Study to Establish the Bioavailability and Pharmacokinetic Measures of H. Procumbens Extract in Humans
Phase: EARLY_PHASE1
Conditions: Osteoarthritis, Knee
Sponsor: University of Missouri-Columbia

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Clinical Intervention Study 
Protocol and Consent 
 
 
ClinicalTrials.Gov ID: 2010425     Bioavailability and 
Pharmacokinetic Measures of H. 
Procumbens Extract 
    NCT03641248 
 
Date: 2.25.2020 
 
 
 
 

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PREFACE 
Musculoskeletal conditions represent a major source of pain, loss of function, and health care 
expenditure that costs Americans many billions, yearly. People with conditions causing chronic 
pain turn to integrative health practices to supplement other conventional medical treatment, or 
when their pain is resistant to or in an effort to avoid side effects of medications. Clinical 
research has provided evidence that Harpagophytum procumbens (Devil's Claw) is an effective 
and safe treatment for patients suffering from arthritis and chronic low back pain. The variability 
in the natural products, however, and lack of a well-defined biological signature necessitate 
additional studies with well-characterized products, so that subsequent clinical studies of 
appropriate methodological rigor can be conducted. This study will use the best-characterized H. 
Procumbens product to assess a biological signature for a hypothesized mechanism of action that 
can provide the basis for subsequent definitive clinical efficacy studies.  
The R21 phase of this project (PK Study: Study to Establish the Bioavailability and 
Pharmacokinetic Measures of H. procumbens Extract in Humans; Dosing Study: Study of 
Change in Systemic Inflammatory Markers after 4-Week Consumption of H. procumbens 
Extract by Humans) addresses the following objectives: (1) further define the bioavailability and 
short term pharmacokinetics of the principal secondary metabolites of a well-characterized 
aqueous-ethanolic extract of H. procumbens in non-enteric and enteric capsules; (2) define the 
biological signature and hypothetical mechanism of action of the H. procumbens extract in 
patients with knee osteoarthritis over four-week dosing; and, (3) develop protocol, data and 
safety monitoring plan and manual of operations/procedures and obtain all necessary regulatory 
approvals for the R33 phase. Following successful completion of the R21 phase, these objectives 
will be addressed during the R33 phase: (1) confirm and extend assessment of the impact of the 
H. procumbens extract upon the biological signature of the above referenced systemic 
inflammatory biomarkers and biomarkers in synovial fluid of patients consuming either of two 
doses over twelve weeks, as well as these markers in cultures of joint tissue; and, (2) evaluate the 
relationship between changes in systemic and local joint biomarker levels and clinical outcomes 
(pain, stiffness, functional difficulty). Completion of these studies will ensure that future clinical 
trials can be conducted with the methodological rigor and outcome measures needed to evaluate 
the effectiveness of such H. procumbens extracts. 

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FULL PROTOCOL TITLE 
Study to Establish the Bioavailability and Pharmacokinetic Measures 
of H. procumbens Extract in Humans 
 
Study Chairman or Principal Investigator:   
William R. Folk, PhD 
Professor 
Department of Biochemistry 
University of Missouri 
Columbia, Missouri;  
573-882-4857; folkw@missouri.edu 
 
Supported by:  
The National Center for Complementary and Integrative Health Grant Number: 
7R21AT009086-03 and the University of Missouri 
 
Study Intervention Product:  
Harpagophytum procumbens aqueous ethanolic extract  
 
Sponsor of FDA-IND127849 : Principal Investigator  Dr. William R. Folk  
Revision History 
Version Number: 
 
 
1.0 
Version Date:  
 
 
02/25/2020

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TABLE OF CONTENTS 
Page 
Clinical Intervention Study Protocol Template ......................................................................... 1 
PREFACE ...................................................................................................................................... 2 
FULL PROTOCOL TITLE ......................................................................................................... 3 
Tool Revision History ................................................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................. 4 
STUDY TEAM ROSTER........................................................................................................... 6 
PARTICIPATING STUDY SITES ............................................................................................ 9 
PRÉCIS ....................................................................................................................................... 9 
1. STUDY OBJECTIVES ........................................................................................................... 10 
1.1 
Primary Objective ......................................................................................................... 10 
1.2 
Secondary Objectives.................................................................................................... 10 
2. BACKGROUND AND RATIONALE .................................................................................. 11 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 11 
2.2 
Study Rationale ............................................................................................................. 11 
3. STUDY DESIGN ..................................................................................................................... 13 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS .............................................. 14 
4.1 
Inclusion Criteria .......................................................................................................... 14 
4.2 
Exclusion Criteria ......................................................................................................... 14 
4.3 
Study Enrollment Procedures ....................................................................................... 15 
5. STUDY INTERVENTIONS .................................................................................................. 16 
5.1 
Interventions, Administration, and Duration ................................................................ 16 
5.2 
Handling of Study Interventions ................................................................................... 17 
5.3 
Concomitant Interventions ............................................................................................ 17 
5.3.1 Allowed Interventions ............................................................................................... 17 
5.3.2 Required Interventions .............................................................................................. 18 
5.3.3 Prohibited Interventions ............................................................................................ 18 
5.4 
Adherence Assessment ................................................................................................. 18 
6. STUDY PROCEDURES ........................................................................................................ 18 
6.1 
Schedule of Evaluations ................................................................................................ 19 

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6.2 
Description of Evaluations ............................................................................................ 20 
6.2.1 Screening Evaluation ................................................................................................ 20 
6.2.2 Enrollment, PK testing, and/or Randomization ........................................................ 21 
6.2.3 Blinding..................................................................................................................... 23 
6.2.4 Followup Visits ......................................................................................................... 23 
6.2.5 Completion/Final Evaluation .................................................................................... 23 
7. SAFETY ASSESSMENTS ..................................................................................................... 24 
7.1 
Specification of Safety Parameters ............................................................................... 24 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters .... 24 
7.3 
Adverse Events and Serious Adverse Events ............................................................... 25 
7.4 
Reporting Procedures .................................................................................................... 26 
7.5 
Followup for Adverse Events ....................................................................................... 27 
7.6 
Safety Monitoring ......................................................................................................... 27 
8. INTERVENTION DISCONTINUATION ........................................................................... 27 
9. STATISTICAL CONSIDERATIONS .................................................................................. 28 
9.1 
General Design Issues ................................................................................................... 28 
9.2 
Sample Size and Randomization .................................................................................. 28 
Treatment Assignment Procedures ....................................................................................... 29 
9.3  
Definition of Populations .............................................................................................. 29 
9.4 
Interim Analyses and Stopping Rules ........................................................................... 30 
9.5 
Outcomes ...................................................................................................................... 30 
9.5.1 Primary Outcome ...................................................................................................... 30 
9.5.2 Secondary Outcomes ................................................................................................ 30 
9.6 
Data Analyses ............................................................................................................... 30 
10. DATA COLLECTION AND QUALITY ASSURANCE .................................................. 31 
10.1 
Data Collection Forms .................................................................................................. 31 
10.2 
Data Management ......................................................................................................... 31 
10.3 
Quality Assurance ......................................................................................................... 32 
10.3.1 
Training ................................................................................................................. 32 
10.3.2 
Quality Control Committee................................................................................... 32 
10.3.3 
Metrics .................................................................................................................. 32 
10.3.4 
Protocol Deviations ............................................................................................... 32 
10.3.5 
Monitoring ............................................................................................................ 32 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................... 33 
11.1 
Institutional Review Board (IRB) Review .................................................................... 33 

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11.2 
Informed Consent Forms .............................................................................................. 33 
11.3 
Participant Confidentiality ............................................................................................ 33 
11.4 
Study Discontinuation ................................................................................................... 33 
12. COMMITTEES..................................................................................................................... 34 
13. PUBLICATION OF RESEARCH FINDINGS .................................................................. 34 
14. REFERENCES ...................................................................................................................... 34 
15. SUPPLEMENTS/APPENDICES ........................................................................................ 37 
 
I.   
United States Patent – Harpagoside-enriched Extract from Harpagophytum 
 
procumbens and Processes for Producing Same 
 
 
 
 
 
II.  
Biosketches –   Study Team:  
 
 
 
 
William Folk, PhD (Principal Investigator) 
Chokkalingam Siva, MD (Co-Investigator) 
 
 
 
 
Christine Spinka, PhD (Study Biostatistician) 
   
DSMB:  
David Mehr, MD,   
Ravi Nistala, MD 
Mojgan Golzy, PhD 
 
 
III. Letter of Support from the University of Missouri Heath Sciences Clinical Research 
Center  
 
STUDY TEAM ROSTER  
 
William R. Folk, PhD (Principal Investigator) 
University of Missouri  
Biochemistry Department 
117 Schweitzer Hall 
Columbia, Missouri  65211 
573-882-4857 (phone) 
573-882-5635 (fax) 
folkw@missouri.edu 
 
Chokkalingam Siva, MD (Co-Investigator) 
University of Missouri Health Sciences Center 
Department of Medicine, Division of Rheumatology-Immunology 

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Columbia, Missouri 65211 
573-882-8095 (phone) 
SivaC@health.missouri.edu 
 
Christine Spinka, PhD Co-Investigator and Study Biostatistician 
Division of Plant Sciences 
2-42 Agriculture Building 
University of Missouri,  
Columbia Missouri 65211 
spinkac@missouri.edu 
 
PARTICIPATING STUDY SITES 
University of Missouri Health Sciences Center 
Department of Medicine, Division of Rheumatology-Immunology 
Chokkalingam Siva, MD (Co-Investigator) 
Columbia, Missouri 65211 
573-882-8095 (phone) 
SivaC@health.missouri.edu 
 
University of Missouri Health Sciences Clinical Research Center 
N508 Medical Sciences Bldg 
Dean Hainsworth, MD, Medical Director 
Columbia Missouri 65211 
Phone: 573-882-4894  
Fax: 573-884-4779 
ClinicalResearch@health.missouri.edu 
 
 
PRÉCIS  
Study Title: Study to Establish the Bioavailability and Pharmacokinetic 
Measures of H. procumbens Extract in Humans (PK Study) 
Objectives  
Primary Objective: To determine bioavailability and pharmacokinetic properties of 
harpagoside, harpagide, verbascoside, 8-p-coumarylharpagide and eicosanoids 
(product markers) after oral consumption of a daily dose of H. procumbens (i.e., 
capsules containing a total amount of extract yielding 100mg harpagoside) in patients 
with knee, hip, or hand osteoarthritis. We hypothesize that the pharmacokinetic 
properties of the H. procumbens aqueous - ethanolic extract as described in US Patent 
6,280,737 B1 (Appendix 1; Example 2), will resemble the results obtained with 
healthy subjects without osteoarthritis, as reported by Loew et al.1 
Secondary Objective: Compare the bioavailability and pharmacokinetic properties 
after dosing with an enteric coated capsule to changes found after dosing with a non-
enteric coated capsule. We hypothesize the Cmax, tmax, and AUC values for product 

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markers will be enhanced by the cellulose (enteric) coating. 
Design and Outcomes   
A one-dose design will be used to measure bioavailability and pharmacokinetic 
properties of the H. procumbens study product, which is an aqueous extract enriched 
in harpagoside from which pro-inflammatory mediators have been removed by 
precipitation with ethanol, as described in U.S. Patent 6,280,737 B1.  Dosing level for 
this study will be extract containing 100mg harpagoside, previously shown to be 
safe.2,3 Level of product markers will be measured for 24 hours following a single 
dose of H. procumbens study product, with blood collections taken at timed intervals.  
Interventions and Duration  
Dosing level for this study will be extract containing 100mg harpagoside (HP 
extract). Levels of product markers will be measured for 24 hours following a single 
dose of H. procumbens study product, with blood collections taken at timed intervals. 
Participants will be randomly assigned to receive HP extract in either enteric coated 
or non-enteric coated capsules.  
Sample Size and Population  
The study sample recruited into the study will consist of adults with knee 
osteoarthritis (n = 12 participants with complete data). Six of the participants will 
receive the HP extract in enteric coated capsules and the other six will receive the   
HP extract in non-enteric coated capsules.  
The study size was determined based on a conservative estimate of the sample size 
needed based on the exemplar research used for comparison that used 6 healthy male 
volunteers.1 We will balance both arms of the study with regards to sex (6 male and 6 
female).  
 
