Conditions: Pharmacokinetics
Keywords: kava dietary supplement anxiety generalized anxiety disorder (GAD)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: yes

Brief summary:
Kava is a dietary supplement on the US market and is experiencing a resurgence of its use. Its pharmacokinetic information, however, is lacking which is important for its future effective usage as a dietary supplement or potentially as a botanical therapeutics. This phased trial, based on the recommendation from NIH, is to collect pharmacokinetic data of kava in healthy subjects.

Detailed description:
Kava is used in the South Pacific Islands for relaxation and socialization. It is available in the US as a dietary supplement, and was used in Europe in the 1990s to treat mild to moderate anxiety. Some clinical trials suggested kava's efficacy in treating generalized anxiety disorder (GAD), although a recent meta-analysis was inconclusive. While the mechanisms behind kava's anxiolytic activity are not well-established, its clinical use shows no signs of addiction or withdrawal. Kava thus is a promising and potentially novel anxiolytic with a unique mechanism of action. Although kava has been extensively consumed by humans for centuries, its pharmacokinetics have never been characterized in humans. Such knowledge is essential for its future studies of its anxiolytic potential and dose optimization. This study will characterize kava pharmacokinetics, which will set a solid foundation for its future clinical development. To establish kava pharmacokinetics, each participant will take three 75 mg kava capsules in a single dose and the absorption, distribution, metabolism and excretion of kava will be assessed, corresponding to the pharmacokinetic curve. Serum liver biochemistries will then be monitored for up to three months to test liver function response to kava.

Arms:
arm 1: Each subject will take three 75 mg kava dietary supplement capsules in a single dose/timepoint and nine blood draws will be collected over an eight hour period following adminstration of kava.

Interventions: intervention 1: Kava Dietary Supplement
Intervention descriptions: intervention 1: Participants will be given three 75mg kava capsules.

Protocol document:
Prot_SAP_000.pdf: 
A Phased Clinical Trial of a Dietary Supplement Kava: Biomarker Changes and Anxiolytic Effects Phase 
1: Kava Pharmacokinetics 
Version 5.000
Protocol PAR-18-829  
11 May 2021
NIH-FDA Clinical Trial Protocol Template – v1.0 2017-04-07 
1
A Phased Clinical Trial of a Dietary Supplement Kava: 
Biomarker Changes and Anxiolytic Effects Phase 1: Kava 
Pharmacokinetics 
Unique Protocol Identification Number: PAR-18-829  
National Clinical Trial (NCT) Identified Number: NCT03843502 
Principal Investigator: Chengguo Xing, Carol Mathews 
[IND/IDE] Sponsor:  
Funded by: NCCIH 
Version Number: 5.000 
11 May 2021 
 
Summary of Changes from Previous Version: 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
3 
Exploratory objectives 
Plasma cortisol changes in the already 
collected plasma samples will support 
kava-induced pharmacodynamics 
9.4.9. 
Changes of plasma cortisol levels 
as an exploratory endpoint 
To analyze the already collected plasma 
samples that will not impose any 
foreseeable risk to the participants. 
Plasma cortisol level is a biomarker 
candidate in the biomarker phase of this 
study. The changes of the plasma cortisol 
level from the already collected pk plasma 
sample therefore will support the 
biomarker phase evaluations, including 
method validation and potential 
pharmacodynamics of kava on cortisol. 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
 
Statement of Compliance .............................................................................................................................................. 5 
1 Protocol Summary ...................................................................................................................................................... 6 
1.1 Synopsis ............................................................................................................................................................... 6 
1.2 Schema ................................................................................................................................................................ 7 
1.3 Schedule of Activities (SoA) ................................................................................................................................. 8 
2 Introduction ................................................................................................................................................................ 9 
2.1 Study Rationale .................................................................................................................................................... 9 
2.2 Background .......................................................................................................................................................... 9 
2.3 Risk/Benefit Assessment.................................................................................................................................... 10 
2.3.1 Known Potential Risks ................................................................................................................................. 10 
2.3.2 Known Potential Benefits ........................................................................................................................... 11 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 11 
3 Objectives and Endpoints ......................................................................................................................................... 14 
4 Study Design ............................................................................................................................................................. 15 
4.1 Overall Design .................................................................................................................................................... 15 
4.2 Scientific Rationale for Study Design ................................................................................................................. 15 
4.3 Justification for Dose ......................................................................................................................................... 15 
4.4 End of Study Definition ...................................................................................................................................... 16 
5 Study Population ...................................................................................................................................................... 17 
5.1 Inclusion Criteria ................................................................................................................................................ 17 
5.2 Exclusion Criteria ............................................................................................................................................... 17 
5.3 Lifestyle Considerations ..................................................................................................................................... 17 
5.4 Screen Failures ................................................................................................................................................... 17 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 18 
6 Study Intervention .................................................................................................................................................... 19 
6.1 Study Intervention(s) Administration ................................................................................................................ 19 
6.1.1 Study Intervention Description ................................................................................................................... 19 
6.1.2 Dosing and Administration ......................................................................................................................... 19 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 19 
6.2.1 Acquisition and accountability .................................................................................................................... 19 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 19 
6.2.3 Product Storage and Stability ..................................................................................................................... 19 
6.2.4 Preparation ................................................................................................................................................. 20 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 20 
6.4 Study Intervention Compliance ......................................................................................................................... 20 
6.5 Concomitant Therapy ........................................................................................................................................ 20 
6.5.1 Rescue Medicine ......................................................................................................................................... 20 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 21 
7.1 Discontinuation of Study Intervention .............................................................................................................. 21 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 21 
7.3 Lost to Follow-Up ............................................................................................................................................... 21 


