Trial Outcomes & Findings for Pharmacokinetics Centella Asiatica Product (CAP) in Mild Cognitive Impairment (NCT NCT03937908)

Last Updated: 2022-05-04

Results Overview

Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (maximum concentration) for each of the two doses (2g and 4g).

Recruitment status

TERMINATED

Study phase

EARLY_PHASE1

Target enrollment

5 participants

Primary outcome timeframe

A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes).

Results posted on

2022-05-04

Participant Flow

Participant milestones

Participant milestones
Measure	Experimental: 2g CAP Then 4g CAP Participants first received one single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. After a washout period of 14 days, they then received one single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	Experimental: 4g CAP Then 2g CAP Participants first received one single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. After a washout period of 14 days, they then received one single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Overall Study STARTED	2	3
Overall Study COMPLETED	2	2
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Experimental: 2g CAP Then 4g CAP Participants first received one single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. After a washout period of 14 days, they then received one single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	Experimental: 4g CAP Then 2g CAP Participants first received one single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. After a washout period of 14 days, they then received one single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Overall Study Study discontinuation due to pandemic restrictions	0	1

Baseline Characteristics

Pharmacokinetics Centella Asiatica Product (CAP) in Mild Cognitive Impairment

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=5 Participants Baseline values for all participants before randomization
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants
Age, Categorical >=65 years	5 Participants n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	5 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	5 participants n=5 Participants
Body mass index	28 kg/m^2 STANDARD_DEVIATION 2 • n=5 Participants
White blood cells	7.28 x10^3 cells/uL STANDARD_DEVIATION 0.60 • n=5 Participants
Systolic blood pressure	132 mmHg STANDARD_DEVIATION 7 • n=5 Participants
Diastolic blood pressure	81 mmHg STANDARD_DEVIATION 3 • n=5 Participants
Body temperature	36.7 Celsius STANDARD_DEVIATION 0.1 • n=5 Participants
Heart rate	68 beats per minute STANDARD_DEVIATION 5 • n=5 Participants
Red blood cells	4.64 x10^6 cells/uL STANDARD_DEVIATION 0.21 • n=5 Participants
Hemoglobin	14.3 g/dL STANDARD_DEVIATION 0.6 • n=5 Participants
Hematocrit	44 percentage STANDARD_DEVIATION 2 • n=5 Participants
Platelets	259 x10^3 platelets/uL STANDARD_DEVIATION 20 • n=5 Participants
Blood glucose	81 mg/dL STANDARD_DEVIATION 3 • n=5 Participants
Blood urea nitrogen	17 mg/dL STANDARD_DEVIATION 3 • n=5 Participants
Creatinine	0.9 mg/dL STANDARD_DEVIATION 0.1 • n=5 Participants
Total bilirubin	0.6 mg/dL STANDARD_DEVIATION 0.1 • n=5 Participants
Aspartate aminotransferase	26 U/L STANDARD_DEVIATION 3 • n=5 Participants
Alanine aminotransferase	32 U/L STANDARD_DEVIATION 3 • n=5 Participants
Alkaline phosphatase	87 U/L STANDARD_DEVIATION 12 • n=5 Participants
Total protein	7.7 g/dL STANDARD_DEVIATION 0.1 • n=5 Participants
Albumin	3.8 g/dL STANDARD_DEVIATION 0.1 • n=5 Participants
Sodium	141 mmol/L STANDARD_DEVIATION 1 • n=5 Participants
Chloride	108 mmol/L STANDARD_DEVIATION 1 • n=5 Participants
Total CO^2	29 mmol/L STANDARD_DEVIATION 1 • n=5 Participants
Potassium	3.8 mmol/L STANDARD_DEVIATION 0.1 • n=5 Participants
Calcium	9.3 mg/dL STANDARD_DEVIATION 0.1 • n=5 Participants
Anion gap	5 mEq/L STANDARD_DEVIATION 1 • n=5 Participants

PRIMARY outcome

Timeframe: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480, and 600 minutes).

Population: The pharmacokinetic parameter (Cmax) and time curves was calculated using non-compartmental analysis of plasma concentration versus time data using Excel software PK-solver (version 2.0).

