Evaluation of Soy-protein Russian Tarragon (Artemisia Dracunculus L.) Complex as a Dietary Supplement to Improve Carbohydrate Metabolism; Dosing, Safety and Tolerability
Phase: PHASE1
Conditions: Diabetes Prevention
Sponsor: Pennington Biomedical Research Center

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Protocol Version 4.1
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Clinical Intervention Study
Protocol Template
Evaluation of soy-protein isolate Russian tarragon (Artemisia dracunculus L.) 
complex as a dietary supplement to improve carbohydrate metabolism; 
Dosing, safety and tolerability
Submitted by:
Botanical Research Center: Pennington Biomedical Research Center, LSU 
System and Rutgers University
Principal Investigator: 
Jennifer Rood, Ph.D. 
Pennington Biomedical Research Center
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Protocol Version 4.1
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FULL PROTOCOL TITLE
Evaluation of soy-protein isolate Russian tarragon (Artemisia dracunculus L.) complex as a dietary 
supplement to improve carbohydrate metabolism; Dosing, safety and tolerability
Study Chairman or Principal Investigator:
Jennifer Rood, Ph.D., Associate Executive Director for Core Services and Resources, Pennington 
Biomedical Research Center, 6400
Perkins Road, Baton Rouge, LA 70808
Supported by:
The National Center of Complementary and Alternative Medicine
Supported by P50AT002776 from the National Center for Complementary and Alternative 
Medicine (NCCAM) and the Office of Dietary Supplements (ODS) which funds the Botanical 
Research Center of Pennington Biomedical Research Center and the Department of Plant Biology 
and Pathology in the School of Environmental and Biological Sciences (SEBS) of Rutgers 
University.
Study Intervention Provided by:
The product for the clinical studies will be obtained from the Botanical Core Lab of the Rutgers 
Component of the Botanical Research Center. Working in collaboration with Dr. John Finley at the 
Louisiana State University Food Science department, the final product will be delivered to the 
Pennington Biomedical Research Center where the clinical study will be performed. Specifically, 
Artemisia dracunculus herb was grown from seed by ARC Greenhouses in cooperation with 
Rutgers University.
Sponsor of IND (IDE):
No IND is required for this study, see attached letter (Appendix A)
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Protocol Version 4.1
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Tool Revision History
Version Number: Version 4
Version Date: January 20, 2014
Summary of Revisions Made: Have revised Figure 1 to add a ten and 22 hour time point 
corresponding to “hour of OGTT”. Have added a new Table 2 to provide clarification of time points 
and blood draws of bioactives in relations to OGTT blood draws
Version Number: 4.0 Version Date: 05Oct2016
Summary of Revisions Made: Dosing of MAD phase will be done overlapping as opposed to 
consecutively. The change is suggested based on safety profile observed for the SAD study 
utilizing all doses proposed in the current proposal  
Version Number: Version Date:
Summary of Revisions Made:
Version Number: Version Date:
Summary of Revisions Made:
TABLE OF CONTENTS
Page
Clinical Intervention Study Protocol Template ....................................................................... 1
FULL PROTOCOL TITLE ........................................................................................................... 2
Tool Revision History ...................................................................................................... 3
TABLE OF CONTENTS ............................................................................................................. 4
STUDY TEAM ROSTER ................................................................................................ 7
PARTICIPATING STUDY SITES ................................................................................... 8
PRÉCIS........................................................................................................................... 9
1. STUDY OBJECTIVES ........................................................................................................... 9
1.1
Primary Objective ............................................................................................... 9
1.2
Secondary Objectives ....................................................................................... 10
2. BACKGROUND AND RATIONALE .................................................................................... 10
2.1
Background on Condition, Disease, or Other Primary Study Focus ................ 10
2.2
Study Rationale ................................................................................................ 11
3. STUDY DESIGN .................................................................................................................. 12
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .................................................... 16
4.1
Inclusion Criteria................................................................................................ 16
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4.2
Exclusion Criteria .............................................................................................. 17
4.3
Study Enrollment Procedures............................................................................ 18
5. STUDY INTERVENTIONS.................................................................................................... 19
5.1
Interventions, Administration, and Duration ....................................................... 20
5.2
Handling of Study Interventions ......................................................................... 20
5.3
Concomitant Interventions................................................................................. 20
5.3.1
Allowed Interventions ....................................................................................... 20
5.3.2
Required Interventions ..................................................................................... 20
5.3.3
Prohibited Interventions..................................................................................... 21
5.4
Adherence Assessment .................................................................................... 21
6. STUDY PROCEDURES ....................................................................................................... 22
6.1
Schedule of Evaluations..................................................................................... 22
6.2
Description of Evaluations.................................................................................. 23
6.2.1
Screening Evaluation ......................................................................................... 24
6.2.2
Enrollment, Baseline, and/or Randomization ..................................................... 25
6.2.3
Blinding............................................................................................................... 25
6.2.4
Followup Visits ................................................................................................... 25
6.2.5
Completion/Final Evaluation............................................................................... 25
7. SAFETY ASSESSMENTS..................................................................................................... 26
7.1
Specification of Safety Parameters .................................................................... 26
7.2
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .......26
7.3
Adverse Events and Serious Adverse Events ................................................... 27
7.4
Reporting Procedures ....................................................................................... 28
7.5
Followup for Adverse Events............................................................................. 28
7.6
Safety Monitoring .............................................................................................. 28
8. INTERVENTION DISCONTINUATION................................................................................. 29
9. STATISTICAL CONSIDERATIONS ..................................................................................... 29
9.1
General Design Issues ....................................................................................... 29
9.2
Sample Size and Randomization ....................................................................... 30
9.3
Definition of Populations..................................................................................... 31
9.4
Interim Analyses and Stopping Rules ................................................................ 31
9.5
Outcomes ........................................................................................................... 31
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9.5.1
Primary Outcome ............................................................................................... 31
9.5.2
Secondary Outcomes ........................................................................................ 31
9.6
Data Analyses ................................................................................................... 31
10. DATA COLLECTION AND QUALITY ASSURANCE ........................................................ 31
10.1
Data Collection Forms........................................................................................ 31
10.2
Data Management.............................................................................................. 32
10.3
Quality Assurance .............................................................................................. 33
10.3.1 Training .............................................................................................................. 33
10.3.2 Quality Control Committee …............................................................................. 33
10.3.3 Metrics ............................................................................................................... 34
10.3.4 Protocol Deviations ............................................................................................ 34
10.3.5 Monitoring........................................................................................................... 34
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ........................................................... 34
11.1
Institutional Review Board (IRB) Review........................................................... 34
11.2
Informed Consent Forms.................................................................................... 34
11.3
Participant Confidentiality................................................................................... 34
11.4
Study Discontinuation........................................................................................ 35
12. COMMITTEES .................................................................................................................... 35
13. PUBLICATION OF RESEARCH FINDINGS ...................................................................... 35
14. REFERENCES ................................................................................................................... 35
15. SUPPLEMENTS/APPENDICES......................................................................................... 36
Appendix A: Letter from Department of Health & Human Services, Food and Drug
Administration 8/21/12. IND NOT REQUIRED (SENT WITH PRIOR VERSION)
Appendix B: Targeted/Planned Enrollment Table (SENT WITH PRIOR VERSION)
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STUDY TEAM ROSTER
Jennifer Rood, Ph.D.
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road Baton Rouge, LA 70808 
(225)763-2524  ph 
(225)763-3057 fax
John Finley, PhD
Department of Food Science
Louisiana State University
111 Food Science Building Baton Rouge, LA 70803-4200 
(225)578-5085 ph
(225)578-5300 fax
JFinley@agcenter.lsu.edu
Elizabeth Floyd, PhD
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road Baton Rouge, LA 70808 
(225)763-2724 ph 
(225)763-0273 fax
 elizabeth.floyd@pbrc.edu
Frank Greenway, MD
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road Baton Rouge, LA 70808 
(225)763-2313 ph 
(225)763-3022 fax
 frank.greenway@pbrc.edu
William Johnson, PhD
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road Baton Rouge, LA 70808 
(225)763-2932 ph 
(225)763-2755 fax
 william.johnson@pbrc.edu
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Ilya Raskin, PhD
Department of Plant Biology and Pathology
Rutgers University
59 Dudley Road
New Brunswick, NJ 08901 
(848)932-6267 ph 
(732)932-6535 fax
raskin@AESOP.Rutgers.edu
David Ribnicky, PhD
Department of Plant Biology and Pathology
Rutgers University
59 Dudley Road
New Brunswick, NJ 08901 
(848)932-6365 ph 
(732)932-6535 fax
ribnicky@AESOP.Rutgers.edu
Jennifer Rood, PhD
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road Baton Rouge, LA 70808 
(225)763-2524 ph 
(225)763-3057 fax
 jennifer.rood@pbrc.edu
Jacqueline Stephens, PhD
Pennington Biomedical Research Center
Louisiana State University System
6400 Perkins Road Baton Rouge, LA 70808 
(225)763-2648 ph 
(225)763-2525 fax
jacqueline.stephens@pbrc.edu
PARTICIPATING STUDY SITES
Pennington Biomedical Research Center
6400 Perkins Road
Baton Rouge, LA 70808
Jennifer Rood, Ph.D. 
(225)763-2524 ph 
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(225)763-3057 fax
Jennifer.rood@pbrc.edu 
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Protocol Version 4.1
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PRÉCIS
Study Title
Evaluation of soy-protein isolate Russian tarragon (Artemisia dracunculus L.) complex as a 
dietary supplement to improve carbohydrate metabolism: Dosing, safety and tolerability
Objectives
The primary objective of this study is to evaluate the effect of nutritional supplementation with a 
well characterized preparation of Artemisia dracunculus L. on safety and tolerability of the 
preparation. Secondary objectives will evaluate the metabolism of the preparation by assessing 
the appearance of bioactive compounds in the plasma.
Design and Outcomes
We will employ 3-treatment crossover designs in which each subject will receive a sequence of
3 mono treatments with washout periods between distinct treatments (extract doses). We will 
use ascending single oral dose evaluation in a randomized controlled trial and multiple oral dose 
evaluation  in  an  additional  randomized  controlled  trial  to  investigate  extract  safety  and 
tolerability in healthy lean subjects and in healthy subjects who are non-diabetic but with 
obesity. We will assess safety in the form of biochemical assessments, collection of data on 
clinical adverse events and will assess plasma appearance of proposed bioactive compounds.
Interventions and Duration
A soy-protein isolate Russian tarragon (Artemisia dracunculus L.) complex will be used as the 