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8 Study Assessments and Procedures ......................................................................................................................... 22 
8.1 Efficacy Assessments ......................................................................................................................................... 22 
8.2 Safety and Other Assessments .......................................................................................................................... 22 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 22 
8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 22 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................................ 22 
8.3.3 Classification of an Adverse Event .............................................................................................................. 22 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................................ 23 
8.3.5 Adverse Event Reporting ............................................................................................................................ 23 
8.3.6 Serious Adverse Event Reporting................................................................................................................ 24 
8.3.7 Reporting Events to Participants ................................................................................................................ 24 
8.3.8 Events of Special Interest ........................................................................................................................... 24 
8.3.9 Reporting of Pregnancy .............................................................................................................................. 24 
8.4 Unanticipated Problems .................................................................................................................................... 24 
8.4.1 Definition of Unanticipated Problems (UP) ................................................................................................ 24 
8.4.2 Unanticipated Problem Reporting .............................................................................................................. 25 
8.4.3 Reporting Unanticipated Problems to Participants .................................................................................... 25 
9 Statistical Considerations ......................................................................................................................................... 26 
9.1 Statistical Hypotheses ........................................................................................................................................ 26 
9.2 Sample Size Determination................................................................................................................................ 26 
9.3 Populations for Analyses ................................................................................................................................... 26 
9.4 Statistical Analyses............................................................................................................................................. 26 
9.4.1 General Approach ....................................................................................................................................... 26 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................................................. 26 
9.4.3 Analysis of the Secondary Endpoint(s) ....................................................................................................... 26 
9.4.4 Safety Analyses ........................................................................................................................................... 27 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 27 
9.4.6 Planned Interim Analyses ........................................................................................................................... 27 
9.4.7 Sub-Group Analyses .................................................................................................................................... 27 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 27 
9.4.9 Exploratory Analyses .................................................................................................................................. 27 
10 Supporting Documentation and Operational Considerations ................................................................................ 28 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 28 
10.1.1 Informed Consent Process ........................................................................................................................ 28 
10.1.2 Study Discontinuation and Closure ........................................................................................................... 28 
10.1.3 Confidentiality and Privacy ....................................................................................................................... 29 
10.1.4 Future Use of Stored Specimens and Data ............................................................................................... 29 
10.1.5 Key Roles and Study Governance ............................................................................................................. 29 
10.1.6 Safety Oversight ........................................................................................................................................ 29 
10.1.7 Clinical Monitoring .................................................................................................................................... 30 
10.1.8 Quality Assurance and Quality Control ..................................................................................................... 30 
10.1.9 Data Handling and Record Keeping .......................................................................................................... 30 
10.1.10 Protocol Deviations................................................................................................................................. 31 
10.1.11 Publication and Data Sharing Policy ....................................................................................................... 31 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 32 
10.2 Additional Considerations ............................................................................................................................... 32 


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10.3 Abbreviations ................................................................................................................................................... 32 
10.4 Protocol Amendment History .......................................................................................................................... 33 
11 References .............................................................................................................................................................. 36 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the [specify NIH Institute or Center (IC) [ Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the funding agency and documented approval from the 
Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 


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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
 A Phased Clinical Trial of a Dietary Supplement Kava: Biomarker 
Changes and Anxiolytic Effects  
Study Description: 
  
Objectives: 
Primary Objective: To characterize pharmacokinetics of 
flavokavain A/B free kava. 
Secondary 
Objectives: 
 None 
Endpoints: 
Primary Endpoint: 
Examining the half life of each of the six major 
kavalactones. 
Secondary 
Endpoints: 
 None 
Study Population: 
We will recruit 10 healthy participants. There are no restrictions on 
ethnicity, social background, or gender. All subjects must meet the 
following criteria at baseline to be eligible for participation in the 
pharmacokinetic study (a) be between the ages of 18 and 50 years (b) 
Females of potential childbearing status must use adequate 
contraceptive precautions. 
Phase: 
1 
Description of 
Sites/Facilities 
Enrolling Participants: 
The University of Florida Clinical Research Center will be used to 
enroll participants and conduct research procedures. This facility is 
designed for clinical research. 
Description of Study 
Intervention: 
Ten subjects will be recruited and enrolled into the pilot 
pharmacokinetic study. Each subject will stay in the out-patient 
Clinical Research Center (CRC) at the CTSI during the 8-h study 
period. Participants will be asked to refrain from food, liquids other 
than water, and medications for 12 hours prior to entering the Clinical 
Research Center of the UF CTSI. They will have an indwelling 
venous catheter placed in the lower arm to facilitate the multiple 
blood collections during the study. Each subject will take three 75 mg 
kava capsules and ten blood draws (2 mL EDTA vacutainer) will be 
collected corresponding to the absorption, distribution, metabolism 
and excretion phase of the pharmacokinetic curve. Specifically, blood 
will be withdrawn at baseline and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours 
after kava ingestion. The blood samples will be processed and then 
stored at -80ºC till analysis. The period of follow up for any delayed 
adverse effects (e.g, monitoring of liver function) will be extended 
such that all participants will be followed for a full 12 weeks after 
their last kava ingestion. 


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Study Duration: 
24 weeks 
Participant Duration: 
12 weeks 
  
 
 
1.2 SCHEMA 
• Obtain informed consent 
• Screen potential participants by inclusion and exclusion criteria 
• Obtain medical history 
• Height and weight 
• Concomitant medication review 
• Lab testing (CMP, PT/INR, Indirect bilirubin, CYP2D6) 
• Urine Drug Screen 
• Urine Pregnancy test (for women on child bearing potential) 
• C-SSRS 
• HAM-A 
 
• Concomitant medication review 
• Adverse event review and evaluation 
• Administer study medication 
• Urine drug screen 
• Urine pregnancy test (for women of child bearing potential) 
• PK sampling (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 hours post dose) 
• Lab testing (CMP) 
• Lab testing (CMP) 
• Adverse event review and evaluation 
• Concomitant medication review 
• Lab testing (CMP) 
• Adverse event review and evaluation 
• Concomitant medication review 
• Lab testing (CMP) 
• Adverse event review and evaluation 
• Concomitant medication review 
• Lab testing (CMP, PT/INR) 
• Adverse event review and evaluation 
• Concomitant medication review 
 
 
Screening 
Week/Day (-14 to -1) 
Visit1 /Day 
Baseline assessments/Study intervention 
Visit 2/Week 1 
Visit 3/Week 4 
Visit 4/Week 8 
Final assessments 
Visit 5/Week 12 


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1.3 SCHEDULE OF ACTIVITIES (SOA) 
Procedures 
Phone 
Screen 
Screening 
Day -14 to 
-1 
Baseline 
Visit 1, 
Day 1 
Week 1 
Study Visit 
2 
Day 7     +/-
1 day 
Week 4 
Study Visit 
3 
Day 28 +/- 
1 day 
Week 8 
Study Visit 
4 
Day 56 +/-1 
day 
Week 
12/Final 
Visit 
Study Visit 
5 
Day 84 +/-
1 day 
Informed consent 
  
X 
  
  
  
  
  
Demographics 
  
X 
  
  
  
  
  
Inclusion/exclusion 
review 
X 
X 
  
  
  
  
  
Medical History 
 
X 
  
  
  
  
  
Administer study 
intervention 
  
  
X 
  
  
  
  
Concomitant 
medication review 
 
X 
X 
Height and weight 
  
X 
  
  
  
  
  
Vital signs 
  
X 
  
  
  
  
  
CYP2D6 testing 
  
X 
  
  
  
  
  
Comprehensive 
Metabolic Panel 
testing  
  
X 
 X b 
X 
X 
X 
X 
PT/INR 
 
X 
 
 
 
 
X 
Urine pregnancy test a   
X 
X 
  
  
  
  
Urine drug screen 
  
X 
X 
  
  
  
  
Adverse event review 
and evaluation 
  
X 
Pharmacokinetic 
sampling 
  
  
X 
  
  
  
  
HAM-A 
 X 
  
  
  
  
  
C-SSRS 
 
X 
 
 
 
 
 
Complete Case 
Report Forms (CRFs) 
  
X 
X 
X 
X 
X 
X 
  
  
  
a:      for women of child bearing potential 
b:      test will be performed at 12 hours post initial kava ingestion 
 
 


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2 INTRODUCTION 
2.1 STUDY RATIONALE 
To determine the pharmacokinetics of flavokavain A/B-free kava in order to determine optimal dosing 
for a planned study of biomarkers of anxiolysis following kava administration. 
 
