JOTROL administered to assess influence of food	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official 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
• Actual Study Start Date: Jan 21, 2021
• Actual Primary Completion Date: Feb 28, 2021
• Actual Study Completion Date: May 31, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: JOTROL (Resveratrol) 200 mg (Treatment A) 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.	Drug: 200 mg resveratrol as JOTROL; Low (first) dose of single ascending dose study
Experimental: Part 1: JOTROL (Resveratrol) 500 mg (Treatment B) 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.	Drug: 500 mg resveratrol as JOTROL; Second (intermediate) dose of single ascending dose study
Experimental: Part 1: JOTROL (Resveratrol) 700 mg (Treatment C) 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.	Drug: 700 mg resveratrol as JOTROL; Third (highest) dose of single ascending dose study
Experimental: Part 2: JOTROL (Resveratrol) 500 mg (Treatment D) 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.	Drug: 500 mg resveratrol as JOTROL administered to assess influence of food; 500 mg resveratrol as JOTROL administered to assess influence of food

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From first dose of study drug administration up to 131 days]

   An adverse event (AE) was defined as any untoward medical occurrence (including clinically significant [CS] vital signs measurements or laboratory results) or worsening of a pre-existing condition in a participant administered a pharmaceutical product during the course of the study, whether related or not to the study medication. TEAEs were defined as AE that occurred on or after the date and time of study drug administration or those that first occurred pre-dose but worsened by increase in occurrence or severity after study drug administration. TEAEs includes both serious and non-serious TEAEs.

2. Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity (AUC0-inf) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate) [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 on Day 1]

   AUC(0-infinity) of resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma were reported. AUC(0-infinity) of resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma were reported and calculated as AUC0-t + Ct/Kel, where Ct is the last observed measurable concentration, AUC0-t is Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration and Kel is Elimination rate constant.

3. Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate) [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 on Day 1]

   AUC0-t was Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration. AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.

4. Maximum Observed Plasma Concentration (Cmax) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate) [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 on Day 1]

   Cmax was the maximum observed plasma concentration obtained directly from the concentration versus time curve.

Secondary Outcome Measures

1. Residual Area for Resveratrol [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 on Day 1]

   Residual area for resveratrol in plasma was calculated and reported. The residual area was calculated as 100*(1- AUC0-t / AUC0-inf) where AUC0-t (h*ng/mL) = area under the concentration-time curve from time zero to the last measurable concentration and AUC0-inf (h*ng/mL) = area under the plasma concentration-time curve from time 0 to time of infinity.

2. Time to Maximum Observed Plasma Concentration (Tmax) for Resveratrol [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 on Day 1]

   Tmax was time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

3. Elimination Half-Life (T1/2 el) for Resveratrol [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 on Day 1]

   Elimination half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

4. Elimination Rate Constant (Kel) for Resveratrol [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 on Day 1]

   Kel was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

5. Cumulative Urinary Excretion From Time Zero to Time t (Ae0-t) for Resveratrol [Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1]

   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 was calculated as the urine concentration multiplied by the urine volume.

6. Maximum Rate of Urinary Excretion (Rmax) for Resveratrol [Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1]

   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.

7. Time of Rmax (Tmax) for Resveratrol [Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1]

   Tmax was the time after administration of a drug when the Rmax is reached.

8. Renal Clearance (CLr) for Resveratrol [Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1]

   CLr was calculated as Ae0-t/AUC0-t (plasma) where t is Tlast.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Normal healthy male or female volunteers, non-smokers (no use of tobacco products within 3 months prior to screening), ≥ 18 and ≤ 75 years of age, with BMI > 18.5 and < 30.0 kg/m 2 and body weight ≥ 50.0 kg for males and ≥ 45.0 kg for females

2. Healthy as defined by:

3. 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.

4. 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.

5. 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:

6. intra-uterine contraceptive device without hormone release system placed at least 4 weeks prior to study drug administration;

7. male condom with intravaginally applied spermicide starting at least 21 days prior to study drug administration;

8. sterile male partner (vasectomized since at least 6 months).