specific intervention. Dosing for the single ascending dose will be based on preclinical data and 
on referenced formulas that have been used to scale doses from mice to man or vice versa.
Sample Size and Population
For the safety and tolerability studies, healthy subjects who have passed all screening 
evaluations and have given informed consent will be recruited. Approximately 27 subjects (3 
cohorts of 9 subjects) will participate in the single dose studies. For the multiple dose studies, 
we plan to enroll an additional 27 participants (3 cohorts of 9 subjects). In the single dose 
studies, participants will be healthy adults with BMI 18.5 – 32 kg/m2. In the multiple dose 
studies, participants will be stratified by body mass index (BMI) so that 1 normal weight (BMI <
25), 1 overweight (BMI 25-29) and 1 obese (BMI 30+) participant will be in each treatment 
sequence. Observers will be blinded to treatment sequence for each participant until the 
database has been locked.
1. STUDY OBJECTIVES
1.1
Primary Objectives
Phase 1 Studies: Ascending Single Oral Dose Evaluation
The Primary objective will be to assess the safety and tolerability of a single dose of the soy- 
protein isolate Russian tarragon (Artemisia dracunculus L.) complex in healthy lean subjects. 
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Although this study is not designed to evaluate efficacy, we will assess the effect of a single 
dose of the botanical complex on glucose tolerance to determine if there is an acute effect.
Phase 1 Studies: Multiple Oral Dose Evaluation
A Primary objective is to assess the safety and tolerability of multiple daily doses of the soy- 
protein isolate Russian tarragon (Artemisia dracunculus L.) complex in healthy lean subjects 
and in healthy subjects who are considered overweight or obese.
1.2
Secondary Objectives
A secondary objective is to assess the metabolism of the preparation by assessing plasma 
appearance of proposed bioactives after dosing.
A secondary objective is to assess possible mechanism of action operative in vivo for the soy- 
protein isolate Russian tarragon (Artemisia dracunculus L.) complex by determining effect on 
insulin secretion and/or effects on lipid profiles.
2. BACKGROUND AND RATIONALE
2.1
Background on Condition, Disease, or Other Primary Study Focus
It is well known that Type 2 diabetes is a progressive disorder whose pathophysiology consists 
of pancreatic dysfunction, hepatic glucose overproduction and insulin resistance in peripheral 
tissues.1  As such, clinical strategies to achieve glycemic control endorse the use of a 
combination of agents from multiple pharmacologic classes and which target specific 
pathophysiologic defects.1,2  In particular, the enhancement of insulin sensitivity remains as a 
primary clinical strategy given the role of insulin resistance in the pathophysiology of type 2 
diabetes. Recent data, however, have questioned the safety of the current pharmacologic 
agents used to enhance insulin sensitivity.2,3  As such, alternative strategies, e.g., nutritional 
supplementation with over-the-counter agents, are extensively practiced by a large number of 
patients and are frequently done so without the knowledge of the provider.4,5 Based on historical 
human use, there has been great interest in plant extracts (botanicals) as a source for nutritional 
supplements intended as adjunctive therapies for human diseases. Specifically, isolated 
compounds identified from plant sources, i.e. phytochemicals or bioactives, have served as a 
source for therapeutic agents for many diseases, including malignancy, infectious diseases and 
diabetes.6 Interestingly, the development of one of the most commonly used anti-hyperglycemic 
agents in  the world today, i.e.  metformin, can be  traced to  the traditional use of  Galega 
officinalis to treat diabetes, and the subsequent search to  identify active compounds with 
reduced toxicity.7 However, the concern with most nutritional supplements, including those 
considered “natural” (e.g. botanicals) by the consumer, is the paucity of data in humans in 
regard to efficacy to improve metabolic abnormalities.8,9 Thus, there remains considerable 
controversy regarding the use of botanical supplements for human health.
Despite the stated concerns for botanical supplements, many botanicals have shown 
considerable promise for human use. In particular, plants from the genus Artemisia, and 
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specifically Artemisia dracunculus L. (Russian tarragon) have a long history of medicinal and 
culinary use and have been reported to have efficacy as a traditional treatment for diabetes in 
various parts of the world.10 Specifically, the ethanolic extract of A. dracunculus L. significantly 
decreased blood glucose levels and improved insulin levels in both genetic and chemically 
induced murine models.11,12 As a proposed mechanism of action, enhanced insulin receptor 
signaling was demonstrated in primary human skeletal muscle culture exposed to specific 
concentrations of the A. dracunculus L. extract. In addition, at least 5 bioactive compounds have 
been identified  in  A.  dracunculus  L. that have  specific  effects  in  vitro  on  mechanisms 
contributing to gluco-regulation.13-16 Yet, despite the promising in vitro studies, clinical efficacy 
data for the extract in carefully controlled clinical research studies are lacking. Thus, the overall 
objective of this study is to conduct early human investigation and to evaluate the effect of 
nutritional supplementation with a well characterized extract of Artemisia dracunculus L. The 
primary objectives would be to evaluate safety, tolerability and effective dose in non-diabetic 
human subjects. Secondary objectives would assess metabolism of the extract and evaluate 
effects on proposed mechanisms such as insulin secretion, lipid levels and/or insulin resistance.
2.2
Study Rationale
Our  pre-clinical  studies  have  confirmed  the  potential  of  Artemisia  dracunculus  L.  to  be 
developed  as  an  effective  nutritional  supplement  to  address  components  of  metabolic 
syndrome. The completed studies as proposed will provide the necessary data for large scale 
Phase III randomized clinical intervention trials.
Experiments Proposed. Studies will assess the effect of a soy-protein isolate Russian tarragon 
(Artemisia dracunculus L.) complex (termed 5011-Nutrasorb®) as a dietary supplement to 
improve carbohydrate metabolism. Protocols will be designed to evaluate feasibility, dose range 
effects, pharmacology, safety and biological efficacy of the botanical complex. We submitted an 
application for review to the FDA and were informed that “use of this product in the manner 
described in the information you submitted does not require an IND”. The soy-protein isolate 
Russian tarragon complex will primarily be tested in this application with use of ascending single 
and multiple oral dose Phase 1 studies.
Source  and  Preparation:  As  outlined,  PMI-5011  is  an  ethanolic  extract  of  Artemisia 
dracunculus L., also known as Russian tarragon. The plant has been used as a medicinal 
botanical or food for centuries and continues to be cultivated in Europe. PMI-5011 has been the 
primary study focus of our NIH Botanical Research Center since 2005 and a study focus at 
Rutgers University for at least 10 additional years. Extensive safety testing has been conducted 
with the botanical extract including complete Ames analysis, a 14-day repeated-dose oral 
toxicity study in rats and an oral subchronic 90-day toxicity study in rats, none of which showed 
any indication of toxicity. Based on these studies, it was felt that PMI-5011 would be an 
attractive dietary supplement for human use in the area of improving glucose metabolism.
In the proposed clinical study, we will use an alternative preparation of Artemisia dracunculus L. 
Rather than extracting the herb with 60% ethanol and drying the extract into a sticky paste-like 
residue, we propose to make a hot water tea-like extract which will be mixed with soy protein 
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isolate, a common component of many foods. The polyphenols that have been identified as 
bioactive from the ethanolic extract will bind to the soy protein isolate, which can then be 
separated from the water and dried. This process has been used successfully to concentrate 
polyphenols from green tea and anthocyanins from sugary berry juices. Since the basic process 
involves the mixing of two foods and removal of water, it is equivalent to cooking. The resulting 
product remains a food, and we feel it can be Generally Regarded as Safe (GRAS). In addition 
to eliminating the need for organic solvent (ethanol) use and disposal, this process removes 
chlorophyll and other non-polar compounds which are retained when ethanol is used as an 
organic solvent for Artemisia dracunculus and which tend to make the extract insoluble and less 
bioavailable. Polyphenol concentrations in the soy protein mixture are comparable to those in 
the ethanol extract. 5011-Nutrasorb is not intended to cure, prevent or mitigate a disease. Its 
suggested use is to maintain normal functions of the human body. Because it is made by simple 
mixing and separating of two foods (Russian tarragon tea and soy protein), we believe that the 
resulting substance can be Generally Regarded as Safe (GRAS).
3. STUDY DESIGN
A.  Phase 1 Studies: Ascending Single Oral Dose Evaluation
Objective: The primary objective will be to assess the safety and tolerability of a single 
dose of the 5011-Nutrasorb in healthy subjects. Although this study is not designed to evaluate 
efficacy, we will assess the effect of a single dose of the botanical complex on glucose tolerance 
to determine if there is an acute effect.
Subjects: Twenty seven healthy subjects (3 cohorts of 9 subjects) who have passed all 
screening evaluations and have given informed consent will be recruited for the Phase I studies. 
Healthy subjects are defined as individuals who are free of significant cardiac, pulmonary, 
gastrointestinal, hepatic, renal, hematological, endocrine, neurological and psychiatric disease 
as determined by history, physical examination and clinical laboratory tests.
Dosing: A representative dosing schedule and randomization for this study is outlined in 
Table 1. We will begin dosing at very low doses based on the dose response data generated 
from the mice studies. Based on dosing considerations (see Section 5.1), the suggested dosing 
range would be 3-30 g subject. Thus, our suggested doses will be 0.3, 1, 3, 10, 20 and 30 g. We 
will use the same extract dose for all participants irrespective of their weight.  Each subject will 
receive three single doses (two doses of 5011-Nutrasorb and one of placebo) separated by 
washout periods of at least 7 days. In each treatment period a single dose of extract will be 
administered on day 1. Up to 9 treatment sequences (3 sequences in each of 3 cohorts) are 
planned for the single dose evaluations (Table 1).
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Table 1. Ascending Oral Dose Randomization
Period 1
Period 2
Period 3
COHORT 1
Sequence 1 (n=3)
Dose 1
Dose 2
Placebo
Sequence 2 (n=3)
Dose 1
Placebo
Dose 2
Sequence 3 (n=3)
Placebo
Dose 1
Dose 2
COHORT 2
Sequence 4 (n=3)
Dose 3
Dose 4
Placebo
Sequence 5 (n=3)
Dose 3
Placebo
Dose 4
Sequence 6 (n=3)
Placebo
Dose 3
Dose 4
COHORT 3
Sequence 7 (n=3)
Dose 5
Dose 6
Placebo
Sequence 8 (n=3)
Dose 5
Placebo
Dose 6
Sequence 9 (n=3)
Placebo
Dose 5
Dose 6
Complete blood chemistry will be obtained prior to and after dosing. After dosing, glucose 
tolerance studies are conducted. As part of the glucose tolerance, both glucose and insulin will 
be obtained at baseline, and at 30, 60, 90, 120, and 180 minutes after dosing. Plasma will also 
be stored and archived for later analysis of proposed bioactive compounds.
Before the next cohort is commenced, subjects in the previous cohort must have received all 3 
treatments and the safety and tolerability data assessed and show good tolerability and the 
following information must be available in a safety summary provided by the investigator: (1) 
adverse events, (2) complete hematologic and biochemistry profile in blood, (3) measures of 
glucose and insulin response to glucose tolerance. Statistical analyses will be conducted to 
assess whether there is residual effect of extract after washout.
Assessments and Evaluations:
Baseline/Screening Evaluation: For the single dose study, all subjects will undergo an 
outpatient screening evaluation to assess their eligibility prior to entrance into the study. A 
complete medical history and physical examination will be performed. Blood samples will be 
taken for a complete blood chemistry, blood counts, thyroid hormone panel and urinalysis. 
Subjects with impaired glucose tolerance or diabetes will be excluded. During baseline, subjects 
will be assessed for dietary intake data and instructed on weight maintenance diets. A taste 
(small sip) of the study product (30g) will also be administered during screening. 
Study Design of Ascending Single Dose
Objective: The Primary objective will be to assess the safety and tolerability of a single 
dose of the 5011-Nutrasorb in healthy subjects. Although this study is not designed to evaluate 
efficacy, we will assess the effect of a single dose of the botanical complex on glucose tolerance 
to determine if there is an acute effect.
Design: After all inclusion and exclusion criteria are met, subjects will be admitted to the 
inpatient unit of the Pennington Biomedical Research Center. After meeting inclusion and 
exclusion  criteria,  they  will  be  randomized  by  the  study  statistician  to  receive  a  specific 
sequence of 3 treatments (3 doses of extract).  Participants will be randomly assigned to 
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treatment sequences as this design balances order of treatment consumption with respect to 
the distribution of extraneous factors, known or unknown, that may potentially confound the 
association and assessment of botanical supplement use and carbohydrate metabolism. After 
baseline evaluation, subjects within each cohort will be randomized to one of 3 treatment 
sequences (order of receiving 2 doses of 5011-Nutrasorb and placebo based on the dosing plan 
outlined in Table 1. The statistician will prepare and give to the pharmacist a randomization 
schedule that is divided into 3 parts, one for each cohort. Nine treatment sequences will be 
indicated for each cohort in 3 permuted blocks of 3 treatment sequences where each treatment 
sequence appears exactly once in permuted block. This balances the use of treatment 
sequences throughout the duration of participants in the event that anticipated dose usage 
requires adjusting before completion of all treatment sequence assignments.
Figure 1: Single Ascending Dose Study
Day of Study
Scr
-3
1
1
1
1
1
1
1
1
1
1
2
2
Hour of OGTT
-2
-1.5
-1
-0.5
0
1
2
4
10
12
22
24
Randomization

