Conditions: Helminthic Infection
Keywords: Helminths Oxfendazole Pharmacokinetics Safety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: yes

Brief summary:
This Phase I study is an open label multiple ascending dose evaluation of the safety and PK of oxfendazole (3, 7.5, or 15 mg/kg) given orally daily to healthy adult men and nonpregnant women aged 18-45 followed by a single dose cross over trial evaluating the safety and pharmacokinetics of a single dose of oxfendazole (3 mg/kg) given following an 8 hour fast or following a high fat meal. The study duration will be approximately 12 months with each subject participation lasting approximately 6 weeks. In the multiple ascending dose evaluation, between 8 and 24 subjects will be enrolled; each dose group will be comprised of eight volunteers. To enhance safety, one sentinel subject will be dosed for five days and monitored for 7 days from the time of the first dose for predefined adverse events. If there are no predefined safety events, a second sentinel subject will be enrolled and followed for a total of 7 days. If there are no predefined safety signals identified for either of these two sentinel subjects, the remaining subjects in the group will be enrolled. After all eight subjects have completed the 10 day follow up period, an electronic safety review of the electronic data will be performed. If none of the predefined safety events have occurred DMID will approve enrollment into the second dose group (7.5 mg/kg oxfendazole daily x 5 days) and will be monitored for a total of 7 days each for predefined adverse events prior to enrolling the remaining subjects in the group. After the 10 day follow up period has been completed for group 2, an electronic safety review will be completed and if no predefined events have occurred two sequential subjects (one at a time with 7 days between each subject) will be enrolled into the third dose group (15 mg/kg oxfendazole daily x 5 days) and will be monitored for a total of 7 days each for predefined safety events prior to enrolling the remaining subjects in the group. In the food effects evaluation, 12 subjects will be enrolled into the single dose cross over group where half of the subjects will initially receive a single dose of 3 mg/kg of oxfendazole following an 8 hour fast and the other half will receive a single dose of 3 mg/kg of oxfendazole following a high fat meal. Subjects will then cross over to receive a single dose following a high fat breakfast or fasting period (water is permitted). All subjects will have received a dose of oxfendazole following both a fasting period and a meal. The primary objectives are: 1) To assess the safety of oxfendazole administered daily for five days; and 2) To assess the safety of oxfendazole administered as a single dose with or without food.

Detailed description:
This Phase I study is an open label multiple ascending dose evaluation of the safety and PK of oxfendazole (3, 7.5, or 15 mg/kg) given orally daily to healthy adult men and nonpregnant women aged 18-45 followed by a single dose cross over trial evaluating the safety and pharmacokinetics of a single dose of oxfendazole (3 mg/kg) given following an 8 hour fast or following a high fat meal. The study duration will be approximately 12 months with each subject participation lasting approximately 6 weeks. In the multiple ascending dose evaluation, between 8 and 24 subjects will be enrolled; each dose group will be comprised of eight volunteers. To enhance safety, one sentinel subject will be dosed for five days and monitored for 7 days from the time of the first dose for predefined adverse events. If there are no predefined safety events, a second sentinel subject will be enrolled and followed for a total of 7 days. If there are no predefined safety signals identified for either of these two sentinel subjects, the remaining subjects in the group will be enrolled. After all eight subjects have completed the 10 day follow up period, an electronic safety review of the electronic data will be performed. If none of the predefined safety events have occurred DMID will approve enrollment into the second dose group (7.5 mg/kg oxfendazole daily x 5 days) and will be monitored for a total of 7 days each for predefined adverse events prior to enrolling the remaining subjects in the group. After the 10 day follow up period has been completed for group 2, an electronic safety review will be completed and if no predefined events have occurred two sequential subjects (one at a time with 7 days between each subject) will be enrolled into the third dose group (15 mg/kg oxfendazole daily x 5 days) and will be monitored for a total of 7 days each for predefined safety events prior to enrolling the remaining subjects in the group. In the food effects evaluation, 12 subjects will be enrolled into the single dose cross over group where half of the subjects will initially receive a single dose of 3 mg/kg of oxfendazole following an 8 hour fast and the other half will receive a single dose of 3 mg/kg of oxfendazole following a high fat meal. Subjects will then cross over to receive a single dose following a high fat breakfast or fasting period (water is permitted). All subjects will have received a dose of oxfendazole following both a fasting period and a meal. The primary objectives are: 1) To assess the safety of oxfendazole administered daily for five days; and 2) To assess the safety of oxfendazole administered as a single dose with or without food. The secondary objectives are: 1) To define the multi-dose kinetics of oxfendazole; and 2) To determine the effect of food on the kinetics of oxfendazole.

Arms:
arm 1: 3 mg/kg orally once daily for 5 days (n = 8) arm 2: 7.5 mg/kg orally once daily for 5 days (n = 8) arm 3: 15 mg/kg orally once daily for 5 days (n = 8) arm 4: 3 mg/kg orally, one dose received following a fast (n=6) or high fat meal (n=6) on Day 1 and crossed over to opposite arm to receive drug following high fat meal or fast on Day 8

Interventions: intervention 1: Oxfendazole
Intervention descriptions: intervention 1: methyl-5 (6)-phenylsulfiyl-2-benzimidazole carbamate, is a broad spectrum benzimidazole antihelminthic. It is the sulphoxide metabolite of fenbendazole.

Protocol document:
Prot_000.pdf: 
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A Phase 1 Open Label, Multiple Ascending Dose Study of 
Oxfendazole in Healthy Adult Volunteers 
DMID Protocol Number:  16-0005 
 
DMID Funding Mechanism:  VTEU Contract Support 
Pharmaceutical Support Provided by:  Oxfendazole Development Group 
IND Sponsor:  Division of Microbiology and Infectious Diseases 
The National Institute of Allergy and Infectious Diseases 
The National Institutes of Health 
 
Principal Investigator:   Patricia Winokur, MD 
DMID Medical Officer:  Gregory Deye, MD 
DMID Medical Monitor: Soju Chang, MD 
DMID Clinical Project Manager: Effie Nomicos, RN, MSN, CCRP 
Version Number:  4.0 
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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation guideline E6:  Good Clinical Practice: Consolidated Guideline, the applicable 
regulatory requirements from US Code of Federal Regulations (CFR) (Title 45 CFR Part 46 and 
Title 21 CFR including Parts 50 and 56) concerning informed consent and Institutional Review 
Board regulations, and the NIAID Clinical Terms of Award. 
All individuals responsible for the design and conduct of this study have completed Human 
Subjects Protection Training and are qualified to be conducting this research prior to the 
enrollment of any subjects.  Curricula vitae for all investigators and subinvestigators participating 
in this trial are on file in a central facility (21 CFR 312.23 [a] [6] [iii] [b] edition). 
 


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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator: Patricia Winokur, MD 
 
Signed:  
Date: 
 
 
Name 
Title 
 
 
 


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TABLE OF CONTENTS 
Page 
Statement of Compliance 
ii 
Signature Page 
iii 
Table of Contents 
iv 
List of Abbreviations 
vii 
Protocol Summary 
ix 
1 
Key Roles 
1 
2 
Background Information and Scientific Rationale 
3 
2.1 
Background Information .......................................................................................... 3 
2.1.1 
Oxfendazole ................................................................................................ 3 
2.1.2 
Human Phase I Safety and Pharmacokinetics ............................................. 6 
2.2 
Rationale ................................................................................................................ 6 
2.3 
Potential Risks and Benefits ................................................................................... 7 
2.3.1 
Potential Risks ............................................................................................ 7 
2.3.2 
Known Potential Benefits............................................................................. 8 
3 
Objectives 
9 
3.1 
Study Objectives ..................................................................................................... 9 
3.2 
Study Outcome Measures ...................................................................................... 9 
3.2.1 
Primary endpoint: ........................................................................................ 9 
3.2.2 
Secondary endpoints: .................................................................................. 9 
4 
Study Design 
10 
4.1 
Substudies (if applicable) ...................................................................................... 12 
5 
Study Enrollment and Withdrawal 
13 
5.1 
Subject Inclusion Criteria ...................................................................................... 13 
5.2 
Subject Exclusion Criteria ..................................................................................... 14 
5.3 
Treatment Assignment Procedures ....................................................................... 16 
5.3.1 
Enrollment and Randomization Procedures .............................................. 16 
5.3.2 
Masking Procedures .................................................................................. 16 
5.4 
Withdrawal ............................................................................................................ 17 
5.4.1 
Reasons for Withdrawal and Discontinuation of Study Product 
Administration ........................................................................................... 17 
5.4.2 
Handling of Withdrawals ............................................................................ 17 
5.5 
Termination of Study ............................................................................................. 18 
6 
Study Intervention/Investigational Product 
19 
6.1 
Study Product Description .................................................................................... 19 
6.1.1 
Acquisition ................................................................................................. 19 
6.1.2 
Study product (Synanthic ® suspension) will be shipped from the DMID 
CAR to the study site upon request and approval by DMID.  
Formulation, Packaging, and Labeling....................................................... 19 
6.1.3 
Product Storage and Stability .................................................................... 19 


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6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 20 
6.3 
Modification of Study Intervention/Investigational Product for a Participant ........... 20 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 20 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 21 
6.6 
Concomitant Medications/Treatments ................................................................... 21 
7 
Study Schedule 
22 
7.1 
Screening (Day -28 to -1): Clinic Visit 00............................................................... 22 
7.2 
Enrollment/Baseline - GROUPS 1, 2 and 3 ........................................................... 24 
7.3 
Follow-up – GROUPS 1, 2 and 3 .......................................................................... 25 
7.4 
Final Study Visit 08 – Day 10 (+/- 2 days) ............................................................. 28 
7.5 
Enrollment/Baseline- GROUP 4 ............................................................................ 28 
7.6 
Follow-up – GROUP 4 .......................................................................................... 29 
7.7 
Final Study Visit 06 Day 14 (+/- 2 days) - GROUP 4 ............................................. 31 
7.8 
Early Termination Visit .......................................................................................... 31 
7.9 
Unscheduled Visit ................................................................................................. 31 
8 
Study Procedures/Evaluations 
33 
8.1 
Clinical Evaluations ............................................................................................... 33 
8.2 
Laboratory Evaluations ......................................................................................... 33 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 33 
8.2.2 
Special Assays or Procedures ................................................................... 34 
8.2.3 
Specimen Preparation, Handling, Storage, and Shipping .......................... 34 
9 
Assessment of Safety 
35 
9.1 
Specification of Safety Parameters ....................................................................... 35 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 35 
9.2.1 
Adverse Events ......................................................................................... 35 
9.2.2 
Serious Adverse Events ............................................................................ 36 
9.2.3 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ........................................................ 37 
9.3 
Reporting Procedures ........................................................................................... 37 
9.3.1 
Serious Adverse Events ............................................................................ 38 
9.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ............................................................................................................ 38 
9.3.3 
Regulatory Reporting for Studies Not Conducted Under 
DMID-Sponsored IND ............................................................................... 39 
9.3.4 
Other Adverse Events (if applicable) ......................................................... 39 
9.3.5 
Reporting of Pregnancy ............................................................................. 39 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 39 
9.5 
Halting Rules ........................................................................................................ 39 
9.5.1 
Sentinel Subject Halting Rules .................................................................. 39 
9.5.2 
Dose Escalation Halting Criteria ................................................................ 40 


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9.5.3 
Study Halting Rules ................................................................................... 40 
9.5.4 
Individual Halting Rules ............................................................................. 41 
9.6 
Safety Oversight (ISM plus SMC) ......................................................................... 41 
9.6.1 
Independent Safety Monitor (ISM) ............................................................. 42 
9.6.2 
Safety Monitoring Committee (SMC) ......................................................... 42 
10 
Clinical Monitoring 
43 
10.1 
Site Monitoring Plan .............................................................................................. 43 
11 
Statistical Considerations 
44 
11.1 
Study Hypotheses ................................................................................................. 44 
11.2 
Sample Size Considerations ................................................................................. 45 
11.3 
Planned Interim Analyses (if applicable) ............................................................... 46 
No interim analyses are planned. .......................................................................... 46 
11.3.1 Safety Review ........................................................................................... 46 
11.4 
Final Analysis Plan ............................................................................................... 46 
11.4.1 Populations for Analysis ............................................................................ 46 
11.4.2 Analysis of Demographics ......................................................................... 46 
11.4.3 Analysis of Safety ...................................................................................... 47 
11.4.4 Pharmacokinetic Analysis.......................................................................... 47 
12 
Source Documents and Access to Source Data/Documents 
49 
13 
Quality Control and Quality Assurance 
50 
14 
Ethics/Protection of Human Subjects 
51 
14.1 
Ethical Standard ................................................................................................... 51 
14.2 
Institutional Review Board .................................................................................... 51 
14.3 
Informed Consent Process ................................................................................... 51 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) ............................ 52 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 52 
14.5 
Subject Confidentiality .......................................................................................... 52 
14.6 
Study Discontinuation ........................................................................................... 52 
14.7 
Future Use of Stored Specimens .......................................................................... 52 
15 
Data Handling and Record Keeping 
53 
15.1 
Data Management Responsibilities ....................................................................... 53 
15.2 
Data Capture Methods .......................................................................................... 53 
15.3 
Types of Data ....................................................................................................... 54 
15.4 
Timing/Reports ..................................................................................................... 54 
15.5 
Study Records Retention ...................................................................................... 54 
15.6 
Protocol Deviations ............................................................................................... 54 
16 
Publication Policy 
56 
17 
Literature References 
57 
Appendix A: Schedule of Events 
58 
Appendix B: DMID Adult Toxicity Tables Non-Serious Adverse Events 
62 
Appendix C: GRADE THRESHOLDS FOR EKG 
67 
Appendix D: University of Iowa Normal Laboratory Values 
68 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC0-t 
Area Under the Curve to the Final Sample 
AUC 
Area Under the Curve to Infinity 
CBER 
Center for Biologics Evaluation and Research 
CDER 
Center for Drugs Evaluation and Research 
CFR 
Code of Federal Regulations 
CL/F 
Oral Clearance 
Cmax 
Maximum Plasma Concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Insurance Portability and Accounting Act 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
IV 
Intravenous 
λz 
Elimination Rate Constant 
LOQ 
Limits of Quantitation 
LLN 
Lower Limit of Normal 
MedDRA  
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NF 
National Formulary 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 


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NIH 
National Institutes of Health 
NOEL 
No Observed Effect Level 
OCRA 
Office of Clinical Research Affairs, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
OXF 
Oxfendazole 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SRC 
Safety Review Committee 
t1/2 
Elimination Half-life 
TBL 
Total Bilirubin 
Tmax 
Time to Cmax 
ULN 
Upper Limit of Normal 
US 
United States 
USP 
United States Pharmacopeia 
VTEU 
Vaccine Treatment and Evaluation Unit 
VZ/F 
Oral Volume of Distribution 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SUMMARY 
 
Title: 
A Phase 1, Open-Label, Multiple Ascending Dose Study of 
Oxfendazole in Healthy Adult Volunteers  
Phase: 
I 
Population: 
Up to 36 healthy males and nonpregnant females, ages 18-45, 
recruited from around Iowa City, IA 
Number of Sites: 
One site, the University of Iowa 
Study Duration: 
Approximately 12 months 
Subject Participation 
Duration: 
Approximately 6 weeks 
Description of Agent or 
Intervention: 
Two to five oral doses of an aqueous suspension of 
oxfendazole, a benzimidazole carbamate antiparasitic drug 
Objectives: 
 