9. 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

1. Positive pregnancy test at screening.

2. Breast-feeding subject.

3. 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.

4. 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]).

5. 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.

6. 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.

7. 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.

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):

1. prescription medication within 14 days prior to the first dosing;

2. 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);

3. use of any drugs known to induce or inhibit hepatic drug metabolism within 30 days prior to the first study drug administration, including St John's wort;

4. depot injection or an implant of any drug within 3 months prior to the first dosing.

5. 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.

6. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	inVentiv Health Clinical Research Services LLC, a Syneos Health company (" Syneos Health ")	Miami	Florida	United States	33136

Sponsors and Collaborators

• Jupiter Orphan Therapeutics Inc.
• National Institute on Aging (NIA)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 25, 2020
• Statistical Analysis Plan - Nov 19, 2020
• Informed Consent Form - Nov 17, 2020

More Information

Publications

None provided.

• Responsible Party: Jupiter Orphan Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT04668274
• Other Study ID Numbers: Protocol 202016; R44AG067907-01A1
• First Posted: Dec 16, 2020
• Last Update Posted: Aug 12, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Resveratrol

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in the United States from 21 January 2021 to 31 May 2021.
Pre-assignment Detail	A total of 83 healthy participants were screened, of which 29 participants were eligible for this study. Of 29 eligible participants, a total of 24 participants were treated in this single ascending dose study.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	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.	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.	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.	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.
Period Title: Part 1 Study Period 1
STARTED	21	0	0	0
COMPLETED	16	0	0	0
NOT COMPLETED	5	0	0	0
Period Title: Part 1 Study Period 1
STARTED	0	16	0	0
COMPLETED	0	15	0	0
NOT COMPLETED	0	1	0	0
Period Title: Part 1 Study Period 1
STARTED	0	0	18	0
COMPLETED	0	0	15	0
NOT COMPLETED	0	0	3	0
Period Title: Part 1 Study Period 1
STARTED	0	0	0	15
COMPLETED	0	0	0	14
NOT COMPLETED	0	0	0	1

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants who received JOTROL (resveratrol) 200 (2*100) mg (Treatment A) gelcap, orally once on Day 1 in Study period 1 followed by 500 (5*100) mg (Treatment B) gelcap, orally once on Day 1 in Study period 2 further followed by 700 (7*100) mg (Treatment C) gelcap, orally, on Day 1 in Study period 3 in fasted conditions of Part 1 of the study, followed by JOTROL (resveratrol) 500 (5*100) mg (Treatment D) gelcap, orally, once on Day 1 in fed condition in Study Period 4 of Part 2 of the study. There was a washout period of 14 days between each study period.
Overall Participants	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.7 (12.6)
Sex: Female, Male (Count of Participants)
Female	14 58.3%
Male	10 41.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	24 100%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 16.7%
White	20 83.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	An adverse event (AE) was defined as any untoward medical occurrence (including clinically significant [CS] vital signs measurements or laboratory results) or worsening of a pre-existing condition in a participant administered a pharmaceutical product during the course of the study, whether related or not to the study medication. TEAEs were defined as AE that occurred on or after the date and time of study drug administration or those that first occurred pre-dose but worsened by increase in occurrence or severity after study drug administration. TEAEs includes both serious and non-serious TEAEs.
Time Frame	From first dose of study drug administration up to 131 days

Outcome Measure Data

Analysis Population Description

The safety population was defined as all participants who received at least one dose of the study medication.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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 day washout period was maintained in study period 1 and 2.	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 day washout period was maintained in study period 2 and 3.	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 day washout period was maintained in study period 3 and 4.
Measure Participants	21	16	18	15
Count of Participants [Participants]	7 29.2%	4 NaN	6 NaN	6 NaN

2. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity (AUC0-inf) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate)
Description	AUC(0-infinity) of resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma were reported. AUC(0-infinity) of resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma were reported and calculated as AUC0-t + Ct/Kel, where Ct is the last observed measurable concentration, AUC0-t is Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration and Kel is Elimination rate constant.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. "Number analyzed" signifies to participants evaluable for given categories.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	21	16	18	14
Resveratrol	214.73	499.73 (56.54)	595.75 (28.19)	553.77 (60.84)
Resveratrol-3-Glucuronide	4821.18 (29.37)	16390.55 (27.25)	29570.84 (34.08)	11834.05 (28.41)
Resveratrol-3-Sulfate	11668.98 (27.75)	35063.90 (31.67)	53845.25 (20.62)	31133.94 (33.24)
Resveratrol-4'-Glucuronide	4591.06 (27.34)	15387.06 (29.76)	22934.42 (29.90)	14528.02 (21.95)

3. Primary Outcome

Title	Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate)
Description	AUC0-t was Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration. AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	21	16	18	14
Resveratrol	112.32 (72.49)	422.85 (53.24)	785.29 (51.52)	263.75 (65.72)
Resveratrol-3-Glucuronide	4796.08 (29.58)	16347.62 (27.21)	29492.22 (34.04)	11775.27 (28.51)
Resveratrol-3-Sulfate	11593.20 (26.78)	34854.48 (31.49)	53351.47 (20.04)	31018.49 (33.26)
Resveratrol-4'-Glucuronide	4550.27 (27.58)	15337.45 (29.70)	22845.47 (29.36)	14502.21 (21.93)

4. Primary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate)
Description	Cmax was the maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	21	16	18	14
Resveratrol	94.70 (91.46)	326.32 (89.76)	648.08 (73.29)	140.09 (100.84)
Resveratrol-3-Glucuronide	2292.84 (29.69)	8334.08 (48.84)	14558.05 (46.33)	4173.48 (59.28)
Resveratrol-3-Sulfate	6204.37 (36.00)	16863.57 (48.55)	22856.79 (27.23)	10696.58 (65.43)
Resveratrol-4'-Glucuronide	1649.08 (33.30)	5340.95 (56.63)	7663.09 (40.20)	3742.71 (48.44)

5. Secondary Outcome

Title	Residual Area for Resveratrol
Description	Residual area for resveratrol in plasma was calculated and reported. The residual area was calculated as 100*(1- AUC0-t / AUC0-inf) where AUC0-t (h*ng/mL) = area under the concentration-time curve from time zero to the last measurable concentration and AUC0-inf (h*ng/mL) = area under the plasma concentration-time curve from time 0 to time of infinity.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. Here "overall number of participants analyzed" included all participants who were evaluable for this outcome measure.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	1	5	3	2
Geometric Mean (Geometric Coefficient of Variation) [percentage AUC]	5.48	4.56 (73.50)	3.58 (38.56)	2.29 (111.16)

6. Secondary Outcome

Title	Time to Maximum Observed Plasma Concentration (Tmax) for Resveratrol
Description	Tmax was time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	21	16	18	14
Median (Full Range) [hour]	0.999	1.003	1.025	1.497

7. Secondary Outcome

Title	Elimination Half-Life (T1/2 el) for Resveratrol
Description	Elimination half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. Here "overall number of participants analyzed" included all participants who were evaluable for this outcome measure.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	1	5	3	2
Geometric Mean (Geometric Coefficient of Variation) [hour]	1.26	2.36 (62.56)	1.56 (25.19)	1.47 (71.72)

8. Secondary Outcome

Title	Elimination Rate Constant (Kel) for Resveratrol
Description	Kel was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time Frame	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 on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. Here "overall number of participants analyzed" included all participants who were evaluable for this outcome measure.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)	Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.	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.
Measure Participants	1	5	3	2
Geometric Mean (Geometric Coefficient of Variation) [1 per hour (1/h)]	0.5520	0.2932 (48.70)	0.4436 (28.56)	0.4712 (71.72)

9. Secondary Outcome

Title	Cumulative Urinary Excretion From Time Zero to Time t (Ae0-t) for Resveratrol
Description	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 was calculated as the urine concentration multiplied by the urine volume.
Time Frame	Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. As pre-specified, this outcome measure was planned to be assessed for Part 1 only.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.
Measure Participants	21	16	18
Geometric Mean (Geometric Coefficient of Variation) [nanogram (ng)]	16927.35 (75.39)	48454.76 (49.88)	109323.50 (88.32)