2.2 BACKGROUND 
There is a critical need for new anxiolytics with novel mechanisms for GAD treatment. GAD is a common, 
chronic, and impairing psychiatric disorder that affects more than 16 million American adults annually 
(1). Evidence-based treatments for GAD include selective serotonin reuptake inhibitors (SSRIs), 
serotonin norepinephrine reuptake inhibitors (SNRI’s), serotonin type 1A partial agonists, and 
benzodiazepines (BZD) (47). Unfortunately, many patients with GAD report only a partial response with 
these treatments or cannot tolerate their side effects. These patients continue to suffer with high levels 
of anxiety and impairment throughout their lives. BZDs are of particular concern because they often 
become the only treatment option for patients with GAD but carry a risk of chemical dependency, 
tolerance to the therapeutic effects, cognitive impairment, and in the long term, dementia and even 
death (3). Specifically, there is an unmet clinical need for new anxiolytics with a mechanism different 
from BZDs and free of the associated adverse effects (4). Kava is a promising candidate as a 
mechanistically novel anxiolytic. Kava is derived from Piper methysticum, a shrub that grows in the 
South Pacific islands. Extracts from the roots of this shrub (kava) are traditionally consumed as a daily 
beverage to help people relax, socialize, and improve sleep quality. Kava was used to treat anxiety in 
Europe in the 1990s (7-13). Clinical studies have shown that kava is effective for anxiolysis across a 
variety of patient groups (7-13). A recent meta-analysis of four randomized placebo-controlled trials that 
examined kava use for GAD favored improvement of anxiety symptoms with kava over placebo, 
although the results were not statistically significant (standardized mean difference = -0.99, CI -2.12 to 
0.14) (14, 15). Importantly, current studies demonstrate no signs of addiction or withdrawal from kava, a 
clear advantage over the BZDs (23). These results not only suggest that kava is a promising candidate for 
treatment of GAD, but also clearly indicate that more research is needed to confirm its utility. The 
mechanisms behind kava’s anxiolytic activity are far from established. Several targets have been 
proposed based on biochemical or cellular results at human irrelevant concentrations without in vivo 
validation, including GABAA (17-19), dopamine receptors (18), opioid receptors (18), histamine receptors 
(18), MAO-B (20), or ion channels (21). A few in vivo studies indicate that kava’s anxiolytic effect is not 
mediated through GABAA (24, 25), consistent with its lack of addiction or withdrawal in clinic. Given that 
most of currently available treatments for GAD work via serotonin reuptake or GABAA, this study has the 
potential to identify an anxiolytic with a unique mechanism of action. Kava use as a dietary supplement 
is increasing. Kava has long been available as a dietary supplement in the US market with a resurgence 
recently – the amount of kava exported from Vanuatu, Fiji and Tonga (the major kava producing 
countries) increased by ~25% annually between 2008 – 2013 and the U.S.A. is a major destination of 
kava export (30). Quality control and standardization, however, are lacking – we have analyzed the 
composition of 25 commercial kava products by LC-MS/MS. The abundance of the major kavalactones 


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varied by 10 – 30 fold (30) despite the fact that these kavalactones have been recommended for 
standardization (48). These products therefore likely vary significantly in their anxiolytic efficacies. The 
abundance of the hepatotoxic compounds, flavokavains A and B (32), varies even more (30), such that 
some products may impose higher risk of hepatotoxicity than others. Rigorous research therefore is 
needed to characterize kava’s pharmacology in conjunction with accurate characterization of its 
chemical compositions, essential to maximize kava’s benefit and to minimize its potential adverse risk. 
Kava is safe for use in clinical populations, especially when properly prepared. Kava was banned for 
clinical use in Europe from 2001 – 2014 because of concerns about potential hepatotoxicity (26). 
However, the purported incidence rate of kava-induced hepatotoxicity is extremely low (0.3 – 1 cases 
per one million daily doses) (48-56), much lower than BZD-based anxiolytics (57, 58). In addition, the 
WHO found that kava-related hepatotoxicity was likely due to quality problems, adulteration of the root 
with other parts of the plant, use of ethanol- rather than water-based extraction, and in some cases, 
interactions between kava and other drugs/herb preparations or chronic alcohol use (5, 49, 50, 59). As a 
result of these assessments, the ban on kava use was lifted in 2014, and kava is again available for use in 
Europe (26). We have closely monitored the safety of kava and its ingredients in all of our studies. We 
detected no signs of hepatotoxicity when kava was evaluated alone, even at elevated dosages and 
extended exposures (27-29, 32, 36, 60, 61). This was further supported by the results of our recent 
study, demonstrating that kava was safe unless co-administered with acetaminophen, due to 
flavokavains A and B (32), two lipophilic chemicals low in aqueous extracts (30). This finding suggests 
that the already low rate of potential hepatotoxicity with kava can be further mitigated by the use of 
preparations that have low (or no) levels of flavokavains A and B, and by excluding patients who are 
taking medications known to have potential hepatotoxicity. The risk of observing an instance of 
hepatotoxicity according to the WHO is less than 0.03% in the R61 phase and less than 0.9% in the R33 
phase of this study; this risk is further mitigated by our use of flavokavain A/B-free kava. 
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
The risks of participating in this project include those incurred during the administration of rating scales, 
blood drawing, and the administration of study medication (kava). 
Drawing blood requires venipuncture and is associated with the momentary discomfort of the needle 
stick. The risks of venipuncture include discomfort at the site of puncture, possible bruising and swelling 
around the puncture site, rarely an infection and uncommonly faintness. 
Potential side effects from the administration of Kava include: excessive sedation if combined with 
alcohol, rare allergic reactions and rare liver toxicity. The frequency of liver injury in Kava is not 
known.  Based upon reported cases, liver injury due to kava is less than 1:1,000,000 daily doses, and is 
likely due to the presence of flavokavains A and B in the kava preparation.  A few cases of clinically 
apparent liver injury have been published in the literature.  One of the potential risks with kava is an 
acute liver injury with severe hepatitis ending in fulminant hepatic failure, requiring liver 
transplantation, or even leading to death. Preliminary data from a previous human study by our group 
did not identify any adverse events due to the consumption of kava supplementation. In addition, we 