1. STUDY OBJECTIVES 
1.1 
Primary Objective 
 
To determine bioavailability and pharmacokinetic properties of product markers after 
oral consumption of a daily dose of H. procumbens (i.e., capsules containing a total 
amount of extract yielding 100mg harpagoside) in patients with  knee osteoarthritis. 
We hypothesize that the pharmacokinetic properties of the H. procumbens aqueous-
ethanolic extract as described in US Patent 6,280,737 B1 (example 2), will resemble 
the results obtained with healthy subjects without osteoarthritis, as reported by Loew 
et al.1 
1.2 
Secondary Objectives 
The secondary objective of the study is to compare the bioavailability and 
pharmacokinetic properties after dosing with an enteric coated capsule to changes 
found after dosing with a non-enteric coated capsule. We hypothesize the Cmax, tmax, 
and AUC values for product markers will be enhanced by the cellulose (enteric) 
encapsulation. 

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2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Musculoskeletal conditions represent a major source of pain, loss of function, and 
health care expenditure that costs Americans billions of dollars, yearly. Clinical 
research has provided evidence for safety and efficacy of the botanical dietary 
supplement Harpagophytum procumbens (H. procumbens or Devil's Claw) for many 
patients suffering from arthritis and chronic low back pain.4-10 The variability in the 
natural products, however, and lack of a well-defined biological signature necessitate 
additional exploratory studies with well-characterized products, so that subsequent 
clinical studies of appropriate methodological rigor can be conducted.8,10-17 For 
osteoarthritis (OA), there are currently no biomarkers qualified as surrogate clinical 
endpoints, and assessment of the efficacy of disease-modifying osteoarthritis drugs 
(DMOADs) in patients has provided only sparse understanding of the relationship 
between biomarkers and the effects of the medication.18-20 These shortcomings may 
be due to the complex nature of deteriorating diarthrodial joints and the symptoms 
experienced by patients. 
The study will use a well-characterized H. procumbens extract (HP extract) to assess 
the bioavailability and pharmacokinetic properties of product markers after oral 
consumption of a daily dose of H. procumbens (i.e., capsules containing a total 
amount of extract yielding 100mg harpagoside). Completion of this study will ensure 
that future clinical trials can be conducted with the methodological rigor and outcome 
measures needed to appropriately evaluate the effectiveness of this H. procumbens 
product. 
2.2 
Study Rationale 
Commercially available Devil’s Claw products may contain material from H. 
procumbens and  Harpagophytum zeyheri, and both species may vary in their pro- 
and anti-inflammatory constitutents; this has undoubtedly contributed to the lack of 
agreement between published reports of efficacy of such products.21-25 The anti-
inflammatory and analgesic properties of H. procumbens have been ascribed to 
inhibition of eicosanoid and nitric oxide (NO) biosynthesis, by altering expression 
and inhibition of cyclooxygenases (COX1, 2) and lipoxygenases (LOX) and nitric 
oxide synthase (iNOS), and to altered expression of pro- and anti-inflammatory 
cytokines and other mediators (recently reviewed).23,24 Harpagoside, 8-p-
coumarylharpagide and related metabolites have been implicated as primary anti-
inflammatory effectors.22-24,26   
For these studies, we will use botanically verified H. procumbens plant material and 
an extraction procedure comparable to WS1531 extract used in the human clinical 
trial reported by Chrubasik and colleagues27 and the in vivo and ex vivo studies 
reported by Loew et al.1 In the former study, extract WS1531 extract was compared 
with placebo in a randomized, double blind study of 197 patients with chronic 
susceptibility to back pain.  At four weeks, three pain-free patients occurred in the 
placebo group, six in the group receiving extract containing 50mg harpagoside/day, 
and ten in the group receiving extract with100mg harpagoside/day. This significant 

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dose-dependent pain relief was explored pharmacologically1 where basal and 
A23187-induced synthesis of cysteinyl-leukotrienes (Cys-LT) was determined ex vivo 
to be dependent upon the content of harpagoside and the absence of pro-inflammatory 
components, as detailed in U.S. Patent 6,280,737 B1. This effect was supported by in 
vivo analyses, in which three subjects received, in a crossover fashion, 600mg, 1200 
mg and 1800mg extract resulted in a statistically significant decrease (~58%) in Cys-
LT levels in blood at 8hrs after treatment.  
We have based our sample size on previous research published by Loew and 
colleagues1 in which six healthy adult males received a single 150mg harpagoside 
dose through consumption of 600mg Harpagophytum extract HF 8858. The Cmax 
value was reached within 1.3 hours following dosing and was calculated as 32.2 
ng/mL; the half-life of this dose level was 5.6 hours. Given our plan to compare 
pharmacokinetic parameters between participants who are dosed with enteric versus 
non-enteric coated capsules, we doubled the sample size used by Loew and 
colleagues in order to do this comparison. We will collect complete data from 12 
participants.   
The PK Study will use HP extract with a daily harpagoside dose (100mg) that is 
equivalent to the dosing used in previous clinical studies that have demonstrated 
beneficial effects and been shown to be safe.3,27 The study will provide data that can 
confirm the bioavailability and pharmacokinetic properties of harpagoside and 8-p-
coumarylharpagide following a single dose administration. Oral administration of the 
study product was selected based on previous clinical research and based on the 
administration route that would be used in clinical practice.  
Previous research indicates that risks of taking H. procumbens extracts are limited. 
Devil’s Claw supplements are widely prescribed in Europe and available in the 
United States in grocery stores, health food stores, and pharmacies.  Previous research 
using dose levels in the range of 50-100mg harpagoside daily dose has shown it to be 
at least as well tolerated as more traditional pain medication (e.g., nonsteroidal anti-
inflammatory drugs)8,9 and allergies have been rare.  
We have established screening criteria to address any possible risks by excluding 
people with conditions that might be contraindicated. We will monitor possible side 
effects and adverse events throughout study participation, and participants will be 
given a phone number to contact study staff and/or the investigators to report side 
effects or adverse events, if needed. We will follow NIH guidelines for reporting 
adverse events to the Data Safety Monitoring Board (DSMB) and IRB. Any problems 
needing medical attention will immediately be triaged by Dr. Siva and when 
appropriate, referred to the participant’s personal physician or other health care 
providers.  
Other risks of participating in the study are minimal and include providing samples 
for clinical tests, having an electrocardiogram (ECG), and the inconvenience of 
completing questionnaires. The blood draws and ECG will be done following 
standard clinical guidelines to ensure no greater risk than what is expected with 
routine medical care. Study staff will be trained and will follow GCP and HIPAA 
guidelines in order to prevent any breach of participants’ confidentiality and privacy 

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as a result of contacts with study staff. 
3. STUDY DESIGN 
Study Design - A one-dose randomized design will be used to measure bioavailability 
and pharmacokinetic properties of the H. procumbens study product, an aqueous 
extract enriched in harpagoside from which pro-inflammatory mediators have been 
removed by precipitation with ethanol, as described in U.S. Patent 6,280,737 B1 (HP 
extract).  Dosing level for this study will be extract containing 100mg harpagoside, 
previously shown to be safe.2,3 Level of product markers will be measured for 24 
hours following a single dose of HP extract, with blood collections taken at timed 
intervals.  
Primary Outcomes – pharmacokinetic metrics:  
 
Cmax (ng/mL) – first maximal concentration, 
 
tmax (h) – time to reach the Cmax, 
 
AUC (0-t) (ng/mL) – Area under the curve, and 
 
Terminal t1/2 (h) – terminal half-life.  
Study Population - Adults with knee osteoarthritis (n = 12). Equal numbers of 
participants will be randomly assigned to receive study product in either enteric or 
non-enteric coated capsules.  
Study Location - Participants will be recruited from MU Healthcare clinics that treat 
patients diagnosed with knee osteoarthritis. Participants will be treated at the 
University of Missouri Health Sciences Clinical Research Center (CRC). A letter of 
support from the Medical Director of the CRC is provided in the Appendix   
 
Duration of Enrollment Period and Follow-up – Enrollment should be completed 
within 2 months after the final protocol is approved by the NIH, IRB and FDA. Each 
person enrolled in the study will be followed throughout the PK testing session and 
for the 24 hour period following the end of the testing session blood draw schedule.  
Intervention and Administration - The study product will be packaged in either 
enteric or non-enteric capsules by Sonja Grinfeld, Pharm D, (MU-IDS Pharmacist). 
Participants will be randomly assigned to receive HP extract in either capsule type. At 
the PK testing session, all participants will receive capsules to deliver an oral dose of 
HP extract which provides 100mg of harpagoside.  
Randomization, Blinding, and Stratification – Participants will be randomized to 
receive HP extract in either enteric coated or non-enteric coated capsules. Assignment 
to study group will be conducted double-blind. A pilot study indicated participants 
will not be able to distinguish between enteric and non-enteric capsules. 
Other Protocol Specific Details - Analysis of all serum and urine samples will be 
processed using standard protocols following good clinical practices. Samples to 
measure study product markers will be processed at the University of Missouri (MU) 
and will be supervised by Dr. Folk (PI). Samples to measure safety endpoints 