Primary: 
• 
To assess the safety of oxfendazole administered daily 
for five days 
• 
To assess the safety of oxfendazole administered as a 
single dose with or without food 
Secondary: 
• 
To define the multi-dose kinetics of oxfendazole  
• 
To determine the effect of food on the kinetics of 
oxfendazole 
Description of Study 
Design: 
This Phase I study is an open label evaluation of the safety and 
pharmacokinetics of escalating oral doses of oxfendazole (3 
mg/kg, 7.5 mg/kg or 15 mg/kg) given daily for five days in 
healthy volunteers. Up to eight volunteers will be enrolled and 
receive one oral dose of 3 mg/kg given daily for 5 days.  To 
enhance safety, one sentinel subject will be enrolled and 
followed for 7 days for defined safety events.  A second sentinel 
subject will then be enrolled and followed for 7 days.  If no 


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predefined safety events are identified, the remaining six 
subjects in this group will be enrolled.  All volunteers will be 
followed for 10 days and   pharmacokinetic, safety laboratory 
and EKG studies will be performed as outlined in the study visit 
table in Appendix A.  A safety review of the electronic data will 
be completed and the DMID Medical Monitor will receive a dose 
escalation report from the Statistical and Data Coordinating 
Center (SDCC) including whether dose escalation halt criteria 
were or were not met. If no predefined safety events occur after 
all eight subjects have completed the day 10 visit, the DMID 
Medical Monitor will issue approval to proceed with enrollment 
of the second group of eight subjects will be enrolled to receive 
five days of 7.5 mg/kg of oxfendazole using the same enrollment 
plan as outlined above. If no predefined safety events are 
encountered, the third group of eight subjects will be enrolled to 
receive five days of 15 mg/kg using the same enrollment plan. A 
fourth group of 12 subjects will participate in a single dose cross 
over evaluation of the effects of food on the pharmacokinetics of 
oxfendazole.  Half of these subjects will fast for 8 hours and 
then will receive a single dose of 3 mg/kg of oxfendazole on day 
1.  The other half will receive a single dose of 3 mg/kg of 
oxfendazole following a high fat breakfast.  All 12 subjects will 
be followed for seven days and on day 8 each subject will cross 
over to receive drug following a high fat breakfast or following an 
8 hour fast and will be followed for another seven days.  
Pharmacokinetic studies will be performed for 24 hours following 
each dose of oxfendazole. 
Group 
N 
Study Dose 
Timing of Study Dosing 
1 
8 
3 mg/kg  
Days 1-5 
2 
8 
7.5 mg/kg 
Days 1-5 
3 
8 
15 mg/kg 
Days 1-5 
4 
12 
3 mg/kg  
Days 1 and 8 
Dose received following a fast (n=6) or high fat 
meal (n=6) on Day 1 and crossed over to opposite 
arm to receive drug following high fat meal or fast 
on Day 8 
Estimated Time to 
Complete Enrollment: 
12 months 


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*Schematic of Study Design:  
 
 
Consent and perform screening 
activities (Total  n= 24)
Enroll 1 subject (3 mg/kg daily x 5 days)
Follow for 7 days for PK and safety
Enroll 1 subject (3 mg/kg daily x 5 days)
Follow for 7 days for PK and safety
If no safety signals, enroll 6 subjects        
(3 mg/kg daily x 5 days)
Follow for 10 days for PK and safety
 Safety review for entire group (n=8)
Screen and enroll group 2 using same 
strategy as above
(7.5 mg/kg daily x 5 days)
 Safety review for entire group (n=8)
Screen and enroll group 3 using same 
strategy as above
(15 mg/kg daily x 5 days)
Safety Monitoring Committee Review for 
Groups 1, 2 and 3 (n=24)
Day 1
n=6 to receive 3 mg/kg 
following a fast
n=6 to receive 3 mg/kg 
following a high fat breakfast
Follow for 7 days for PK and Safety
Day 8
n=6 to cross over to receive 
3 mg/kg following a high fat 
breakfast
n=6 to cross over to receive 
3 mg/kg following a fast
Follow for 7 days for PK and Safety
Consent and perform screening 
activities (Total  n= 12)
Multiple Dose Ascending 
Evaluation
Food Effects Evaluation


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1 
KEY ROLES 
Refer to ICH E6, Section 6.1 
(http://www.fda.gov/downloads/Drugs/Guidance/ucm073122.pdf) 
For questions regarding this protocol, contact <<insert name of appropriate DMID staff>> at 
<<NIAID/DMID (insert contact information)>>. 
 
Principal Investigator  
Patricia Winokur, MD 
University of Iowa  
University of Iowa Hospitals and Clinics 
200 Hawkins Drive 
Iowa City, IA  52242 
Phone: 319-384-1735 
Fax: 319-335-8318 
E-mail: patricia-winokur@uiowa.edu 
 
DMID Medical Monitor  
Soju Chang, MD 
Office of Clinical Research Affairs (OCRA) 
DMID/ NIAID/ NIH 
5601 Fishers Lane, 7E59 
Bethesda,  MD   20852 
Phone: 240-292-4178 
E-Mail: changsoju@niaid.nih.gov 
 
DMID Scientific Lead 
Greg Deye, MD 
CAPT, USPHS 
Medical Officer  
DMID/NIAID/NIH/PIPB 
5601 Fishers Lane, 8A39 
Bethesda,  MD   20852 
Phone:      240-292-4199 
E-Mail: gregory.deye@nih.gov 
 
DMID Clinical Project 
Manager  
Effie Nomicos, RN, MSN, CCRP 
Clinical Project Manager 
NIH/NIAID/DMID/PIPB 
5601 Fisher’s Lane, Room 8A35 
Bethesda, MD  20892 
Tel. 240-627-3329 
Email:  enomicos@niaid.nih.gov 
 


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Regulatory Affairs 
Specialist: 
Blossom T. Smith, MS 
Office of Regulatory Affairs (HNM5G) 
National Institute of Allergy & Infectious Diseases 
National Institutes of Health 
BG 5601FL RM 7F45 
Mail Stop 9826 
5601 Fishers Lane 
Bethesda, MD 20852 
Tel: 240-627-3376 
E-mail:  blossom.smith@nih.gov 
 
Statistical and Data 
Management Center 
The Emmes Corporation 
401 N. Washington St., Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161 
Fax: 301-251-1355 
 
Institutions: 
University of Iowa  
 
 
 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
The three major soil transmitted helminthes, Ascaris lumbricoides (roundworm), Necator 
americanus/Ancylostoma duodenale (hookworms) and Trichuris trichiura (whipworm) are 
among the most prevalent parasites worldwide.  They are highly prevalent in developing 
countries that suffer from poverty and poor sanitation.  It is estimated that these three helminths 
have an overall prevalence of one billion cases worldwide.  Nearly half of these cases result in 
significant morbidity especially affecting young children (1).   Current control measures require 
the periodic administration of one of the four antihelminthics: mebendazole, albendazole, 
levamisole or pyrantel.  Of these drugs, the benzimidazoles (mebendazole and albendazole) are 
the most frequently used antihelminthics.  However, these drugs show varying efficacy against 
the array of human helminths.  Single oral doses of these compounds are highly effective 
against Ascaris lumbricoides, but have significantly less efficacy for hookworms and Trichuris 
trichiura (2). 
 
Oxfendazole (OXF) is a potent, broad-spectrum antihelminthic drug that is approved and 
marketed for veterinary use.  Oxfendazole is currently marketed for use against lungworms and 
enteric helminths in beef livestock. In humans, current benzimidazoles include albendazole and 
mebendazole.  Though all of the benzimidazoles show chemical similarities, the compound 
oxfendazole reaches peak blood levels more slowly following absorption from the intestinal tract 
than many other benzimidazoles, thereby maintaining effective concentrations for a longer time 
in both the serum and intestinal tract.  This prolonged half-life is attractive for pursuing single 
dose therapy for certain helminths including uncomplicated cysticercosis. However, even with 
this more prolonged half-life it is likely that extended therapy will likely be required for the soil 
transmitted helminthes such as Trichuris trichiura and hookworm infections.  Given the 
potentially favorable pharmacokinetics, oxfendazole is an attractive compound for transition to 
human use and animal and human studies outlined below have begun to define the safety and 
pharmacokinetic parameters of this compound.   
2.1.1 Oxfendazole 
2.1.1.1 
Structure and Formulation 
Oxfendazole, or [5-(phenylsulphinyl)-1H-benzimidazole-
2-yl]carbamic acid methyl ester (Synanthic®), was first 
identified in the laboratories of Syntex Research, Palo 
Alto, California, and shown to have anthelminthic 
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gastrointestinal cestodes and nematodes in various animal species (3). The structure consists 
of the benzimidazole carbamate characteristic of this group of drugs, with a phenylsulphinyl 
substituent in position 5 (4). Oxfendazole (Synanthic®) is formulated as an aqueous suspension 
of either 9.06% or 22.5%, manufactured by Boehringer Ingelheim Animal Health.  At the current 
time, only the 22.5% formulation is available, though production of the lower concentration may 
return in the future.    
The introduction of thiabendazole as the first benzimidazole anthelminthic in the early 1960s 
provided a significant advance in veterinary antiparasitic treatment (7). However, thiabendazole 
has a short biological half-life, due to rapid hydroxylation of the 5 (8) position of the 
benzimidazole ring and extensive urinary clearance (9). Further efforts were directed toward the 
production of compounds with a variety of substitutions in this metabolically labile position, 
leading to different pharmacological behavior, and increased potency and spectrum of 
antiparasitic activity (10). The more potent later generations of benzimidazoles include 
fenbendazole, oxfendazole, and albendazole, with efficacy against roundworms, tapeworms, 
and even parasites residing outside the gastrointestinal tract (11). Thiabendazole, mebendazole 
and albendazole are currently approved and marketed in the US for treatment of helminth 
infections in humans.  
2.1.1.2 
Mechanism of Action 
Benzimidazoles appear to have multiple molecular mechanisms of action. They interfere with 
bioenergetics in the parasite by inhibiting glucose transport and the fumarate reductase 
reaction, as well as restricting glucose uptake (11). They also alter the tubulin-microtubule 
equilibrium, by binding at the colchicine site in the tubulin dimer (12). Inhibition of tubulin 
polymerization induces disintegration of the microtubular network in parasites (13).  
2.1.1.3 
Prediction of Human No Effect Dose from Chronic Toxicology 
and Carcinogenicity Studies 
No effect dose in chronic preclinical toxicology studies 
Oxfendazole has been evaluated in numerous safety and toxicology studies in ruminants as well 
as in more traditional preclinical species.  The results of the most important chronic toxicology 
studies, with doses adjusted for surface area, are summarized and projected to human doses 
below. 
 
Table 1.  Calculated no effect dose in humans based on outcomes from preclinical 
toxicology studies 
Species 
Study 
No Effect Dose 
Preclinical toxicology studies 
Calculated 
adult 
human 
equivalent 
mg/kg/day 
Syntex 
study 
number(21) mg/kg/day mg/m2/day 


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Species 
Study 
No Effect Dose 
Mouse 
18 mo 
carcinogenicity 
66-M-84 
150 
375 
9.91 
 
 
 
 
 
 
Rat 
1 yr chronic toxicity 
101-R-74 
0.7 
4.73 
0.13 
2 yr carcinogenicity 
53-R-83 
0.7 
4.73 
0.13 
Dog 
1 yr chronic toxicity 
18-D-84 
13.5 
265 
7.00 
Rat 
14 d sub-acute 
toxicity 
xxx 
5 
 
0.8 
Mouse 
Single dose 
xxx 
6400 
 
512 
Rat 
Single dose 
xxx 
3200 
 
512 
Dog 
Single dose 
 
1600 
 
864 
 
2.1.1.4 
Animal Safety  
The potential cardiovascular or toxicity effects of oxfendazole (OXF) were investigated after 
drug administration to beagle dogs (14).  Following administration of single oral doses of 
oxfendazole at 0, 5, 25 or 100 mg/kg, no changes in body weight, body temperature, clinical 
laboratory evaluations (hematology, serum chemistry, and coagulation studies), changes in vital 
signs (blood pressure, heart rate) or changes in electrocardiogram evaluations were noted. 
A two week toxicology study of oxfendazole administered orally to rats at doses from 0-200 
mg/kg, was recently performed (15).  There were no changes in feeding, behavior or 
physiological measurements (15).  Animals in the highest dose groups were euthanized on day 
8 because of severe toxicity and mortality.  Females had a higher incidence of mortality and 
more severe adverse effects than did males administered the same dose; correspondingly 
higher OXF exposure was found in females than in males. At the higher doses, WBC depletion 
was dose related, being severe in females at the highest dose.  WBC recovered when OXF 
administration was suspended. Target organs of toxicity were bone marrow, epididymis, liver, 
spleen, testis and thymus.  Hepatic midzonal fatty change was present in male and female rats 
administered the higher doses; these changes were still present after a 14-day recovery period. 
However, no effects on liver enzymes were seen in the clinical chemistry results, suggesting 
that these effects did not result in overt hepatotoxicity or compromised hepatic function; 
therefore, the toxicologic significance of this observation is unclear. 
Several toxicology studies were performed at the time of Synanthic® approval.  In single dose 
toxicology studies in mice, rats and dogs.  One rat that received a dose of 6400 mg/kg, orally 
died from enteropathy.  In subchronic toxicology studies in which rats and dogs were dosed 
over a two week period at doses ranging from 11-200 mg/kg, orally, decreases in neutrophil 
count, hemoglobin and hematocrit were seen at the higher doses, as were pathological changes 
in the liver (with hepatocyte vacuolation), gastroenteropathy, testes, bone marrow, liver, spleen, 
and thymus.  Toxicology studies demonstrated mild hepatotoxicity in rats fed 2.1 or 7 mg/kg 


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daily for a year (16).  Similar dog studies showed no toxicity (16).  Fetotoxicity was noted in rats 
and mice (16).  
2.1.2 Human Phase I Safety and Pharmacokinetics 
A recent dose escalation study has been performed evaluating 70 healthy adult men and 
women of non-child bearing potential who were age 18-45 (NCT02234570, DMID 12-0053, 
unpublished). Seven dose groups were studied (0.5, 1, 3, 7.5, 15, 30 and 60 mg/kg) and each 
dose group was comprised of 10 subjects of whom eight received study drug and two received 
placebo.  All subjects received a single dose of study drug or placebo and were followed for 14 
days for safety and the pharmacokinetics of oxfendazole and metabolites including 
fenbendazole and oxfendazole sulfone were evaluated in blood and urine.  There were no study 
drug associated serious adverse events identified.  Sixteen unsolicited adverse events were 
experienced by 10 subjects.  Six were considered related to the study treatment.  Five of the 
events were mild and included one subject with an increased PR interval 14 days following the 
dose of study drug, and the remaining events were gastrointestinal events (nausea, loose 
stools, intestinal gas, and diarrhea, all of which occurred in the 30 or 60 mg/kg dose groups.  
There was one event, a sore throat that was considered moderate in intensity.  Mild to moderate 
laboratory events were seen in hematology and chemistry tests.  There were no patterns 
identified related to timing of the abnormal laboratory studies or dose of oxfendazole and the 
placebo group had similar rates of abnormal laboratory values.   
The median time of maximum concentration (Tmax) occurred at 2 hours and the geometric mean 
maximum concentration (Cmax) ranged from 943.9-6768.4 ng/mL.  The exposure was non-linear, 
plateauing at 15 mg/kg.  The half-life (t 1/2) was consistent between groups and ranged from 8.5-
11 hours.  The overall fraction of drug excreted in the urine was very low and the geometric 
mean AUC0-t for the sulfone metabolite was 11.5-15% of oxfendazole AUC0-t while fenbendazole 
AUC0-t was less than 1% of oxfendazole AUC0-t for each dose group. 
2.2 
Rationale 
The first Phase 1 study outlined above demonstrated the safety of a single dose of oxfendazole 
and established the pharmacokinetic parameters for the drug.  Though single dose therapy for 
some helminths may be adequate, more resistant soil transmitted species such as Necatur 
americanus and Trichuris trichiura and even more complicated neurocysticercosis may require 
extended therapy.  The purpose of this study is to establish the safety and pharmacokinetic 
activity of multiple doses of oxfendazole.  In this study, three dose levels each given daily for 
five days will be studied in a dose escalation design.    
The other important parameter that remains unanswered is the effect of food on the absorption 
of oxfendazole.  Therefore, this study will also include an arm that includes a single dose cross 
over design in which individuals will receive drug following an 8 hour fast or following a high fat 
meal.    