Outcome measures

Outcome measures
Measure	2g CAP n=4 Participants Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 2g Centella asiatica water extract product: 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=4 Participants Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 4g Centella asiatica water extract product: 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Asiatic acid	124 ng/mL Standard Error 29	259 ng/mL Standard Error 24
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Caffeic acid	0.3 ng/mL Standard Error 0.2	1 ng/mL Standard Error 0.1
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Dihydrocaffeic acid	1 ng/mL Standard Error 0.4	2 ng/mL Standard Error 0.2
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Dihydroferulic acid	11 ng/mL Standard Error 5	20 ng/mL Standard Error 6
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Dicaffeoylquinic acids	18 ng/mL Standard Error 10	3 ng/mL Standard Error 0.3
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Ferulic acid	1 ng/mL Standard Error 0.2	1.4 ng/mL Standard Error 0.1
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) 3-(3-hydroxyphenyl)propionic acid	32 ng/mL Standard Error 18	42 ng/mL Standard Error 18
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Isoferulic acid	0.9 ng/mL Standard Error 0.3	2 ng/mL Standard Error 0.1
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Madecassic acid	38 ng/mL Standard Error 3	63 ng/mL Standard Error 10
Peak Plasma Concentration of Centella Asiatica Bioactive Compounds (Cmax) Monocaffeoylquinic acids	14 ng/mL Standard Error 7	7 ng/mL Standard Error 2

PRIMARY outcome

Timeframe: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150, 180, 240, 360, 480 and 600 minutes).

The time of maximum concentration (Tmax) of the known bioactive compounds and their metabolites will be calculated from the concentrations measured by high performance liquid chromatography tandem mass spectrometry in order to help determine dosage intervals

Outcome measures

Outcome measures
Measure	2g CAP n=4 Participants Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 2g Centella asiatica water extract product: 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=4 Participants Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 4g Centella asiatica water extract product: 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Time of Maximum Concentration (Tmax) Asiatic acid	2 hours Standard Error 0.6	2 hours Standard Error 0.6
Time of Maximum Concentration (Tmax) Caffeic acid	4 hours Standard Error 2	4 hours Standard Error 1
Time of Maximum Concentration (Tmax) Dihydrocaffeic acid	3.25 hours Standard Error 0.5	3.5 hours Standard Error 0.5
Time of Maximum Concentration (Tmax) Dihydroferulic acid	3.4 hours Standard Error 1	3.5 hours Standard Error 0.5
Time of Maximum Concentration (Tmax) Dicaffeoylquinic acids	6 hours Standard Error 2	0.6 hours Standard Error 0.3
Time of Maximum Concentration (Tmax) Ferulic acid	5 hours Standard Error 0.6	5.5 hours Standard Error 0.5
Time of Maximum Concentration (Tmax) 3-(3-hydroxyphenyl)propionic acid	6 hours Standard Error 1.4	5.5 hours Standard Error 1.7
Time of Maximum Concentration (Tmax) Isoferulic acid	1.3 hours Standard Error 0.6	1 hours Standard Error 0.4
Time of Maximum Concentration (Tmax) Madecassic acid	2 hours Standard Error 0.5	2 hours Standard Error 0.5
Time of Maximum Concentration (Tmax) Monocaffeoylquinic acids	4 hours Standard Error 2	2 hours Standard Error 0.4

PRIMARY outcome

Timeframe: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480, and 600 minutes).

The half-life (t1/2) of the known bioactive compounds and their metabolites will be calculated from the plasma concentrations measured by high performance liquid chromatography tandem mass spectrometry to help determine dosage intervals.