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(complete blood count [CBC], basic metabolic panel [BMP], and liver function test 
[LFT]) will be processed by CLIA certified laboratories. 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
To be eligible to participate, patients must meet all of the following inclusion criteria:  
- 
adult (at least 18 years of age);  
- 
diagnosed with knee osteoarthritis (OA);  
- 
body mass index (BMI) of less than 40;  
- 
willing to use only the H. procumbens (Devil’s Claw) study product (HP extract) 
during study participation; 
- 
able to use tramadol or Tylenol as a rescue pain medication during participation in 
the study; 
- 
willing and able to monitor blood glucose levels if diabetic;  
- 
willing to abstain from caffeine-containing drinks and food before participation in 
the study; 
- 
able to read and understand English, and have the cognitive capacity to give 
consent; and, 
- 
willing to abstain from use of the following during participation in the study: 
prescription and over-the-counter non-steroidal anti-inflammatory medications, 
(e.g., aspirin, ibuprofen, Advil, Motrin, Nuprin, Naproxen, etc.); any dietary 
supplements (St. John’s Wort, etc.); and, grapefruit and/or products containing it.  
4.2 
Exclusion Criteria 
Patients who have any of the following diagnoses or conditions will be excluded from 
participating: 
- 
cardiovascular disease, previous myocardial infarction, stent, CABG, arrhythmia, 
high or low blood pressure;  
- 
recurrent stomach upset, or gastric or duodenal ulcers; 
- 
gallstones or gall bladder disease (cholelithiasis); 
- 
liver or kidney disease; high alcohol use (more than two drinks per day on a 
regular basis);   
- 
Coumadin or anti-platelet drug use; 
- 
at risk for respiratory depression, history of seizures, or taking drugs that reduce 
the seizure threshold or may increase the risk for development of serotonin 
syndrome;  
- 
pregnant or breast feeding, or intention to become pregnant during the study;  
- 
pronounced allergies, or known allergy to H. procumbens or corn starch;  
- 
have had an injection to treat OA within the past three months;  
- 
currently taking  NSAIDs, unless they are willing to stop  for a 1-week wash-out 
period;   
- 
currently on a SSRI but are poorly stabilized, or have evidence of suicidal 
ideation and/or suicide attempts in the past year; and,  

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- 
reported use during the 7 days prior to study drug administration of: prescription 
medicines, or over-the-counter medications;  non-steroidal anti-inflammatory 
medications (e.g., NSAIDs); dietary supplements; grapefruit and/or its juice 
products; or products containing St. John’s Wort. 
4.3 
Study Enrollment Procedures  
The study team will work with MU Healthcare physicians to ensure that patients 
with qualifying diagnosis of knee osteoarthritis are identified and approached about 
participating in the study. Electronic medical records for potentially eligible patients 
will be reviewed for recorded information relevant to inclusion and exclusion 
criteria. A screening log will be maintained to track the patients who have been 
screened for eligibility, approached, and scheduled for a screening session; each 
individual will be assigned a screening identification (SID) number. The screening 
log will be used to document reasons for ineligibility and to record reason for non-
participation for possibly eligible patients who decline to participate. These data will 
be collected in a manner to meet CONSORT guidelines. 
Written informed consent (approved by the IRB) will be obtained at the screening 
session The study staff will ensure that the participant is given full and adequate oral 
and written information about the nature, purpose, and possible risk and benefit of 
the study.  Participants will also be notified that they are free to discontinue from the 
study at any time. The participant will be given the opportunity to ask questions and 
allowed time to consider the information provided. The participant’s signed and 
dated informed consent will be obtained before conducting any study specific 
procedure. The investigator will store the original, signed Participant Informed 
Consent Form and a copy will be given to the participant.   
A Case Report Form (CRF) will be used to record the consenting and screening 
session procedures including determination of eligibility based on analysis and 
interpretation of laboratory, physical examination, and electrocardiogram (ECG) 
measurements. After eligibility is determined, patients will be contacted and the PK 
testing session will be scheduled.  
Randomized assignment into enteric or non-enteric capsule study group will occur at 
the beginning of the PK testing session. All study staff who have direct contact with 
study participants and/or are involved in data collection or analysis will be blinded as 
to randomization assignment. Knowledge of random assignment will remain blinded 
until all preliminary data reviews and quality checks are completed.  
The randomization procedures and assignment list will be the responsibility of Dr. 
Mojgan Golzy, Dept of Health Management and Informatics, and member of the 
DSMB. Dr. Golzy will have no direct involvement with the study participants, data 
collection, or statistical analysis of the study data. 
Product capsules (i.e., enteric and non-enteric) will be labeled with a product code 
number; Dr. Golzy will be the only person with the master list that links the product 
code number to the type of capsule.  Dr. Golzy will generate a participant list that 
identifies the product code associated with each participant identification (PID) 
number; this product/participant code match will be based on the randomization 

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process. Study staff who work with participants and study data will only know the 
match of participant and product code numbers and will not know the study product 
material encapsulation type.  
5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
The intervention to be tested in this study is oral doses of HP extract packaged in 
capsules prepared under GMP with extract containing approximately 25mg of 
harpagoside, without or with enteric coating. Comparison of enteric and non-enteric 
formulations is warranted by reports the anti-inflammatory and analgesic activity of 
HP extracts, and purified harpagoside, are sensitive to gastric acid.28-30 A dose will 
consist of sufficient capsules to achieve consumption of 100mg harpagoside daily. 
H. procumbens supplements are widely used in Europe and are widely-available in 
the United States in grocery stores, health food stores, and pharmacies.  Previous 
research using dose levels in the range of 50-100mg harpagoside daily dose has 
shown it to be at least as well tolerated as more traditional pain medication (e.g., 
nonsteroidal anti-inflammatory drugs)8,9 and allergies have been rare.  
Screening criteria address any possible risks by excluding people with conditions that 
might be contraindicated. We will monitor possible side effects and adverse events 
during the PK testing session and at each post PK testing session contact. In addition, 
participants will be given a phone number to contact study staff and/or the 
investigators to report side effects or adverse events that occur following the testing 
session. Any problems needing medical attention will immediately be triaged by Dr. 
Siva and when appropriate, referred to the participant’s personal physician or other 
health care providers. Diagnostic laboratory tests will be ordered as specified by the 
study physician.  
Potential side effects of H. procumbens supplements include mild gastrointestinal 
symptoms such as diarrhea, nausea, vomiting, abdominal pain; headaches; ringing in 
the ears; loss of appetite; and, loss of taste. It may also be related to allergic skin 
reactions, menstrual problems, and changes in blood pressure.41 These were reported 
in less than 10% of people who took it in previous research; no serious adverse events 
were reported.3 These side effects may be treated with an appropriate medication 
determined by Dr. Siva or the subject’s personal physician.  
5.2 
Handling of Study Interventions  
Aqueous-ethanolic extract of dried, milled secondary tubers of botanically verified H. 
procumbens as described in U. S. Patent 6,280,737 B131 were obtained from Parceval 
Herbal Pharmaceuticals, LLC, South Africa (Appendix II). Sufficient product for all 
planned studies have been obtained as a single batch. The product complies with the 
FDA Guidance for Industry-Botanical Drug Products and NCCIH Natural Product 
Integrity Policy, and with RSA biodiversity regulations, and has received an open 
IND by the FDA, which must be renewed upon approval of this protocol. The content 
of harpagoside has been determined by HPLC-MS to be the same as that when the 

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FDA provided the open IND. Since that time, more extensive toxicology studies in 
rats have been performed and published.43  
Encapsulated study product will be prepared at the MU-IDS Pharmacy.  Study 
product will be kept at room temperature in secure storage cabinets that are accessible 
only to authorized staff.  
The dose of study product for the PK Study will be labeled with the appropriate 
participant identification (PID) number based on a list that links product code number 
to participant identification number. At the PK testing session, participants will be 
given one daily dose of study product. Any unused study product will be stored in the 
secured project storage cabinet until the completion of study data collection.  
Study product accountability records will be maintained at the University of Missouri 
and will document:  (1) the processing of the study product and packaging it with 
appropriate product code numbers; and, (2) the labeling of study product with 
participant identification number, based on the master list that documents the 
assignment of participant identification number for each product code.  
5.3 
Concomitant Interventions  
5.3.1 Allowed Interventions 
Participants will be allowed to use tramadol or Tylenol as a rescue medication for 
pain relief during the PK study data collection period; the prescription and dosing 
recommendations for the use of tramadol will be provided to the participant by 
his/her own physician. Participants will be asked to record the dates and times when 
they took tramadol, and the dose that was taken. This information will be provided to 
study staff at the follow-up contact.  
5.3.2 Required Interventions 
There are no required interventions in addition to the single dose of study product that 
each participant will receive. 
5.3.3 Prohibited Interventions 
Participants must agree to not use the following classes of medications while on 
study: medications prescribed to treat any of the exclusionary diagnoses or 
conditions; Coumadin or anti-platelet drug treatment; non-steroidal anti-inflammatory 
drugs; changes in SSRI treatment due to change in status; prescription and over-the-
counter medications and dietary supplements; grapefruit and/or its products; and, St. 
John’s Wort.  
5.4 
Adherence Assessment  
Adherence will be documented through the CRF that will record the time of dosing. 
No additional dosing will be involved, and participants will not be responsible for any 
dosing.  

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6. STUDY PROCEDURES  
6.1 
Schedule of Evaluations 
Assessment 
Screening: 
Visit (2 – 14 
days Before 
Testing 
Session) 
PK Testing 
Session – 
Visit 1 
(Time 0) 
Follow-up 
- Visit 2 
(24 hr) 
Follow-
up: 
Phone 
Contact 
(36 hr) 
Informed Consent Form   
X 
 
 
 
Demographics 
X 
 
 
 
Medical History  
X 
 
 
 
Current Medications 
X 
X 
  
 
Vital Signs 
X 
X 
X 
 
General Physical 
Examination 
X 
 
 
 
Electrocardiogram 
(ECG) 
X 
 
X 
 
Laboratory Values (CBC, 
CMP, LFT) 
X 
 
X 
 
Randomization 
 
X 
 
 
Receive Daily Dose of 
Study Product 
 
X 
 
 
Study Product Markers  
 
X 
X 
 
Measures of Side Effects 
 
X 
X 
 
Report of Adverse 
Events 
 
X 
X 
X 
Patient Reimbursement 
$50 
$125 
$50 
 

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6.2 
Description of Evaluations  
6.2.1 Screening Evaluation 
The Screening Evaluation session to determine whether the patient is eligible to 
participate in the PK Study will occur from 2 to 14 days before the PK testing 
session. The Screening session will include the informed consent procedure and 
screening activities to ensure eligibility (described below).    
Consenting Procedure 
Prior to participants’ participation in the study, written informed consent for the 
study, including screening and study procedures, will be obtained from each 
participant. CRC project staff or Dr. Siva will ensure that the participant is given full 
and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. The participant’s signed and dated informed consent will be 
obtained before conducting any study specific procedures. The CRC will store the 
original, signed Participant Informed Consent Form and a copy will be given to the 
participant.  
Screening 
Only volunteers who consent and pass all screening assessments will be scheduled for 
a PK testing session. Study participation will begin within 14 days of the Screening 
Evaluation session. At the screening session, the individual’s SID number will be 
used to label all study data collected at the Screening session. 
Following the completion of the informed consent procedures during the Screening 
session, a brief survey will be completed before other screening procedures are 
conducted. The survey will include items to record demographic information needed 
to describe the study sample (e.g., age, gender, race and ethnicity) and items to record 
contact information (e.g., address, phone number / email address). 
The following eligibility screening evaluations will be completed.  
- 
Medical history interview – Medical history will be collected via interviews. 
Participants will be asked about all previous diagnoses, allergies, procedures, and 
treatments to verify relevant inclusion/exclusion criteria (Section 4). 
- 
Current medication use – Participants will provide a listing of all medications 
(prescription and over-the-counter) they are currently taking.. Anyone who 
reports using medications listed in Section 4.2 Exclusion Criteria will be asked to 
stop use of the product for 14 days before the PK testing session.  
- 
Vital signs – The following vital signs will be recorded to verify they are within 
normal ranges: heart rate, blood pressure, respiration rate.  
- 
General physical examination – A general physical examination will be 
conducted. 
- 
Electrocardiogram (ECG) – Standard 12-lead ECGs will be performed at the 
Screening and 24-hour follow-up sessions. The site study physician will review 