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2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
 
Oxfendazole has been studied in a single human phase I trial in doses that are similar to those 
proposed in this study.  Seventy healthy adults were evaluated in a dose escalation trial where 
each individual received a single dose of oxfendazole with dosage levels ranging from 0.5 to 60 
mg/kg.  The drug was well tolerated though a few subjects experienced mild gastrointestinal 
symptoms (mild nausea and short duration diarrhea) seen on the day of dosing in the 30 mg/kg 
and 60 mg/kg dosage levels.  One individual had a grade 1 increase in the PR interval seen on 
EKG 14 days after the study drug had been administered.  Fifteen subjects reported 37 
abnormal hematology results, 27 were mild, 7 were moderate and 3 were severe.  All three 
severe results were elevated APTT levels experienced by a single subject who had the 
abnormal PTT prior to receiving study drug.  He was evaluated and found to have an acquired 
factor XI or XII deficiency that was not related to study drug.  A total of 64 abnormal 
biochemistry results were reported by 34 subjects of which 58 were mild and 6 were moderate.  
There was no association between the timing of study drug the dose of study drug, and the 
placebo group demonstrated similar rates of abnormal laboratory tests and all abnormalities 
resolved.   
 
There are approved antiparasitic agents that have chemical similarities to oxfendazole.  A single 
dose of the approved antiparasitic agent albendazole in humans is largely without side effects. 
More prolonged courses have been associated with liver abnormalities and bone marrow 
suppression. Albendazole has also been associated with headache, gastrointestinal side effects 
(abdominal pain and nausea) in less than 10 % of subjects as well as rare allergic reactions 
(rash, urticaria, Stevens-Johnson syndrome) in less than 1 %.  
 
In animal studies, lower OXF doses and shorter periods of administration similarly result in no 
observable toxicity.  At higher doses, the principal target organs are bone marrow and liver, 
WBC count rapidly recovers when OXF administration is discontinued.  
In animal studies, fetotoxicity was reported and changes in the testes were seen.  
 
Subjects will be closely monitored by history, physical examination and laboratory tests to 
assess safety and tolerability. Subjects will be carefully monitored for AEs and blood studies will 
be monitored to assess for any changes in the complete blood counts, liver and renal function 
and coagulation factors. As for any experimental drug, there may be side effects of oxfendazole 
that are not presently known. EKG studies will be performed to assess for cardiac effects. 
 
Men will be counseled to use condoms and women will be counseled to avoid pregnancy 
attempts for 4 months following drug administration. It is unknown if Oxfendazole pose any risks 
to an unborn child.  
 
There are no significant side effects from electrocardiogram (EKG) other than cosmetic 
annoyance from the glue employed to hold the leads. Venipuncture can result in pain or 
discomfort, and less likely, the possibility of bruising, or infection at the site, or fainting. Loss of 
confidential health information could occur.  


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Subjects will be asked to provide personal health information (PHI).  All attempts will be made to 
keep this PHI confidential within the limits of the law.  However, there is a chance that 
unauthorized persons will see the subjects’ PHI.  All records will be kept in a locked file cabinet 
or maintained in a locked room at the participating VTEU sites.  Electronic files will be password 
protected.  Only people who are involved in the conduct, oversight, monitoring, or auditing of 
this study will be allowed access to the PHI that is collected.  Any publications from this study 
will not use information that will identify subjects by name. Organizations that may inspect 
and/or copy research records maintained at the participating VTEU sites for quality assurance 
and data analysis include groups such as: National Institute of Allergy and Infectious Diseases 
(NIAID) and Food and Drug Administration (FDA). There may be other unknown side effects. 
2.3.2 Known Potential Benefits 
There is no known benefit to this study product.  However, oxfendazole has antiparasitic activity 
in animals and may have similar activities in humans.  There is the potential that participation in 
this study could have societal benefits as knowledge about new antiparasitic agents could help 
in the creation of new drugs for difficult to treat helminthic infections.  
 


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3 
OBJECTIVES 
3.1 
Study Objectives 
Primary: 
• 
To assess the safety of oxfendazole administered daily for five days 
• 
To assess the safety of oxfendazole administered as a single dose with or without food 
Secondary: 
• 
To define the multi-dose kinetics of oxfendazole  
• 
To determine the effect of food on the kinetics of oxfendazole 
3.2 
Study Outcome Measures 
3.2.1 
 Primary endpoint: 
 
• 
The rate of adverse events (AEs) related to oxfendazole within 10 days of 
receipt of oxfendazole given for 5 sequential, daily oral doses of either 3, 
7.5 or 15 mg/kg 
 
• 
The rate of adverse events (AEs) related to oxfendazole within 7 days of 
receipt of oxfendazole given as a single daily dose of 3 mg/kg on days 1 
and 8 either following an 8 hour fast or following a high fat meal. 
 
3.2.2 
Secondary endpoints: 
• 
Plasma Cmax, Tmax, AUC, T1/2 of oxfendazole at specified time points 
following each dose of a 5 day daily regimen of either 3, 7.5 or 15 
mg/kg 
• 
Plasma Cmax, Tmax, AUC, T1/2 of oxfendazole at specified time points 
following a single dose of oxfendazole of 3 mg/kg on days 1 and 8 
administered after an 8 hour fast or after a high fat meal.  


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4 
STUDY DESIGN 
This Phase I study is an open label multiple ascending dose evaluation of the safety and PK of 
oxfendazole (3, 7.5, or 15 mg/kg) in healthy adult men and nonpregnant women aged 18-45 
(inclusive) followed by a single dose cross over trial evaluating the safety and pharmacokinetics 
of a single dose of oxfendazole (3 mg/kg) given following an 8 hour fast or following a high fat 
meal. In the multiple ascending dose evaluation, each dose group will be comprised of eight 
volunteers.  In the food effects evaluation, evaluating the effects of food on drug absorption, 12 
subjects will be enrolled into the single dose cross over group where half of the subjects will 
initially receive a single dose of 3 mg/kg of oxfendazole following an 8 hour fast and the other 
half will receive a single dose of 3 mg/kg of oxfendazole following a high fat meal. Subjects will 
then cross over to receive a single dose following a high fat breakfast or fasting period (water is 
permitted).  All subjects will have received a single dose of oxfendazole (3 mg/kg) following both 
a fasting period and a meal.   
 
For the multiple ascending dose evaluation, each subject in the first dose group (3 mg/kg) will 
receive an oral daily dose of oxfendazole for five sequential days and will be monitored for a 
total of 10 days.  Each subject will be followed with blood, urine and EKG studies for safety and 
will provide plasma samples for oxfendazole PK studies as outlined in the study visit schedule in 
Appendix A.  To enhance safety, one sentinel subject will be dosed for five days and monitored 
for 7 days from the time of the first dose for predefined adverse events, which will include any 
drug related SAEs, any study drug-related Grade 3 AEs or laboratory abnormalities or two study 
drug-related Grade 2 AEs or laboratory abnormalities in the same laboratory parameter.  If there 
are no predefined safety events, a second sentinel subject will be enrolled and followed for a 
total of 7 days.  If there are no predefined safety signals identified for either of these two sentinel 
subjects, the remaining subjects in the group will be enrolled. 
 
After all eight subjects have completed the 10 day follow up period, an electronic safety review 
of the electronic data will be performed and the SDCC will issue a report to DMID stating that 
the predefined halting rules have or have not been met. If none of the predefined safety events 
(any study drug related SAE, any study drug related Grade 3 AE or laboratory abnormality or 
two study drug related Grade 2 AEs or laboratory abnormalities in the same laboratory 
parameter have occurred (one study drug related two sequential subjects (one at a time with 7 
days between each subject) DMID will approve enrollment into the second dose group (7.5 
mg/kg oxfendazole daily x 5 days) and will be monitored for a total of 7 days each for predefined 
adverse events prior to enrolling the remaining subjects in the group.  After the 10 day follow up 
period has been completed for group 2, an electronic safety review will be completed and if no 
predefined events have occurred two sequential subjects (one at a time with 7 days between 
each subject) will be enrolled into the third dose group (15 mg/kg oxfendazole daily x 5 days) 
and will be monitored for a total of 7 days each for predefined safety events prior to enrolling the 
remaining subjects in the group.  
 
 
For the multiple ascending dose evaluation, between 8 and 24 subjects will be enrolled. This 
number should be small enough to perform the study safely and efficiently, yet large enough for 
an estimation of the oxfendazole PK and the identification of any common side effects of 
oxfendazole following multiple doses. 


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During the screening process written informed consent will be obtained prior to any study 
activities.  A complete medical history will be obtained including review of medications, 
supplements and vitamins. Vital signs including oral temperature, blood pressure, pulse, height, 
weight and an EKG will be performed and a routine physical exam will be performed by a 
licensed clinician. Laboratory tests for hemoglobin, white blood cell count with neutrophil, 
platelet count, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
total bilirubin, random glucose, urine dipstick for protein and glucose, INR and partial 
thromboplastin time (PTT), hepatitis B surface antigen, hepatitis C antibody, and human 
immunodeficiency virus serology (HIV). Eligible subjects will be invited to join the study.  They 
will be advised to abstain from drug or alcohol use for the 48 hours prior to return on Day 1 and 
to avoid tobacco use from the day of screening through the end of the study. 
 
On study day 1, a review of the inclusion/exclusion criteria will be conducted with subjects and 
vital signs, including oral temperature, blood pressure and pulse will be obtained.  A review of 
medication history since the screening visit will be obtained and a physical exam will be 
performed by a licensed clinician.   Blood will be drawn for baseline PK and safety laboratory 
tests (hemoglobin, white blood cell count with neutrophil, platelet count, creatinine, Na, K, Cl, 
CO2, blood urea nitrogen, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
INR and PTT, total bilirubin, and urine dipstick for protein and glucose).   
Subjects will be administered oxfendazole by a study nurse or investigator on days 1, 2, 3, 4 
and 5. Subjects will be fasting (water is permitted) for eight hours prior to, and for two hours 
after, the administration of drug.  On the 1st and 5th day of drug administration intensive blood 
sampling will be performed for PK studies (pre-dose and 30 minutes, 1, 2, 3, 4, 6, 9, and 12 
hours following the dose).  On days 2, 3 and 4, blood sampling for PK studies will be performed 
prior to each dose and 2 hours after each dose. On day 6, blood sampling for PK studies will be 
performed approximately 24 hours following the dose on day 5. Monitoring will start immediately 
after dosing and will continue for 10 days.  Safety laboratories will be performed on days 1, 3, 5, 
8 and 10.  EKG studies will be performed at screening, two hours after doses on days 1, 3 and 
5, and day 8.  Subjects will be interviewed to monitor for AEs and SAEs.  Blood sampling for PK 
studies will be performed on days 8 and 10. In addition, prior to study drug administration on 
days 2-5, if subjects self-report any new signs or symptoms a targeted physical exam may be 
performed, if indicated, and the new signs or symptoms will be recorded as an AE or SAE as 
appropriate.  
 
Following blood sampling performed on each day of dosing, subjects will be allowed to return 
home.  Subjects will be counseled to avoid drug, alcohol and tobacco use through the end of the 
study (Day 10 for groups 1-3 and Day 14 for group 4).  
 
In the food effects evaluation, 12 subjects will be enrolled into the single dose cross over group. 
Group 4 can be enrolled concurrently with groups 1, 2, and 3. In group 4, half of the subjects will 
receive a single dose of 3 mg/kg of oxfendazole following an 8 hour fast and the other half will 
receive a single dose following a high fat meal.  Each subject will be followed with safety 
laboratories, EKGs and PK studies for 7 days at which time they will cross over to receive a 
single dose of oxfendazole (3mg/kg) following either a high fat meal or following an 8 hour fast.  


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Individuals will be followed for 7 days after this second dose.  During the food effects evaluation, 
each subject will receive study drug following a fast or a high fat meal.  This will allow direct 
comparison for an individual as to the effect of food on the PK parameters of the study drug.   
Individuals will have EKG studies will be performed at screening, and two hours after dosing on 
days 1 and 8. Safety laboratories will be performed on day 1, 4 and 14.  Blood sampling for PK 
studies will be performed (pre-dose and 30 minutes, 1, 2, 3, 4, 6, 9, 12 and 24 hours following 
each dose and on day 14).  
  
The study will be conducted on an outpatient basis at the University of Iowa. Screening for 
subject recruitment will continue throughout the study until the requisite number of volunteers is 
enrolled. Each subject will be evaluated over a 10-14 day period. Projected duration of subject 
participation will be 3-6 weeks of face-to-face visits, including the screening period.  It is 
anticipated that it will take 12 months to finish the study.   
 
 
4.1 
Substudies (if applicable) 
No substudies are planned 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Up to 36 males and nonpregnant females, 18-45 years old, inclusive, who are in good health 
and meet all eligibility criteria, will be enrolled at the University of Iowa. Estimated time to 
complete enrollment in this study is 12 months.   
The target population will reflect the community at large in the Iowa City area.  Volunteers will 
be sought from the University of Iowa VTEU registry of previous participants, web 
announcements and other mechanisms.  Information regarding the study may be provided to 
the subjects who have previously participated in trials conducted at the participating VTEU sites.  
Other forms and/or mechanisms of recruitment may also be used.   
The University of Iowa IRB will approve all methods of recruitment and recruitment materials 
prior to use.   
The initial responders will be screened by telephone to eliminate those who do not meet 
inclusion criteria or who have exclusion criteria. Successful candidates will be asked to come to 
the clinic to further assess their eligibility.  
Subject Inclusion and Exclusion Criteria must be assessed by a study clinician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or sub-
investigator. 
No exemptions are granted on Subject Inclusion/Exclusion Criteria in DMID- sponsored studies. 
Questions about eligibility should be directed toward the DMID Medical Officer. 
 
5.1 
 Subject Inclusion Criteria 
It is the intent of this study to enroll subjects who are considered healthy volunteers. Subjects 
with pre-existing clinically significant conditions are not considered normal, healthy volunteers. 
Inclusion criteria must be assessed by a clinician licensed to make medical diagnoses. Subjects 
must meet all of the following inclusion criteria to participate in this study:  
1. Males and nonpregnant females between the ages of 18 and 45 years, inclusive. 
 
2. Women of childbearing potential* must agree to practice adequate contraception** for the 
28-day period before Day 0 through 4 months after the last dose of study medication.  
 
* A woman is considered of childbearing potential unless surgically sterile (tubal ligation, bilateral 
oophorectomy, or hysterectomy) or post-menopausal (≥1 year). 
 