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are using a kava preparation that has been rigorously tested for the removal of flavokavains A and B, 
which are thought to cause the rare cases of liver toxicity that have been observed. 
2.3.2 KNOWN POTENTIAL BENEFITS 
None 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
All study personnel are accustomed to maintaining and ensuring patient confidentiality in the course of 
their work. In addition, all study personnel are highly trained in research procedures and in issues 
regarding protection of participants’ rights and privacy. All members of the research team, including the 
PIs, coinvestigators, study coordinator, data collectors, research assistants, data manager, and all 
students associated with the project will complete UF-mandated human subject training prior to study 
commencement. Participants’ identities will be protected through the following measures: consent 
forms will be stored behind a locked door and in a locked filing cabinet accessible only by the PI, and all 
identifying information will be stored in a separate, secured location from data that is collected during 
the study. Access to locked files will be restricted to essential personnel only. In addition to consent and 
identification files that are secured, all data files will be coded in a manner that makes identification of 
the participants extremely unlikely. Indeed, participants will be given a numerical ID code to ensure that 
inadvertent or unauthorized identification does not occur. Data will receive additional layers of security 
because the whole building, floor, and office in which locked records are maintained have restricted, 
keyed access. The anonymous codes assigned to participants will be verified and maintained throughout 
the study, and codes with names will be provided only to meet federal guidelines applicable to the 
facility. Data will be entered into a REDCap data base developed for the project. REDCap (Research 
Electronic Data Capture) is a secure, HIPAA-aligned web-based application designed to support 
traditional case report form data capture. REDCap’s automated export procedure will be utilized to 
export data into a SAS data set for analysis. 
The study coordinator for the proposed project has 6 years of experience and will be trained in all study 
procedures. She will coordinate the screening of potential participants and will meet with Dr. Mathews 
weekly to discuss study progress. Dr. Firpi-Morell, a gastroenterologist with expertise in hepatology and 
liver transplantation, will be responsible for overseeing the medical safety monitoring for this trial. He 
has extensive experience as a medical monitor for national clinical trials of multiple medications. He will 
communicate with Dr. Mathews on a regular basis, and will also communicate any and all adverse 
events to the data safety monitoring board. He will interpret the results of the liver biochemistries (all 
results will be blinded to treatment condition) and will be responsible for referring participants to 
appropriate additional clinical evaluation and intervention if needed. 
Effective screening will rule out active medical or psychiatric conditions, including supplement or 
medication use, chronic alcohol use, and evidence of pre-existing liver disease that may prevent 
someone from participating in the studies.   Once the subject enters the study, an experienced research 
team will closely follow him or her. The research team has developed considerable expertise in 
monitoring the safety of subjects participating in research studies. An experienced research psychiatrist 
and the hepatologist is available 24 hours a day, 7 days a week. If at any point in the procedures 


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symptoms become distressing or dangerous, subjects will be withdrawn from the study and, if 
necessary, treatment instituted. 
This project will be conducted in compliance with research statutes outlined in the Health Insurance 
Portability and Accountability Act. Each participant will be assigned a unique identification number, and 
this number will be used to link all subsequent information collected. This file will be secured with 
password access, since it represents a direct link between the name and identification number of a 
participant. All paper files and data are kept in locked file cabinets to ensure confidentiality. The other 
procedures to ensure confidentiality follow the regulations and policies of the University of Florida and 
UF Health. Data file archival and back-up will be performed on a regular basis. The routine monitoring, 
maintenance, and quality control of the databases will be the responsibility of Dr. Mathews. 
Participant distress during evaluations: All evaluations have been designed to minimize burden on 
patients with respect to fatigue, stress and/or discomfort. Only trained individuals will administer study 
tests and questionnaires. These individuals will be trained to be sensitive to signs of patient fatigue, 
stress or discomfort. Breaks during testing will be scheduled, and can be initiated by the patient if they 
desire. Participants may choose whether or not to receive the results of their clinical interviews. 
Participants who are assessed as suffering from an untreated psychiatric disorder and choose to obtain 
the results of their interview will be offered referrals to treatment locally if they choose. Participants will 
be free to discontinue their participation at any time if they feel that it is causing unacceptable distress 
or discomfort. 
Loss of Confidentiality: All research material will be treated in a confidential manner, and only research 
staff will have access to the data. Confidentiality will be maintained by assigning identification numbers 
for all aspects of the project; all data entered into computer databases will use only this identifier. Data 
are kept in separate coded REDCap data sets and in locked cabinets in locked rooms at UF with access 
limited to a small number of study personnel. All clinical and other records have identifying names of 
participants and relatives removed. Electronic data will be password protected and stored in a database 
on a secure server that is also password protected, with no patient identifying information. No 
identifiable individual data are presented in scientific publications. Only research personnel will have 
access to this data. 
Risks of Treatments of Unknown Efficacy: Participants will be informed by the investigators and through 
the written consent that few studies exist for kava treatment, and kava for GAD in particular has not 
been adequately tested. 
Emergence of Depressive or other Psychiatric Symptoms or Suicidality: The research team will receive 
training in the rapid assessment and management of distress or emergence of psychiatric symptoms 
that may arise during the PK protocol. If a participant’s status raises concern, Dr. Mathews will offer a 
clinical evaluation and, when appropriate, the study is discontinued, and the participant is referred for 
treatment according to clinical indication (hospitalization, partial hospitalization, other psychosocial 
interventions, pharmacotherapy, etc.). If a participant’s psychiatric state worsens at any point such that 
they are no longer able to participate in the treatment, the participant will be withdrawn from the 
research protocol and referred for the appropriate treatment according to clinical indication. The same 
procedures apply to any participant who reports suicidal intent or plan or makes a suicide attempt at 
any point in the study. Dr. Mathews is a licensed psychiatrist and will provide clinical oversight over 
assessments of suicidal ideation and safety. 


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Management of psychiatric emergencies: We believe that the risk of psychiatric emergencies occurring 
during the execution of this study is low, based on the pilot data and because participants are healthy 
volunteers who have been pre-screened for psychiatric stability. However, should such an emergency 
arise (such as an acute decompensation, statement or demonstration of active suicidal ideation, 
violence, etc), we have procedures in place to ensure the safety of the participant and the staff. 
Liver function abnormalities: We will use a kava product that has removed the potentially liver toxic 
elements, flavokavain A and B, and has been rigorously tested for quality. However, we will nevertheless 
closely monitor serum liver biochemistries (AST, ALT, ALP, bilirubin and albumin) at screening, at hour 12 
post-kava ingestion, and at weeks 1, 4, 8 and 12. Although the timing of any potential liver toxicity with 
kava is not known, the timing of the few reported cases in the NIH liver tox database suggests that the 
onset of symptoms related to hepatotoxicity (including nausea, fatigue) is likely to be between 2 weeks 
and 12 weeks following initial ingestion. We will also encourage participants to contact the study team 
for any concerning symptoms that they may have for up to 6 months post-treatment to ensure that no 
delayed reactions, no matter how unlikely, are missed. We will carefully educate participants about 
symptoms to watch for throughout the study and following treatment. 
 