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the recording and verify that the participant has a normal ECG.  
- 
Laboratory values – Blood samples will be obtained for CBC, BMP, LFT and 
HCG (pregnancy) for baseline product marker assays. The study physician will 
review the CBC, BMP, LFT and HCG (pregnancy) results to verify eligibility.  
6.2.2 Enrollment, PK testing, and/or Randomization 
Enrollment 
Participants who are judged to be eligible to participate by the study physician 
following all screening procedures will be contacted and scheduled for the PK testing 
session. At the testing session, participants will be assigned a participant 
identification number (PID). This PID is linked to their blinded randomization 
assignment, and linked to their SID.  
PK Testing 
During the PK testing session (Visit 1) the following assessments will be obtained.  
- 
Current medication use – Participants will provide a listing of any and all 
medications (prescription and over-the-counter) they have taken since the 
Screening Session. Anyone who reports using any product listed in Section 4.2 
Exclusion Criteria will have the PK testing session rescheduled to allow for a 7-
day washout period during which they do not take any of the restricted 
medications.   
- 
Vital signs – The following vital signs will be recorded as baseline values: heart 
rate, blood pressure, respiration rate.  
- 
Study product markers – Blood samples will be obtained in order to assess 
product markers at timed intervals during the 10-hour testing session. Using an 
indwelling catheter that is inserted in the arm, two samples of blood will be 
collected at the following intervals following dosing: 0hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 
hr, 6 hr, 8 hr, 10 hr. This data collection timing schedule is based on previous 
research.1  
An exploratory examination of the presence of study product markers in urine will 
be conducted by collecting random urine samples that are timed, to the extent 
possible, to blood collection time points. Examination of study product markers in 
urine is exploratory, and will be conducted with the goal of further informing our 
understanding of the PK parameters obtained from blood samples. Samples for 
the measurement of study product markers will be analyzed under the supervision 
of Dr. Folk. 
- 
Side effects – Study staff will record occurrence of any side effects during the PK 
testing session.  
- 
Adverse Events – Any occurrence of an adverse event noted by study staff or 
reported by a participant will be recorded and categorized by system.  
Following all testing session assessments, the appointment time for the follow-up 
session will be confirmed and the participant will be paid for the testing session.  

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Randomization 
Random assignment into study group will occur upon arrival at the PK testing 
session. Participants will be assigned to one of two study groups – enteric capsules or 
non-enteric capsules.  
6.2.3 Blinding 
All study staff who have direct contact with study participants and/or are involved in 
data collection or analysis, including the PI and the study biostatistician, will be 
blinded as to randomization assignment into study group. Knowledge of random 
assignment will remain blinded until all preliminary data reviews and quality checks 
are completed. Dr. Golzy will be authorized to break the blind for the DSMB as 
needed to respond to adverse events.  
6.2.4 Follow-up Evaluations 
24 hr Evaluation 
The following measurements and procedures will be completed at the 24-hour follow-
up session.  
Visit 2 (24 hours following dosing during the PK Testing Session):  
- 
Vital signs – The following vital signs will be recorded: heart rate, blood pressure, 
respiration rate.  
- 
Electrocardiogram (ECG) – Standard 12-lead ECGs will be performed at the 24-
hour follow-up session. A study physician will review the recording and interpret 
the findings. 
- 
Laboratory values (CBC, BMP, LFT) – Blood samples will be obtained and CBC, 
BMP, and LFT assays will be assayed. Dr. Siva will review and interpret the lab 
results.  
- 
Study product markers – Blood and urine samples will be obtained in order to 
assess level of product markers.  
- 
Side effects – Study staff will record any side effects reported by the participant.  
- 
Adverse Events – Any occurrence of an adverse event reported by a participant 
will be recorded and categorized by system (i.e., cardiovascular, dermatologic, 
endocrine/metabolic, gastrointestinal, hematologic, hepatic, musculoskeletal, 
neurologic, renal, reproductive, or respiratory).  
36 hr Follow-up.  A phone contact will be made at 36 hours following the dosing 
time at the PK testing session (i.e., 24 hours following the end of the testing session). 
During this contact, information regarding any side effects or adverse events that 
were experienced since the last study visit will be collected.  
 

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7. SAFETY ASSESSMENTS  
Any occurrence of a self-reported adverse event will be recorded and categorized by 
system (i.e., cardiovascular, dermatologic, endocrine/metabolic, gastrointestinal, 
hematologic, hepatic, musculoskeletal, neurologic, renal, reproductive, or 
respiratory).  
7.1 
Specification of Safety Parameters 
Safety and potential toxicity of HP extract ingestion will be evaluated by measuring 
vital signs; capturing adverse events; and, screening for potential renal, hepatic, 
metabolic, muscle, cardiac and hematological toxicity (by measuring biochemical and 
hematological parameters and by recording electrocardiograms (ECG). Based on 
previous research and standard practice regarding monitoring the use of NSAIDs, 
CBC, BMP, and LFT assay results will be evaluated as primary safety measures. 
Examples of parameters that will be indicative of safety concerns include: a clinically 
meaningful drop in hemoglobin which could indicate GI bleeding; clinically 
meaningful changes in creatinine; and, clinically meaningful changes in liver function 
test parameters. 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
H. procumbens (Devil’s Claw) is a widely-prescribed product in Europe and is 
widely-available in the United States in grocery stores, health food stores, and 
pharmacies. Numerous reviews provide a summary of safety-related 
information.3,10,34-41 Previous research using dose levels in the range of 50-100mg 
harpagoside daily dose has shown it to be at least as well tolerated as more traditional 
pain medication (e.g., nonsteroidal anti-inflammatory drugs),8,9 and allergies have 
been rare. Potential side effects of H. procumbens (Devil’s Claw) include mild 
gastrointestinal symptoms such as diarrhea, nausea, vomiting, abdominal pain; 
headaches; ringing in the ears; loss of appetite; and, loss of taste. It may also be 
related to allergic skin reactions, menstrual problems, and changes in blood 
pressure.41  
Screening criteria address possible risks by excluding people with conditions that 
might be contraindicated. We will monitor possible side effects and adverse events 
during the testing session and at each follow-up contact, and participants will be 
given a phone number to contact study staff and/or the investigators to report side 
effects or adverse events, if needed. Any problems needing medical attention will 
immediately be triaged by Dr. Siva and when appropriate, referred to the participant’s 
personal physician or other appropriate health care providers.  
Laboratory-based safety measures and the ECG will be assessed at the screening 
session to determine eligibility and at the 24-hour follow-up session (Visit 2) to 
assess health status following dosing. Vital signs will be collected at each study visit. 
Self-reported adverse events and side effects will be recorded at the follow-up 
sessions, and participants will be instructed to contact a member of the study team at 
any time during participation to report an adverse event.  

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7.3 
Adverse Events and Serious Adverse Events  
The following definitions will be used in the study when recording adverse events 
(AE), serious adverse events (SAE), and Unanticipated Problems.  
An adverse event (AE) is any untoward medical occurrence to a subject during 
participation in the clinical study. This can include a sign, symptom, abnormal 
assessment (laboratory test value, vital signs, electrocardiogram finding, etc.), or any 
combination of these regardless of relationship to participation in the study. 
 
SAE will be defined 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. An important 
medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Unanticipated Problems are those that involve risks to participants to include, in 
general, any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document, and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and, 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
Laboratory values from CBC, BMP, and LFT assays will be examined. Any values 
that indicate a safety concern will be identified, reported to a study physician within 
48 hours of the laboratory report being received by study staff, and followed-up by a 
study physician within 48 hours of notification. Abnormal laboratory values will be 
defined as values that are outside the reference range for a laboratory.  
Participants will be given the name and phone number for study staff to report any 
adverse event that occurs. In addition, participants will be asked at the follow-up 
study session (Visit 2) and the follow-up phone contact to report any side effect or 
adverse event that might have occurred since the previous report. The timing of any 
reported adverse event will be recorded to ensure that an AE is not recorded as two 
separate events.  

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7.4 
Reporting Procedures 
Dr. Folk will review all AE/SAE related data within 24 hours of data collection. Any 
problems needing medical attention will be triaged by Dr.Siva, and when appropriate, 
referred to the patient’s personal physician or other health care providers. Dr. Folk 
and Dr. Siva will determine whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for H. procumbens.  
Dr. Folk will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after 
the last day of study participation. Unanticipated Problems will be recorded in the 
data collection system throughout the study. At each study visit/contact, the 
investigator will inquire about the occurrence of AE/SAE since the last visit. Events 
will be followed for outcome information until resolution or stabilization.   
Dr. Folk will report to the DSMB and IRB unanticipated problems using the 
following guidelines. 
• Unanticipated AE/SAE resulting in death – within 24 hours of becoming aware of 
the event.  
• Unanticipated SAE not resulting in death – within 24 hours of becoming aware of 
the event.  
• All other AE that meet the definition of an Unanticipated Problem – within 5 
business days of notification of the event.  
 