**Acceptable birth control methods include but are not limited to: abstinence from sexual intercourse 
with men; monogamous relationship with a vasectomized partner; double-barrier methods 
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1. In good health, as judged by the investigator and determined by vital signs*  
2. *Temperature < 38°C, heart rate ≤ 100 bpm and > 50 bpm, systolic blood pressure ≤ 140 
mmHg and > 89 mmHg, diastolic blood pressure ≤ 90 mmHg and ≥ 60 mm Hg, medical 
history and a targeted physical examination.  BMI ≥18 and ≤ 35.  Athletically trained 
subjects with a pulse ≥ 45 may be enrolled at the discretion of the principal investigator or 
designated licensed clinical investigator. Acceptable screening laboratories*  
 
*Hemoglobin, white blood cell (WBC) count, neutrophil, and platelet counts, INR and PTT 
within normal ranges. AST < 44 and ALT < 44 and total bilirubin, creatinine must be equal to 
or below the upper limit of normal (creatinine values below the normal range are 
acceptable). Random blood glucose must be <140. Urine dipstick testing must be negative 
for glucose and negative or trace for protein. The following serology tests must be negative: 
HIV 1/2 antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibody.  
HIV and hepatitis C viral load PCR testing may be performed for individuals suspected of 
having indeterminate antibody testing. 
3. Male participants must be willing to ensure use of condoms and spermicides for 4 months 
after the last dose of study medication.  
4. Provide written informed consent before initiation of any study procedures.  
5. Willing to be available for all study-required procedures, and visits for the duration of the 
study. 
6. Individuals must agree to abstain from drug or alcohol use for 48 hours prior to enrollment 
through day 10 or 14. 
7. Able to provide a home phone number, and the name, address, and/or email of a person 
willing to assist with making contact during the follow-up phase of the study. 
 
5.2 
Subject Exclusion Criteria 
Subjects who meet any of the exclusion criteria at Screening/Baseline will be excluded from 
study participation. Exclusion criteria must be assessed by a clinician licensed to make medical 
diagnoses. Subjects will not be able to participate if they have any of the following: 
1. Pregnant women, women who are planning to become pregnant in the next 4 months, or 
women who are breastfeeding. 
2. Body temperature ≥100.4°F (≥38.0°C) or acute illness within 3 days before administration 
of study drug (subject may be rescheduled).  
3. Chronic or acute medical disorder*  
*Disorders of the cardiac, pulmonary, liver, kidney, neurologic, gastrointestinal or other 
system, such that in the opinion of the investigator participation in the study creates 
additional risk to the subject, or to the validity of the study.  
4. Use of chronic systemic medications*   


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*Intermittent use of over the counter medications such as acetaminophen, ibuprofen, cold 
and sinus medications are permitted for enrollment (please see section 6.6 for instructions 
on medication use during the study). Topical medications, nasal steroids are permitted 
throughout the study.  Use of prescription medications used less than once per week on 
average are permitted for enrollment (see section 6.6 for instructions on medication use 
during the study).  If the subject has taken a short term prescription medication within the 
past 30 days (e.g. an antibiotic), they should be postponed from enrollment until 30 days 
have elapsed since the last dose.  
5. Has history of sensitivity to related benzimidazole compounds (e.g., albendazole, 
mebendazole). 
6. A diagnosis of schizophrenia, bipolar disease, or history of hospitalization for a psychiatric 
condition or previous suicide attempt.  
7. A history of treatment for any other psychiatric disorder in the past 3 years.*   
*Past treatment for ADHD does not exclude participants from enrollment as long as the 
medications have been discontinued for a minimum of 3 months and symptoms are well 
controlled.   
8. Received an experimental agent* within 1 month before administration of study drug or 
expect to receive an experimental agent during the 10 or 14-day study period.  
*Vaccine, drug, biologic, device, blood product, or medication. 
9. Any condition that would, in the opinion of the investigator, interfere with the study.* 
*This includes any condition that would place them at an unacceptable risk of injury, render 
them unable to meet the requirements of the protocol, or that may interfere with successful 
completion of the study.  
10. A history of heavy alcohol* or illicit drug use†, or history of substance abuse#.  
*On average, greater than 7 alcoholic drinks per week. .  
†Other than occasional marijuana use (less than once per week for the past 60 days is 
acceptable).  
#Alcohol or illicit drugs within the past 3 years.    
11.  History of chronic tobacco use in the past 60 days.*  
*A history of occasional tobacco use (less than 1 pack per week on average) is acceptable.  
Individuals will be counseled to abstain from use of tobacco and marijuana from screening 
through day 10 or 14.   
Vital signs may be performed up to three times to allow for transient conditions to resolve.  
Screening laboratory values that are abnormal, but are considered to be abnormal due to an 
acute illness or process may be repeated once. Creatinine values that fall below normal values 
specified in the DMID Toxicity Table are not considered abnormal for the purposes of this study.  
Additionally, abnormalities in the RBC parameters other than hemoglobin and abnormalities in 
the WBC differential not specified in the inclusion criteria above (e.g. low basophils or 


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eosinophils) will not be considered exclusionary for this study and will be followed with the 
standard safety laboratory follow-up outlined in the protocol.  Laboratory values that are 
performed as a standard panel by the clinical laboratory, but are not requested for the study, will 
be reviewed by a licensed study clinician and the clinician will determine whether the laboratory 
abnormality is clinically significant and should be considered exclusionary. If determined to be 
clinically insignificant, the study team is not required to follow the laboratory until resolution or 
the value is determined to be clinically stable. 
5.3 
Treatment Assignment Procedures 
 
5.3.1 
Enrollment and Randomization Procedures 
Per International Conference on Harmonisation (ICH) guideline E6: Good Clinical Practice 
(GCP), screening records will be kept at the participating site to document the reason why an 
individual was screened, but failed trial entry criteria. The reasons why individuals failed 
screening will be recorded in the SDCC’s AdvantageEDCSM (Electronic Data Capture system). 
 
Once consented, the subject will be enrolled by entry of demographic data and confirmation of 
eligibility for the trial. This is an open label study and subjects will be enrolled sequentially into 
groups 1, 2, 3 and 4 until each group has been completely enrolled.  Enrollment of subjects will 
be done online using the enrollment module of AdvantageEDCSM. AdvantageEDCSM will 
generate a treatment number for each subject after the demographic and eligibility data have 
been entered into the system.  
All participants in group 4 will receive oxfendazole in two conditions: after a high-fat breakfast 
and after fasting (separated by one week).  The order of conditions will be randomly assigned 
upon enrollment in a 1:1 ratio. The randomization code will be prepared by statisticians at the 
SDCC and included in the enrollment module for the trial.  When the subject is randomized and 
enrolled, AdvantageEDCSM will generate a treatment assignment number.  
 
Instructions for use of the enrollment module are included in the AdvantageEDCSM User’s 
Guide. Manual back-up procedures and instructions are provided for use in the event that the 
site temporarily loses access to the Internet or the online enrollment system is unavailable. 
  
5.3.2 Masking Procedures 
There is no masking planned for this study. 
 


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5.4 
Withdrawal 
5.4.1 
Reasons for Withdrawal and Discontinuation of Study Product 
Administration 
 
Subjects may voluntarily withdraw their consent for study participation at any time and for any 
reason, without penalty. 
Any enrolled subject may withdraw or be withdrawn from the study for the following reasons: 
• 
Medical disease or condition, or any new clinical findings for which continued 
participation, in the opinion of the site principal investigator or appropriate sub-
investigator, would compromise the safety of the subject, or would interfere with the 
subject's successful completion of the study, or would interfere with the evaluation of 
responses. 
• 
Subject no longer meets eligibility criteria. 
• 
As deemed necessary by the site principal investigator or appropriate sub-
investigator for noncompliance or other reasons. 
• 
Subject withdrawal of consent. 
• 
Subject lost to follow-up. 
• 
Termination of the study. 
• 
New information becomes available that makes further participation unsafe. 
If a subject withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the case report forms (CRFs).  Refer to Section 7.8 for procedures 
to be followed if a subject withdraws from the study. 
 
For the multiple ascending dose groups, if the subject develops a study drug related SAE or 
grade 3 AE or laboratory abnormality during the five days of study drug administration, study 
drug will be discontinued though the subject will continue with safety monitoring through the 
completion of the study.  If the subject in the food effect study develops a study drug related 
SAE or grade 3 AE or laboratory abnormality during the seven days following the first dose of 
the study drug, they will be discontinued from receiving the second dose of study drug, though 
the subject will continue with safety monitoring through the completion of the study.   
 
5.4.2 Handling of Withdrawals 
The primary reason for withdrawal from the study will be recorded on the Study Status data 
collection form.  Subjects will be encouraged to complete the Early Termination Visit.  The Early 


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Termination Visit procedures are listed in Section 7.8.  Although subjects are free to withdraw at 
any time or may be withdrawn by the site principal investigator or appropriate sub-investigator at 
any time, subjects who receive study drug will be encouraged to remain in the study for follow-
up safety assessments and collection of venous blood samples for safety testing.  Every attempt 
will be made to follow all adverse events, including systemic reactions, serious adverse events, 
ongoing at the time of early withdrawal to resolution. 
In the case of subjects who fail to appear for a follow-up safety assessment, extensive effort 
(i.e., three documented contact attempts via phone calls, e-mails, etc., made on separate 
occasions and followed by a certified letter) will be made to locate or recall them, or at least to 
determine their health status.  These efforts will be documented in the subject’s records. 
Subjects who withdraw, or are withdrawn or terminated from the study, or are lost to follow-up 
after signing the informed consent form, randomization, and receipt of 3 or more doses of study 
drug will not be replaced.  If the subject has only received two or fewer doses of study drug prior 
to termination from the study, the subject will be replaced. If a subject vomits more than two 
doses (i.e. if vomiting occurs within 1 hour of study drug administration and the subject vomits 
on two days or more), the subject will be replaced. Additionally, if the subject vomits within 1 
hour after the receipt of the dose on day 1, the subject will be replaced.  No more than two 
subjects will be replaced in any group.  Unless prohibited by the volunteer, data and samples 
obtained prior to withdrawal will be included in study analysis. Subjects who withdraw, or are 
withdrawn or terminated from the study, or are lost to follow-up after signing the informed 
consent form and enrollment but before receipt of study product may be replaced. If a subject in 
Group 4 is lost to follow up after the first dose, the subject will be replaced. 
 
5.5 
Termination of Study  
The NIAID/DMID has the right to terminate this study at any time.  Reasons for terminating the 
study may include, but are not limited to, the following: 
• 
Incidence or severity of AEs indicating a potential health hazard 
• 
Data recording is inaccurate or incomplete 
• 
The Investigator has not been adhering to the protocol or applicable regulatory 
guidelines in conducting the study 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
Oxfendazole, methyl-5 (6)-phenylsulfiyl-2-benzimidazole carbamate, is a broad spectrum 
benzimidazole antihelminthic.  It is the sulphoxide metabolite of fenbendazole.  Oxfendazole is 
marketed for cattle in the United States as SYNANTHIC®. 
6.1.1 Acquisition 
Study product (Synanthic ® suspension) will be purchased through a commercial supplier.  
 
Upon request by DMID, the investigational product will be shipped to the following address: 
 
DMID-Clinical Agents Repository (CAR) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: (240) 477-1350 
Fax: (240) 477-1360 
Email: DMID.CAR@ThermoFisher.com 
 
 
6.1.2 Study product (Synanthic ® suspension) will be shipped from the DMID 
CAR to the study site upon request and approval by DMID.  
Formulation, Packaging, and Labeling 
Oxfendazole is formulated as a white to grey powder; insoluble in water, slightly soluble in 
acetone, chloroform, ether, and methanol. The study product will be supplied as the commercial 
veterinary product Synanthic ®, which consists of an aqueous suspension in the following 
strength: 225 mg/mL (5).   
6.1.3 Product Storage and Stability 
Oxfendazole should be stored at room temperature (20º- 25º C) though excursions between 15º 
and 30ºC for less than 24 hours are acceptable. 
 
 
 
 
 


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6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
6.2.1 Dosage 
Oxfendazole  
In Groups 1-3, subjects will receive a total of five oral doses (3 mg/kg, 7.5 mg/kg or 
15mg/kg), given daily for 5 days (Study Days 1-5). In Group 4, subjects will receive a 
total of two oral doses of 3 mg/kg, given on Study Days 1 and 8.  
6.2.2 Preparation  
The site Research Pharmacist will prepare study products for dispensing to the subject. 
Additional details regarding subsequent labeling, and procedures for dispensing or 
administration of study product will be described in the protocol-specific MOP. 
6.2.3 Administration 
All study product will be orally administered vial oral dosing syringe(s). 
6.3 
Modification of Study Intervention/Investigational Product for a 
Participant 
No modifications of study product dosing are planned at this time. 
6.4 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
 
After receipt of study products, the site Principal Investigator (PI) is responsible for distribution 
and disposition of the study product, and has ultimate responsibility for study product 
accountability.  The site PI may delegate this responsibility to the site pharmacist (or designee). 
The site pharmacist (or designee) must maintain study product records and document logs of 
receipt, accountability, and storage temperature conditions. These study product accountability 
and dispensing logs must be maintained in the study file.  Upon completion of the study and 
after the final monitoring visit, unused study product will be retained until monitored and 
released for disposition, as applicable. Final disposition of the unused study product will be 
determined by DMID and communicated by the DMID Clinical Project Manager. 
 


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6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
Oral intake of the study product by the subject will be observed by study personnel.  Subjects 
will be provided the dose in an oral dosing syringe.  Immediately following administration of the 
dosethe subject will drink 100 mL of water to assure the entire dose is ingested.  If vomiting 
occurs on the day of dosing and occurs at any time following ingestion of the study product, the 
dose for that day will not be replaced and subject will continue to be followed for safety and 
pharmacokinetic analyses.  
 
6.6 
Concomitant Medications/Treatments 
It is the goal of this study to enroll subjects who are healthy and on no chronic medications.  
Subjects will be counseled to refrain from taking prescription medications other than topical 
agents during the study period.  If a prescription is authorized by their primary care provider or 
other licensed medical provider, we will counsel them to discuss the medication with the study 
team prior to starting the medication.   One of the licensed clinical providers from the study team 
will help determine whether the prescription medication can be postponed until the study is 
completed. Additionally, subjects will be counseled to avoid all over the counter medications 
unless absolutely necessary and will be asked to consult with a study investigator prior to use of 
over the counter medications.  Subjects will be counseled to avoid acetaminophen since this 
medication can be associated with hepatotoxicity.   
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
data collection form.  Concomitant medications will include all current medications and 
medications taken within 30 days prior to signing the informed consent form through the last day 
of the study visit schedule.  Prescription and over-the-counter drugs will be included as well as 
vitamins and supplements. 
Use of new medication should prompt evaluation for the presence of a new diagnosis of chronic 
medical disease or chronic medical condition. 


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7 
STUDY SCHEDULE 
7.1 
Screening (Day -28 to -1): Clinic Visit 00 
Informed Consent.  Written informed consent will be obtained prior to any other study 
procedures.  
Assessment of Eligibility Criteria including:  
Medical History.  A complete medical history will be obtained by interview of the subjects.  
Emphasis will be placed on the absence of significant medical or psychiatric illness and the 
absence of recent illness and recent or current medication, except use of over the counter or 
prescription medications that are taken on average less than once per week. 
 
Physical Examination. 
• 
A routine physical examination that assesses general appearance and the following 
areas/systems, including skin, lymph nodes, HEENT, neck, respiratory, cardiovascular, 
pulmonary, abdomen, extremities, musculoskeletal, and neurological will be performed 
by a clinician licensed to make diagnoses.  
• 
Height, weight, vital signs including oral temperature, blood pressure, and pulse will be 
obtained. 
 