Dosing
taste

Vital Signs







Body Weight


Complete Blood Chemistry


Physical Exam


EKG


OGTTa


Adverse Event Assessment




Fasting Lipds


Insulin/Glucose
b



Bioactives:Plasma










Figure 1: Proposed Study Design Assessing Ascending Single Dose for each period in Table 1
a OGTT will be conducted as described in Section 6.2 and will include assessment of insulin and glucose at -15 
and 0 timepoints prior to ingestion of oral glucose load and at 30, 60, 90, 120 and 180 minutes post glucose load.
b Indicates insulin and glucose assessments conducted in addition to assessments as part of the OGTT
Parameters assessed as part of SAD study will consist of assessing safety with biochemical 
measures, and effect on insulin action (with use of HOMA-IR), and use of insulin response to 
glucose as assessed during oral glucose tolerance testing (OGTT) and with HOMA-. The 
OGTT will be obtained at two time points, specifically at Day -3 (prior to randomization) and at 
Day 1. The protocol for OGTT in regard to timing of dosing of study intervention and for 
insulin/glucose assessments are summarized below;
1) Day -3: OGTT will be conducted according to the specific method as outlined in Section
6.2, entitled “Glucose Tolerance”. Specifically, a 75–g oral glucose tolerance test will be 
used to assess for glucose tolerance and insulin secretory function according to the 
guidelines of the American Diabetes Association. Time points for assessment of insulin 
glucose will be at -15, 0, 30, 60, 90, 120, and 180 minutes.
2) Day  1:  
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The  subject  will  be  given  either  the  placebo  or  specified  dose  of  the  
study intervention two hours prior to the OGTT. This time point on the figure is termed “-
2 hours” and specified as “Hour of OGTT”.

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3) Day 1: At 1 hour and 45 minutes post study intervention dosing on Day 1 (corresponding 
to time point -15 minutes of the OGTT)  and at two hours post study intervention dosing 
(corresponding to 0 time point of the OGTT), insulin and glucose levels will be obtained 
in the fasting state and will represent baseline labs for the OGTT.  After obtaining the 0 
time point baseline labs of the OGTT, 75 grams of oral glucose will be ingested. Repeat 
insulin and glucose levels will be obtained at 30, 60, 90, 120 and 180 minutes after 
glucose ingestion.
4) Day 1: To evaluate effect of extract dosing on insulin/glucose over time, repeat insulin 
and glucose level will be evaluated at 12 hours after the start of the OGTT. These levels 
are outlined in Figure 1
5) Day 2: To evaluate effect of extract dosing on insulin/glucose over time, repeat insulin 
and glucose levels will be evaluated at 24 hours after the start of the OGTT that was 
conducted on Day 1. These levels are outlined in Figure 1.
Fasting lipids will be obtained 24 hours after dosing. Figure 1 outlines the schedule plan for 
metabolic testing in our single dose studies.  We do not feel we need to alter any testing 
based on hormone/menstrual cycle issues that need to be timed, monitored, or controlled for 
with respect to the study outcomes.
Assessing Botanical Levels/Compliance: Levels of the bioactive components will be 
assessed by determining concentrations of the component in blood plasma (circulating levels) 
and urine (excretion) on inpatient days. Subjects will be given their randomized intervention 
(5011-Nutrasorb or placebo) at the -2.0 hour of OGTT (considered as 0 Hour of Bioactives) (see 
Table 2). Plasma will be obtained at the -2.0 hour of OGTT (i.e. 0 hours of Bioactive) then at -
1.5, -1.0, -0.5, 0, 1, and 2 hour of OGTT.  These time points labeled as “Hour of OGTT 
correspond to the following time points for bioactive assessment [Labeled as “Hour of 
Bioactives”] as outlined in the Table 2 which occur as follows: 0, 0.5, 1, 1.5, 2, 3, and  4  hours 
post ingestion (Hour of Bioactive). Blood for bioactives will also be obtained at 6, 12 and 24 
hours (hours of Bioactives) after extract or placebo ingestion corresponding to 4, 10 and 22 
hours post OGTT (“Hour of OGTT”) (see Table 2). After initial void, urine will be collected over 
the 6 hour interval (corresponding to 0 through hour 6 of “hour of bioatives”. These specimens 
will be assessed for bioactives in the Botanical Core lab.
    Table 2: Correlation of Blood Draws for OGTT in relation to Bioactive Assessment Blood Draws
Day of Study
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
Hour of OGTT
-2
-1.5
-1
-0.5
-0.25
0
0.5
1
1.5
2
3
4
10
12
22
24
OGTT Draws
X
X
X
X
X
X
X
X
X
Hour of Bioactives
0
0.5
1
1.5
1.75
2
2.5
3
3.5
4
5
6
12
14
24
26
Bioactive Draws
X
X
X
X
X
X
X
X
X
X
B.  Phase 1 Studies: Multiple Oral Dose Evaluation
Objective: The primary objective is to assess the safety and tolerability of multiple 
daily doses of the 5011-Nutrasorb complex in healthy subjects that include subjects whose 
phenotype as assessed by BMI are in the lean, overweight and obese categories. The 
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secondary objective is to assess the pharmacodynamic effect of multiple daily doses of the 
extract on glucose tolerance. We will evaluate other proposed mechanisms of action including 
assessment of insulin secretion with OGTTs, plasma lipid levels and plasma appearance of 
proposed metabolites.
Table 3. Multiple Oral Dose Randomization
Period 1
Period 2
Period 3
Cohort 1
          Sequence 1 (n=3)
D1
Placebo
D2
          Sequence 2 (n=3)
D1
D2
Placebo
          Sequence 3 (n=3)
Placebo
D1
D2
Cohort 2
          Sequence 4 (n=3)
D2
Placebo
D3
          Sequence 5 (n=3)
D2
D3
Placebo
          Sequence 6 (n=3)
Placebo
D2
D3
Cohort 3
          Sequence 7 (n=3)
D1
Placebo
D3
          Sequence 8 (n=3)
D1
D3
Placebo
          Sequence 9 (n=3)
Placebo
D1
D3
Dosing: Twenty Seven subjects (3 cohorts of 9 subjects with 3 subjects (1 normal weight, 1 
overweight and 1 obese) randomly assigned to each of 3 treatment sequences) will participate 
in a three period crossover treatment regimen with each treatment period comprising once daily 
dosing for 21 days.  Subjects will be randomly assigned to receive the treatments in the 
sequence orders shown in Table 2: 1) Cohort 1 will comprise 3 sequences of 3 treatments 
where placebo is dose 0 of 5011-Nutrasorb, D1 is a low dose (0.3 g) of 5011-Nutrasorb and D2 
a medium dose (1 g) of 5011-Nutrasorb; 2) Cohort 2 will comprise 3 sequences of 3 treatments 
where D2 is a medium dose (1 g) of the 5011-Nutrasorb and D3 (30 g) a high dose of the 5011-
Nutrasorb; and 3) Cohort 3 will comprise 3 sequences of 3 treatments where D1 is a low dose 
(0.3 g) of the 5011- Nutrasorb and D3 a high dose (30 g) of the 5011-Nutrasorb. Dosing for the 
MAD study was determined by data obtained in the SAD study as outlined above. Specifically, 
as outlined in Table 1, we will have data on PK studies, safety and tolerability, and biological 
response. In addition, based on information from the plasma appearance data and from 
assessment of biological response, consideration will be given to providing dosing on a BID or 
TID regimen. All doses used in this phase have been tested in the single-dose portion of the 
protocol. In the single dose protocol, there was no observed signal for toxicity, tolerability or 
other adverse events noted. The doses evaluated in the single dose study  are spread among 
all 3 cohorts and no new dose is being introduced in this phase. . Blinded analysis of the 
glucose tolerance will be on-going during the study and dose changes will be made if 
necessary. Additionally, as stated, if none of these doses show adequate glucose tolerance 
effects then an additional cohort may be added to investigate a twice daily or three times a day 
dose. In each treatment period a single dose of the 5011- Nutrasorb will be administered daily 
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from days 1 to 21. Complete biochemical and hematologic assessments to evaluate safety will 
be obtained in addition to clinical monitoring for adverse events.
Assessments and Evaluations:
Baseline/Screening Evaluation: All subjects will undergo an outpatient screening 
evaluation to assess their eligibility prior to entrance into the study. A complete medical history 
and physical examination will be performed. Blood samples will be taken for a complete blood 
chemistry, blood counts, thyroid hormone panel and urinalysis. Subjects with impaired glucose 
tolerance or diabetes will be excluded. During baseline, subjects will be assessed for dietary 
intake data and instructed on weight maintenance diets.
Study Design of Multiple Ascending Dose
Subjects: We will test safety, tolerability and metabolism in individuals with a wide range 
of BMIs representing lean, overweight and obese subjects.
Design: After meeting inclusion and exclusion criteria, subjects will be randomized by 
the study statistician to one of the treatment sequences within each subject’s appropriate BMI 
stratum. Participants will be randomly assigned to treatment sequences as this design balances 
order of treatment consumption with respect to  the distribution of extraneous factors, known or 
unknown,  that  may  potentially  confound  the  association  and  assessment  of  botanical 
supplement use and insulin sensitivity. After baseline evaluation, subjects will have an OGTT, 
insulin/glucose and effect on insulin action and response on Day -3. They will also have a 
baseline DXA. There will be three (3) study periods each evaluating exposure through 21 days 
(see Figure 2). At day 1, of each treatment period, subjects will be randomly assigned to 
treatment sequence based on the dosing scheme proposed in Table 2. Repeat insulin/glucose, 
safety labs, OGTT and fasting lipid profile will be assessed at 7, 14, and 21 days. Parameters 
assessed will consist of assessing safety with biochemical measures, bioactive metabolites and 
effect on insulin action (with use of HOMA-IR) and insulin response to glucose as assessed 
during OGTT and with use of HOMA-β. Fasting lipids will be obtained at 7, 14 and 21 days of 
each treatment period. Figure 2 outlines the schedule plan for metabolic testing in our multiple 
dose studies. We do not feel we need to alter any testing based on hormone/menstrual cycle 
issues that need to be timed, monitored, or controlled for with respect to the study outcomes.
Assessments and Evaluations: 
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Figure 2: Multiple Dose Study
Day of Study
Scr
-3
1
3
7
10
14
17
21
Randomization