Dr. Folk will report all AE/SAE to the DSMB, IRB, FDA and NCCIH in accordance 
with requirements.  
• 7-day IND Safety Report (unexpected fatal or life-threatening AE related to HP 
extract); a copy of the report sent to the FDA will be submitted to the NCCIH 
Program Officer within 24 hours of FDA notification.  
• 15-day IND Safety Report (any other serious and unexpected AE related to HP 
extract); a copy of the report submitted to the FDA will be submitted to the 
NCCIH Program Officer within 24 hours of FDA notification.  
• 
All other AE documented during the course of the trial will be reported to NCCIH 
on an annual basis by way of inclusion in the annual report and in the annual AE 
summary which also will be provided to the FDA, IRB and the DSMB.   
7.5 
Follow-up for Adverse Events 
Dr. Folk will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after 
the last day of study participation. Events will be followed for outcome information 
until resolution or stabilization. 
7.6 
Safety Monitoring  
The DSMB will perform the following activities for the study: monitor participant 

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safety; assess study progress (including participant confidentiality, recruitment, and 
retention); and, monitor data quality and management. The DSMB members are not 
recent or active collaborators with any of the project investigators.  
8. INTERVENTION DISCONTINUATION  
HP extract will be delivered as a single dose; therefore, discontinuation of dosing is 
not relevant. All side effects and/or adverse events that occur following the single 
dosing will be recorded and tracked in order to identify a pattern of response that 
could have an impact on continued study enrollment.  
9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Issues  
The primary objective of the PK Study is to determine bioavailability and 
pharmacokinetic properties of product markers after oral consumption of a daily dose 
of H. procumbens (i.e., capsules containing a total amount of extract yielding 100mg 
harpagoside) in patients with knee, hip, or hand osteoarthritis. We hypothesize that 
the pharmacokinetic properties of the H. procumbens aqueous-ethanolic extract as 
described in US Patent 6,280,737 B1 (Appendix 1, example 2), will resemble the 
results obtained with healthy subjects without osteoarthritis, as reported by Loew et 
al.1 
Secondary Objective: Compare the bioavailability and pharmacokinetic properties 
after dosing with an enteric coated capsule to changes found after dosing with a non-
enteric coated capsule. We hypothesize the Cmax, tmax, and AUC values for product 
markers will be enhanced by the cellulose (enteric) coating. 
Outcome measures: For each of the study product markers we will examine measures 
reflecting the pharmacokinetic properties of the HP extract. Specifically, we will 
measure and evaluate Cmax, tmax, and AUC values. 
The study will be conducted using a double-blind randomized control study design. 
Participants will be randomly assigned at the PK testing session to receive either 
enteric coated or non-enteric coated capsules containing HP extract. 
9.2 
Sample Size and Randomization 
Sample size is based upon previous research published by Loew and colleagues1 in 
which six healthy adult males received a single 150mg harpagoside dose through 
consumption of 600mg Harpagophytum extract HF 8858. The Cmax value was 
reached within 1.3 hours following dosing and was calculated as 32.2 ng/mL; the 
half-life of this dose level was 5.6 hours. Given our plan to compare pharmacokinetic 
parameters between participants who are dosed with enteric versus non-enteric coated 
capsules, we doubled the sample size used by Loew and colleagues in order to do this 
comparison. We will collect complete data from 12 participants.    

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Treatment Assignment Procedures 
Group assignment will be linked to the participant identification (PID) number that 
will be assigned at the start of the PK Testing Session. Study staff responsible for the 
PK Testing Session will be given the appropriate PID number to use for the 
participant attending the Testing Session; the PID number will not indicate specifics 
of the study product assigned to the individual.  
 
All study staff who have direct contact with study participants and/or are involved in 
data collection or analysis, including the PI and the study biostatistician, will be 
blinded as to randomization assignment into study group (i.e., enteric or non-enteric 
capsules). Knowledge of random assignment will remain blinded until all preliminary 
data reviews and quality checks are completed.  
 
The randomization procedures and assignment list will be the responsibility of Dr. 
Golzy, DSMB member. She will have no direct involvement with the study 
participants, data collection, or statistical analysis of the study data. 
 
Study capsules (i.e., enteric and non-enteric capsules containing HP extract) will be 
labeled with a product code number; Dr. Golzy will develop the master list that links 
the product code number to the specifics of the capsule material.  She will send this 
list to the University of Missouri Healthcare Inpatient Pharmacy which is responsible 
for preparing the study material. Dr. Golzy will also generate a list that identifies the 
product code associated with each participant study code (PID) number; this 
product/participant study code match will be based on the randomization list. Study 
staff who prepare the dosing of product to be given to each participant will only know 
the match of participant study identification code and product code numbers and will 
not know the study product capsule type (i.e., enteric or non-enteric). Study staff who 
are working directly with study participants and study data will only know the 
participant study identification code for an individual. Dr. Golzy will be authorized to 
break the blinding process as needed to evaluate SAE and/or Unanticipated Problems.  
9.3  
Definition of Populations 
The PK Study will continue until complete data over the 24-hour period following 
dosing are collected from 12 participants. Analyses will be conducted on the data 
collected from these participants. Comparisons between values obtained from 
participants who received the dose of HP extract in the enteric coated capsules versus 
data from those who received HP extract in non-enteric coated capsules (6 in each 
group) will be compared.   
9.4 
Interim Analyses and Stopping Rules 
No interim analyses are planned for the PK Study.  
Monitoring of AE, SAE, and Unanticipated Problems will be conducted as described 
in Section 7. It is possible that enrollment in the study will be suspended based on a 
review of safety findings. Findings that might trigger a safety review include: the 
occurrence of SAE; AE or increased frequency of unexpected events.  

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9.5 
Outcomes  
9.5.1 Primary Outcomes   
Blood samples will be collected on the time schedule listed in sections 6.2.2 and 6.2.5 
above. These samples will be assayed in order to determine the following PK 
parameters for the study product markers. 
 
Cmax (ng/mL) – first maximal concentration, 
 
tmax (h) – time to reach the Cmax, 
 
AUC (0-t) (ng/mL) – Area under the curve, and 
 
Terminal t1/2 (h) – terminal half-life.  
Measures of the study product markers obtained from the random urine collections 
will also be examined and compared to the pattern of change seen from the serum 
samples. 
9.5.2 Secondary Outcomes   
There are no secondary outcomes in the PK Study. 
9.6 
Data Analyses  
Statistical analyses will be conducted to address the study objective to determine 
bioavailability and pharmacokinetic properties of product markers after oral 
consumption of a daily dose of HP extract. The analyses will follow the statistical 
method used by Loew and colleagues.1  
The maximal concentration (Cmax) and the time to reach Cmax (tmax) will be computed 
for each study product marker using the assay values obtained from the repeated 
serum collections. The area under the curve (AUC) will be calculated using the 
trapezoidal rule. The terminal half-life (t1/2) will be calculated using linear regression 
from the log-linear slope of at least three concentrations.  
In order to test the hypothesis that these values will be enhanced for those who 
received the HP extract in the enteric coated capsules, the outcome measures for the 
two groups will be compared.  
Analyses of the primary outcome measures (Cmax, tmax, AUC, and t1/2) will be 
conducted on the timed interval blood samples collected from 12 participants who 
complete the study protocol. Missing data, therefore, should not be a significant issue, 
resulting only from cases of an accident or assay problem with a specific sample. If 
there is a missing value for a specific timed interval sample for an individual, the 
missing value will be replaced in one of two ways in order to compute the primary 
outcome measures. (1) The missing value will be replaced with the average of the 
surrounding values if the missing value is a sample other than the first or last timed 
interval sample. (2) The missing value will be replaced with the immediately adjacent 
value if it is either the first timed sample or the last timed sample.    

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10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection Forms  
All data collected for each participant by trained and authorized study staff will be 
labeled with the participant’s study identification number. The association of study 
identification number and participant identity will be kept stored in secured project 
file storage that will be accessible only to authorized study personnel. Therefore, no 
identifying information will be directly associated with study data.  
Study group assignment will be blinded until after all preliminary data quality 
reviews have been conducted and any decisions on handling of missing data have 
been completed. Therefore, any interpretation of clinical data will be conducted under 
blind conditions.  
Source data will include: (a) records of clinical data results, including laboratory, 
ECG, and product marker data; and, (b) direct recording of data collected during 
study visits, including vital signs, physical examinations, reports of side effects, and 
adverse events.  
10.2 Data Management  
Study staff will work closely with Dr. Folk and Dr. Siva to coordinate study activities 
and data collection. All study-related data will be collected and will be part of the 
research study database. The project biostatistician (Dr. Spinka) and the PI (Dr. Folk) 
will be responsible for coordination and management of study data.  
Case report forms (CRF) will be used for all study visits to record data that are 
collected at the session. In addition, CRF will be used to record laboratory and ECG 
data that are part of the study data record. An electronic database of all study data will 
be created using the REDCap (Research Electronic Data Capture)42 system.  
10.3 Quality Assurance  
10.3.1 Training 
All study personnel will complete human subjects training and good clinical practices 
(GCP) training.  
10.3.2 Quality Control Committee  
The project leadership team (PIs and Co-Investigators) will comprise the study 
quality control committee. Dr. Folk will have overall responsibility for quality control 
on the study as a whole. Dr. Folk and Dr. Spinka (study biostatistician) will be 
responsible for quality control related to management of the study database, data 
management, and statistical analysis.   
10.3.3 Metrics 
The analysis of HP extract marker samples will be performed under the supervision 
of Dr. Folk. These assays will be performed following analysis protocols, and quality 
measures (e.g., coefficient of variation) will be monitored to ensure quality control.  

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10.3.4 Protocol Deviations 
Any protocol deviation that occurs will be recorded on the study visit CRF. The 
documentation will include a complete description of the deviation. Dr. Folk will 
review the deviation and will determine, in consultation with other members of the 
project leadership team as needed, how the deviation should be addressed. 
10.3.5 Monitoring 
The IRB and DSMB will review study protocols, consent forms, CRFs, and 
additional source documents.   
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
The study will be conducted with ethical oversight by the MU Health Sciences 
Institutional Review Board (IRB).  
11.2 Informed Consent Forms 
The study investigators will ensure that voluntary informed consent is provided by 
study participants indicated by signature on the informed consent document. The 
consent form includes a description of study procedures, the time involved, the right 
to withdraw at any time without penalty, procedures used to protect participant 
confidentiality, use of data, and potential benefits and risks of participating in the 
study. Consent procedures will include a verbal presentation of the information 
contained in the consent form and the opportunity for the volunteer to ask questions. 
Volunteers will indicate consent by signing the consent form; each participant will 
receive a copy of the consent form. Signed consent forms will be kept in a locked 
cabinet in the project office.  
11.3 Participant Confidentiality  
The project will use a database system that will support screening and recruitment, 
management and tracking, and data collection activities. To create a unified data 
management system, we will identify all participants with a study identification 
number. To ensure participant confidentiality, no names, social security numbers, 
hospital or clinic numbers will be included in the central study database. All computer 
files and systems will be password protected and accessible only by authorized study 
staff. Any records that contain identifying information that is needed for study 
activities (e.g., participant name and address so reminder cards for follow-up 
appointments can be sent) will be kept secured in the study locked file in the project 
office.  All study staff will complete appropriate human subjects training, and HIPAA 
training. 
11.4 Study Discontinuation  
The study may be discontinued at any time by the DSMB, the IRB, the FDA, the 
NCCIH, or the OHRP.  