Obtain 15 mL of blood for the following studies: 
• 
Hematology: Hemoglobin, white blood cell count with neutrophil count, platelet count. 
• 
Coagulation Studies:  INR and partial thromboplastin time (PTT) 
• 
Chemistry: Creatinine, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), random glucose and total bilirubin will be used as screening tests.  
• 
Serology: Hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency 
virus (HIV). If the subject tests positive for HIV or Hepatitis, they will be referred for 
medical follow-up and counseling. 
Obtain urine sample for: 
• 
Urine analysis: Urine dipstick for protein and glucose 
• 
Urine pregnancy test: for females of childbearing potential. 
 
EKG.  Perform 12 lead electrocardiogram.  EKG will be reviewed by a cardiologist.   
 
Subjects that qualify for enrollment will be asked to agree to the following requirements prior to 
receipt of the study product: 
• 
Abstain from taking medications, recreational drugs or engaging in alcohol intake 48 
hours prior to receipt of the study product and through Day 10 or 14. 
• 
Abstain from tobacco use from the time of screening through Day 10 or 14. 
• 
Fasting (water is permitted) 8 or more hours prior to receipt of study product (except 
subjects in the fourth group who are to receive study product following a high fat meal.  


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These subjects will be provided breakfast in the Clinical Research Unit prior to receipt of 
the study product)  
• 
Counseling on avoidance of pregnancy. 


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7.2 
Enrollment/Baseline - GROUPS 1, 2 and 3 
Clinic Visit 01, Day 1   
Eligible subjects will be asked to return to the Clinical Research Unit (CRU) having fasted for 8 
or more hours. 
 
General. 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food intake 
and laboratory results obtained at the screening visit, Day 00). 
• 
Absence of medications in the past 48 hours will be confirmed. 
• 
A brief interim medical history will be taken. 
• 
A routine physical examination that assesses general appearance and the following 
areas/systems, including skin, lymph nodes, HEENT, neck, respiratory, cardiovascular, 
pulmonary, abdomen, extremities, musculoskeletal, and neurological will be performed 
by a clinician licensed to make diagnoses.  
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Perform a urine pregnancy test for female subjects of childbearing potential. 
• 
A heparin lock will be inserted, blood will be drawn (10 mL) for baseline PK ( prior to 
product administration), and (15 mL) for safety labs (hemoglobin, white blood cell count, 
including neutrophil count, platelet count, INR, partial thromboplastin time, creatinine, 
Na, K, CL, CO2, blood urea nitrogen, ALT, AST, and total bilirubin. 
• 
Collect urine for  dipstick testing for protein and glucose  
• 
Enter subject into electronic data entry system. 
    
Administration of Study Medication  
A study nurse will administer a single oral dose of oxfendazole to the subject. Escalating dose 
levels of 3, 7.5 and 15 mg/kg will be evaluated sequentially.  
• 
Subjects will remain fasting (water is permitted) for two hours after the administration of 
drug.  
• 
Lunch and dinner will be provided. Subjects will be allowed to eat snacks but will be 
asked to avoid drinking grapefruit juice and excessive (>2 cups) coffee.   
• 
10 mL of blood for oxfendazole level will be drawn predose and at 30 minutes, 1, 2, 3, 4, 
6, 9, and 12 hours (all times have a window of +/- 15 minutes except the 9 and 12 hour 
samples which have a window of +/- 30 minutes- it is critical to record the exact time of 
blood draw).  
• 
Obtain EKG 2 hr after study drug administration (+/- 20 minutes) 
• 
Assess AEs and SAEs throughout the day and prior to discharge from the CRU. 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Counseling on avoidance of pregnancy. 
• 
Ask subject to remain fasting (water is permitted) for 8 hours prior to returning to the 
clinic in the morning. 


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7.3 
Follow-up – GROUPS 1, 2 and 3 
Clinic Visit 2, Day 2   
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food 
intake). 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
Draw 10 mL of blood for oxfendazole level prior to study drug administration -
approximately 24 hours after dosing on day 1 (+/- 4 hours) 
 
Administration of Study Medication  
A study nurse will administer a single oral dose of oxfendazole to the subject. Escalating dose 
levels of 3, 7.5 and 15 mg/kg will be evaluated sequentially.  
• 
Subjects will remain fasting (water is permitted) for two hours after the administration of 
drug.  
• 
Obtain 10 mL of blood 2 hr after study drug administration (+/- 20 minutes) for 
oxfendazole level. 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Ask subject to remain fasting (water is permitted) for 8 hours prior to returning to the 
clinic in the morning. 
 
Clinic Visit 03, Day 3 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food 
intake). 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
Draw 10 mL of blood for oxfendazole levels prior to study drug administration -
approximately 24 hours after dosing on day 2 (+/- 2 hours) 
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil count, platelet count, INR, partial thromboplastin time, Na, K, Cl, CO2, blood 
urea nitrogen, creatinine, ALT, AST, and total bilirubin).  
• 
Collect urine for dipstick testing for protein and glucose.  
 
Administration of Study Medication  
A study nurse will administer a single oral dose of oxfendazole to the subject. Escalating dose 
levels of 3, 7.5 and 15 mg/kg will be evaluated sequentially.  


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• 
Subjects will remain fasting (water is permitted) for two hours after the administration of 
drug.  
• 
Obtain EKG 2 hr after study drug administration (+/- 20 minutes) 
• 
Obtain 10 mL of blood  2 hr after study drug administration (+/- 20 minutes) for 
oxfendazole levels 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Ask subject to remain fasting (water is permitted) for 8 hours prior to returning to the 
clinic in the morning. 
Clinic Visit 04, Day 4  
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food 
intake). 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
Collect 10 mL of blood for oxfendazole level approximately 24 hours following dosing on 
day 3 (+/- 2 hours). 
 
Administration of Study Medication  
A study nurse will administer a single oral dose of oxfendazole to the subject. Escalating dose 
levels of 3, 7.5 and 15 mg/kg will be evaluated sequentially.  
• 
Subjects will remain fasting (water is permitted) for two hours after the administration of 
drug.  
• 
Obtain 10 mL of blood  2 hr after study drug administration (+/- 20 minutes) for 
oxfendazole levels 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Ask subject to remain fasting (water is permitted) for 8 hours prior to returning to the 
clinic in the morning. 
 
Clinic Visit 05, Day 5: 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food 
intake). 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
A heparin lock will be inserted, blood will be drawn (10 mL) for oxfendazole levels prior 
to study drug administration -approximately 24 hours after dosing on day 4 (+/- 2 hours) 


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• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil count, platelet count, INR, partial thromboplastin time, Na, K, Cl, CO2, blood 
urea nitrogen, creatinine, ALT, AST, and total bilirubin). 
• 
Collect urine for dipstick testing for protein and glucose.  
 
 
Administration of Study Medication  
A study nurse will administer a single oral dose of oxfendazole to the subject. Escalating dose 
levels of 3, 7.5 and 15 mg/kg will be evaluated sequentially.  
• 
Subjects will remain fasting (water is permitted) for two hours after the administration of 
drug.  
• 
Lunch and dinner will be provided. Subjects will be allowed to eat snacks but will be 
asked to avoid drinking grapefruit juice and excessive (>2 cups) coffee.   
• 
10 mL of blood for oxfendazole level will be drawn predose and at 30 minutes, 1, 2, 3, 4, 
6, 9, and 12 hours (all times have a window of +/- 15 minutes except the 9 and 12 hour 
samples which have a window of +/- 30 minutes- it is critical to record the exact time of 
blood draw).  
• 
Obtain EKG 2 hr after study drug administration (+/- 20 minutes) 
• 
Assess AEs and SAEs throughout the day and prior to discharge from the CRU. 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Counseling on avoidance of pregnancy. 
• 
Ask subject to remain fasting (water is permitted) for 8 hours prior to returning to the 
clinic in the morning. 
Clinic Visit 06, Day 6 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam will be performed if indicated 
• 
Review concomitant medications 
• 
Review for AEs and SAEs.  
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Collect 10 mL of blood for oxfendazole level approximately 24 hours after dosing on day 
5 (+6 hours) 
Clinic Visit 07, Day 8 (+/- 1 day) 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs.  
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Collect 10 mL of blood for oxfendazole level  
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil count, platelet count, INR, partial thromboplastin time, Na, K, Cl, CO2, blood 
urea nitrogen, creatinine, ALT, AST, and total bilirubin).  


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• 
Collect urine for dipstick testing for protein and glucose. 
• 
An EKG will be performed and will be reviewed by a cardiologist. 
7.4 
Final Study Visit 08 – Day 10 (+/- 2 days) 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs.  
• 
Collect 10 mL of blood for oxfendazole level. 
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil count, platelet count, INR, partial thromboplastin time, Na, K, Cl, CO2, blood 
urea nitrogen, creatinine, ALT, AST, and total bilirubin).  
• 
Collect urine for dipstick testing for protein and glucose. 
• 
Counseling on avoidance of pregnancy. 
7.5 
Enrollment/Baseline- GROUP 4 
Clinic Visit 01, Day 1   
Eligible subjects will be asked to return to the Clinical Research Unit (CRU) having fasted for 8 
or more hours. 
 
General 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food intake 
and laboratory results obtained at the screening visit, Day 00). 
• 
Randomize to either fasting (water is permitted) or fed using the IDES system 
• 
Review concomitant medications including confirmation of absence of medications in the 
past 48 hours. 
• 
A brief interim medical history will be taken. 
• 
A routine physical examination that assesses general appearance and the following 
areas/systems, including skin, lymph nodes, HEENT, neck, respiratory, cardiovascular, 
pulmonary, abdomen, extremities, musculoskeletal, and neurological will be performed 
by a clinician licensed to make diagnoses.  
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Perform a urine pregnancy test for females of childbearing potential.  
• 
A heparin lock will be inserted, blood will be drawn (10 mL) for baseline PK (prior to 
product administration), and (15 mL) for safety labs (hemoglobin, white blood cell count, 
including neutrophil count, platelet count, INR, partial thromboplastin time, creatinine, 
Na, K, CL, CO2, blood urea nitrogen, ALT, AST, and total bilirubin). 
• 
Collect urine for dipstick testing for protein and glucose. 
• 
For subjects randomized to receive a high fat meal during the first dose, provide high fat 
breakfast.  For subjects randomized to receive the first dose following an 8 hour fast, 
proceed to next steps without providing food. 


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Administration of Study Medication  
A study nurse will administer a single 3 mg/kg oral dose of oxfendazole to the subject.   
• 
Fasting (water is permitted) subjects will remain fasting (water is permitted) for two hours 
after the administration of drug. 
• 
Fed subjects will receive a high fat breakfast. Approximately 30 minutes (+/- 15 minutes) 
following completion of the meal, the study nurse will administer a single 3 mg/kg oral 
dose of oxfendazole.    
• 
Lunch and dinner will be provided. Subjects will be allowed to eat snacks but will be 
asked to avoid drinking grapefruit juice and excessive (>2 cups) coffee.   
• 
10 mL of blood for oxfendazole level will be drawn at 30 minutes, 1, 2, 3, 4, 6, 9, and 12 
hours (all times have a window of +/- 15 minutes except the 9 and 12 hour samples 
which have a window of +/- 30 minutes- it is critical to record the exact time of blood 
draw).  
• 
Perform EKG approximately 2 hours following study drug (+/- 20 minutes) 
• 
Assess AEs and SAEs throughout the day and prior to discharge from the CRU. 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Counseling on avoidance of pregnancy. 
7.6 
Follow-up – GROUP 4 
Clinic Visit 02, Day 2   
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
Draw 10 mL of blood for oxfendazole level -approximately 24 hours after dosing on day 
1 (+/- 4 hours) 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
 
Clinic Visit 03, Day 4 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil and eosinophil counts, platelet count, INR, partial thromboplastin time, Na, K, 
Cl, CO2, blood urea nitrogen, creatinine, ALT, AST, and total bilirubin). 
• 
Collect urine for dipstick testing for protein and glucose. 
• 
Remind subjects to remain fasting (water is permitted) for 8 or more hours prior to study 
visit 04. 


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• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
 
Clinic Visit 04, Day 8 (+/- 1 day) 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Review inclusion/exclusion criteria (including assessment of time of last oral food 
intake). 
• 
Perform a urine pregnancy test for females of childbearing potential.  
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
A heparin lock will be inserted, blood will be drawn (10 mL) for baseline PK (prior to 
product administration) 
 
 
Administration of Study Medication  
A study nurse will administer a single 3 mg/kg oral dose of oxfendazole to the subject.  
• 
For subjects who fasted during the first day of study drug administration, provide high fat 
breakfast prior to study drug administration.  Approximately 30 minutes (+/- 15 minutes) 
following completion of the meal, the study nurse will administer a single 3 mg/kg oral 
dose of oxfendazole.    
• 
For subjects who received a meal prior to the first day of study drug administration, 
subjects should fast for 8 hours prior to receipt of study drug and remain fasting (water is 
permitted) for two hours after the administration of drug.  
• 
Lunch and dinner will be provided. Subjects will be allowed to eat snacks but will be 
asked to avoid drinking grapefruit juice and excessive (>2 cups) coffee.   
• 
10 mL of blood for oxfendazole level will be drawn at 30 minutes, 1, 2, 3, 4, 6, 9, and 12 
hours (all times have a window of +/- 15 minutes except the 9 and 12 hour samples 
which have a window of +/- 30 minutes- it is critical to record the exact time of blood 
draw).  
• 
Perform EKG approximately 2 hours following study drug (+/- 20 minutes) 
• 
Assess AEs and SAEs throughout the day and prior to discharge from the CRU. 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Counseling on avoidance of pregnancy. 
 
Clinic Visit 05, Day 9: (or 1 day following second dose) 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  


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• 
Draw 10 mL of blood for oxfendazole level -approximately 24 hours after dosing on day 
8 (+/- 2 hours) 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
7.7 
Final Study Visit 06 Day 14 (+/- 2 days) - GROUP 4 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
A targeted physical exam may be performed, if indicated. 
• 
Review concomitant medications 
• 
Review for AEs and SAEs  
• 
Draw 10 mL of blood for oxfendazole level 
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil count, platelet count, INR, partial thromboplastin time, Na, K, Cl, CO2, blood 
urea nitrogen, creatinine, ALT, AST, and total bilirubin).  
• 
Collect urine for dipstick testing for protein and glucose. 
• 
Counseling on avoidance of pregnancy. 
7.8 
Early Termination Visit 
If a subject withdraws from the study early, the following procedures should be performed at the 
early termination visit. 
• 
Review current health status (interim medical history) and note any changes since the 
last visit 
• 
Review concomitant medications 
• 
Vital signs including oral temperature, blood pressure, and pulse will be obtained. 
• 
Blood and urine will be collected for safety laboratory tests  
• 
Blood will be obtained for PK studies 
• 
A targeted physical examination may be performed, if indicated. 
• 
Information regarding AEs and SAEs will be solicited.  Any ongoing AEs or SAEs will be 
followed to resolution or until a stable chronic condition has been established. 
Follow-up assessments will be completed according to the protocol schedule, if possible. 
7.9 
Unscheduled Visit  
Unscheduled visits may occur at any time during the study. Unscheduled visits may occur after 
the scheduled final study visit (Day 10 or 14, depending on Study Group) if necessary to follow 
any AE occurring during the study period to resolution or stability. The procedures below are to 
be performed at any unscheduled visit. See the Manual of Procedures (MOP) for instructions on 
documentation and data reporting. 
• 
Interim medical history will be reviewed. 
• 
Review concomitant medications. 
• 
Vital signs (P, BP, oral T), if clinically indicated will be obtained. 