 


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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
To characterize pharmacokinetics 
of flavokavain A/B-free kava 
Examining the half-life of each of 
the six major kavalactones 
This is a standard marker 
for pharmacokinetics 
studies 
Secondary 
None 
None 
N/A 
Tertiary/Exploratory 
To characterize plasma cortisol 
level upon A/B-free kava use 
Validate the method and provide 
pharmacodynamic knowledge of 
kava on plasma cortisol, which is a 
biomarker candidate for the 
biomarker phase of this study 
The results will support the 
studies proposed in the 
biomarker phase of this 
study. 


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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
• 
To develop a pharmacokinetic model to identify the best dose and dosage regimens of flavokavain A/B 
free kava for its further development as a drug for the treatment of GAD 
• 
Phase 1 Single site study 
• 
Open-label  
• 
An equal number of male and female subjects will be enrolled in study. All races and ethnicities will be 
included. A dose of supplement kava 225 mg will be administered at baseline either in a single dose or 
dosed at three times during the study visit. Study group-Pharmacokinetics is a single day intervention with 
12 week follow up post study drug ingestion. Ten subjects will be recruited and enrolled into the pilot 
pharmacokinetic study. Each subject will stay in the out-patient Clinical Research Center (CRC) at the CTSI 
during the 12 hour study period. Participants will be asked to refrain from food, liquids other than water, 
and medications for 12 hours prior to entering the Clinical Research Center of the UF CTSI. They will have 
an indwelling venous catheter placed in the lower arm to facilitate the multiple blood collections during 
the study. Each subject will take three 75 mg kava capsules and ten blood draws (2 mL EDTA vacutainer) 
will be collected corresponding to the absorption, distribution, metabolism and excretion phase of the 
pharmacokinetic curve. Specifically, blood will be withdrawn at baseline and 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 
hours after kava ingestion. The blood samples will be processed and then stored at -80ºC till analysis. The 
period of follow up for any delayed adverse effects (e.g, monitoring of liver function) will be extended 
such that all participants will be followed for a full 12 weeks after their last kava ingestion. CYP2D6 testing 
will be conducted to determine if the genotype affects the pharmacokinetics of kava. 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Determining the clearance (Cl/F) and volume of distribution (Vd/F) of each of the major kavalactones will 
allow us to determine the optimal dosing regimen to maximize the pharmacodynamics and optimize 
compliance.  
 
4.3 JUSTIFICATION FOR DOSE 
We have isolated the major chemicals in kava and determined their benefits (66) and risks (32) in vivo. 
With such knowledge, we screened twenty-five commercially available kava products and quantified the 
major beneficial kavalactones, including kavain, dihydrokavain, methysticin, and dihydromethysticin 
(DHM, the chemopreventive ingredient), and the hepatotoxic compounds – flavokavains A and B (30). 
We identified one dietary kava product from Gaia Herbs (Kava Root) for our pilot human trial that has a 
high DHM content and low flavokavain A and B content. To ensure consistency, we characterized the 
content of three batches of this product by HPLC and NMR. Each capsule contained 75 ± 3 mg of 
kavalactones (the anxiolytic ingredients), consistent with the labeled 75 mg kavalactone per capsule. 
Each capsule also contained ~20 mg DHM. With three capsules per day, the human daily dose of kava is 
within the proposed anxiolytic range (120-280 mg daily (14)); the amount of DHM would be comparable 


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to its in vivo chemopreventive dose. This kava product also contained minimal flavokavains A and B 
(<1.0 mg/capsule). 
 
4.4 END OF STUDY DEFINITION 
The study will come to an end when the data for 10 healthy subjects has been collected and analyzed. 
 
 


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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
All subjects must meet the following criteria at baseline to be eligible for participation in the 
pharmacokinetic study: 
• 
Be between the ages of 18 and 50 years 
• 
Females of potential childbearing status must use adequate contraceptive precautions. 
 
5.2 EXCLUSION CRITERIA 
Subjects will be excluded if they meet any of the following criteria at the time of screening or at their 
baseline visit:  
• 
Currently taking any medication or supplement other than vitamins 
• 
Inability to refrain from acetaminophen, alcohol, or other potentially hepatotoxic substances during the 
study 
• 
Have a history of liver disease or currently have liver disease. (d) Elevation in serum ALT, AST, ALP or total 
bilirubin that reaches clinical significance (as determined by the PI) at screening. Have an unstable 
medical, psychiatric, or neurological condition determined by history taken during the screening visit and 
a physical examination at the baseline visit. 
• 
Have a positive urine drug screen for substances of abuse. 
• 
Current tobacco users will be excluded. 
 
 
5.3 LIFESTYLE CONSIDERATIONS 
This study will exclude any individual who is a current tobacco smoker and anyone who is not able to 
abstain from alcohol consumption for the duration of the study. 
 
 
5.4 SCREEN FAILURES 
Subjects who do not meet inclusion and/or meets criteria for any of the exclusion criteria will be 
deemed a screen fail. 
 
 


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5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
We will recruit and screen potential participants until we are able to randomize and enroll 10 healthy 
individuals in the R61 pk phase trial. We will recruit males and females of all races/ethnicities ages 18-50 
from the following locations. 
  
Recruitment sites will include: 
Gainesville and the surrounding community: Gainesville has a population of approximately 100,000 
people, not including the student population. Alachua County, which includes Gainesville and the 
surrounding towns and rural areas, has a population of over 250,000 residents 
 
 


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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Participants will be asked to refrain from food, liquids other than water, and medications for 12 hours 
prior to entering the Clinical Research Center of the UF CTSI. They will have an indwelling venous 
catheter placed in the lower arm to facilitate the multiple blood collections during the study (Support 
Letter from CTSI and its quote of estimated cost attached in Appendix). Each subject will take three 75 
mg kava capsules and ten blood draws (2 mL EDTA vacutainer) will be collected corresponding to the 
absorption, distribution, metabolism and excretion phase of the pharmacokinetic curve. Specifically, 
blood will be withdrawn at baseline and 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 hours after kava ingestion, based 
on our mouse pharmacokinetic knowledge of kava. The blood samples will be processed and then stored 
at -80ºC till analysis. The period of follow up for any delayed adverse effects (e.g, monitoring of liver 
function) will be extended such that all participants will be followed for a full 12 weeks after their last 
kava ingestion. 
6.1.2 DOSING AND ADMINISTRATION 
Each subject will take three 75 mg kava capsules and 10 blood draws (2 mL EDTA vacutainer) will be 
collected corresponding to the absorption, distribution, metabolism and excretion phase of the 
pharmacokinetic curve 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Subjects will be provided with either a onetime dosage or a three time dose of kava (each capsule being 
75mgs for a total of 225 mgs for a daily total dose) at the baseline visit. Ingestion of kava will be 
monitored by the research coordinator and documented on a study drug accountability log. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Bottles of flavokavain AB-free kava (75 mg kavalactones/capsule) with the same lot number will be 
directly purchased from Thorne Research Inc. This product will be used because 
of its lack of flavokavains A and B (<0.2 mg/capsule) and consistent content of total kavalactones. For 
ongoing quality control, three capsules from each bottle will be analyzed via our established method to 
ensure adequate and constant content of total kavalactones and no flavokavains A and B. The 
Investigational Drug Service (IDS) pharmacy will package the investigational kava. Supplies with the 
appropriate number of capsules for each subject will be prepared and bottled for administration. 
6.2.3 PRODUCT STORAGE AND STABILITY 
Product will be stored according to manufacturer recommendations. All unused supplement will be 
returned to IDS via study personnel and destroyed by IDS. 