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12. COMMITTEES 
The project leadership team (PI and Co-Investigators) will provide oversight and 
review of the study, including decisions regarding preparation of publications 
reporting the study. 
13. PUBLICATION OF RESEARCH FINDINGS  
Publication and presentation of the study and study results will be governed by 
procedures established by the project leadership team. Any presentation, abstract, or 
manuscript will be made available to the NCCIH at the time of submission.  
14. REFERENCES  
1. Loew D, Mollerfeld J, Schrodter A, Puttkammer S, Kaskin, M Investigations on the 
pharmacokinetic properties of Harpagophytum extracts and their effects on eicosanoid 
biosynthesis in vitro and ex vivo. Clin Pharmacol Ther. 2001; 69(5): 356-364. [PMID: 
11372004] 
 
2. Chrubasik S, Junck, H, Breitschwerdt H, Conradt C, Zappe H.  Effectiveness of 
Harpagophytum extract WS 1531 in the treatment of exacerbation of low back pain: a 
randomized, placebo controlled double blind study. Eur J of Anaesthesiology. 1999; 16(2): 118-
129. [PMID: 10101629] 
 
3. Vlachojannis J, Roufogalis BD, Chrubasik S. Systematic review on the safety of 
Harpagophytum preparations for osteoarthritic and low back pain. Phytotherapy Res. 2008; 
22(2): 149-52. [PMID: 18236448] 
 
4. Wegener, T, Lupke NP. Treatment of patients with arthrosis of hip or knee with an aqueous 
extract of Devil’s Claw (Harpagophytum procumbens DC.).  Phytother Res. 2003; 17(10): 1165-
72. [PMID: 14669250] 
 
5. Chrubasik S, Zimpfer CH, Schutt U, Ziegler R. Effectiveness of Harpagophytum procumbens 
in treatment of acute low back pain. Phytomedicine. 1996; 3(1): 1-10. [PMID: 23194854] 
 
6. Laudahn D, Walper A. Efficacy and tolerance of Harpagophytum extract LI 174 in patients 
with chronic non-radicular back pain. Phytother Res.  2001; 15(7): 621-4. [PMID: 11746846] 
 
7. Warnock M, McBean D, Suter A, Tan J, Whittaker P. Effectiveness and safety of Devil’s 
Claw tablets in patients with general rheumatic disorders. Phytotherapy Res. 2007; 21(12): 1228-
33. [PMID: 17886223] 
 
8. Chrubasik S, Model, A, Black A, Pollak, S. A randomized double blind pilot study comparing 
Doloteffin and Vioxx in the treatment of low back pain. Rheumatol. 2003; 42: 141-148. [PMID: 
12509627] 
 

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9. Chantre P, Cappelaere A, Leblan D et al. Efficacy and tolerance of Harpagophytum 
procumbens versus Diacerhein in treatment of osteoarthritis. Phytomedicine. 2000; 7: 177-83. 
[PMID: 11185727] 
 
10. Gagnier JJ, van Tulder MW, Berman B, Bombardier C. Herbal medicine for low back pain: a 
Cochrane review. Spine (Phila Pa 1976). 2007; 32(1): 82-92. [PMID: 17202897] 
 
11. Chrubasik JE, Roufogalis BD, Chrubasik S. Evidence of effectiveness of herbal 
antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain. 
Phytother Res. 2007; 21(7): 675-83. [PMID: 17444576] 
 
12. Chrubasik S, Kunzel, O, Thanner, J, Conradt C, Black A. A one year follow-up after a pilot 
study of Doloteffin for low back pain. Phytomedicine. 2005; 12(1-2): 1-9. [PMID: 15693701] 
 
13. Chrubasik S, Chrubasik C, Kunzel O, Black A. Patient perceived benefit after one year of 
treatment with Doloteffin. Phytomedicine. 2007; 14(6): 371-376. [PMID: 17521896] 
 
14. Grant L, McBean DE, Fyfe L, Warnock AM. A review of the biological and potential 
therapeutic actions of Harpagophytum procumbens. Phytother Res. 2007; 21(3): 199-209. 
[PMID: 17128436] 
 
15. van Tulder MW, Furlan AD, Gagnier JJ. Complementary and alternative therapies for low 
back pain. Best Pract & Res Clin Rheumatology. 2005; 19: 639-54. [PMID: 15949781] 
 
16. DeSilva V, El-Metwally A, Ernst E et al. Evidence for the efficacy of complementary and 
alternative medicines in the management of osteoarthritis: a systematic review. Rheumatol. 2011; 
50: 911-20. [PMID: 21169345] 
 
17. Wachtel-Galor S, Benzie IFF. Herbal medicine: an introduction to its history, usage, 
regulation, current trends, and research needs. In Benzie IFF, Wachtel-Galor S, editors. Herbal 
Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FLO): CRC Press; 2011.  
 
18. Pelletier J-P, Raynald J-P, Caron J, et al. Decrease in serum level of matrix 
metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed 
by quantitative MRI in patients with knee osteoarthritis. Ann Rheum Dis. 2010; 69(12): 2095-
2101. [PMID: 20570834] 
 
19. Van Spil WE, Degroot J, Lems WF, et al. Serum and urinary biochemical markers for knee 
and hip osteoarthritis: A systematic review applying the consensus BIPED criteria. Osteoarthritis 
Cartilage. 2010; 18(5): 605-612. [PMID: 20175979] 
 
20. Lotz M, Martel-Pelletier J, Christiansen C, et al. Value of biomarkers in osteoarthritis: 
Current status and perspectives. Ann Rheum Dis. 2013; 72(11): 1756-1763. [PMID: 23897772] 
 
21. Eich J, Schmidt M, Betti G. HPLC analysis of iridoid compounds of Harpagophytum taxa: 
Quality control of pharmaceutical drug material. Pharm Pharmacol Lett. 1998; 8: 75-78.  

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22. Abdelouahab N, Heard C. Effect of the major glycosides of Harpagophytum procumbens 
(Devil’s Claw) on epidermal cyclooxygenase-2 (COX-2) in vitro. J Nat Prod. 2008; 71(5): 746-
749. [PMID: 18412394] 
 
23. Mncwangi N, Chen W, Vermaak I, Viljoen AM, Gericke N. Devil’s Claw—A review of the 
ethnobotany, phytochemistry and biological activity of Harpagophytum procumbens. J 
Ethnopharmacol. 2012; 143(3): 755-771. [PMID: 22940241] 
 
24. Georgiev MI, Ivanovska N, Alipieva K, Dimitrova P, Verpoorte R. Harpagoside: From 
Kalahari Desert to pharmacy shelf. Phytochemistry. 2013; 92: 8 – 15. [PMID: 23642455] 
 
25. Mncwangi NP, Viljoen AM, Zhao J, Vermaak I, Chen W, Khan I. What the devil is in your 
phytomedicine? Exploring species substitution in Harpagophytum through chemometric 
modeling of 1H-NMR and UHPLC-MS datasets. Phytochemistry. 2014; 106: 104-115. [PMID: 
25041697] 
 
26. Zhang L, Feng L, Jia Q, et al. Effects of β-glucosidase hydrolyzed products of harpagide and 
harpagoside on cyclooxygenase-2 (COX-2) in vitro. Bioorg Med Chem. 2011; 19(16): 4882-
4886. [PMID: 21775152] 
 
27. Chrubasik S, Junck, H, Breitschwerdt H, Conradt C, Zappe H.  Effectiveness of 
Harpagophytum extract WS 1531 in the treatment of exacerbation of low back pain: a 
randomized, placebo controlled double blind study. Eur J of Anaesthesiology. 1999; 16(2): 118-
129. [PMID: 10101629] 
 
28. Lanhers MC, Fleurentin J, Mortier F, Vinche A, Younos C. Anti-inflammatory and analgesic 
effects of an aqueous extract of Harpagophytum procumbens. Planta Medica. 1992; 58(2); 117-
123. [PMID: 1529021] 
 
29. Soulimani R, Younos C, Mortier F. Derrieu C. The role of stomachal digestion on the 
pharmacological activity of plant extracts, using as an example extracts of Harpagophytum 
procumbens. Canadian Journal of Physiology and Pharmacology. 1994; 72(12): 1532-1536. 
[PMID: 7736345] 
 
30. Chrubasik S, Sporer F, Dillmann-Marschner R, Friedmann A, Wink M. Physicochemical 
properties of harpagoside and its in vitro release from Harpagophytum procumbens extract 
tablets. Phytomedicine. 2000; 6(6): 469-473. [PMID: 10715851] 
 
31. Stumpf KH, Jaggy HE, Oschmann, RA, Koch EG, Simmet, TO, inventors; Dr. Willmar 
Schwabe Gmbh & Co, assignee. Harpagoside-enriched extract from harpagophytum procumbens 
and processes for producing same. US Patent 6,280,737 B1. August 28, 2001.  
 
32. Goggin K, Gerkovich MM, Williams KB, et al. (2013). A randomized control trial examining 
the efficacy of motivational counseling with observed therapy for antiretroviral therapy 
adherence. AIDS and Behavior. 2013; 17: 1992-2001. [PMID: 23568228] 

Protocol Template, Version 1.0 
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33. Wilson D, Goggin K, Williams K, et al. Consumption of Sutherlandia frutescens by HIV-
seropositive South African adults: An adaptive double-blind randomized placebo controlled trial. 
PLoS ONE. 2015 July 17; 10(7): e0128522.doi:10.1371/journal.pone.0128522. 
 
34. Long L, Soeken K, Ernst E. Herbal medicines for the treatment of osteoarthritis: A 
systematic review. Rheumatology. 2001; 40: 779-793. [PMID: 11477283] 
 
35. Gagnier JJ, Chrubasik S, Manheimer E. Harpagophytum procumbens for osteoarthritis and 
low back pain: A systematic review. BMC Complementary and Alternative Medicine. 2004; 4: 
13-22. [doi: 10.1186/1472-6882-4-13] 
 
36. Brendler T, Gruenwald J, Ulbricht C, Basch E. Devil’s Claw (Harpagophytum procumbens 
DC): An evidence-based systematic review by the Natural Standard Research Collection. 
Journal of Herbal Pharmacotherapy. 2006; 6: 89-126. [doi: 10.1080/J157v06n01_09] 
 
37. Brien S, Lewith GT, McGregor G. Devil’s Claw (Harpagophytum procumbens) as a 
treatment for osteoarthritis: A review of efficacy and safety. The Journal of Alternative and 
Complementary Medicine. 2006; 12: 981-993. [doi: 10.1089/acm.2006.12.981] 
 
38. Denner SS. A review of the efficacy and safety of Devil’s Claw for pain associated with 
degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis. Holistic Nursing Practice. 
2007; 21: 203-207. [PMID: 17627199] 
 
39. Prescrire. Devil’s claw root: Ulcers and gastrointestinal bleeding? Rev Prescrire. 2013; 
33(355): 352. (translation) 
 
40. Cameron M, Gagnier JJ, Little CV, Parsons TJ, Blumle A, Chrubasik S. Evidence of 
effectiveness of herbal medicinal products in the treatment of arthritis. Part 1: Osteoarthritis. 
Phytotherapy Research. 2009; 23: 1497-1515. [doi: 10.1002/ptr.3007] 
 
41. MedlinePlus. Devil’s Claw. National Institutes of Health / U.S. National Library of 
Medicine. https://medlineplus.gov/druginfo/natural/984.html#safety. Updated March 13, 2017. 
Accessed July 17, 2017. 
 
42. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data 
capture (REDCap) – A metadata-driven methodology and workflow process for providing 
translational research informatics support. J Biomed Inform. 2009; 42: 377-81. [PMID: 
18929686] 
 
43. Joshi, K., Parrish, A., Grunz-Borgmann, E.A., Gerkovich, M., Folk, W.R. (2020) Toxicology 
studies of aqueous-alcohol extracts of Harpagophytum procumbens subsp. procumbens (Burch.) 
DC.Ex Meisn. (Pedaliaceae) in female and male rats. BMC Complement Med Ther 20, 9 
doi:10.1186/s12906-019-2789-9 
 
 

 
 
 
 
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CONSENT FORM FOR PARTICIPATION IN A RESEARCH STUDY  
 
INVESTIGATOR’S NAME: WILLIAM R. FOLK, PHD 
 
 
 
 
PROJECT IRB #:  2010425 
 
STUDY TITLE: Study to Establish the Bioavailability and Pharmacokinetic 
Measures of H. procumbens Extract in Humans 
 
We invite you to take part in this research study. This consent form tells you why we are 
doing the study, what will happen if you participate in the study, and other information 
about the study. 
 
Please take as much time as you need to read this consent form. You can discuss it 
with your family, friends, or personal doctor. If there is anything you do not understand, 
please ask us to explain. Then you can decide if you want to take part in the study or 
not.  
 
The study Principal Investigator is Dr. William R. Folk, University of Missouri Professor 
of Biochemistry. The Study Physician is Dr. Chokkalingam Siva, University of Missouri 
Professor of Medicine. They and the nurses and other people working with them are the 
Study Team. 
The U.S. National Institutes of Health (also called the sponsor) is paying for this study.  
 
WHAT SHOULD I KNOW BEFORE I DECIDE WHETHER TO TAKE PART IN THIS STUDY?  
• Medical research studies help us to learn new information about means of 
treating certain conditions/diseases.  
• Taking part in this medical research study is voluntary. You decide if you want to 
take part, and you can stop taking part at any time.  

 
 
 
 
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• Your regular medical care at the University of Missouri Hospitals and Clinics will 
not be affected now or in the future if you do not participate in this study. 
• This study is being conducted to find better ways to reduce pain and 
inflammation in people with osteoarthritis. We wish to learn about a dietary 
supplement from a plant called Harpagophytum procumbens (Devil’s Claw) that 
is often used for pain and other inflammatory conditions.  
• We invite you to take part in this study because you have been diagnosed with 
knee osteoarthritis. 
• Twelve people will take part in this study at the University of Missouri Hospitals 
and Clinics. 
• If you take part in this study, you will come to the University of Missouri Clinical 
Research Center (N508 Health Sciences Center) three times. You will be asked 
questions about your medical history and have vital signs measured, a physical 
exam and electrocardiogram (ECG), and blood and urine samples will be 
collected. A telephone follow-up call will occur after the third visit. 
• If you take part in this study, you will have to stop taking anti-inflammatory pain 
medicines and dietary supplements you are taking for two weeks (fourteen days) 
before the study begins and while you are in the study. 
• The total amount of time you could be in this study is thirty six hours.  
• There is no guarantee that taking part in this study will result in any 
improvement in your condition. 
• As with any research study, there are risks that we know about and there may be 
some risks we don’t know about. We will explain these risks in this consent form. 
• We will only include you in this study if give us your permission first, by signing 
this consent form. 
 
WHY ARE WE DOING THIS STUDY? 
In this study, we want to find out how quickly components of the dietary supplement 
(Harpagophytum procumbens (Devil’s Claw) extract) appear in the blood and urine of 
patients with osteoarthritis. This study includes two groups of six individuals (twelve 

 
 
 
 
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total). One group will take capsules that release the dietary supplement into the 
stomach, and individuals in the second group will take capsules that release the dietary 
supplement after passing through the stomach. The ingredients in the dietary 
supplement that appear in the blood and urine will be determined. This information may 
be useful for treating future patients.  
 
The study has been approved by the U.S. Food and Drug Administration (FDA); but not 
enough is known about how this dietary supplement can affect people. This study will 
likely not help you or your osteoarthritis. We hope the information we get from the study 
will help develop a better treatment for osteoarthritis. 
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS STUDY? 
Screening Tests 
If you decide to participate in this study, you will have these screening tests to see if you 
are eligible and that any risks are minimized: 
• Medical Chart Review: The Study Doctor will review your medical chart to 
determine if it is safe for you to take part in the study. 
• Physical Exam: You will have a physical exam, similar to what happens during 
regular doctor visits. 
• Measurement of your heart rate and rhythm (ECG) 
• Urine Sample: We will ask you to collect a sample of urine. 
• Blood Tests: We will take about one and a half teaspoons of blood from a vein in 
your arm. 
• Pregnancy Tests: If you are a female who can become pregnant (you have had 
your first period and have not reached menopause), a urine pregnancy test will 
be conducted to make sure you are not pregnant. (Pregnant and nursing women 
cannot take part in this study, because it is not known how the dietary 
supplement might affect them or their infants.) 
 

 
 
 
 
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If the screening tests indicate that you are eligible and you agree to participate, you will 
be scheduled for two test sessions and a follow-up telephone call. If you are not eligible 
to participate or decide not to participate, the study team will reimburse you for your 
time and trouble.  
 
Study Test Sessions and Procedures 
If you have recently used, or are using any of the following: prescription and over-the-
counter non-steroidal anti-inflammatory medications, (e.g., aspirin, ibuprofen, Advil, 
Motrin, Nuprin, Naproxen, etc.); dietary supplements (St. John’s Wort, etc.); and, 
grapefruit and/or products containing it; you will be asked to discontinue their use for 14 
days before visit #2 and until after visit #3.  
 
You should not drink coffee or tea or other drinks that contain caffeine on the morning of 
visit #2 (test session) and until after the visit #3 (follow-up test session), as these might 
affect the results.  
 
Visit # 2 - Test Session 
This will require visiting the research clinic for 13 hours. You will be given lunch and 
dinner meals during this visit, and may rest in a pleasant room. You may bring reading 
materials or other quiet activities to occupy your time.  
These are the medical procedures that will occur: 
• Vital signs will be measured: heart rate, blood pressure, and breathing 
rate will be monitored and recorded at several times during the visit. 
• Study team will collect a blood sample from a catheter inserted into the 
arm. 
• You will collect a urine sample. 
• You will be given 3-4 capsules of dietary supplement to take with water. 
• Study team will collect blood samples (approximately 2.5 teaspoons each 
time) at the following times after taking the capsules: 0 min,  1 hr, , 2 hr,  3 
hr, 4 hr, 5 hr, 6 hr, , 8 hr, , 10 hr. (Approximately 21 teaspoons of blood will 
be collected during this test session. ) 
• You will collect a urine sample. 
• Study team will remove catheter from arm and record information on any 
side effects (gastrointestinal disturbance, itching, etc.) you might have 
experienced.  
 

 
 
 
 
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Visit # 3 - Follow-up Session at the research clinic the next morning: 
These are the medical procedures that will occur: 
• Vital signs (heart rate, rhythm, blood pressure, and breathing rate) will be 
monitored. 
• You will collect a urine sample. 
• Study team will collect a blood sample (2.5 teaspoon) from  the arm. 
• Study team will collect information on any possible side effects 
(gastrointestinal disturbance, itching, etc.) experienced. 
 
Phone Contact (approximately 36 hours after taking capsules during Visit #2) 
• The study team will call you to ask about any side effects or other health 
symptoms that you experienced following last visit. 
 
 
The results of the medical procedures can be made available to you and your doctor, if 
you request them.  
 
HOW LONG WILL I BE IN THE STUDY? 
If the screening tests indicate that you are eligible and you agree to participate, this 
study will take about one and a half days. After you arrive for visit #2 (test session) you 
will spend about 13 hours in the research clinic. The next morning you will return for a 
brief follow-up session (visit #3) and the study team will call you that afternoon to collect 
additional health information.  
 
CAN I STOP BEING IN THE STUDY? 
 
You can stop participating in the study at any time without giving a reason. This  
will not affect your future medical care at the University of Missouri Hospital or Clinics.  
 
The Study Doctor may decide to take you off this study at any time. You will be told why 
- these reasons may be: 
• If it is in your medical interest 
• Your health has changed 
• You are not able to follow the study rules 
• The study is stopped 

 
 
 
 
MU IRB: BIOMEDICAL CONSENT FOR FEDERALLY FUNDED  
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WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
There are certain risks to taking part in any medical research study. This dietary 
supplement may cause health problems (side effects), some of which we do not know 
about. However, from what is known about this dietary supplement, we believe risks are 
very low. This dietary supplement have been sold in the U.S.A., Europe and Africa in 
grocery stores, health food stores, pharmacies, and over the internet for many years.  
Previous medical research has shown the dietary supplement to be tolerated as well as 
pain medications such as nonsteroidal anti-inflammatory drugs. In these studies, the 
side effects that people have experienced with various preparations of the dietary 
supplement have been rare, but include:  
• Gastrointestinal (stomach) disturbances, including nausea, vomiting, stomach 
pain or diarrhea; loss of appetite or loss of taste. 
• Allergies, including itching. 
• Headaches or ringing in the ears. 
• Menstrual problems. 
• Changes in blood pressure. 
The study screening session is intended to identify anyone who might experience such  
problems, and those people will not be eligible to participate in the study.  
 
Medical procedures used in this study might also involve some risks. These include: 
• Taking blood from you may cause some discomfort from the needle stick, 
bruising, or very rarely, infection. However, the study team is experienced in such 
procedures. 
• The dietary supplement might affect an infant, before or after it is born, so 
anyone who might be pregnant or nursing an infant cannot participate in the 
study. If you are female, we will ask you to take a pregnancy test in the screening 
session to be sure you are not pregnant. 
• Participation in the study might uncover health information that you might not 
wish to learn.  

 
 
 
 
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ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
This study is not likely to help you; but it is intended to provide information about future 
treatments for osteoarthritis that can help patients.  
 
WHAT OTHER CHOICES DO I HAVE? 
You can decline to participate or stop participating in the study at any time without 
giving a reason. This will not affect your future medical care at the University of Missouri 
Hospital or Clinics.  
 
WHAT ABOUT PRIVACY AND CONFIDENTIALITY? 
The study team needs to review your health/personal information. This information 
comes from questions we ask you, forms you fill out, and your medical record. We must 
ask your permission to obtain this health/personal information. We are committed to 
respecting your privacy and to keeping your health/personal information confidential.  
 