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• 
A targeted physical exam, if indicated based on symptoms will be performed. 
• 
Adverse events and serious adverse events will be reviewed. 


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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
Medical History: Will be obtained by interview of the subjects. Subjects will be queried 
regarding a history of significant medical disorders of the head, eyes, ears, nose, throat, mouth, 
cardiovascular system, lungs, gastrointestinal tract, liver, pancreas, kidney, nervous system, 
blood, lymph glands, endocrine system, musculoskeletal system, skin, and genital/reproductive 
tract. A history of any allergies, cancer, immunodeficiency, psychiatric illness, substance abuse, 
and autoimmune disease will be solicited.  
Interim Medical History: Will be obtained by interview of the subjects. Subjects will be queried 
regarding new signs or symptoms that have occurred since the screening medical history was 
obtained.  
Concomitant Medications: All current medications and medications taken in the 30 days 
before the screening visit (prescription and over-the-counter drugs) will be documented, as well 
as vitamins and supplements, and alternative/complementary medications through the last 
study visit. Assessment of eligibility also will include a review of prohibited medications (per the 
exclusion criteria).  
Physical Examination: This examination will be conducted at Screening and Visit 1 and will 
assess general appearance including height and weight (at Screening only), vital signs (blood 
pressure, temperature, pulse), and the following areas/symptoms: skin, lymph nodes, head, 
eyes, ears, nose, throat, respiratory, cardiovascular, abdomen, extremities, musculoskeletal, 
and neurological.  
Vital Signs and Targeted Physical Examination: Vital signs will be collected at each 
scheduled study visit and at the Early Termination Visit. Vital signs will be collected if indicated 
at the unscheduled visit.  A targeted physical examination may be conducted at any study visit 
based on interim medical history. 
Adverse Events Assessments: Subjects will be asked if they have any new symptoms since 
the prior visit. Please see section 9.2.1 and 9.2.2. 
8.2 
Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed by the University of Iowa Clinical Pathology 
Laboratory.  
Specific tests to be performed are described below: 
Hematology includes: hemoglobin, WBC count, neutrophil count, platelets 
  
Coagulation includes: INR and partial thromboplastin time 
 


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Clinical chemistry includes: Na, K, Cl, CO2, blood urea nitrogen, creatinine, ALT, AST, 
total bilirubin  
Serology: HIV 1/2 antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
(HCV) antibody 
Urinalysis will be performed by dipstick testing for proteinuria and glucose in the 
research clinic.  Confirmatory testing may be sent to the University of Iowa Clinical 
Pathology Laboratory for reflectance spectrophotometry analysis. Note: Urinalysis may 
be deferred if a participant is menstruating, but should be performed as soon as 
possible. 
Urine Pregnancy Test: will be performed at screening and Day 1 in females of child 
bearing potential for all groups.  
EKG: will be performed in the research clinic by research personnel trained in EKG 
administration. EKG tracings will be interpreted by a board certified cardiologist.   
One or more of the laboratory parameters may be repeated at any time during the study as 
determined by the PI, if indicated by an AE. A clinically significant abnormal value should be 
repeated within 10 days if possible and followed up as clinically relevant. 
8.2.2 Special Assays or Procedures 
Oxfendazole drug concentrations will be performed by Dr. Guohua An lab at the University of 
Iowa.  
Blood samples for PK analysis will be collected in tubes containing sodium heparin as the 
anticoagulant at baseline. The blood samples (10 mL) will be placed on ice after draw, and 
centrifuged within 1 hour at 4-8°C at approximately 3000 rpm for 15 min. The plasma will then 
be collected and stored frozen at –80°C until analyzed. Plasma samples will be shipped to the 
analytical lab frozen. Validated methods will be used to assay the oxfendazole concentration in 
each sample. 
8.2.3 Specimen Preparation, Handling, Storage, and Shipping 
8.2.3.1 
Instructions for Specimen Preparation, Handling, Storage, and 
 
Shipping 
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9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
Safety outcome measures are defined in Section 3.2 and include the rate of SAEs and non-
serious severe AEs. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events 
 
Adverse Event:   
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product regardless of its causal relationship to the study 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of medicinal 
(investigational) product.  The occurrence of an AE may come to the attention of study 
personnel during study visits and interviews of a study recipient presenting for medical care, or 
upon review by a study monitor.  
All AEs including local and systemic reactions not meeting the criteria for “serious adverse 
events” should be captured on the appropriate CRF.  Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis, which would 
include MD, PA, Nurse Practitioner, DO, or DDS), and time of resolution/stabilization of the 
event.  All AEs occurring while on study must be documented appropriately regardless of 
relationship.  All AEs will be followed to adequate resolution.  
Any medical condition that is present at the time that the patient is screened should be 
considered as baseline and not reported as an AE.  However, if it deteriorates at any time 
during the study, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to study product.  
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 


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Severity of Event:  All AEs will be assessed by the clinician using a protocol defined grading 
system.  For events not included in the protocol defined grading system, than the following 
guidelines will be used to quantify intensity.  
Grade 1:  Mild:  events require minimal or no treatment and do not interfere with the patient’s 
daily activities. 
Grade 2:  Moderate:  events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
Grade 3:  Severe:  events interrupt a patient’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity to be performed.  Adverse events characterized as 
intermittent require documentation of onset and duration of each episode. 
Relationship to Study Products:  The clinician’s assessment of an AE's relationship to test 
article (vaccine or study drug) is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study.  If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported.  All AEs must have their relationship to 
study product assessed using the terms:  related or not related.  In a clinical trial, the study 
product must always be suspect.  To help assess, the following guidelines are used. 
• 
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.2 Serious Adverse Events 
Serious Adverse Event (SAE):  
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death, 
• 
 a life-threatening adverse event*,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
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• 
a congenital anomaly/birth defect.   
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical 
judgment they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the view 
of either the investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death.  It does not include an adverse event, had it occurred in a more severe form, might 
have caused death. 
All SAEs will be: 
• 
recorded on the appropriate SAE CRF 
• 
followed through resolution by a study clinician 
• 
reviewed and evaluated by a study clinician 
9.2.3 Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
The site principal investigator or appropriate sub-investigator is responsible for reporting all 
AE/SAEs that are observed or reported during the study, regardless of the relationship to study 
product.  All clinically significant EKG abnormalities will be reported as an AE.   
AE/SAEs, abnormal clinical laboratory test values or clinically significant EKG changes, or 
abnormal clinical findings will be documented, reported, and followed until the event has 
resolved or has stabilized.  
If baseline clinical labs fall within Grade 1 parameters, then an AE is reported only if the value 
changes such that it falls into Grade 2 or higher at subsequent visits. For laboratory results that 
are abnormal according to the local laboratory reference range, but not considered a Grade 1 
abnormality, these will not be considered AEs and will thus not be graded, but will be followed-
up clinically at the discretion of the study site physician. 
  
9.3 
Reporting Procedures 
AEs will be documented from the time of receipt of study drug on Day 1 (Visit 02) through the 
final study visit (approximately 10 or 14 days after receipt of study product). 
SAEs will be documented from the time of receipt of study drug on Day 1 (Visit 02) through the 
final study visit. 


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AEs will be followed until resolution even if this extends beyond the study-reporting period.  
Resolution of an AE is defined as the return to pretreatment status or stabilization of the 
condition with the expectation that it will remain chronic.  
 
9.3.1 Serious Adverse Events 
 
Any AE that meets a protocol-defined serious criterion must be submitted immediately 
(within 24 hours of site awareness) on an SAE form to the DMID Pharmacovigilance 
Group, at the following address:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible.  
 
The DMID medical monitor and clinical protocol manager will be notified of the SAE by the 
DMID Pharmacovigilance Group.  The DMID medical monitor will review and assess the SAE 
for regulatory reporting and potential impact on study subject safety and protocol conduct.  
 
At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event to the DMID 
Pharmacovigilance Group.  
9.3.2 Regulatory Reporting for Studies Conducted Under 
DMID-Sponsored IND 
Following notification from the investigator, DMID, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected.  DMID will report an adverse event as a 
suspected adverse reaction only if there is evidence to suggest a causal relationship between 
the drug and the adverse event.  DMID will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, but in no case later than 15 calendar days after the sponsor determines that 
the information qualifies for reporting as specified in 21 CFR Part 312.32. DMID will also notify 
FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible 
but in no case later than 7 calendar days after the sponsor’s initial receipt of the information. 
Relevant follow up information to an IND safety report will be submitted as soon as the 
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or information that the agency deems necessary, as soon as possible, but in no case later than 
15 calendar days after receiving the request. 
All serious events designated as “not related” to study product(s), will be reported to the FDA at 
least annually in a summary format. 
9.3.3 Regulatory Reporting for Studies Not Conducted Under 
DMID-Sponsored IND 
N/A. 
9.3.4 Other Adverse Events (if applicable) 
N/A 
9.3.5 
Reporting of Pregnancy 
Pregnancies occurring in study subjects will be reported in IDES. No further study medication 
will be administered to pregnant subjects, but all study-mandated blood samples will be 
obtained and the subject will continue in follow-up for safety events. Pregnancies will be 
followed to pregnancy outcome pending the subject’s permission. 
9.4 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
AEs and SAEs will be followed from the time of the first receipt of study drug Day 1 (Visit 02) 
through the last subject’s study visit.  
AEs and SAEs will be followed until resolution even if this extends beyond the study-reporting 
period.  Resolution of an AE/SAE is defined as the return to pretreatment status or stabilization 
of the condition with the expectation that it will remain chronic. 
If the site principal investigator or appropriate sub-investigator becomes aware of a sign or 
symptom and the site principal investigator or appropriate sub-investigator decides to bring the 
subject in for an evaluation to determine etiology, then the site principal investigator or 
appropriate sub-investigator, at their own discretion, can determine what further testing is 
appropriate. 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate data 
collection form. 
9.5 
Halting Rules 
9.5.1 
Sentinel Subject Halting Rules 
For each of the multiple dose ascending groups (Groups 1-3), one sentinel subject will be dosed 
and monitored for 7 days after receiving the first dose of study product. If there are no 


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predefined safety events, a second sentinel subject will be enrolled and followed for a total of 7 
days.  If none of the sentinel subjects’ halting criteria are met: 
•         any study drug related SAE  
•         any study drug related grade 3 AE or laboratory abnormality   
•         any two Grade 2 AE or laboratory abnormalities of the same laboratory parameter 
that are study drug related 
then the remaining subjects in each group may be enrolled.  
9.5.2 
Dose Escalation Halting Criteria 
Prior to dose escalation to the next cohort, the Statistical and Data Coordinating Center (SDCC) 
will notify the study PIs, DMID medical monitor (MM), and DMID Independent Safety Monitor 
(ISM) whether the below dose escalation criterion were met.  Following enrollment and 10 days 
of safety follow up of the eight subjects in the dose group.  
Dose escalation will not proceed if any of the following dose escalation criteria occur:  
•         any study drug related SAE  
•         any study drug related grade 3 AE or laboratory abnormality   
•         any two Grade 2 AE or laboratory abnormalities of the same laboratory parameter  
In addition to these criteria, dose escalation may also stop for other reasons per the advice of 
the SMC, ISM, or DMID Medical Monitor for further evaluation, discussion, and 
recommendations from the SMC.  
If the above dose escalation halting criteria are NOT met, the dose escalation may proceed with 
agreement of DMID.   
9.5.3 
Study Halting Rules 
Enrollment, dosing and study procedures will be halted for SMC review/recommendation if any 
of the following are reported: 
• 
Any death occurring after administration of study drug through the subject’s last study 
visit that was not the result of trauma or accident, regardless of relatedness to study 
product. 
• 
Any subject experiences laryngospasm, bronchospasm, or anaphylaxis within one day 
after administration of study product. 
• 
Any subject experiences a study drug-related Stevens Johnson Syndrome. 
• 
Two or more subjects experience generalized urticaria within three days after 
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• 
Any subject experiences a study drug-related SAE from the time of receipt of study drug 
through the subject’s last study visit. 
• 
Two or more subjects develop new QTc prolongation on EKG that are deemed clinically 
significant by a reviewing cardiologist.  
• 
Two or more subjects develop grade 3 laboratory abnormalities deemed related to the 
study drug. 
If any of the halting rules are met following any subject receipt of study drug, the study will not 
continue with the remaining enrollments without a review by and recommendation from the SMC 
to proceed. 
DMID retains the authority to suspend additional enrollment and study 
interventions/administration of study product during the entire study, as applicable. 
9.5.4 
Individual Halting Rules 
• 
Subject experiences laryngospasm, bronchospasm, or anaphylaxis within 24 hours after 
administration of study product. 
• 
Subject experiences a study drug-related Stevens Johnson Syndrome. 
• 
Subject experience generalized urticaria within 72 hours after administration of study 
product. 
• 
Subject experiences a study drug-related SAE from the time of receipt of study drug 
through the subject’s last study visit. 
• 
Subject develops new QTc prolongation on EKG that are deemed clinically significant by 
a reviewing cardiologist.  
• 
 Subject develops any grade 3 laboratory abnormalities deemed related to the study 
drug. 
• 
Subject develops any grade 3 AE deemed related to the study drug. 
 
9.6 
Safety Oversight (ISM plus SMC) 
Safety oversight will be under the direction of an SMC.  The SMC will have a formal meeting 
after the third study group has completed the day 10 study visit.   The SMC will review available 
safety data for Groups 1-3, after the third study group has completed the day 10 study visit.  
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meetings may be held.  The SMC will operate under the rules of a DMID-approved charter that 
will be written at the organizational meeting of the SMC.  At this time, each data element that 
the SMC needs to assess will be clearly defined.  The SMC will advise DMID of its findings. 
 
9.6.1 
Independent Safety Monitor (ISM) 
The ISM is a physician with relevant expertise whose primary responsibility is to provide 
independent safety monitoring in a timely fashion. The ISM will review SAEs and other AEs as 
needed and provide an independent assessment to DMID. The University of Iowa will have an 
ISM with experience in infectious diseases or internal medicine. 
9.6.2 
Safety Monitoring Committee (SMC) 
The SMC is an independent group of experts that advises DMID and the study investigators for 
many Phase 1 and smaller Phase 2 trials.  The primary responsibility of the SMC is to monitor 
subject safety.  The SMC is external to DMID, composed of at least three voting members.  The 
SMC will consist of members with appropriate expertise to contribute to the interpretation of the 
data from this trial. Its activities will be delineated in an SMC charter that will delineate 
membership, responsibilities, and the scope and frequency of data reviews.   
The SMC will operate on a conflict-free basis independently of the study team. DMID and the 
SMC may convene ad hoc meetings of the SMC according to protocol criteria or if there are 
concerns that arise during the study.  The ISM or principal investigator may request DMID to 
convene an ad hoc SMC meeting if a safety concern is identified.  A computerized system will 
be used to acquire any data regarding halting criteria throughout the study.  If any of the halting 
rules are met, the study will not proceed with the remaining enrollments without a review by the 
SMC.  After its assessment, the SMC will recommend continuation, modification, or termination 
of the clinical trial.  The SMC will have access to unblinded data during its closed session.   
  
The SMC will review and discuss safety data at the following milestones:  
 
• 
The SMC will review available safety data for Groups 1-3, after the third study group 
has completed the day 10 study visit.  Ad hoc review: may be in response to an 
anticipated safety issue such as a dose escalation or study halting rule being met.  
 