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6.2.4 PREPARATION 
Bottles of flavokavain AB-free kava (75 mg kavalactones/capsule) with the same lot number will be 
directly purchased from Thorne Research Inc. This product will be used because of its lack of 
flavokavains A and B (<0.2 mg/capsule) and consistent content of total kavalactones. 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
There is no randomization process in this study. All qualified and consented study participants will 
receive the same total daily dose of kava and will follow through will all follow up procedures. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
Study subjects will have one day screening and one day of study intervention therefore compliance is 
highly achievable. 
 
6.5 CONCOMITANT THERAPY 
No concomitant medications will be allowed during this study with the exception of multi vitamins and 
contraception. 
6.5.1 RESCUE MEDICINE 
Diphenhydramine will be available for use in the case of any allergic response for subjects who have 
ingested the study drug. 
 
 


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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse 
effects that call into question the safety of the intervention; (2) difficulty in study recruitment or 
retention will significantly impact the ability to evaluate the study endpoints; (3) any new information 
becomes available during the trial that necessitates stopping the trial; or (4) other situations occur that 
might warrant stopping the trial. If at any time during the study the participants are found to be at 
excessive risk, the study will be terminated. All key research personnel have completed the required 
human subjects training course. Key personnel include all individuals responsible for the design and 
conduct of the study. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Study subjects will be informed that they are welcome to withdrawal or discontinue the study at any 
time should they feel this is not their best interest, does not meet their time availability, or for any other 
reason they see fit. Subjects will be asked to speak with the study coordinator or the investigator to 
indicate their request for withdrawal and all study related activity will stop. 
 
7.3 LOST TO FOLLOW-UP 
NCCIH considers lost to follow-up as a research subject who was participating in the study at a certain 
point in time and subsequently missed two consecutive study visits and is unresponsive to study 
contact, or is no longer participating in study activities. The anticipated lost to follow-up rate for this 
study will be 20% of total enrolment (e.g., N=2). 
 
 


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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
There is no intention of determining efficacy during this phase of the study. 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
All subjects will undergo lab testing at various time points. Before ingestion of kava and at weeks 1, 4, 8, 
and 12 to monitor for safety. 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject during participation in the clinical 
study or with use of the experimental agent being studied. An adverse finding can include a sign, 
symptom, abnormal assessment (laboratory test value), or any combination of these regardless of 
relationship to participation in the study. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect 
• 
An important medical event that may not result in death, be life threatening, or require hospitalization 
may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 Any undesirable and unintended (although not necessarily unexpected) effect occurring as a result of 
interventions, interactions, or collection of identifiable private information in research. In medical 
research, any untoward physical or psychological occurrence in research, including abnormal laboratory 
finding, symptom, or disease temporally associated with the use of (although not necessarily related to) 
a medical treatment or procedure. Adverse events involving drugs are also referred to as adverse drug 
experiences. The PI will review and access for any adverse event classification in this study. 


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8.3.3.1 SEVERITY OF EVENT 
The following scale will be used to grade adverse events: 
1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact on ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical attention, needs 
major assistance with ADL 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
To assess relationship of an event to study intervention, the following guidelines are used: 
1. Related (Possible, Probable, Definite)  
1. The event is known to occur with the study intervention. 
2. There is a temporal relationship between the intervention and event onset. 
3. The event abates when the intervention is discontinued. 
4. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related)  
1. There is no temporal relationship between the intervention and event onset. 
2. An alternate etiology has been established. 
8.3.3.3 EXPECTEDNESS 
The Study PI and Independent Monitoring Committee will be responsible for determining whether an 
SAE is expected or unexpected. An adverse event will be considered unexpected if the nature, severity, 
or frequency of the event is not consistent with the risk information previously described for the 
intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Unanticipated problems will be recorded in the data collection system throughout the study. 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING 
AEs documented during the course of the trial will be reported to NCCIH on an annual basis by way of 
inclusion in the annual report and in the annual AE summary which will be provided to NCCIH and to the 
Independent Monitors. The Independent Safety Monitor(s) Report will state that all AEs have been 
reviewed. 


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8.3.6 SERIOUS ADVERSE EVENT REPORTING 
SAEs that are unanticipated, serious, and possibly related to the study intervention will be reported to 
the Independent Monitors(s), IRB, FDA, and NCCIH in accordance with requirements. For the IND: 
• 
7-day IND Safety Report (unexpected fatal or life-threatening AEs related to the intervention); a copy of 
the report sent to the FDA will be submitted to the NCCIH Program Officer and Independent Safety 
Monitor(s) within 24 hours of FDA notification. 
• 
15-day IND Safety Report (any other serious and unexpected AE related to the intervention); a copy of the 
report submitted to the FDA will be submitted to the NCCIH Program Officer and Independent Safety 
Monitor(s) within 24 hours of FDA notification. 
All other AEs documented during the course of the trial will be reported to NCCIH on an annual basis by 
way of inclusion in the annual report and in the annual AE summary which will be provided to NCCIH 
and to the Independent Monitors. The Independent Safety Monitor(s) Report will state that all AEs have 
been reviewed 
8.3.7 REPORTING EVENTS TO PARTICIPANTS 
 In the case of abnormal lab values (liver functions), the PI will address these findings with the study 
subjects and provide the subject with a copy of the result for their current physician. 
8.3.8 EVENTS OF SPECIAL INTEREST 
 None 
8.3.9 REPORTING OF PREGNANCY 
All individuals of child bearing age range will be required to provide a urine sample for pregnancy testing 
at the screening PK visit. If they are determined to be pregnant they will be excluded from the study. 
The pharmacokinetics phase of the study is a one day visit. 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
subjects or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in 
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• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation and 
completion of an unanticipated problem report form. OHRP recommends that investigators include the 
following information when reporting an adverse event, or any other incident, experience, or outcome 
as an unanticipated problem to the IRB: 
• 
Appropriate identifying information for the research protocol, such as the title, investigator’s name, and 
the IRB project number; 
• 
A detailed description of the adverse event, incident, experience, or outcome; 
• 
An explanation of the basis for determining that the adverse event, incident, experience, or outcome 
represents an unanticipated problem; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using the 
following timeline: 
• 
Unanticipated problems that are serious adverse events will be reported to the IRB, Independent Safety 
Monitor(s), and NCCIH within 7 days of the investigator becoming aware of the event. 
• 
Any other unanticipated problem will be reported to the IRB, Independent Safety Monitor(s), and NCCIH 
within 14 days of the investigator becoming aware of the problem. 
All unanticipated problems should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), and OHRP within 
one month of the IRB’s receipt of the report of the problem from the investigator. 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
During this study we will follow the NIH and UF IRB guidelines on reporting unanticipated problems to 
study participants. 
 