Vital Signs/Body Weight









Complete Blood Chemistry




Physical Exam/EKG




OGTT




Plasma Metabolites



Insulin Secretory Assessment




Fasting Insulin/Glucose




Bioactives: Plasma/Excretion*



DXA


Adverse Event Assessment








Figure 2: Proposed Study Design Assessing Multiple Dose Study for each Period. There will
be three study periods of assessment (see Table 2). SCR; Screening (only done in the first study period).
A one day +/- visit window is allowed.
*NOTE Subjects will be given their intervention (low or high dose 5011-Nutrasorb or placebo)
two hours prior to start of OGTT (0 hour) and will have plasma obtained at 0, 30 minutes, 1, 1.5,
2, 3, and 4 hours post ingestion. After initial void, urine will be collected over the 6 hour interval. These specimens will 
be measured in the Botanical Core lab. Note: Intervention will not be administered at Day -3 of each test period. 
Baseline/Screening Evaluation: All subjects will undergo an outpatient screening evaluation to 
assess their eligibility prior to entrance into the study. A complete medical history and physical 
examination will be performed. Blood samples will be taken for a complete blood chemistry, 
blood counts, thyroid hormone panel and urinalysis. Subjects with impaired glucose tolerance or 
diabetes will be excluded. During baseline, subjects will be assessed for dietary intake data and 
instructed on weight maintenance diets. A taste (small sip) of the study product will also be 
administered during screening. 
Randomization: After completing initial physiological sequence, each subject will be assigned to 
a treatment sequence as follows: Nine subjects will be enrolled for each of the 3 cohorts to 
investigate 3 doses of extract as compared to placebo (Low Dose, Medium Dose and High 
Dose). These 9 subjects will be enrolled in 3 strata by body weight (BMI 18.5-24.9 kg/m2, BMI 
25-29.9 kg/m2, and BMI 30-40 kg/m2). Further, in each cohort, there are 3 possible orders 
(treatment sequences) in which the extract doses can be administered. In each cohort, it is 
desirable to have 1 participant from each BMI stratum in each treatment sequence. In each 
cohort, the first 3 participants enrolled in each BMI stratum will be randomly assigned to one of 
the 3 treatment sequences for that cohort. The statistician, Dr. Johnson, will use SAS V9.3 to 
prepare 3 randomization schedules (one for each BMI stratum) for the pharmacist. Each list will 
have 3 blocks of the 3 randomly permuted treatment sequences. The pharmacist will determine 
the BMI stratum for each enrollee in turn and dispense the treatments according to the next 
Placebo
Artemisia sp.
Baseline
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available treatment sequence assignment on the randomization schedule for that participant’s 
BMI stratum. Dr. Johnson and the Pennington pharmacist have a long history of collaboration in 
this type of trial.
The dose to be used in the multiple dose study will be based on our dose ranging Phase I study. 
As outlined in Section 2B, based on the data collected in the SAD study which will consist of 
plasma appearance of bioactives, safety and tolerability, and biological response, the dosing for 
the MAD will be determined. As also stated, consideration will be given to providing the extract 
in BID or TID dosing if data suggests that approach.   The 5011-Nutrasorb used in human 
studies will be standardized using QA/QC concentration parameters established by the 
Botanical Core. The randomization will be blinded to the staff performing the physical measures, 
metabolic testing, performance of assays, entering or calculating data related to the study and 
study investigators to assure minimal potential sources of bias.
Nutrition Assessment: Subjects' usual dietary intake will be assessed by a research dietitian at 
screening and monitored throughout the study. The dietary intake analysis will be valuable as a 
method of evaluating consistency in dietary regimen over the study period. Biochemical profiles 
will be monitored to assess safety and body weights will be obtained at each study visit.
4. SELECTION AND ENROLLMENT OF PARTICIPANTS
4.1
Inclusion Criteria
Participants must meet all of the inclusion criteria to participate in this study.
SINGLE AND MULTIPLE DOSE COHORT
For the single and multiple dose studies to assess safety and tolerability, we will evaluate 
healthy subjects. Deviations from inclusion criteria for these studies are not allowed because 
they can potentially jeopardize the scientific integrity of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be deemed as “healthy” and eligible for inclusion in this study only if all of the 
following criteria apply:

Healthy  as  assessed  on  a  medical  evaluation  including  medical  history,  physical 
examination, laboratory tests and cardiac monitoring.

Males and females between 18 and 65 years of age inclusive at the time of signing the 
informed consent.

Women of child-bearing potential must agree to use one of the approved contraception 
method [(i.e., barrier method, intrauterine and cervical devices, oral contraceptives, 
hormonal injections (Depo Provera®), condoms with spermicidal gel or foam, 
contraceptive patch (Ortho Evra), diaphragm, or abstinence)], prior to the start of dosing 
to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree 
to use contraception until the follow-up visit.
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
BMI within the range 18.5 – 32 kg/m2 (rounding up or down as appropriate is permitted 
for calculation), for both males and females for the single dose studies, and a BMI of 
18.5 – 40 kg/m2 for the multiple dose study.

Capable  of  giving  written  informed  consent,  which  includes  compliance  with  the 
requirements and restrictions listed in the consent form.
4.2   Exclusion Criteria
SINGLE AND MULTIPLE DOSE COHORT
A subject will not be eligible for inclusion in this study if any of the following criteria apply:

Subjects with a prior history of Type 2 diabetes.

Women who are pregnant or who are lactating. 

Women of childbearing potential who are not using an effective method of birth 
control(i.e., barrier method, intrauterine and cervical devices, oral contraceptives, 
hormonal injections (Depo Provera® ), condoms with spermicidal gel or foam, 
contraceptive patch (Ortho Evra), diaphragm, or abstinence), are not surgically 
sterilized (including tubal ligation and hysterectomy), or not at least 2 years 
postmenopausal. All women of childbearing potential will have a pregnancy test 
performed prior to starting the study treatment in each phase. If a subject becomes 
pregnant during the study, they will be dropped from the study.

Subjects who have type 1 diabetes.

Subjects who are on concomitant therapy with glucocorticoids (except topical or inhalant 
glucocorticoids). Other medications that have an effect on glucose homeostasis (i.e. 
ACE inhibitors) are acceptable if they have been administered in a stable dosage during 
the preceding 6 months and dosage will continue unchanged during the study.

Subjects  with  a  history  or  evidence  of  significant  gastrointestinal  dysfunction,  e.g. 
irritable  bowel  syndrome;  inflammatory  bowel  disease;  ulcerative  colitis  or  Crohn's 
disease; regional enteritis; diverticulosis or diverticulitis; significant gastroparesis; GI 
stricture,  partial  or  complete  gastrectomy  or   small  bowel  resection;  autonomic 
neuropathy consisting of  dysphasia; delayed  gastric  emptying  or  diarrhea;  chronic, 
severe constipation; peptic ulceration, colonic ulceration, or GI bleeding.

Subjects who are taking concomitant therapy with medications known to be nephrotoxic, 
such as aminoglycosides, methicillin, and cyclosporin.

Subjects who have evidence of clinically significant renal dysfunction or disease, e.g. 
serum creatinine >1.5 mg/dL in males and >1.4 mg/dL in females and/or BUN >50

mg/dL, proteinuria of >1 gram/day or 4+ proteinuria on dipstick urinalysis.

Subjects with clinically significant cardiovascular dysfunction and/or history (within the 
preceding 6 months) of significant cardiovascular dysfunction, e.g., congestive heart 
failure or serious arrhythmia, myocardial infarction, cardiac surgery; transient ischemic 
attacks or cerebrovascular accident during the preceding six months; diagnosis of 
symptomatic autonomic neuropathy with a history of orthostatic hypertension, syncope, 
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or hypertension with a systolic blood pressure of ≥180 mm Hg and diastolic blood 
pressure ≥110 mm Hg at the time of screening visit.

Subjects with EKG findings deemed by the medical investigator as “clinically significant” 
will be excluded. These findings include: ST changes suggesting ischemia, myocarditis, 
infarction, bundle branch blocks, PVCs, ventricular arrhythmias, or ventricular paced 
beats from pacemaker.

Subjects who have evidence within the  preceding 6  months of  hepatic disease or 
dysfunction, e.g. AST, ALT, alkaline phosphatase or total bilirubin twice the upper limit of 
normal; hepatitis; jaundice; cirrhosis.

Subjects with clinically significant pulmonary, neurologic, hematologic, immunologic, 
neoplastic or metabolic disease.

Subjects with evidence or recurrence of malignancy within the past five years, other than 
excised basal cell carcinoma.

Subjects for whom surgery is anticipated during the study period.

Subjects with a history of substance abuse or alcoholism within the past 5 years, or 
significant psychiatric disorder that would interfere with the subject's ability to complete 
the study.

Subjects who have donated blood during the month prior to study entry or planned 
during the study.

Subjects who have participated in other studies using an investigational drug during the 
preceding 3 months.

Subjects who are current smokers or have smoked within the previous 6 months. No 
smoking will be allowed during the study.

Subjects that have had a fluctuation in body weight >5% in the preceding 2 months.

Subjects who are taking prescription or over the counter medication or supplements for 
desired weight loss.

Subjects who have an allergy to soy
4.3 Study Enrollment Procedures

The goal is to enroll and complete all subjects in a 9 month period. This will require 
enrolling 9 subjects per month.

Potential participants will be identified through the Pennington Biomedical Research 
Center’s participant database (over 70,000 people are in the database). The 
database can be queried for specific inclusion and exclusion criteria after receiving 
approval from the Pennington Biomedical Research Center’s privacy board. 
Pennington Biomedical has an exceptional track record for recruiting healthy 
individuals into early phase trials.

Enrollment rates will be monitored by the study coordinator, investigator and 
recruiting department in order to ensure goals are met.

Alternate methods of recruitment will be implemented as needed. Examples include 
community events, radio advertisements, television advertisements, newspaper 
articles and/or advertisements.
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
Screening  logs  will  be  kept  and  all  eligibility  criteria  reviewed  by  both  the  
study coordinator and the investigator.