 
• 
Final review meeting: 6 to 8 months after clinical database lock to review the 
cumulative unblinded safety data for the study.  The data will be provided in a 
standard summary format.  The SMC may be asked to provide recommendations in 
response to questions posed by DMID. 
 
 
 


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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Site monitoring will be conducted to ensure that human subject protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet sponsor, ICH/GCP guidelines and applicable regulatory requirements, 
and that the study is conducted in accordance with the protocol and sponsor’s standard 
operating procedures. The DMID or its designee will conduct site-monitoring visits as specified 
in the monitoring plan. 
Monitoring visits will include, but are not limited to, review of regulatory files, accountability 
records, CRFs, informed consent forms, medical and laboratory reports, and protocol 
compliance. Study monitors will meet with investigators to discuss any problems and actions to 
be taken and document visit findings and discussions. 


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11 
STATISTICAL CONSIDERATIONS 
This is an open-label Phase I study to assess the safety and pharmacokinetics of oxfendazole in 
healthy males and nonpregnant females, ages 18-45.  The primary objectives are to assess the 
safety of oxfendazole administered daily for five days and to assess the safety of oxfendazole 
administered as a single dose with or without food.  The secondary objectives are to define the 
multi-dose kinetics of oxfendazole and to determine the effect of food on the kinetics of 
oxfendazole. 
Primary endpoints: 
1. The rate of adverse events (AEs) related to oxfendazole within 10 days of receipt of 
oxfendazole given for 5 sequential, daily oral doses of either 3, 7.5 or 15 mg/kg 
 
2. The rate of adverse events (AEs) related to oxfendazole within 7 days of receipt of 
oxfendazole given as a single daily dose either following an 8 hour fast or following a 
high fat meal. 
 
 
Secondary endpoints: 
1. Plasma Cmax, Tmax, AUC, T1/2 of oxfendazole at specified time points following each 
dose of a 5 day daily regimen of either 3, 7.5 or 15 mg/kg 
 
2. Plasma Cmax, Tmax, AUC, T1/2 of oxfendazole at specified time points following a single 
dose of oxfendazole administered after an 8 hour fast or after a high fat meal. 
 
11.1 Study Hypotheses 
The primary objective of this study will be assessed through estimation rather than hypothesis 
testing, as this is a Phase I study with small sample sizes.  The study includes eight subjects in 
each of the first three cohorts and twelve subjects in the fourth cohort. 
The secondary objective of defining the multi-dose kinetics of oxfendazole will be assessed 
using a descriptive analysis with no formal hypothesis test. For the secondary objective of the 
determination of the effect of food on the kinetics of oxfendazole, equivalence between the 
fasting (water is permitted) and fed conditions will be tested using 90% confidence intervals and 
80-125% equivalence limits for AUC0-, AUC0-24, and Cmax in accordance with FDA guidance. 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126833.pdf 


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11.2 Sample Size Considerations 
The sample sizes were selected to obtain preliminary safety information on a small cohort of 
subjects before proceeding to larger trials.  In this Phase 1 study, we are concerned with rates 
of adverse events, which theoretically could occur due to oxfendazole treatment.  The dosing 
regimens with respective sample sizes are described in Table 4 below: 
Table 4.  Sample sizes for each dose regimen 
Cohort 
Dose Regimen 
Sample size 
1 
3 mg/kg daily for 5 days 
8 
2 
7.5 mg/kg daily for 5 days 
8 
3 
15 mg/kg daily for 5 days 
8 
4 
Single dose of 3 mg/kg after fasting (water is permitted) with 
cross-over to single dose of 3 mg/kg after high-fat meal. 
12 
 
The study will produce preliminary estimates of adverse event rates for each dosing regimen.   
The true adverse event rates within each dosing regimen are unknown.  The below table 
displays probabilities of observing at least one adverse event within a cohort assuming different  
true underlying event rates and sample sizes.  For example, if an adverse event has a true rate  
of 0.20, then the probability of observing at least one adverse event among 8 subjects is 0.83.   
There is a 0.93 probability of observing the event among 12 subjects.  The probabilities were  
calculated using R statistical software, version 3.2.2. 
 
Table 5.  Probabilities of observing adverse events for various event rates and sample sizes 
 
Probability of observing at least one 
adverse event within a cohort 
True Rate of 
Adverse Event 
Among 8  
subjects 
Among 12 
subjects 
0.01 
0.08 
0.11 
0.05 
0.34 
0.46 
0.08 
0.49 
0.63 
0.10 
0.57 
0.72 
0.15 
0.73 
0.86 
0.20 
0.83 
0.93 


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With 12 total participants to assess the secondary objective of the determination of the effect of 
food on the kinetics of oxfendazole, the power is 80% when the coefficient of variation is less 
than 0.175 and 64% when the coefficient of variation is 0.2. 
11.3 Planned Interim Analyses (if applicable) 
No interim analyses are planned. 
11.3.1 Safety Review  
The SMC will have a formal meeting after all subjects in groups 1-3 have completed the day 10 
study visit.  This meeting will be scheduled expeditiously, but this SMC review is not required 
prior to enrollment into study group 4.  This report will summarize adverse events as described 
in section 11.4.3 below.  Additional safety review may occur if halting rules are met.   
11.4 Final Analysis Plan 
The final analysis will be performed and clinical study report completed when all primary and 
secondary endpoint data are available.  This study, like other Phase 1 studies, is exploratory 
rather than confirmatory; its purpose is to estimate adverse event rates and characterize 
pharmacokinetic profiles than to test formal statistical hypotheses.  Estimates will be presented 
with their 95% confidence intervals.  Results will be presented in tabular format, as well as 
graphically when appropriate.   
11.4.1 Populations for Analysis 
Safety Population 
All participants who receive study drug and for whom any safety data are available will be 
included in the safety population.   
PK Analysis Population  
All participants who receive study drug and have at least one evaluable PK concentration will be 
eligible for the PK analysis population. 
11.4.2 Analysis of Demographics 
Demographic characteristics (age, gender, race, ethnicity) of each cohort will be summarized 
numerically. 


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11.4.3 Analysis of Safety 
Adverse experiences (spontaneous reports) will be coded into MedDRA® preferred terms. The 
number of subjects experiencing unsolicited adverse events and the number of spontaneous 
events, classified using MedDRA® System Organ Classes and Preferred Terms, reported 
throughout the study after treatment administration will be tabulated by cohort.  The severity and 
relationship to study product of the unsolicited adverse events will also be assessed.  Serious 
adverse events will be described.  A complete listing of adverse experiences for each subject 
will provide details including severity, relationship to treatment, onset, duration, and outcome. 
Solicited clinical laboratory results and vital signs will be graded and summarized by cohort and 
study day.   
11.4.4 Pharmacokinetic Analysis 
PK parameters for oxfendazole will be calculated using non-compartmental analysis. 
Parameters will be summarized separately by group and dose.  
Maximum concentration (Cmax), time of maximum concentration (Tmax), and the pre-dose trough 
concentrations (Ctrough) will be directly estimated from the observed concentration-time curve. 
Area under the curve (AUC) will be calculated using the linear up-log down trapezoidal method.  
λz will be calculated as the negative of the slope of the terminal log-linear segment of the 
plasma concentration-time curve. The range of data to be used for each subject and treatment 
will be determined by visual inspection of a semi-logarithmic plot of concentration vs. time, but 
will include at least three plasma concentration-time points for λz to be estimable. Half-life (t½) 
will be calculated as ln(2)/λz.  
In Groups 1-3, AUC0-τ will be calculated as AUC to the end of the 24-hour dosing interval. Oral 
clearance at steady state will be calculated using AUC0-τ,ss after the Day 5 (expected steady 
state) dose as 
ss
ss
AUC
Dose
F
CL
,
0
/

−
=
. 
The observed accumulation ratio (AR) following multiple dosing will be estimated using the ratio 
of AUC0-τ following multiple and single dosing. When λz is estimable, AR will also be estimated 
using λz calculated following multiple dosing:  
𝐴𝑅=
1
1 −𝑒−λ𝑍𝜏 
 
The relationship between exposure (Cmax and AUC) and dose, i.e., dose proportionality, will be 
examined using ANOVA or the power model 
b
Dose
a
P

=
 
where P represents the parameter and a and b are constants.  A value of b of approximately 1 
indicates linear PK.  
 
Group 4 parameters will be summarized by condition (fasting (water is permitted) or fed). In 
group 4, 90% confidence intervals for ratios of key exposure parameters will be estimated using 
appropriate analysis of variance (ANOVA) models on the log-transformed parameters. Key 
exposure parameters will be Cmax, AUC to the time of the last quantifiable concentration 
(AUC0-t), and, when λz is estimable, AUC extrapolated to infinity (AUC0-∞). 


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Listings of individual subject plasma concentrations, actual blood sampling times, PK 
parameters, and graphs of concentration vs. time will be prepared by group. Parameter 
estimation using noncompartmental analysis will be done using appropriate computer software, 
such as Phoenix WinNonlin, as determined by the sponsor. 
 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Describe who will have access to records.  As part of participating in 
a DMID-sponsored, DMID-affiliated, or manufacturer-sponsored study, each site will permit 
authorized representatives of the sponsor(s), DMID, and regulatory agencies to examine (and 
when required by applicable law, to copy) clinical records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ memory aid or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. It is acceptable to use CRFs as source documents.  If this is the case, it should be stated in 
this section what data will be collected on CRFs and what data will be collected from other 
sources.   


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Following a written DMID-accepted site quality management plan, the investigational site is 
responsible for conducting routine quality assurance and quality control activities to internally 
monitor study progress and protocol compliance. The PI will provide direct access to all trial-
related sites, source data/documents, and reports for the purpose of monitoring and auditing by 
the sponsor, and inspection by local and regulatory authorities. The PI will ensure all study 
personnel are appropriately trained and applicable documentation is maintained on site.  
DMID-designated clinical monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, ICH/GCP 
guidelines, and the applicable regulatory requirements. Clinical monitoring reports will be 
submitted to DMID. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997).   
14.2 Institutional Review Board 
 
Prior to enrollment of subjects into this trial, the approved protocol and the informed consent 
form will be reviewed and approved by the appropriate IRB. The responsible official for the IRB 
will sign the IRB letter of approval of the protocol prior to the start of this trial and a copy will be 
provided to DMID. Notification of the IRB’s composition, or the IRB’s Federal Wide Assurance 
number, will be provided to DMID. Should amendments to the protocol be required, the 
amendments will be written by the investigator and approved by DMID prior to submission to the 
IRB. 
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation.  Extensive discussion of 
risks and possible benefits of this therapy will be provided to the subjects and their families.  
Consent forms describing in detail the study interventions/products, study procedures, and risks 
are given to the subject and written documentation of informed consent is required prior to 
starting intervention/administering study product.  Consent forms will be IRB-approved and the 
subject will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may 
arise.  The subjects will sign the informed consent document prior to any procedures being done 
specifically for the study.  The subjects should have the opportunity to discuss the study with 
their surrogates or think about it prior to agreeing to participate.  The subjects may withdraw 
consent at any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the subjects for their records.  The rights and welfare of the subjects 
will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 


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14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
Not applicable 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This study will be inclusive of all healthy adults who meet the inclusion/exclusion criteria, 
regardless of religion, sex, or ethnic background. Only individuals, who are 18 to 45 years old, 
inclusive, will be included at this time. Women of childbearing potential and children are 
excluded for safety reasons.  Prisoners are excluded due to the rigorous study schedule that 
would not be feasible in an incarcerated population.  Should the outcome of this study be 
deemed acceptable, additional trials may be initiated in other populations. 
14.5 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents.  This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participating subjects. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence.  No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
The study monitor or other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the subjects in this study.  The 
clinical study site will permit access to such records. 
14.6 Study Discontinuation 
If the study is discontinued, enrolled subjects will continue to be followed for safety 
assessments.  
Subjects will be compensated for their participation in this study. Compensation will be in 
accordance with the local IRB’s policies and procedures and subject to IRB approval. 
14.7 Future Use of Stored Specimens 
No specimens will be saved for future use.  Once the study has been completed DMID will 
instruct the site and Fisher BioServices to destroy all residual samples. The destruction of 
residual samples will be appropriately documented.  


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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported.  All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data.  Black ink is required to ensure clarity of reproduced 
copies.  When making changes or corrections, cross out the original entry with a single line, and 
initial and date the change.  DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID 
OR TAPE ON THE ORIGINAL. 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each subject enrolled in the study.  Data reported in the eCRF 
derived from source documents should be consistent with the source documents or the 
discrepancies should be explained 
DMID and/or it designee will provide guidance to investigators on making corrections to the 
source documents and eCRF. 
15.1 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be 
graded, assessed for severity and causality, and reviewed by the site PI or designee. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  During the study, the investigator must maintain complete and accurate 
documentation for the study. 
The EMMES Corporation will serve as the Statistical and Data Coordinating Center for this 
study and will be responsible for data management, quality review, analysis, and reporting of 
the study data. 
15.2 Data Capture Methods 
Clinical data (including AEs, concomitant medications, and reactogenicity data) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant Internet Data Entry System 
(IDES) provided by The EMMES Corporation.  The data system includes password protection 
and internal quality checks, such as automatic range checks, to identify data that appear 
inconsistent, incomplete, or inaccurate.  Clinical data will be entered directly from the source 
documents.  


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15.3 Types of Data 
Data for this study will include safety, laboratory studies, EKG data and pharmacokinetic data 
for the study drug. 
15.4 Timing/Reports 
Safety data will be reviewed by the SMC per the SMC charter for this study.  The SMC will 
review available safety data for Groups 1-3, after the third study group has completed the day 
10 study visit.     A second report will be generated approximately 6-8 months after study 
completion that will include all unblinded safety data for groups 1-4.  Interim statistical reports 
may be generated as deemed necessary and appropriate by DMID. 
15.5 Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents should 
be retained for a longer period, however, if required by local regulations.  No records will be 
destroyed without the written consent of the sponsor, if applicable.  It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
15.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements.  The noncompliance may be either on the part of 
the subject, the investigator, or the study site staff.  As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity.  All deviations must be promptly reported to DMID, via The 
EMMES Corporation’s IDES or via the TRI/ICON DMID-Clinical Research Operations and 


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Management Support (CROMS) email (protocoldeviations@dmidcroms.com), web- 
(www.dmidcroms.com) or fax-based system (1-215-699-6288).  
Note:  Those sites participating in trials with a designated ‘central unit’ will follow the reporting 
requirements specified in their protocols and MOPs.  The ‘central unit’ will be responsible for 
submission of the protocol deviation information to TRI/ICON DMID-CROMS. 
All deviations from the protocol must be addressed in study subject source documents.  A 
completed copy of the DMID Protocol Deviation Form (TRI/ICON DMID-CROMS or IDES form) 
must be maintained in the regulatory file, as well as in the subject’s source document.  Protocol 
deviations must be sent to the local IRB/IEC per their guidelines.  The site PI/study staff is 
responsible for knowing and adhering to their IRB/IEC requirements. 


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16 
PUBLICATION POLICY 
 
Following completion of the study, the investigator is expected to publish the results of this 
research in a scientific journal.  The International Committee of Medical Journal Editors (ICMJE) 
member journals have adopted a trials-registration policy as a condition for publication. This 
policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov*, which is sponsored by the National Library of Medicine.  Other biomedical 
journals are considering adopting similar policies.  It is the responsibility of DMID to register this 
trial in an acceptable registry.  Any clinical trial starting enrollment after 01 July 2005 must be 
registered on or before patient enrollment.  For trials that began enrollment prior to this date, the 
ICMJE member journals will require registration by 13 September 2005, before considering the 
results of the trial for publication. 
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome.  Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from 
this policy. 
 