 


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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
o 
Primary Efficacy Endpoint(s): 
 Not applicable as this is not an efficacy study. 
  
o 
Secondary Efficacy Endpoint(s): 
N/A 
 
9.2 SAMPLE SIZE DETERMINATION 
We will recruit and screen potential participants until we are able to randomize 10 healthy individuals 
into the pharmacokinetics phase of this study. As kava pharmacokinetics have never been characterized 
in humans, this is a pilot study such that, with 10 participants, these results will provide preliminary data 
of kava pharmacokinetics in humans. The data will be the foundation for future systematic 
characterization of kava pk in humans. 
 
9.3 POPULATIONS FOR ANALYSES 
Healthy adults ages 18-50 
 
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
Plasma concentration-time data of individual kava lactone in will be subjected to non-linear mixed effect 
modeling (NONMEM). Compartmental modeling approach will be applied to achieve the best fit model 
on the basis of residual sum of squared error, Akaike’s Information Criterion and objective function 
value. Chi-squared distribution will be assessed to evaluate the significance; e.g. an objective function 
change (OBJ) of 3.84 is significant at alpha=0.05. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Pharmacokinetic parameters will be derived from this study and these parameters will be used to design 
future efficacy studies 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Not applicable 


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9.4.4 SAFETY ANALYSES 
 At several time points in the study we will be collecting blood to access the study subjects liver 
functions pre and post kava ingestion. In the event that serum liver enzymes become elevated, (e.g., 
greater than 3 times the upper limits or normal for two repeated measures, or greater than 5 times the 
upper limits of normal once) the medical monitor will be notified and results will be communicated with 
the subject along with recommendations for follow up by a hepatologist. 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Gender, age, percentage of subjects on oral contraceptive, percentage of subjects who take multi 
vitamins. 
9.4.6 PLANNED INTERIM ANALYSES 
Not applicable 
9.4.7 SUB-GROUP ANALYSES 
None 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 Plasma concentration-time of all the volunteers will be tabulated in a csv file to do pharmacokinetic 
modeling and simulation. 
9.4.9 EXPLORATORY ANALYSES 
Plasma concentration-time of cortisol levels of all the volunteers will be quantified and tabulated in a csv 
file to explore the potential effects of kava on the plasma cortisol. 
 
 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. Extensive discussion of risks and possible benefits of 
study participation will be provided to subjects and their families, if applicable. A consent form 
describing in detail the study procedures and risks will be given to the subject. Consent forms will be 
IRB-approved, and the subject is required to read and review the document or have the document read 
to him or her. The investigator or designee will explain the research study to the subject and answer any 
questions that may arise. The subject will sign the informed consent document prior to any study-
related assessments or procedures. Subjects will be given the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. They may withdraw consent at any time 
throughout the course of the study. A copy of the signed informed consent document will be given to 
subjects for their records. The rights and welfare of the subjects will be protected by emphasizing to 
them that the quality of their clinical care will not be adversely affected if they decline to participate in 
this study. The consent process will be documented in the clinical or research record. 
To complete the informed consent process at the end of study participation, study staff will inform the 
subject when his/her participation has come to an end and will document the discussion in the study 
record. 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
All consented subjects will be provided a copy of their fully executed informed consent document. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Each subject will review the informed consent document with the study coordinator and will be 
provided time to ask and receive answers to any questions. The name of the person obtaining consent 
will be documented along with date and time consent was obtained. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study will be stopped prior to its completion if: (1) the intervention is associated with adverse 
effects that call into question the safety of the intervention; (2) difficulty in study recruitment or 
retention will significantly impact the ability to evaluate the study endpoints; (3) any new information 
becomes available during the trial that necessitates stopping the trial; or (4) other situations occur that 
might warrant stopping the trial.” 
If at any time during the study the participants are found to be at excessive risk, the study will be 
terminated. All key research personnel have completed the required human subjects training course. 
Key personnel include all individuals responsible for the design and conduct of the study. 


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10.1.3 CONFIDENTIALITY AND PRIVACY 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to any study information relating to subjects. 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all study documents 
and records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) for the study subjects. The clinical study site will permit access to such records. 
All research material will be treated in a confidential manner, and only research staff will have access to 
the data. Confidentiality will be maintained by assigning identification numbers for all aspects of the 
project; all data entered into computer databases will use only this identifier. Data are kept in separate 
coded REDCap data sets and in locked cabinets in locked rooms at UF with access limited to a small 
number of study personnel. All clinical and other records have identifying names of participants and 
relatives removed. Electronic data will be password protected and stored in a database on a secure 
server that is also password protected, with no patient identifying information. No identifiable individual 
data are presented in scientific publications. Only research personnel will have access to this data. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
  
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Medical Monitor 
Chengguo Xing 
Roberto Firpi 
Carol Mathews 
  
  
  
  
  
  
  
  
10.1.6 SAFETY OVERSIGHT 
The Data and Safety Monitoring Plan for this project will also include monitoring by an independent 
Data Safety Monitoring Board (DSMB), consisting of an anxiety disorders expert (Dr. Carr), a hepatologist 
(Dr. Morelli), a statistician (Dr. Wu), and a pharmacologist (Dr. Law). These individuals will have no 
affiliation to the proposed study. The DSMB will review any serious adverse event that is reported within 
48 hours. They will also convene annually and at the end of the study to review all adverse events. 
Adverse events that are serious and unexpected will be immediately reported to the IRB, NIH, and FDA 
(if warranted). Non-serious unanticipated problems shall be described in annual reports to the IRB and 
NIH. The DSMB will review the adverse events and discuss any concerns regarding them with the 
Principal Investigators. 
  


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Study progress and safety will be reviewed monthly (and more frequently if needed). Progress reports, 
including patient recruitment, retention/attrition, and AEs will be provided to the Independent 
Monitor(s) semi-annually. An Annual Report will be compiled and will include a list and summary of AEs. 
In addition, the Annual Report will address (1) whether AE rates are consistent with pre-study 
assumptions; (2) reason for dropouts from the study; (3) whether all participants met entry criteria; (4) 
whether continuation of the study is justified on the basis that additional data are needed to accomplish 
the stated aims of the study; and (5) conditions whereby the study might be terminated prematurely. 
The Annual Report will be sent to the Independent Monitor(s) and will be forwarded to the IRB and 
NCCIH, FDA, and sponsoring industry collaborator. The IRB and other applicable recipients will review 
progress of this study on an annual basis 
10.1.7 CLINICAL MONITORING 
The study team will generate Study Reports for the Independent Monitor and will provide information 
on the following study parameters: liver function, serious adverse events, and pharmacokinetic data. 
  