Informed consent will be obtained according to Pennington Biomedical Research 
Center’s Standard Operating Procedures.
Randomization procedure
Each subject in the cohorts will be randomly assigned one of the relevant treatment sequences 
in order of enrollment. Treatment sequence assignments will be balanced so that each 
sequential block will have unique treatment sequences. This randomization will be done by the 
study statistician. As an example, for the multiple dose study, the first 3 enrolled subjects in 
each  cohort will  be  randomly assigned to  one  of  3  distinct treatment sequences, as  will 
enrollees 4-6 and 7-9. As a result, 3 of the 9 subjects in each cohort will be randomly assigned 
to each of the 3 treatment sequences.
5. STUDY INTERVENTIONS
5.1
Interventions, Administration, and Duration
The product for the clinical studies will be obtained from the Botanical Core Lab of the Rutgers 
Component of the Botanical Research Center. Working in collaboration with Dr. John Finley at 
the  Louisiana  State  University  (LSU)  Food  Science  department,  the  final  product  will  be 
delivered to the Pennington Biomedical Research Center where the clinical study will be 
performed.   Specifically,   Artemisia   dracunculus   herb   was   grown   from   seed   by   ARC 
Greenhouses. This crop of Artemisia dracunculus was grown in the Florida location of ARC 
Greenhouses. Only insecticidal soap approved for food applications was used as a pesticide. 
The herb was harvested and shipped to Shiloh, NJ in a cold container (4 ˚C, together with 
perishable fresh cut flowers) and flash frozen upon arrival. The frozen herb will be shipped 
frozen (-20 ˚C, together with frozen food) to LSU for processing.
The following steps for clinical product use are outlined as follows:
 1.  5011-Nutrasorb preparation
a) Frozen Artemisia dracunculus is extracted in DI water 1:5 (w/v).
b) The water is heated to near boiling for 2 hrs (slow roll) and cooled overnight. Solids are 
removed by filtration using MiraCloth.
c)
The Artemisia “tea” is mixed with soy protein isolate (SPI) at a ratio of 30g of SPI/1Liter 
of water.
d) The pH of the mixture is adjusted to 3.5 as a slurry using HCl.
e) The SPI is separated from the mixture by centrifugation (removing supernatant from NS) 
or using centrifugal filtration.
f)
The PMI-5011 Nutrasorb is lyophilized to dryness.
g) The final product will be administered as a powder and will be mixed with water 
immediately before planned ingestion.
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2.  Scale-up Procedure
a) Scale-up will be conducted in batch wise operations.
b) Frozen Artemisia dracunculus tissue will be prepared in 20 kg batches. 20 kg of plant 
issue will be suspended in 100 kg of water in a steam jacketed kettle equipped with 
mechanical stirring. The suspension will be brought to 100oC for 2 hours and then 
transferred to another kettle, allowed to cool for several hours and filtered through 
multiple layers of cheesecloth followed by filtration through a double layer of miracloth. 
Then 3000g of soy protein will be stirred into the solution. Stirring will be continued for 30 
minutes. The suspension will then be adjusted to pH 3.5 with 1M HCl and allowed to 
settle for one hour.
c)
The bulk of the liquid will be decanted from the surface and the protein rich material will 
be centrifuged and the precipitate spread in trays and freeze dried.
d) The microbial count and heavy metal analysis of the substance used for the trial will be 
performed by a licensed outside laboratory (Medallion Labs - www.medlabs.com/).
Dosing Considerations
For consideration of the initial doses to be used in humans, we are aware that there are two 
ways that have been used to scale doses from mice to man or vice versa.17, 18 The first one is 
based on body surface area and the second is the Kleiber formula of mass to the 0.75 power. 
For this study, we will use the Kleiber formula as we have had experience with this equation in 
the past (http://home.fuse.net/clymer/minor/allometry.html).
For our animal studies, successful effects were seen with PMI-5011 when used at a dose of 1%. 
Essentially, based on our calculations, mice were consuming approx. 4 grams of food per day. 
Given that the mice weigh about 40 g, this dose is approximately 1g/kg.
Based on data from the Botanical Research Center Core lab, the extract generally contains 
about 0.2% DMC-2 which is used as the reference standard. Therefore, based on the 
consumption of food containing 1% extract, the mice will be getting a daily dose of DMC-2 of
0.002 X 1000mg/kg = 2 mg/kg. We have done gavage studies at 500 mg/kg doses which 
translates to a dose of DMC-2 of 1mg/kg. The amount of DMC-2 in the 5011-Nutrasorb is 0.1-
0.2%. Based on these calculations, we would estimate that current dosing for humans would be 
10 grams. However, we would like to evaluate low, middle and high dose for safety, tolerability, 
adverse effects and tolerability, our suggested dosing would be 0.3, 1, 3, 10, 20, and 30 grams 
for the SAD studies. Dosing for the MAD studies will be based on results for the most effective 
dose and side effect profile from the SAD study. As outlined in other sections of the proposal, 
dosing for the MAD studies will be determined based on PK analysis in SAD study in addition to 
assessment of adverse events and biologic response. Based on these parameters, we will have 
comprehensive data to suggest dosing for the MAD studies and frequency of dosing as to once 
daily, twice daily or three times daily.
5.2
Handling of Study Interventions
The product for the clinical studies will be obtained from the Botanical Core Lab of the Rutgers 
Component of the Botanical Research Center. Working in collaboration with Dr. John Finley at 
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the Louisiana State University Food Science department, the final product will be delivered to 
the Pennington Biomedical Research Center where the clinical study will be performed. 
The placebo will be the soy protein that has not been co-dried with the Artemisia dracunculus 
tea and will be modified using common food handling procedures (such as toasting or adding 
food colorant) so that it will have a similar appearance to the test material.
5.3
Concomitant Interventions
5.3.1
Allowed Interventions
As individuals will not be diabetic or have severe hyperglycemia, there is no suggested rescue 
therapy for glucose. Subjects will be allowed to be on medications such as ACE inhibitors, 
statins and other blood pressure medications if they have been administered in a stable dosage 
during the preceding 6 months and dosage will continue unchanged during the study.
Over the counter medications taken as PRN such as Tylenol, antacids, aspirin are acceptable if 
not taken more than twice weekly. The use of stool softeners is acceptable. Use of bulking 
agents, if required, should remain constant.
5.3.2
Required Interventions
The only required intervention will be the study medication, soy-protein isolate Russian tarragon
(Artemisia dracunculus L.) complex (5011-Nutrasorb).
5.3.3
Prohibited Interventions
Subjects who are on concomitant therapy with glucocorticoids (except topical or inhalant 
glucocorticoids) will not be included. Subjects who are currently on thiazolidinediones 
(rosiglitazone or pioglitazone) or who have taken these agents in the previous 12 weeks or on 
medications known to affect glucose metabolism, i.e. metformin, will not be allowed. Subjects 
who have chronic use of laxatives or cathartics will not be enrolled.
5.4
Adherence Assessment
Assessing Botanical Levels/Compliance: Levels of the bioactive components will be assessed 
by determining concentrations of the component in blood plasma (circulating levels) and urine 
(excretion) on inpatient clamp days. Subjects will be given their randomized intervention (5011- 
Nutrasorb or placebo) two hours prior to start of OGTT (0 hour) and will have plasma obtained 
at 0, 30 minutes, 1, 2, 3, and 4 hours post ingestion. For the SAD study, additional plasma will 
be obtained at 12 and 24 hours post ingestion. After initial void, urine will be collected over a 6 
hour interval. These specimens will be measured in the Botanical Core lab.
6. STUDY PROCEDURES
See Figures 1 and 2 for this information
6.1
Schedule of Evaluations (SEE FIGURE 1, page 13 and FIGURE 2, page 16)
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6.2
Description of Evaluations
Specific Methods:
Glucose Tolerance: A 75–g oral glucose tolerance test will be used for screening and to 
assess for glucose tolerance and insulin secretory function in human studies according to the 
guidelines of the American Diabetes Association. Time points for assessment will include -15, 0,
30, 60, 90, 120, and 180 minutes.
Insulin Resistance and Insulin Secretion:
Calculations to assess insulin resistance and insulin secretion:
Insulin sensitivity:  Insulin sensitivity has been identified as a primary clinical parameter 
for which PMI-5011 has an effect. We will estimate insulin sensitivity by the homeostasis
assessment model of insulin resistance (HOMA-IR). HOMA-IR will calculated by the
formula HOMA-IR = fasting insulin (μU/ml) X fasting glucose (mmol/l) / 22.5.
Insulin secretion: Insulin secretion will be estimated by the homeostasis assessment 
model of β-cell function and the insulinogenic index.  HOMA β-cell will be calculated by 
the formula HOMA β-cell = [20 X fasting insulin (μU/ml)] / [fasting glucose (mmol/l)]. The 
insulinogenic index (a measure of insulin secretory capacity) will be defined as the ratio 
of the increment of insulin to the increment of glucose during the first 30 minutes after an 
oral glucose load is administered.
Fasting Lipid Profile: Subjects will be evaluated with fasting lipid profile to assess potential 
changes in lipid parameters including triglycerides, LDL and HDL levels.
Body Composition: Fat-free mass, fat mass and body fat % will be measured by dual-energy
X-ray absorptiometry (DEXA).
Plasma Bioactives: Selective ion monitoring using the molecular masses for the bioactive 
compounds will be used to determine the relative abundance in the plasma and urine derived 
from the consumption of the extract. Amounts of bioactives will be calculated from their 
respective peak areas and normalized with the use of internal standards added before the 
chromatography.
Proposed Bioactives to be assessed: From a series of studies conducted by our group, 5 
bioactive compounds were identified from PMI-5011 using in vitro activity guided fractionation.23
As with all botanical preparations, the identification of bioactive compounds does not preclude 
the presence of additional bioactive compounds that have not been isolated. DMC-2 was 
identified as the most universally active compound since it was active in all in vitro assays and is 
considered the marker compound for the extract. DMC-2 was also chemically synthesized and 
validated as active in vivo, using an acute hypoglycemic assay in mice.23 The bioactive 
compounds identified from the extract were also identified from the plasma of animals treated 
with PMI-5011 as shown in Figure 3 below published by Ribnicky.23  The identification of the 
compounds requires hydrolysis treatment of the plasma using β glucuronidase in order to detect 
them, suggesting that they are present in the plasma as glucuronide conjugates, a common 
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metabolic form of many botanical compounds and drugs.  The compounds were present in the 
plasma over a 6 h period. The compounds could never be detected at 24 h (data not shown).
Figure 3.  Relative abundance of the active compounds of PMI-5011 as measured by LC-MS in the 
blood plasma of C57 mice treated with Pure DMC-2 (2′, 4′–dihydroxy-4-methoxydihydrochalcone) 
formulated with 66% Labrasol or PMI-501l formulated with 66% Labrasol over a 6 h period.  DMC-2, 
Demethcap (6-demethoxycapillarison), DMC-1 (2′,    4–dihydroxy-4′-methoxydihydrochalcone) and 
sakuranetin are components of PMI-5011.
In a recent study that is currently being submitted for publication by Ribnicky et al., the 
glucuronide conjugate of DMC-2 was identified in unhydrolyzed plasma from mice treated with 
the pure DMC-2. This prepublication is based on studies using 5011-Nutrasorb, which is the 
preparation of the Artemisia that will be used in present clinical study. The results of the studies 
showed that Nutrasorb-5011 has improved bioaccessibility characteristics using the TIM-1 
digestive unit, improved bioavailability using hydrolyzed plasma levels of DMC-2 and improved 
bioactivity based on glucose measurements in mice. DMC-2 was also synthesized in gram 
quantities for use as a chemical standard in current and future studies.
In the present clinical study, bioavailability and pharmacokinetic data will be collected from 
plasma samples obtained from subjects (see treatment schedule) using the protocols described 
above.  DMC-2 will be specifically quantified by LC-MS from hydrolyzed plasma samples based 
on a standard curve for DMC-2.  An internal standard (to be determined) will be used to adjust 
for recovery.  The other active compounds (see figure above) will also be analyzed by LC-MS 
relative to the DMC-2 because no chemical standards are available for the other compounds. 
Analysis of the unhydrolyzed plasma will be performed, as described for the mice treated with 
pure DMC-2, in order to determine if the DMC-2 in the plasma of clinical subjects is also 
glucuronidated. The plasma conjugate, however, may not be detectable from treatments with 
the PMI-5011 preparations having low levels of DMC-2 as it is not detectable in mice. Since the 
compounds were detectable in plasma hydrolyzed with glucuronidase in the previous clinical 
study, they are likely to be present in the plasma as glucuronides.
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6.2.1
Screening Evaluation
These evaluations will occur to determine if the candidate is eligible for the study.
Consenting Procedure
Before any screening procedure is performed, informed consent will be obtained. There will be a 
single informed consent form that describes both the screening and study procedures. The 
study coordinator will conduct the consent process and the consent will be provided to the study 
subject in advance of the visit to allow time to read and address any questions. The medical 
investigator or Principal Investigator will also be available if any questions or clarifications are 
required. A copy of the consent form will be given to the subject and consent form placed in 
study source documents and medical records.
Screening
All screening evaluations to determine eligibility must be completed and reviewed by the 
individual providing medical supervision or Principal Investigator prior to study start. Generally, 
all labs to assess entry criteria must be completed no less than 10 days before subject enters 
study. Screening evaluations are outlined in Figure 1.
6.2.2
Enrollment, Baseline, and/or Randomization
Enrollment and Baseline Assessments
All subjects will undergo an outpatient screening evaluation to assess their eligibility prior to 
entrance into the study. After informed consent, the following procedures will be conducted:

A complete medical history and physical examination will be performed.