If you agree to participate and sign this consent form, the form and any medical 
information that is obtained, including the results of tests and procedures, may also be 
entered into in your medical record.  
 
Research information that does not become part of your medical record will be stored in 
the study electronic/computer or paper files. None of these records will contain your 
name or other information that could identify you. Computer files are password 
protected on University of Missouri computers. Paper files are kept in a locked office. 
 
Certain people may see the study research information (without identifiable names or 
other information) include: 
• Those on the study team. 
• The study sponsor, the U.S. National Institutes of Health  
• Members of the University of Missouri Institutional Review Board (IRB) 

 
 
 
 
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• The study Data and Safety Monitoring Board, a group that oversees the study to 
make sure it is being done safely  
• Scientists at the U.S. Food and Drug Administration (FDA)  
 
We may present the results of this study in medical science talks and publications and 
reports, but none of these results can identify you or your participation in the study.   
 
This study is covered by a Certificate of Confidentiality from the U.S. National Institutes 
of Health. The Certificate assures that the researchers cannot disclose or use 
information, documents, or biospecimens that may identify you in any federal, state, or 
local civil, criminal, administrative, legislative, or other action, suit, or proceeding, or be 
used as evidence, for example, if there is a court subpoena, unless you have consented 
for this use.  
 
The Certificate allows use of research information by scientists of the U.S. National 
Institutes of Health needed for auditing or program evaluation or to meet the 
requirements of the U.S. Food and Drug Administration (FDA).  Such research 
information will not include anything that can identify you.  
 
The Certificate of Confidentiality does not prevent you from voluntarily releasing 
information about yourself or your involvement in this research. If you want your 
research information released to an insurer, medical care provider, or any other person 
not connected with the research, you must provide consent to the Principal Investigator. 
 
The Certificate of Confidentiality will not prevent disclosure of your health history and 
other medical information required by the study to the study team. 
 
CAN I SEE MY RESEARCH RECORDS?  
If you participate in this study, you will be given one of two types of capsules with 
dietary supplement, without knowing which one. This is called a “blinded” study, which 
allows the researchers to compare capsules without other factors affecting the results. If 

 
 
 
 
MU IRB: BIOMEDICAL CONSENT FOR FEDERALLY FUNDED  
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you ask to see your health records during this blinded study, the study team cannot tell 
you which capsule you are getting. You would have to wait until all participants have 
completed the study.   
 
ARE THERE ANY COSTS TO BEING IN THE STUDY? 
 
The sponsor (NIH) will pay for all research tests and procedures. You and/or your health 
plan/insurance will not be billed for any visits, tests and procedures that are part of this 
study.  
Some costs to you from being in this study may include: 
• transportation 
• parking  
• childcare  
• time off work  
The study will pay you $50 for study visit #1, $125 for study visit #2 and $50 for study 
visit #3 to cover these costs. The total amount that you will receive if you complete the 
study is $225.00.  
 
If you decide to leave the study early, you will still receive a payment for each test visit 
you completed. 
 
We will need your social security number in order to pay you. A check will be sent to 
you by the University through U.S. Mail. Any payment may need to be reported as 
income on your tax return. If you are not a resident/citizen (non-resident alien) of the 
United States, you may discuss with the MU Nonresident Tax Specialist at 573-882-
5509.  
 
 
WHAT HAPPENS IF I AM INJURED DURING THE STUDY?  
It is not the policy of the University of Missouri to compensate human subjects in the event 
the study results in injury.  The University of Missouri, in fulfilling its public responsibility, 

 
 
 
 
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has provided medical, professional and general liability insurance coverage for any injury 
in the event such injury is caused by the negligence of the University of Missouri, its faculty 
and staff.   
The University of Missouri also will provide, within the limitations of the laws of the State of 
Missouri, facilities and medical attention to subjects who suffer injuries while participating 
in research studies of the University of Missouri.   
 
In the event you have suffered injury as the result of participation in this research study 
you are to contact the Risk Management Officer, at (573) 882-1181, at the Health 
Sciences Center, who can review the matter and provide further information.   
This statement is not to be construed as an admission of liability. 
 
 
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT? 
Taking part in this study is voluntary.  You do not have to take part.  Your present 
or future medical care at the University of Missouri Hospitals and Clinics will not be 
affected if you decide not to take part.   
 
If you do decide to take part, you can change your mind and drop out of the study at any 
time. This will not affect your current or future care at the University of Missouri 
Hospitals and Clinics. There is no penalty for leaving the study and you will not lose any 
benefits that you are entitled to receive. 
 
If the Study Doctor decides to take you off the study, you will be given the reason and 
the study team will help arrange for your continued care by your own doctor, if needed.  
We will tell you about any new information discovered during this study that might affect 
your health, welfare, or change your mind about taking part.  
 
The Data Safety and Monitoring Board, an independent group of experts, will review the 
data collected during this study. We will tell you about any new information discovered 

 
 
 
 
MU IRB: BIOMEDICAL CONSENT FOR FEDERALLY FUNDED  
RESEARCH, CLINICAL TRIALS, AND/OR GREATER THAN MINIMAL 
RISK RESEARCH 
(JAN 2019) 
 
 
 
11 of 14
HS IRB USE ONLY 
Approval Date:  
during this study that might affect your health, welfare, or change your mind about 
taking part.  
 
WHERE CAN I GET MORE INFORMATION ABOUT THIS STUDY? 
 
A description of this clinical trial is available on www.ClinicalTrials.gov, as required by 
U.S. law. This site will not include information that can identify you. At most, the site will 
include a summary of the results. You can search this site at any time. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
If you have more questions about this study at any time, you can call the Principal 
Investigator, Dr. William Folk at 573-882-4857 or contact by email at: 
folkw@missouri.edu. 
 
You may also contact the University of Missouri Institutional Review Board (IRB) if you: 
• Have any questions about your rights as a study participant; 
• Want to report any problems or complaints; or 
• Feel under any pressure to take part or stay in this study.  
 
The IRB is a group of people who review research studies to make sure the rights of 
participants are protected. Their phone number is 573- 882-3181.  
 
If you want to talk privately about your rights or any issues related to your participation 
in this study, you can contact University of Missouri Research Participant Advocacy by 
calling 888-280-5002 (a free call), or emailing MUResearchRPA@missouri.edu. 
 
We will give you a copy of this consent form. Please keep it where you can find it easily. 
It will help you to remember what we discussed today. 
 
SIGNATURE OF STUDY PARTICIPANT  
 

 
 
 
 
MU IRB: BIOMEDICAL CONSENT FOR FEDERALLY FUNDED  
RESEARCH, CLINICAL TRIALS, AND/OR GREATER THAN MINIMAL 
RISK RESEARCH 
(JAN 2019) 
 
 
 
12 of 14
HS IRB USE ONLY 
Approval Date:  
My initials below indicate my choice about using the de-identified data and samples 
collected from my participation in the study for future research: 
 
 
The de-identified data and samples may be stored and used for future research. 
 
 
Yes ___________  
No ____________ 
 
 
Consent to Participate in Research 
 
By signing my name below, I confirm the following: 
• I have read/had read to me this entire consent form. 
• All of my questions were answered to my satisfaction. 
• The study’s purpose, procedures, risks and possible benefits were explained to 
me. 
• I voluntarily agree to take part in this research study. I have been told that I can 
stop at any time. 
 
 
 
 
Subject’s Signature 
Date  
 
 
 
 
 
 
 
*A witness is required when a participant is competent to provide consent but is blind, or 
cannot read or write. 
 
SIGNATURE OF PERSON AUTHORIZED TO OBTAIN CONSENT*  
I have explained the purpose of the research, the study procedures (identifying those 
that are investigational), the possible risks and discomforts and potential benefits of the 
study, and have answered questions regarding the study to the best of my ability. 
 
 
 
 
Signature of Witness (if applicable)* 
Date  

 
 
 
 
MU IRB: BIOMEDICAL CONSENT FOR FEDERALLY FUNDED  
RESEARCH, CLINICAL TRIALS, AND/OR GREATER THAN MINIMAL 
RISK RESEARCH 
(JAN 2019) 
 
 
 
13 of 14
HS IRB USE ONLY 
Approval Date:  
 
 
 
 
*This signature is required for FDA regulated research and/or research that involves any 
medical procedure or surgical treatment. 
 
 
IF THE PARTICIPANT IS DECISIONALLY IMPAIRED, THE LEGALLY AUTHORIZED 
REPRESENTATIVE (LAR) SHOULD READ AND SIGN BELOW: 
 
By signing my name below, I confirm the following: 
• I have read/had read to me this entire consent form. 
• All of my questions were answered to my satisfaction. 
• The study’s purpose, procedures, risks and possible benefits were explained to 
me. 
• I voluntarily agree to this participant taking part in this research study. I have 
been told that they can stop participating at any time. 
 
 
 
 
 
Signature of legally authorized representative 
 
 
 
 
 
 
 
 
 
*A witness is required when a legally authorized representative is blind, or cannot read 
or write. 
 
 
 
 
 
Signature of Person Authorized to Obtain 
Consent 
Date  
 
 
 
 
Relationship of LAR to Participant 
Date  
 
 
 
Signature of Witness 
Date  
 
 

 
 
 
 
MU IRB: BIOMEDICAL CONSENT FOR FEDERALLY FUNDED  
RESEARCH, CLINICAL TRIALS, AND/OR GREATER THAN MINIMAL 
RISK RESEARCH 
(JAN 2019) 
 
 
 
14 of 14
HS IRB USE ONLY 
Approval Date:  
 
 
 
 
 
 
 
*This signature is required for FDA regulated research and/or research that involves any 
medical procedure or surgical treatment. 
 
 
MO Rev Stat 431.064: Experimental treatment, tests, and drugs, consent to 
administer by third party — life-threatening emergencies, consent by whom. —  
1. When an adult person, because of a medical condition, is treated by a teaching 
hospital for a medical school accredited by the American Osteopathic Association or the 
American Medical Association and such person is incapable of giving informed consent 
for an experimental treatment, test or drug, then such treatment, test or drug may 
proceed upon obtaining consent of a legal guardian, attorney-in-fact, or a family 
member in the following order of priority: 
(1) Spouse unless the patient has no spouse, or is separated, or the spouse is 
physically or mentally incapable of giving consent, or the spouse's whereabouts is 
unknown or the spouse is overseas; 
(2) Adult child; 
(3) Parent; 
(4) Brother or sister; 
(5) Relative by blood or marriage. 
 
2. Nothing in this section shall authorize such legal guardian, attorney-in-fact, or family 
member to consent to treatment in contravention to such incapacitated person's 
expressed permission regarding such treatment. 
 
 (L. 1993 H.B. 564 § 33, A.L. 2003 S.B. 431, A.L. 2006 H.B. 1601 merged with S.B. 
765) 
 
Signature of Person Authorized to Obtain 
Consent* 
Date