Study Report tables will be generated only from aggregate (not by group assignment) baseline and 
aggregate safety data for the study population. 
  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The site SC will ensure that all study personnel have completed all required institution-specific and 
protocol-specific trainings and that these trainings are documented appropriately on the Training Log. 
The site SC will also ensure that new personnel are appropriately documented on the Delegation of 
Responsibilities Log (DOR). While training should be completed and documented in real time, the Lead 
SC will verify that all training is current and appropriately documented. All study staff will complete CITI 
or NIH Human Subjects training prior to commencement of study. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
The investigators are responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data. The investigators will maintain adequate case histories of study 
subjects, including accurate case report forms (CRFs), and source documentation. 
All data will be entered into a REDCap (Research Electronic Data Capture) database developed for this 
project. REDCap is a secure, HIPAA-compliant web-based application designed to support traditional 
case report form data capture. Data will be exported into a SAS data set for analysis. Data integrity will 
be evaluated using descriptive statistics (e.g., means, standard deviations, frequencies, percent, range) 
appropriate for measurement levels. Checks for implausible or out-of-range values, distributional forms, 
and missingness will be performed. Data transformations (e.g., Box-Cox family of transforms) and/or 
crossproduct terms will be incorporated, if required, based on evaluation of tenability of statistical 
model assumptions and model fit to the data. All analyses will be conducted using SAS version 9.4 or 
later. 


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10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection and accurate documentation are the responsibility of the study staff under the 
supervision of the investigator. All source documents and laboratory reports must be reviewed by the 
study team and data entry staff, who will ensure that they are accurate and complete. Unanticipated 
problems and adverse events must be reviewed by the investigator or designee. 
10.1.9.2 STUDY RECORDS RETENTION 
During this study we will follow NIH, UF IRB, and FDA regulations on study record retention. Should the 
retention durations differ, we will recognize the longer duration for record retention. 
10.1.10 PROTOCOL DEVIATIONS 
All protocol deviation reporting will follow NIH and UF IRB guidelines. 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
Sharing of data generated by this project is an essential part of our proposed activities and will be 
carried out in several different ways. We will publish the results of our work in appropriate psychiatric 
and pharmacological journals. After the publication of the results of the study, clinical data (without 
identifiers) will be made available to other investigators, if requested. As required by the IRB at UF, 
participants in our study have the option to choose whether or not they agree to allow their data to be 
shared with other investigators. In our experience, the vast majority of participants agree to have their 
information shared with other investigators who are interested in studying neuropsychiatric disorders. 
We also welcome collaboration with others to further explore kava’s clinical potential, its active 
ingredient(s) and detailed mechanism of action. 
  
Our plan includes the following: 
  
• 
Presentations at scientific meetings 
o 
From the projects, it is expected that approximately two to three presentations at scientific 
meetings would be appropriate in the field of anxiety, biomarker or pharmacokinetics. 
• 
Peer-reviewed publications 
o 
The research results will be prepared for peer-reviewed publication. It is expected that the 
results from the proposed studies will be the basis for 2 – 4 manuscripts in the R61 phase, 
including 1) pharmacokinetic characterization of kava and its major ingredients; 2) biomarker 
changes in response to kava treatment and other clinical results. 
• 
Protocol sharing 
o 
We agree to share our experimental protocols and data with other researchers who are PIs and 
co-PIs of NIH grants. The sharing can be arranged through the following approaches: 1) on-line 
data base with a password that can be released to other researchers through the discussion with 


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the program director; and 2) teleconference with other researchers through the arrangement of 
the program director. 
• 
Department websites 
o 
Both multi-PI’s department maintain departmental websites that have “News” section and 
websites for individual faculty. The general clinical trial information will be posted both at the 
“News” site and the multi-PI’s individual faculty website that further detailed information may be 
requested from the multi-PI. 
• 
Clinicaltrials.gov  
o 
The trial will be registered at clinicaltrials.gov and will be updated as the trial proceeds. 
10.1.12 CONFLICT OF INTEREST POLICY 
During this study we will follow the NIH policy pertaining to any current or possible conflicts of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
None 
 
10.3 ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 


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GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
 4.0 
 23Nov2020 
Change to include 10 
timepoints of blood collection 
during PK visit 
This additional time point at 12 
hours post does was added to 
capture the elimination phase of 
the study drug 


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 4.0 
23Nov2020 
Update to the schema to 
include changes in procedures 
which includes CYP2D6 
testing 
Adding the CYP2D6 testing 
will help to determine if 
genotype affects the 
pharmacokinetics of kava 
 4.0 
23Nov2020 
Addition of indirect bilirubin to 
screening labs 
 Adding the indirect bilirubin 
will allow the medical monitor 
and the PI to determine if a 
subject is eligible to move 
forward in the study from a 
safety perspective. 
 4.0 
23Nov2020 
Change from single dosing 
only to allow for single dosing 
for the first 5 participants and 
three times a day dosing for 
second 5 participants 
 This change is implemented 
based on preliminary analysis 
of data from participants. This 
change will be implemented to 
evaluate the pk results of the 
three times a day dosing vs 
single dosing. It will help 
determine dosing regimen for 
2nd phase of the study. 
 1.1 
 
Change to include a 12-hour 
post dosing blood draw during 
pk visit 
 This timepoint will allow 
researchers to capture the 
elimination phase of the study 
drug 
 1.2 
 
Update to schema to include 
the CYP2D6 at the screening 
visit 
 CYP2D6 testing is being done 
to determine if genotype affects 
the pharmacokinetics of kava 
1.2 
 
Update to schema to include 
indirect bilirubin testing at the 
screening visit 
Adding the indirect bilirubin 
will allow the medical monitor 
and PI more information in 
order to determine eligibility 
from a safety perspective 
1.3 
 
Update to correct the study 
visit windows 
Number of days that 
corresponded with days listed 
on previous version were noted 
to be incorrect 
4.1 
23Nov2020 
Change from single dose only 
to single dose for first five 
subjects and three times a day 
dose for second five subjects 
Based on preliminary analysis, 
adding in the three times a day 
dosage will allow for the 
evaluation of optimal dosing 
regimen for phase 2 of the 
study. 
  
  
  
  
  
  
  
  
  
  
  
  


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11 REFERENCES 

ICF_001.pdf: 
CT.GOV Cover page 
Study Title: A phased clinical trial of dietary supplemental kava: kava pharmacokinetics 
NCT: 03843502 
Date of Document: 11Jan2021