Blood samples will be taken for a complete blood chemistry, blood counts, thyroid 
hormone panel and urinalysis.

Subjects with diabetes will be excluded.

Subjects will be assessed for dietary intake data and instructed on weight maintenance 
diets.
Baseline Assessments
See above combined Enrollment and Baseline Assessments section
Randomization
After completing initial physiological sequence, each subject will be randomized by Dr. Johnson 
(study biostatistician). Subjects will be randomized to the 5011-Nutrasorb or placebo. The 5011- 
Nutrasorb used in human studies will be standardized using QA/QC concentration parameters 
established by the Botanical Core.
6.2.3
Blinding/Unblinding
Dr.  William Johnson, Botanical Research Center biostatistician, will be responsible for all 
blinding procedures and for randomization. Randomization will be blinded to the staff performing 
the physical measures, metabolic testing, performance of assays, entering or calculating data 
related to the study and study investigators to assure minimal potential sources of bias. Sealed 
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randomization envelopes will be sent to the pharmacist for emergency unblinding. The 
randomization  envelopes  will  be  maintained  in  a  secure  location  with  access  limited  to 
authorized personnel.
Blinding is critical to the integrity of this clinical trial. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that subject may be broken by the 
medical investigator of the trial. This will be done by a request to the pharmacist to break the 
blind and report the treatment assignment to the medical investigator.
Before breaking the blind of an individual subject’s treatment, the investigator should have 
determined that the information is necessary, i.e., that it will alter the subjects’ immediate 
management. In many cases, particularly when the emergency is clearly not investigational 
product-related, the  problem  may  be  properly  managed  by  assuming  that  the  subject  is 
receiving active product without the need for unblinding.
In case of an emergency, the investigator may open the emergency unblinding envelope to 
reveal the identity of the medication for that subject. If such unblinding occurs, the investigator 
shall notify the DSMB, NCCAM and IRB immediately. This information, including the reason for 
the blind being broken must be recorded in the participant chart and regulatory files.
6.2.4
Follow-up Visits
Follow-up visits will occur as outlined in Figures 1 and 2
6.2.5
Completion/Final Evaluation
Study design for both single and multiple dose studies are listed in detail in Figures 1 and 2
7. SAFETY ASSESSMENTS
7.1
Specification of Safety Parameters
The plant has been used as a medicinal botanical or food for centuries and continues to be 
cultivated in Europe. PMI-5011 has been the primary study focus of our NIH Botanical Research 
Center since 2005 and a study focus at Rutgers University for at least 10 additional years. 
Extensive safety testing has been conducted with the botanical extract including complete Ames 
analysis, a 14-day repeated-dose oral toxicity study in rats and an oral subchronic 90-day 
toxicity study in rats, none of which showed any indication of toxicity.
7.2
Methods and Timing for Assessing, Recording, and Analyzing Safety
Parameters
The study team including coordinator and investigators will inquire regarding adverse events 
while minimizing the chance for bias when detecting AEs and/or SAEs. The study team will 
employ open-ended and non-leading verbal questioning of the subject as the preferred method 
to inquire about AE occurrence. For examples, appropriate questions include: “How are you 
feeling?”, “Have you had any (other) medical problems since your last visit/contact?”, or “Have 
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you taken any new medicines, other than those provided in this study, since your last 
visit/contact?”.
Recording of AEs and SAEs
It is the responsibility of the investigator to review all documentation (e.g., hospital progress 
notes, laboratory, and diagnostics reports) relative to the event when an AE/SAE occurs. The 
investigator will then record all relevant information regarding an AE/SAE in the appropriate data 
collection tool.
We define an adverse event (AE) as any unfavorable and unintended diagnosis, symptom, 
sign (including an abnormal laboratory finding), syndrome or disease which either occurs during 
the study, having been absent at baseline, or if present at baseline, appears to worsen. Adverse 
events are to be recorded regardless of their relationship to the study intervention.
We will define a serious adverse event (SAE) as any untoward medical occurrence that results 
in  death,  is  life  threatening,  requires  inpatient  hospitalization  or  prolongation  of  existing 
hospitalization,  results  in  persistent  or  significant  disability/incapacity,  or  in  a  congenital 
anomaly.
It is the responsibility of the investigator to attempt to establish a diagnosis of the event based 
on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
Evaluating AEs and SAEs
Assessment of Intensity
An assessment of intensity for each AE and SAE reported during the study will be provided by 
the investigator and the investigator will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
activities.

Severe: An event that prevents normal everyday activities.
An AE that is assessed as severe will not be confused with an SAE and both AEs and SAEs 
can be assessed as severe. Severe Adverse Event is a category utilized for rating the intensity 
of an event when it meets at least one of the pre-defined outcomes as described in the definition 
of an SAE.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE. A "reasonable possibility" is meant to convey that there are 
facts/evidence or arguments to suggest a causal relationship, rather than a relationship cannot 
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be ruled out. The investigator will use clinical judgment to determine the relationship. Alternative 
causes, such as natural history of the underlying diseases, concomitant therapy, other risk 
factors, and the temporal relationship of the event to the study treatment will be considered and 
investigated.
7.3
Adverse Events and Serious Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. We define AE as any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of a medicinal product.
Events meeting the definition of an AE include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator.

Exacerbation  of  a  chronic  or  intermittent  pre-existing  condition  including  either  an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though 
it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE).
 Events that do not meet the definition of an AE include:

Any  clinically  significant  abnormal  laboratory  findings  or  other  abnormal  safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE.

Situations  where  an  untoward  medical  occurrence  did  not  occur  (social  and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
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Definition of Serious Adverse Events
If an event is not an AE, then it cannot be an SAE even if serious conditions are met (e.g., 
hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc.).
An SAE is any untoward medical occurrence that, at any dose, results in death, is life- 
threatening, requires hospitalization or prolongation of existing hospitalization, results in 
disability/incapacity or a congenital anomaly/birth defect. We define an SAE as one associated 
with liver injury and impaired liver function defined as: ALT  3xULN, and total bilirubin  
2xULN or INR > 1.5.
7.4 
Reporting Procedures
Once the investigator determines that an event meets the protocol definition of an SAE, the SAE 
will be reported to the IRB and Chair of Data Safety Monitoring Committee within 24 hours and 
notification will be sent to program official at NCCAM/ODS. If the investigator does not have all 
information regarding an SAE, the investigator will not wait to receive additional information 
before notifying the responsible parties of the event and completing the appropriate forms. An 
assessment of causality at the time of the initial report will be provided. Email transmission of 
the SAE data collection tool will be the preferred method to transmit this information followed by 
notification by telephone and/or fax. A copy of the SAE report will also be sent to the institution 
officials and via overnight mail to NCCAM/ODS officials. Initial notification via the telephone 
does not replace the need for the investigator to complete and sign the SAE data collection tool 
within the designated reporting time frames.
7.5 
Follow-up for Adverse Events
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After the initial AE/SAE report is completed and sent, the investigator is required to proactively 
follow each subject at subsequent visits/contacts. As currently practiced, it is planned that all 
AEs and SAEs will be followed in clinic until: 1) resolution; 2) the condition stabilizes; 3) the 
event is otherwise explained; or 4) the subject is lost to follow-up.
Additional measurements and/or evaluations as may be indicated will be conducted by the 
investigator/research team in order to elucidate as fully as possible the nature and/or causality 
of the AE or SAE. These evaluations/measurements may include additional laboratory tests or 
investigations, histopathological examinations, consultation with other health care professionals 
or radiologic examinations. In the event that a subject dies during participation in the study or 
during a recognized follow-up period, the investigator will provide the IRB/DSMB with a copy of 
any post-mortem findings, including histopathology.
New or updated information will be recorded in the originally completed data collection tool. The 
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7.6
Safety Monitoring
As is required of all protocols conducted at Pennington Biomedical Research Center, Human 
Subjects research studies will undergo independent monitoring.  Additional monitoring by 
NCCAM and ODS Program Officials will be expected to provide additional specific guidelines to 
the PI for the study.
8. INTERVENTION DISCONTINUATION
Subject Completion: A completed subject is one who has completed all phases of the study 
including the follow-up visit. The end of the study is defined as the last subject’s last visit.
Subject Withdrawal Criteria: A subject may withdraw from study treatment at any time at his/her 
own request, or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral or administrative reasons.
Subject Withdrawal Procedures
Subject Withdrawal from Study:  Every effort will be made to follow-up subjects who withdraw or 
are withdrawn from the study prematurely.

If a subject withdraws or is withdrawn from the study at a scheduled visit after dosing, 
complete assessments for the scheduled visit and any other assessments specified for 
the follow-up visit that are not included in the regularly scheduled visit, where possible.

If a subject withdraws or is withdrawn from the study between visits after randomization, 
complete assessments for follow-up visit, where possible.