Outcome measures

Outcome measures
Measure	2g CAP n=4 Participants Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 2g Centella asiatica water extract product: 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=4 Participants Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 4g Centella asiatica water extract product: 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Half-life (t1/2) Asiatic acid	3.8 hours Standard Error 1	2.2 hours Standard Error 0.5
Half-life (t1/2) Caffeic acid	2.6 hours Standard Error 1	3.5 hours Standard Error 1.2
Half-life (t1/2) Dihydrocaffeic acid	4.8 hours Standard Error 1.3	1.1 hours Standard Error 0.4
Half-life (t1/2) Dihydroferulic acid	4.5 hours Standard Error 1.6	2.5 hours Standard Error 0.3
Half-life (t1/2) Dicaffeoylquinic acids	0 hours Standard Error 0	3 hours Standard Error 2
Half-life (t1/2) Ferulic acid	13.4 hours Standard Error 5.3	7 hours Standard Error 1.2
Half-life (t1/2) 3-(3-hydroxyphenyl)propionic acid	2.3 hours Standard Error 0.3	1.8 hours Standard Error 0.7
Half-life (t1/2) Isoferulic acid	8.8 hours Standard Error 5.7	2.9 hours Standard Error 0.6
Half-life (t1/2) Madecassic acid	1.7 hours Standard Error 0.5	1.7 hours Standard Error 0.9
Half-life (t1/2) Monocaffeoylquinic acids	2 hours Standard Error 0.5	3 hours Standard Error 0.3

SECONDARY outcome

Timeframe: A 10-hour post-administration period (15, 30, 45, 60, 90, 120, 150,180, 240, 360, 480 and 600 minutes).

Following oral administration of a product made from a water extract of Centella asiatica (CAP), the plasma concentration of Centella asiatica derived bioactive compounds (triterpenes, caffeoylquinic acids, and their metabolites) will be measured in blood samples obtained over a 10 hour period, using high performance liquid chromatography tandem mass spectrometry in order to generate a pharmacokinetic curve, and determine pharmacokinetic parameters (area under the curve) for each of the two doses (2g and 4g).

Outcome measures

Outcome measures
Measure	2g CAP n=4 Participants Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 2g Centella asiatica water extract product: 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=4 Participants Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 4g Centella asiatica water extract product: 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Asiatic acid	364 ng x h/mL Standard Error 114	935 ng x h/mL Standard Error 178
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Caffeic acid	1 ng x h/mL Standard Error 1	3 ng x h/mL Standard Error 0.3
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Dihydrocaffeic acid	3 ng x h/mL Standard Error 0.4	6 ng x h/mL Standard Error 1
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Dihydroferulic acid	42 ng x h/mL Standard Error 18	77 ng x h/mL Standard Error 25
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Dicaffeoylquinic acids	18 ng x h/mL Standard Error 10	6 ng x h/mL Standard Error 4
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Ferulic acid	7 ng x h/mL Standard Error 2	10 ng x h/mL Standard Error 1
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica 3-(3-hydroxyphenyl)propionic acid	100 ng x h/mL Standard Error 46	189 ng x h/mL Standard Error 77
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Isoferulic acid	5 ng x h/mL Standard Error 2	8 ng x h/mL Standard Error 0.4
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Madecassic acid	101 ng x h/mL Standard Error 16	187 ng x h/mL Standard Error 48
Area Under the Curve (AUC) of the Concentration vs Time Profiles of Known Bioactives From Centella Asiatica Monocaffeoylquinic acids	18 ng x h/mL Standard Error 6	23 ng x h/mL Standard Error 4

SECONDARY outcome

Timeframe: Total 10 hours

All urine produced over the 10 hours post-administration was collected into a single container. The concentration of bioactive compounds from Centella asiatica (triterpenes, caffeoylquinic acids, and their metabolites) was measured in the single total urine sample collected over 10 hours after CAP administration. Urine samples were treated with glucuronidase and sulfatase enzymes to release analyte from conjugated (Phase II metabolite) forms of the analyte. All samples were analyzed using high performance liquid chromatography tandem mass spectrometry. The concentrations obtained were multiplied by total urine volume to obtain the total amount of that analyte excreted. The total amount (free and conjugated forms) in micrograms of of each analyte in the 10h urine sample is reported.