10. Secondary Outcome

Title	Maximum Rate of Urinary Excretion (Rmax) for Resveratrol
Description	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.
Time Frame	Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. As pre-specified, this outcome measure was planned to be assessed for Part 1 only.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.
Measure Participants	21	16	18
Geometric Mean (Geometric Coefficient of Variation) [nanogram per hour (ng/h)]	8791.49 (82.45)	26486.23 (136.58)	44737.57 (90.97)

11. Secondary Outcome

Title	Time of Rmax (Tmax) for Resveratrol
Description	Tmax was the time after administration of a drug when the Rmax is reached.
Time Frame	Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. As pre-specified, this outcome measure was planned to be assessed for Part 1 only.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.
Measure Participants	21	16	18
Median (Full Range) [hour]	0.793	0.551	0.698

12. Secondary Outcome

Title	Renal Clearance (CLr) for Resveratrol
Description	CLr was calculated as Ae0-t/AUC0-t (plasma) where t is Tlast.
Time Frame	Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1

Outcome Measure Data

Analysis Population Description

The PK population comprised of all participants who received at least one dose of either study drug and had at least one quantifiable PK concentration. As pre-specified, this outcome measure was planned to be assessed for Part 1 only.

Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)	Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)	Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.	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.	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.
Measure Participants	21	16	18
Geometric Mean (Geometric Coefficient of Variation) [liter per hour (L/h)]	0.15 (112.22)	0.11 (63.04)	0.14 (95.39)

Adverse Events

Time Frame	From first dose of study drug administration up to 131 days
Arm/Group Title	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)		Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)		Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)		Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
Arm/Group Description	Participants received JOTROL (resveratrol) 200 (2*100) mg (Treatment A), gelcap, orally, once on Day 1 in fasted conditions in Study Period 1.		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.		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.		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.
All Cause Mortality
	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)		Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)		Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)		Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/16 (0%)		0/18 (0%)		0/15 (0%)
Serious Adverse Events
	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)		Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)		Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)		Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/16 (0%)		0/18 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: JOTROL (Resveratrol) 200 mg (Treatment A)		Part 1: JOTROL (Resveratrol) 500 mg (Treatment B)		Part 1: JOTROL (Resveratrol) 700 mg (Treatment C)		Part 2: JOTROL (Resveratrol) 500 mg (Treatment D)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/21 (33.3%)		4/16 (25%)		6/18 (33.3%)		6/15 (40%)
Gastrointestinal disorders
Diarrhoea	1/21 (4.8%)		0/16 (0%)		0/18 (0%)		0/15 (0%)
Nausea	0/21 (0%)		0/16 (0%)		0/18 (0%)		1/15 (6.7%)
Vomiting	0/21 (0%)		0/16 (0%)		0/18 (0%)		1/15 (6.7%)
Infections and infestations
COVID-19	2/21 (9.5%)		0/16 (0%)		0/18 (0%)		0/15 (0%)
Investigations
Alanine aminotransferase increased	0/21 (0%)		0/16 (0%)		0/18 (0%)		1/15 (6.7%)
Blood pressure increased	0/21 (0%)		0/16 (0%)		1/18 (5.6%)		0/15 (0%)
Haemoglobin decreased	0/21 (0%)		0/16 (0%)		1/18 (5.6%)		0/15 (0%)
SARS-CoV-2 test positive	0/21 (0%)		0/16 (0%)		1/18 (5.6%)		0/15 (0%)
White blood cells urine	0/21 (0%)		0/16 (0%)		0/18 (0%)		1/15 (6.7%)
Nervous system disorders
Somnolence	3/21 (14.3%)		2/16 (12.5%)		2/18 (11.1%)		2/15 (13.3%)
Headache	3/21 (14.3%)		2/16 (12.5%)		0/18 (0%)		0/15 (0%)
Syncope	0/21 (0%)		0/16 (0%)		1/18 (5.6%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.