At a minimum, the following assessments should be performed for any subject who is 
withdrawn from the study; clinical safety labs and AE assessment.
Subjects who terminate their participation due to adverse events should be followed up as 
appropriate in order to determine the final outcome.
Subject Withdrawal from Study Treatment: Subjects may withdraw from the study at any time 
and for any reason. They are not obliged to state the reason for withdrawal. However, the 
reasons for withdrawal, or failure to provide a reason, must be documented by the physician on 
the case report form.
Treatment After the End of the Study: Subjects will not receive any additional treatment after 
completion of the study because only healthy volunteers are eligible for study participation for 
the safety and tolerability studies and will not be on glucose lowering medication if they have 
obesity or insulin resistance.
Screen and Baseline Failures: Data for screen and baseline failures will be collected in source 
documentation at the site.
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9. STATISTICAL CONSIDERATIONS
9.1
General Design Issues
The trials described in this protocol are the first stage of testing Artemisia sp. extract in humans. 
The studies will be conducted in (1) an ascending single dose evaluation of doses 0.3, 1, 3, 10,
20, and 30 g; and (2) a multiple oral dose evaluation of 3 doses chosen from the first evaluation 
and denoted doses 1, 2, and 3 as described in Section 3, Study Design. The single dose 
evaluation will be conducted by studying 6 doses (amounts) of extract and a placebo in a series 
of 3-treatment, 3-period crossover trials. The 3 treatments (placebo or one of two doses of 
extract) will be given at weekly intervals each in a single dose followed by a 7 day washout 
period. Each  crossover trial  will  consist of  3  sequences of  treatments across the  weekly 
intervals [each sequence being a different order for receiving a triad of 2 doses of extract and a 
placebo (dose 1, dose 2, placebo; dose 3, dose 4, placebo; dose 5, dose 6, placebo). The 
placebo can be taken in period 1, period 2 or period 3 and the extract is taken in the other two 
periods where the lower dose of extract is always taken in a period that precedes that of the 
higher dose]. The primary objective is to assess the safety and tolerability of ascending amounts 
of the extract for each amount given in a single dose. If no adverse effects are observed with a 
given pair of extract doses, the dose escalates (e.g. dose 1, dose 2, placebo escalates to dose
3, dose 4, placebo which escalates to dose 5, dose 6, placebo) and a new cohort of subjects is 
studied in a new crossover trial with each escalation.
The multiple dose evaluation will be conducted similarly by studying 3 doses (amounts) of 
extract and a placebo in a series of 3-treatment, 3-period crossover trials. The 3 treatments 
(placebo or one of two doses of extract) will each be given once daily across a 21 day period 
followed by a 7 day washout period. Each crossover trial will consist of 3 sequences of 
treatment (each sequence being a different order for receiving 2 doses of extract and a placebo 
where the lower dose of extract always precedes the higher dose). The primary purpose is to 
further investigate safety, tolerability and bioavailability of once daily consumption of the extract 
over a 7 day period.
9.2
Sample Size and Randomization
As comparative efficacy of the extracts is not the primary issue in this protocol, power to detect 
efficacious effects is not specifically evaluated to justify sample sizes. A sample of 27 subjects 
(3 subjects in each of 3 treatment sequences in each of 3 cohorts) will be enrolled in the 
ascending single dose evaluation. Thus, all 9 subjects in Cohort 1 will receive the placebo and 
both dose 1 and dose 2 of the extract; similarly all 9 subjects in Cohort 2 will receive the placebo 
and both dose 3 and dose 4 of the extract; and all 9 subjects in Cohort 3 will receive the placebo 
and both dose 5 and dose 6 of the extract. Before the next cohort is commenced, subjects in the 
preceding cohort must have received all 3 treatments and the safety and tolerability data must 
have been assessed showing good tolerability; and information must be available in a safety 
summary of adverse events, complete hematologic and biochemistry profile in blood, and 
measures of glucose and insulin response to glucose tolerance.
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The 9 subjects in each cohort for the SAD study will be enrolled with 3 subjects in each of 3 
strata (normal weight – BMI =18.5-24.9 kg/m2; overweight -- BMI = 25.0-29.9 kg/m2; obese – 
BMI = 30.0-32 kg/m2). The randomization will be carried out within each weight stratum so that 
one normal weight, one overweight, and one obese subject will be assigned to each sequence.
A sample of 27 subjects (3 subjects in each of 3 treatment sequences in each of 3 cohorts) will 
be enrolled in the multiple oral dose evaluation. Thus, all 9 subjects in Cohort 1 will be receive 
the placebo and both dose 1 and dose 2 of the extract; similarly, all 9 subjects in Cohort 2 will 
receive the placebo and both dose 2 and dose 3 of the extract; and all 9 of the subjects in 
Cohort 3 will receive both dose 1 and dose 3 of the extract. Randomization for the multiple dose 
evaluation will be carried out within each weight stratum so that each cohort once completed will 
have one normal weight, one overweight, and one obese subject will be assigned to each 
sequence. Specifically, the 9 subjects in each cohort will be enrolled with 3 subjects in each of 3 
strata (normal weight – BMI =18.5-24.9 kg/m2; overweight -- BMI = 25.0-29.9 kg/m2; obese – 
BMI = 30.0-40.0 kg/m2). The randomization will be carried out within each weight stratum so 
that one normal weight, one overweight, and one obese subject will be assigned to each 
sequence
Both randomizations will be performed using computer generated pseudo-random number 
generators. Because each subject receives each treatment in both studies, among treatment 
comparisons will be made using within-subject data. Thus, the main purpose of stratifying 
treatment assignment by weight category is to ensure good representation of subjects with 
diverse weights in the evaluation of safety and tolerability.
9.3
Definition of Populations
For the single and multiple dose studies to assess safety and tolerability, we will evaluate 
healthy subjects. Deviations from inclusion criteria for these studies are not allowed because 
they can potentially jeopardize the scientific integrity of the study or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be deemed as “healthy” and eligible for inclusion in this study only if all of the 
following criteria apply:

Healthy  as  assessed  on  a  medical  evaluation  including  medical  history,  physical 
examination, laboratory tests and cardiac monitoring.

Males and females between 18 and 65 years of age inclusive at the time of signing the 
informed consent.

Women of child-bearing potential must agree to use one of the approved contraception 
method [(i.e., barrier method, intrauterine and cervical devices, oral contraceptives,

hormonal  injections  (Depo   Provera®),  condoms  with   spermicidal  gel   or   foam, 
contraceptive patch (Ortho Evra), diaphragm, or abstinence)], prior to the start of dosing

to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree

to use contraception until the follow-up visit.
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
BMI within the range 18.5 – 32 kg/m2 (rounding up or down as appropriate is permitted 
for calculation), for both males and females for the single dose studies, and a BMI of

18.5 – 40.0 kg/m2 for the multiple dose study.
Capable of giving written informed consent, which includes compliance with the requirements 
and restrictions listed in the consent. (See Section 4, page 16-18 for exclusions).
9.4
Interim Analyses and Stopping Rules
No Interim analysis is planned.
Stopping Rules
Dosing within a cohort will be stopped and further dosing will be halted until unblinded safety 
information can be reviewed in the event that:

A death occurs

Two or more subjects experience the same SAE following administration of study drug.

Two or more subjects in one dose panel experience the same severe drug-related AE 
following administration of study drug

Based on AEs, laboratory findings, clinical findings or ECGs the Investigator or DSMB 
determine that review of pertinent safety information is required.
Dosing may only resume if, after review of safety information, both the Investigator, DSMB and
IRB agree that it is safe to proceed.
9.5
Outcomes
9.5.1
Primary Outcome
The primary outcome will be to determine the effect of the selected 5011-Nutrasorb complex on 
safety and tolerability based on clinical and biochemical assessment.
9.5.2
Secondary Outcomes
The secondary outcomes will consist of assessing possible mechanisms of action with use of 
OGTT to assess insulin action and insulin secretory effects. Plasma appearance of metabolites 
will be obtained to assess metabolism.
9.6
Data Analyses
Statistical comparisons will focus on comparisons between subjects randomized to the selected 
Artemisia sp. extract and the placebo group with respect to baseline to follow-up change in: (a) 
a descriptive summary of adverse events, complete hematologic and biochemistry profile in 
blood, and measures of glucose and insulin response to glucose tolerance will be compiled for 
both single and multiple dose studies; (b) measurements assessing lipid metabolism, i.e. fasting 
lipid profile; (c) physiologic assessments of insulin action (HOMA-IR) and insulin secretion; and 
(d) body weight/body composition. For each outcome, the equality of the outcome means for
5011-Nutrasorb versus placebo will be tested against a two-directional alternative, controlling 
the type 1 error at α = 0.05. The analyses will be conducted using mixed effects linear statistical 
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models with repeated measures to conduct analysis of variance for crossover designs. Post-hoc 
tests will be conducted for pairwise comparisons of extract doses and placebo employing the 
Tukey method for controlling the global comparison-wise significance at 0.05 level. Logarithms 
or  other  transformations  will  be  analyzed  for  data  seriously  deviating  from  normality; 
alternatively, non-parametric analyses may be conducted.
Handling of missing data;  The data will be analyzed using the procedures PROC MIXED and 
PROC GLIMMIX SAS (v 9.3 or later). Thus, mixed effects models for repeated measures will be 
employed to analyze all available data irrespective of missing or incomplete data attributable to 
dropouts or other phenomena. Our experience in previous studies that employed similar study 
designs resulted in little if any missing data. Nevertheless, in anticipation of the possibility of 
such we plan to conduct sensitivity analyses that compare our findings against protocol 
completer analyses and last observation carried forward analyses in addition to investigating 
characteristics of participants who fail to protocol.
10. DATA COLLECTION AND QUALITY ASSURANCE
10.1
Data Collection Forms
Data will be collected on case report forms at baseline/screening, inpatient visit and outpatient 
visits by trained research staff. Randomization will be blinded to the research staff performing 
the physical measures, metabolic testing, performance of assays, entering or calculating data 
related to the study and study investigators to assure minimal potential sources of bias.
Data collection forms will be created and developed. Specifically, source documents will be 
tailored to each clinical assessment data output for data entry or data upload including: history, 
physical, lab results, MRS scanning, clamp results, dietary intake.
10.2
Data Management
All volunteers are assured of their confidentiality both verbally and in the informed consent form. 
The clinical facilities are strictly limited to the staff of the research institution and to research 
volunteers. This is accomplished by a variety of stringent security measures. All medical records 
are stored in locked areas. Access to these areas is limited to the clinical support staff, director 
of the clinical facilities, and the PI’s. Volunteers' medical records are filed according to ID 
numbers. All forms on the chart, with the exception of consent form, display only the ID number. 
Electronic data storage is similarly restricted with only the PI’s and authorized persons having 
access to databases containing confidential clinical records, i.e. those containing name OR 
other identifying information.
All data are confidentially collected from study participants and are only used for research 
purposes. All records are kept in locked file cabinets, and participant data can be identified only 
by number. Data are used only in aggregate, and no identifying characteristics of individuals are 
published or presented.
Each participant will be issued an ID number that will be utilized throughout the study. A secure 
master file linking names, addresses and ID numbers will be maintained in a confidential 
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computer file accessible only to the investigators. Access to data files can be made only with 
permission of the Principal Investigator. Privacy in the context of this study includes 
confidentiality of data and personal information. During interviews and measurements, the study 
staff will ensure full privacy of participants and will ensure that the data are stored in a secured 
area. All study staff must be HIPAA certified. The Pennington Biomedical Research Center's 
Biostatistics Core will cooperate with the data manager who will manage the data entry into the 
clinical database to ensure quality of data. The Pennington Biomedical Research Center's Data 
Management Core will have the prime responsibility for database design and implementation, 
programming, coordination and manual data entry of the study data into the study database.
Data for common endpoints will be entered directly into the research computing (RCU) data 
management system per the RCU's procedures. All data that are Pennington Biomedical 
Research Center specific will be housed in the Pennington Biomedical Research Center Clinical 
Database. Data from most instruments are directly uploaded into the Clinical Database. Data 
that must be hand entered is entered twice via an established data entry system. Prior to 
analysis, all data will be evaluated for outlying and extreme values. All data manually entered 
must be entered by two clerks before it is considered valid for use in research analysis. Data 
manually  entered  into  the  database  include  anthropometry  (height,  weight,  BMI, 
circumferences), vital signs and adverse events. Data to be manually entered is collected on 
standard case report forms that match the flow of the computerized data entry screens. These 
standardized case report forms are created by the software development team and provided to 
the clinical research staff. Manual double data entry applications are created to include data 
verification checks, numeric value range checks and computerized record comparisons between 
first and second entry. The data entry applications will not allow a data record to be first and 
second entered by the same data entry clerk. The data entry clerk's logon id is stored in the 
database with the data record and flagged as either first entry or second entry. Only records that 
are flagged as second entry and verified are considered valid for research use. Once a record is 
verified this data becomes view only to authorized personnel using the customized Pennington 
Biomedical data entry/viewing applications. Data entry clerks must be trained and certified by a 
member of the software development team before they are granted the necessary computer 
network rights needed to access the data entry applications.
10.3
Quality Assurance
10.3.1 Training
The study personnel and staff working on this study are highly qualified with extensive research 
backgrounds and experience conducting trials involving human participants, both here at the 
Pennington Biomedical Research Center, and at previous institutions. Dr. Rood as PI will 
oversee all aspects of the research project. The Pennington Biomedical Research Center 
Recruiting Core will oversee recruitment for the trial and clinical aspects of screening and 
testing. In addition, Dr. Rood will be engaged in day-to-day scientific decisions and problem 
solving. Dr. William Johnson is the Director of the Pennington Biomedical Research Center's 
Biostatistics and Data Management Core. He supervises a staff that includes PhD and master's 
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level biostatisticians and skilled programmers, and data entry personnel. Dr. Johnson will be 
responsible for statistical analyses relevant to this funding.
Dr. Rood will work closely with the co-investigators and staff to ensure that the study is 
executed with the utmost scientific integrity. Dr. Rood will also provide oversight of the protocol 
to ensure adherence.
All staff has completed GCP training by CITI and will be trained before the study starts on 
protocol interventions and the consent process.
10.3.2 Quality Control Committee
This study will utilize a data and safety monitoring board (DSMB). The DSMB will receive 
quarterly reports via email. A minimum of 2 meetings each year will be conducted in person or 
via conference call and additional meetings may be called if necessary. Prior to the start of 
recruitment the DSMB will give formal approval of the study protocol and informed consent.