Outcome measures

Outcome measures
Measure	2g CAP n=4 Participants Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 2g Centella asiatica water extract product: 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=4 Participants Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 4g Centella asiatica water extract product: 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Total Urinary Excretion Asiatic acid	3 micrograms Standard Error 4	4 micrograms Standard Error 2
Total Urinary Excretion Dihydroferulic acid	145 micrograms Standard Error 60	242 micrograms Standard Error 54
Total Urinary Excretion Dihydrocaffeic acid	47 micrograms Standard Error 25	41 micrograms Standard Error 7
Total Urinary Excretion Ferulic acid	18 micrograms Standard Error 6	24 micrograms Standard Error 5
Total Urinary Excretion 3-(3-hydroxyphenyl)propionic acid	16 micrograms Standard Error 10	13 micrograms Standard Error 7
Total Urinary Excretion Isoferulic acid	18 micrograms Standard Error 6	24 micrograms Standard Error 5
Total Urinary Excretion Madecassic acid	8 micrograms Standard Error 2	14 micrograms Standard Error 4
Total Urinary Excretion Monodicaffeoylquinic acids	17 micrograms Standard Error 8	13 micrograms Standard Error 7
Total Urinary Excretion Madecassoside	1 micrograms Standard Error 8	7 micrograms Standard Error 3

SECONDARY outcome

Timeframe: 0, 1, 2, 3, 4, and 6h following study intervention

NRF2 gene expression was measured in peripheral blood mononuclear cells following consumption of 2g and 4g of Centella asiatica water extract product (CAP).

Outcome measures

Outcome measures
Measure	2g CAP n=2 Participants Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 2g Centella asiatica water extract product: 2g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=2 Participants Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach. 4g Centella asiatica water extract product: 4g of Centella asiatica water extract (CAW) in a standardized product containing excipients to improve palatability, color matching and dispersability. The product (CAP) is a powder which will be dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
NRF2 Expression 3 h	22 fold change in expression from time 0h Standard Error 9	3 fold change in expression from time 0h Standard Error 1
NRF2 Expression 0 h	1 fold change in expression from time 0h Standard Error 0	1 fold change in expression from time 0h Standard Error 0
NRF2 Expression 1 h	2 fold change in expression from time 0h Standard Error 0.2	2 fold change in expression from time 0h Standard Error 0.3
NRF2 Expression 2 h	32 fold change in expression from time 0h Standard Error 4	5 fold change in expression from time 0h Standard Error 2
NRF2 Expression 4 h	12 fold change in expression from time 0h Standard Error 7	2 fold change in expression from time 0h Standard Error 1
NRF2 Expression 6 h	4 fold change in expression from time 0h Standard Error 2	1 fold change in expression from time 0h Standard Error 0.3

Adverse Events

2g CAP

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

4g CAP

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Amala Soumyanath

Oregon Health & Science University

Phone: 503-494-6878

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	2g CAP n=4 participants at risk Single administration of 2g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.	4g CAP n=4 participants at risk Single administration of 4g of Centella asiatica water extract standardized product dissolved in 10-12 ounce of water and consumed by mouth once on an empty stomach.
Musculoskeletal and connective tissue disorders Rigidity of any body part	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Eye disorders Blurred vision	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Gastrointestinal disorders Sore throat	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Immune system disorders Allergy symptoms	50.0% 2/4 • Number of events 2 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Respiratory, thoracic and mediastinal disorders Nasal congestion	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Cardiac disorders Heart racing or irregular beating	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Cardiac disorders Hypertension/elevated blood pressure	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Gastrointestinal disorders Increased appetite	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	50.0% 2/4 • Number of events 2 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Gastrointestinal disorders Dry mouth	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Renal and urinary disorders Increased urination	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	50.0% 2/4 • Number of events 2 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Skin and subcutaneous tissue disorders Sunburn or sensitivity of skin to light	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
General disorders Generalized pain	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Psychiatric disorders Anxiety	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Psychiatric disorders Drowsiness	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Nervous system disorders Headache	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.
Musculoskeletal and connective tissue disorders Inability to sit still	0.00% 0/4 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.	25.0% 1/4 • Number of events 1 • Adverse events were collected during each study visit, 24 hours following study drug administration at each study visit, and 7 days after study visit two (end of study). Vital signs, EKG and CMP were monitored at baseline and during the visit. Adverse events were collected using a multi-system adverse events questionnaire during and after the visit.