Size and Composition. The DSMB will consist of 4-5 members both internal and 
external to the Pennington Biomedical Research Center. The planned composition is as 
follows: Biostatistician (1), Pharmacologist (1), Clinician-Scientist/Trialist(1-2), and 
Layperson (1-2) 
The Major Responsibilities of Members are as follows: 1. Sign and abide by a statement 
of confidentiality; 2. Disclose any actual or potential conflicts of interest; 3. Be familiar 
with research protocol and plans for safety monitoring; 4. Oversee safety of participants 
to include review of adverse events; 5. Review reports of related studies, as appropriate; 
6. Review major proposed modifications; and 7. Monitor recruitment and adherence.

Reports. Following each meeting, the DSMB will provide written documentation 
regarding findings for the study as a whole and any relevant recommendations related to 
continuing, changing, or terminating the study. All DSMB recommendations will be 
submitted to the Principal  Investigator  and/or  his  designee,  with  a  copy  provided  to  
the Pennington Biomedical Research Center IRB and Chair of the Pennington Medical 
Staff Committee. Reports will be made available to NIH Project Officer or designee.

Qualifications and Responsibilities of the Safety Officer. The Safety Officer for this 
trial will be familiar with the adverse event definitions and reporting requirements for the 
study. The Safety Officer will review reports sent by the study coordinator as they occur 
and will determine whether there is any corrective action or stopping rule violation. The 
safety officer will send written documentation of the decision to the PI and NIH.
10.3.3 Metrics
All data will be entered directly into a database maintained by the Pennington’s Data 
Management Core. The core will be responsible for quality control of the database and will 
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generate data queries both at the point of entry and in batch, as well as additional checks for 
data consistency within or across forms.
10.3.4 Protocol Deviations
All major protocol deviations/violations must be reported by the investigator to the IRB within 
five (5) working days of learning of the deviation/violation. If it is necessary to make a 
permanent change to the study procedures in order to avoid harm to other subjects, then a 
protocol modification will be submitted as soon as possible by the investigator. If appropriate to 
maintain safety of the subjects, new subject enrollment will be temporarily stopped by the 
investigator until the modification is approved.
The investigator will report no matter who discovers a major protocol deviation/violation (e.g., 
sponsor or their agent during a monitoring visit), the investigator is responsible for reporting it to 
the IRB.
10.3.5 Monitoring
The data safety monitoring board as described will assess adverse events, subject complaints, 
unanticipated problems, recruiting analysis, interim safety reviews and data collection. The 
results of the DSMB meeting will be given to the IRB and/or any other institutional committees 
required to review the report.
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY
11.1
Institutional Review Board (IRB) Review
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the Pennington Biomedical Research Center IRB responsible for 
oversight of the study. The consent form will be separate from the protocol document.
11.2
Informed Consent Forms
A signed consent form will be obtained from each participant. The population being recruited for 
this study allows for only subjects who can consent themselves. The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A signed copy will be given to each participant and this fact will be documented in 
the participant’s record.
11.3
Participant Confidentiality
All volunteers are assured of their anonymity and confidentiality both verbally and in the 
informed consent form. The clinical facilities are strictly limited to the staff of the research 
institution and to research volunteers. This is accomplished by a variety of stringent security 
measures. All medical records are stored in locked areas. Access to these areas is limited to the 
clinical support staff, director of the clinical facilities, and the PI's. Volunteers' medical records 
are filed according to ID numbers. All forms on the chart, with the exception of consent form, 
display only the ID number. Electronic data storage is similarly restricted with only the PI’s and 
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authorized persons having access to databases containing confidential clinical records, i.e. 
those containing name, Social Security Number or other identifying information. Data, including 
body weight and body composition, will be collected from participants. Data are confidentially 
collected from study participants and are only used for research purposes. All records are kept 
in locked file cabinets, and participant data can be identified only by number. Data are used only 
in aggregate, and no identifying characteristics of individuals are published or presented.
11.4
Study Discontinuation
The study may be discontinued at any time by the IRB, the institution, NCCAM/ODS, the OHRP 
or other government agencies as part of their duties to ensure that research participants are 
protected.
12. COMMITTEES
The study will employ a Data Safety and Monitoring Committee. The PI will update the 
monitoring committee at the specified intervals on recruitment, progress to date, adverse events 
and other details as required to fully evaluate progress and safety of study. The report to the 
DSMB will also be sent to the Medical Staff Committee of the Pennington Biomedical Research 
Center at each quarter. The Medical Staff Committee of Pennington consists of all medical staff 
including physicians, clinical researchers, clinical research staff and IRB official who evaluate 
research activities of the center including evaluating adverse events and reporting of ongoing 
studies.
13. PUBLICATION OF RESEARCH FINDINGS
Being an investigator initiated study, there is no Publication committee and results of study will 
be published by PI and co-investigators.
The study will be registered on ClinicalTrials.gov. Results will be reported on the site following 
data analysis and completion of study procedures.
14. REFERENCES
1.
Cefalu WT. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus:     
rationale and specific agents. Clin Pharmacol Ther 2007; 81(5):636-49.
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Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral 
agents,  insulins and combinations. Endocrinol Metab Clin North Am 2005; 34:77–98.
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Stafylas PC, Sarafidis PA, Lasaridis AN. The controversial effects of thiazolidinediones 
on cardiovascular morbidity and mortality. Int J Cardiol 2009; 131(3): 298-304.
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Neuhouser ML. Dietary supplement use by American women: challenges in assessing 
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Mehta DH, Gardiner PM, Phillips RS, McCarthy EP. Herbal and Dietary Supplement 
Disclosure to Health Care Providers by Individuals with Chronic Conditions. J Altern 
Complement Med 2008; 14 (10): 1263-1269.
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6.
Schmidt B, Ribnicky DM, Poulev A, Logendra S, Cefalu WT, Raskin I. A natural history 
of botanical therapeutics. Metabolism 2008; 57(7 Suppl 1): S3-9.
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 Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects. Diabetes Rev 1998; 
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Cefalu WT, Ye J, Wang ZQ Efficacy of dietary supplementation with botanicals on 
carbohydrate metabolism in humans. Endocr Metab Immune Disord Drug Targets. 
2008;8(2):78-81.
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Cefalu WT, Brantley PJ. Botanicals and cardiometabolic risk: positioning science to 
address the hype. Metabolism 2008; 57(7 suppl 1): S1-2.
10. Swanston-Flatt SK, Flatt PR, Day C, Bailey CJ. Traditional dietary adjuncts for the 
treatment of Diabetes Mellitus. Proc Nutr Soc 1991; 50: 641-651.
11. Ribnicky DM, Poulev A, Watford M, Cefalu WT, Raskin I. Antihyperglycemic Activity of 
TARRALIN™, an Ethanolic Extract of Artemisia dracunculus L. Phytomedicine 2006; 
13:550-557.
12. Zuberi AR Strategies for assessment of botanical action on metabolic syndrome in the 
mouse and evidence for a genotype-specific effect of Russian tarragon in the regulation 
of insulin sensitivity. Metabolism 2008; 57(7 Suppl 1):S10-5.
13. Wang ZQ, Ribnicky DM, Zhang XH, Raskin I, Yu Y, Cefalu WT. Bioactives of Artemisia 
dracunculus L enhance cellular signaling in primary human skeletal muscle culture. 
Metabolism 2008; 57(7): S58-64.
14. Logendra S, Ribnicky DM, Yang H, Poulev A, Ma J, Kennelly EJ, Raskin I.Bioassay-
guided isolation of aldose reductase inhibitors from Artemisia dracunculus. 
Phytochemistry 2006;67, 1539-46.
15. Ribnicky DM, Kuhn P, Poulev A, Logendra S, Zuberi A, Cefalu WT, Raskin Improved 
absorption and bioactivity of active compounds from an anti-diabetic extract of Artemisia 
dracunculus L. Int J Pharm 2009; 370(1-2):87-92.
16. Govorko D, Logendra S, Wang Y, Esposito D, Komarnytsky S, Ribnicky D, Poulev A, 
Wang Z, Cefalu WT, Raskin I. Polyphenolic compounds from Artemisia dracunculus L. 
inhibit PEPCK gene expression and gluconeogenesis in an H4IIE hepatoma cell line. Am 
J Physiol Endocrinol Metab 2007; 293(6):E1503-10.
17. Reagan-Shaw S,  Nihal  M,  Ahmad  N.  Dose translation from animal to human studies 
revisited. FASEB J 2008 Mar;22(3):659-61.
18. Wang Z, O'Connor TP, Heshka S, Heymsfield SB. The reconstruction of Kleiber's law at 
the organ-tissue level. J Nutr 2001 Nov;131(11):2967-70
19. Govorko  D,  Logendra  S,  Wang  Y,  Esposito  D,  Komarnytsky  S,  Ribnicky  D,  et  al. 
Polyphenolic compounds from Artemisia dracunculus L. inhibit PEPCK gene expression 
and gluconeogenesis  in  an  H4IIE  hepatoma  cell  line.  Am  J  Physiol  Endocrinol  
Metab 2007;293(6):E1503-10.
20. Logendra S, Ribnicky DM, Yang H, Poulev A, Ma J, Kennelly EJ, et al. Bioassay-guided 
isolation  of  aldose  reductase  inhibitors  from  Artemisia  dracunculus.  Phytochemistry 
2006;67(14):1539-46.
21. Schmidt B, Ribnicky DM, Poulev A, Logendra S, Cefalu WT, Raskin I. A natural history 
of botanical therapeutics. Metabolism 2008;57(7 Suppl 1):S3-9.
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22. Wang ZQ, Ribnicky D, Zhang XH, Zuberi A, Raskin I, Yu Y, et al. An extract of Artemisia 
dracunculus L. enhances insulin receptor signaling and modulates gene expression in 
skeletal muscle in KK-A(y) mice. J Nutr Biochem 2011;22(1):71-8.
23. Ribnicky DM,  Kuhn  P,  Poulev  A,  Logendra S,  Zuberi  A,  Cefalu  WT,  et  al.  
Improved absorption and bioactivity of active compounds from an anti-diabetic extract of 
Artemisia dracunculus L. Int J Pharm 2009;370(1-2):87-92.
15. SUPPLEMENTS/APPENDICES
Appendix A: IND NOT REQUIRED letter from Department of Health & Human Services, 
Food and Drug Administration 8/21/12
Appendix B: Targeted/Planned Enrollment Table
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Appendix B
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