 
 
 


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17 
LITERATURE REFERENCES 
1. WHO PCT Databank. Geneva, World Health Organization, 2010 
(http://www.who.int/neglected_diseases/preventive_chemotherapy/databank/en/, accessed 
24 January 2012. 
2. Keiser J & Utzinger J.  Efficacy of current drugs against soil-transmitted helminth infections: 
systematic review and meta-analysis.  JAMA.  299:1937-1948, 2008. 
3. Review of Oxfendazole. Parasitology Today.  6(Entire Issue 4):91-140, 1990. 
4. Marriner SE & Bogan JA.  Pharmacokinetics of oxfendazole in sheep.  Am J Vet Res. 
42:1143-1145, 1981. 
5. Synanthic® 22.5% Label. St. Joseph, MO: Boehringer Ingelheim Vetmedica;  [December 6, 
2011]; 2010:[Available from: http://bi-vetmedica.com/products. 
6. Synanthic® 9.06% Label. St. Joseph, MO: Boehringer Ingelheim Vetmedica;  [December 6, 
2011]; 2010:[Available from: http://bi-vetmedica.com/products. 
7. Brown HD, Matzuk AR, Ilves IR, Peterson LH, Harris SA, Sarett LH, Egerton JR, Yakstis JJ, 
Campbell WC, & Cuckler AC.   Antiparasitic Drugs IV. 2-(4’-thiazolyl)-benzimidazole, a new 
anthelminthic.  J Am Chem Soc.  83:1764-1765, 1961. 
8. Garcia HH, Gonzalez AE, & Gilman RH.  Diagnosis, treatment and control of Taenia solium 
cysticercosis.  Curr Opin Infect Dis.  16:411-419, 2003. 
9. Tocco DJ, Buhs RP, Brown HD, Matzuk AR, Mertel HE, Harmon RE, & Trenner NR.  The 
metabolic phase of thiabendazole in sheep.  J Med Chem.  7:399-405, 1964. 
10. Ali DN & Hennessy DR.  The effect of feed intake on the rate of flow of digesta and the 
disposition and activity of oxfendazole in sheep.  Int J Parasitol.  23:477-484, 1993. 
11. Latif LA & Surin J.  Relationships between the anthelmintic activity of eight derivatives of 
benzimidazole carbamates against Trichinella spiralis and their chemical structures.  Jpn J 
Med Sci Biol.  46:203-214, 1993. 
12. Russell GJ, Gill JH, & Lacey E.  Binding of [3H]benzimidazole carbamates to mammalian 
brain tubulin and the mechanism of selective toxicity of the benzimidazole anthelmintics.  
Biochem Pharmacol.  43:1095-1100, 1992. 
13. Lubega GW & Prichard RK.  Interaction of benzimidazole anthelmintics with Haemonchus 
contortus tubulin: binding affinity and anthelmintic efficacy.  Exp Parasitol. 73:203-213, 
1991. 
14. Nash TE & Neva FA.  Recent advances in the diagnosis and treatment of cerebral 
cysticercosis.  N Engl J Med. 311:1492-1496, 1984. 
15. Proano JV, Madrazo I, Avelar F, Lopez-Felix B, Diaz G, & Grijalva I.  Medical treatment for 
neurocysticercosis characterized by giant subarachnoid cysts.  N Engl J Med. 345:879-885. 
2001. 
16. Freedom of Information Summary, NADA 140-854 Synanthic®-original approval. 1990 
[November 7, 2011]; Available from: 
http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSum
maries/ucm049983.html. 


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APPENDIX A: SCHEDULE OF EVENTS 
 
Groups 1,2 and 3 
 
Follow Up Visits 
 
Screening 
Study Visit 00 
Baseline  
Study visit 01 
Study Visit 02 
Study Visit 03 
Study Visit 04 
Study Visit 05 
Study Visit 06 
Study Visit 07 
Study 
Completion 
Visit 08 
Unscheduled 
Visit 
Early 
Termination 
Visit
Study Day  
D-28 
to -1 
D1 
D2 
D3 
D4 
D5 
D6 
D8 
D10 
 
 
Visit Window 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
+/-1 
+/-2 
 
 
Signed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
Assessment of Eligibility 
Criteria 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
Review of Medical History 
X 
X 
 
 
 
 
 
 
 
X 
X 
Review of Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of Study 
Medication 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Physical 
Examination 
Complete 
X 
X 
 
 
 
 
 
 
 
 
 
Symptom-
Directed 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Assessment of Adverse 
Events and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Chemistry 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Hematology 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Coagulation 
Studies  
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
 
Research 
Laboratory 
PK studies 
10 mL whole 
blood 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


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Groups 1,2 and 3 
 
Follow Up Visits 
 
Screening 
Study Visit 00 
Baseline  
Study visit 01 
Study Visit 02 
Study Visit 03 
Study Visit 04 
Study Visit 05 
Study Visit 06 
Study Visit 07 
Study 
Completion 
Visit 08 
Unscheduled 
Visit 
Early 
Termination 
Visit
Study Day  
D-28 
to -1 
D1 
D2 
D3 
D4 
D5 
D6 
D8 
D10 
 
 
Visit Window 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
+/-1 
+/-2 
 
 
Other 
Procedures 
EKG 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
(X) – As indicated/appropriate. 
Hematology – Hemoglobin, WBC and neutrophil count, platelet count. 
Biochemistry – Screening: creatinine, ALT, AST, random glucose, total bilirubin. 
                      – Follow Up Visits: creatinine, sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen ALT, AST, total bilirubin. 
Coagulation Studies– INR, and partial thromboplastin time (PTT) 
Serology – Hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus (HIV) 
Urinalysis – Urine Dipstick for protein and glucose 
Research Laboratory – Days 1 and 5: 10 mL blood for baseline PK (prior to drug administration), 10 
mL blood at 30 minutes,1, 2, 3, 4, 6, 9, and 12 hours (all times have a window of +/- 15 minutes 
except the 9 and 12 hour samples which have a window of +/- 30 minutes) 
Day 2: 10 mL blood prior to study drug administration-approximately 24 hours after dosing on 
previous day (+/- 4 hours) and 2 hours after study drug administration (+/- 20 minutes) 
Days 3 and 4: 10 mL blood prior to study drug administration-approximately 24 hours after dosing 
on previous day (+/- 2 hours) 
Day 6: 10 mL blood-approximately 24 hours after dosing on previous day (+6hours) 
 
 
 
 
 
 


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Group 4 
Follow Up Visits 
 
Screening 
Study Visit 00 
Baseline  
Study visit 01 
Study Visit 02 
Study Visit 03 
Study Visit 04 
Study Visit 05 
Study 
Completion 
Study Visit 06 
Unscheduled 
Visit 
Early 
Termination 
Visit  
Study Day  
D-28 
to -1 
D1 
D2 
D4 
D8 
D9 
D14 
 
 
Visit Window 
N/A 
N/A 
N/A 
N/A 
+/-1 
N/A 
+/-2 
 
 
Signed Consent Form 
X 
 
 
 
 
 
 
 
 
Assessment of Eligibility 
Criteria 
X 
X 
 
 
X 
 
 
 
 
Randomization/Enrollment 
 
X 
 
 
 
 
 
 
 
Review of Medical History 
X 
X 
 
 
 
 
 
X 
X 
Review of Concomitant 
Medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of Study 
Medication 
 
X 
 
 
X 
 
 
 
 
Physical 
Examination 
Complete 
X 
X 
 
 
 
 
 
 
 
Symptom-
Directed 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
(X) 
X 
Assessment of Adverse 
Events and SAEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Chemistry 
X 
X 
 
X 
 
 
X 
 
X 
Hematology 
X 
X 
 
X 
 
 
X 
 
X 
Coagulation 
Studies  
X 
X 
 
X 
 
 
X 
 
X 
Serology 
X 
 
 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
X 
 
 
X 
(X) 
X 
Pregnancy Test 
X 
X 
 
 
X 
 
 
 
 
Research 
Laboratory 
PK Studies 
10 mL whole 
blood 
 
X 
X 
 
X 
X 
X 
 
X 
Other 
Procedures 
EKG 
X 
X 
 
 
X 
 
 
 
 
 
 
 


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(X) – As indicated/appropriate 
Hematology – Hemoglobin, WBC and neutrophil count, platelet count. 
Biochemistry – Screening: creatinine, ALT, AST, random glucose, total bilirubin. 
                      – Follow Up Visits: creatinine, sodium, potassium, chloride, carbon dioxide, blood urea 
nitrogen ALT, AST, total bilirubin. 
Coagulation Studies– INR and partial thromboplastin time (PTT) 
Serology – Hepatitis B surface antigen, hepatitis C antibody, human immunodeficiency virus (HIV) 
Urinalysis – Urine Dipstick for protein and glucose 
Research Laboratory – Days 1 and 8: 10 mL blood for baseline PK (prior to drug administration), 10 mL 
blood at 30 minutes, 1, 2, 3, 4, 6, 9, and 12 hours (all times have a window of +/- 15 minutes except the 9 
and 12 hour samples which have a window of +/- 30 minutes) 
Day 2 and 9: 10 mL blood –approximately 24 hours following study drug dose (+/- 4 hours)  
 
 


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APPENDIX B: DMID ADULT TOXICITY TABLES 
NON-SERIOUS ADVERSE EVENTS  
 
ABBREVIATIONS:  Abbreviations utilized in the Tables: 
ULN = Upper Limit of Normal 
IV = Intravenous 
LLN = Lower Limit of Normal 
 
Clinical Adverse Events 
VITAL SIGNS 
 Grade 1  
 Grade 2  
 Grade 3  
Fever (°C) ** 
38.0 – 38.4 
38.5 – 38.9 
≥39.0 
Fever (°F) ** 
100.4 – 101.1 
101.2 – 102.0 
>102.0  
** Oral temperature; no recent hot or cold beverages or smoking. A protocol should 
select either °C or °F for inclusion. 
Tachycardia – beats 
per minute 
101 – 115 
116 – 130 
> 130 or ventricular 
dysrhythmias 
Bradycardia – beats 
per minute 
50 – 54 or 45-50 
bpm if baseline 5-
60 bpm.  For 
athletically trained 
individuals with a 
pulse 45-49, grade 
1 abnormality = 
pulse 40-44 
45 – 49 or 40-
44 bpm if 
baseline 50-60 
bpm. For 
athletically 
trained 
individuals with 
a pulse 45-49, 
grade 2 
abnormality = 
pulse 35-39 
< 45 or <40 bpm if 
baseline 50-60 bpm. For 
athletically trained 
individuals with a pulse 
45-49, grade 3 
abnormality = pulse less 
than 35 or pulse 35-45 
with symptoms of 
lightheadedness, 
exercise intolerance, 
syncope 
Hypertension 
(systolic)- mm Hg** 
141-150 
151-160 
> 160 
Assuming supine position, 10 min at rest conditions, not sleeping subjects, 
measurements on the same arm and several concordant results. 
Hypertension 
(diastolic) – mm Hg** 
91-95 
96-100 
> 100 
 Hypotension (systolic) 
– mm Hg** 
85-89 
80-84 
< 80 
Tachypnea – breaths 
per minute 
23-25 
26-30 
>30 
CARDIOVASCULAR 
 Grade 1  
 Grade 2  
 Grade 3  


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 Arrhythmia  
Asymptomatic, 
transient signs, 
no Rx required  
Recurrent/persistent; 
symptomatic Rx required  
 Hemorrhage, Blood 
Loss  
Estimated blood 
loss < 100 mL  
Estimated 
blood loss > 
100 mL, no 
transfusion  
required 
Transfusion required  
 RESPIRATORY    
 Grade 1  
 Grade 2  
 Grade 3  
 Cough  
Transient- no 
treatment  
Persistent 
cough;  
Interferes with daily 
activities 
Bronchospasm, Acute 
Transient; no 
treatment; 71% 
- 80% FEV1 of 
peak flow  
Requires 
treatment; 
normalizes with 
bronchodilator; 
FEV1 60% - 
70% (of peak 
flow)  
No normalization with 
bronchodilator; FEV1 
<60% of peak flow 
Dyspnea  
Does not 
interfere with 
usual and social 
activities 
Interferes with 
usual and 
social activities, 
no treatment 
Prevents daily and usual 
social activity or requires 
treatment 
GASTROINTESTINAL    Grade 1  
 Grade 2  
 Grade 3  
 Nausea  
No interference 
with activity 
Some 
interference 
with activity 
Prevents daily activities 
 Vomiting  
No interference 
with activity or 1 
– 2 episodes/24 
hours 
Some 
interference 
with activity or 
> 2 
episodes/24 
hours 
Prevents daily activity or 
requires IV hydration 
 Diarrhea  
2 – 3 loose or 
watery stools  
4 – 5 loose or 
watery stools  
6 or more loose or 
watery stools or requires 
IV hydration 
Reactogenicity 
SYSTEMIC   Grade 1  
 Grade 2  
 Grade 3  
 Allergic Reaction  
Pruritus without 
rash  
Localized 
urticaria  
Generalized urticaria; 
angioedema or 
anaphylaxis  


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Headache  
No interference 
with activity 
Repeated use 
of non-narcotic 
pain reliever > 
24 hours or 
some 
interference 
with activity 
Significant; any use of 
narcotic pain reliever or 
prevents daily activity 
Fatigue  
No interference 
with activity 
Some 
interference 
with activity 
Significant; prevents 
daily activity 
Myalgia 
No interference 
with activity 
Some 
interference 
with activity 
Significant; prevents 
daily activity 
All Other Conditions 
 Grade 1  
 Grade 2  
 Grade 3  
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations) 
No interference 
with activity 
Some 
interference 
with activity not 
requiring 
medical 
intervention 
Prevents daily activity 
and requires medical 
intervention 
 
 


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Laboratory Adverse Events 
Blood, Serum, or Plasma * 
 Grade 1  
 Grade 2  
 Grade 3  
Sodium – Hyponatremia mEq/L 
132 – <LLN 
130 – 131 
<130 
Sodium – Hypernatremia mEq/L 
>ULN – 148 
149 – 150 
>150 
Potassium – Hyperkalemia mEq/L 
>ULN – 5.2 
5.3 – 5.4 
>5.4 
Potassium – Hypokalemia mEq/L 
<LLN-3.1 
<3.1 – 3.0 
<3.0 
CO2 
1-2 mEq/L 
above or 
below normal 
3-4 mEq/L 
above or below 
normal 
5 or more 
mEq/L above 
or below 
normal 
Chloride 
1-3 mEq/L 
above or 
below normal 
4-5 mEq/L 
above or below 
normal 
6 or greater 
above or 
below normal 
Glucose – Hypoglycemia mg/dL 
65 – 67 
55 – 64 
<55 
Glucose – Hyperglycemia  
Fasting (water is permitted) – mg/dL 
>ULN – 120 
121 – 130 
>130 
Glucose – Hyperglycemia  
Random – mg/dL 
140 – 159 
160 – 200 
>200 
Blood Urea Nitrogen mg/dL 
23-26 
27 – 31 
> 31 
Creatinine – mg/dL 
>ULN – 1.7 
1.8 – 2.0 
>2.0 
Calcium – hypocalcemia mg/dL 
8.0 – <LLN 
7.5 – 7.9 
<7.5 
Calcium – hypercalcemia mg/dL 
>ULN – 11.0 
11.1 – 11.5 
>11.5 
Magnesium – hypomagnesemia 
mg/dL 
1.3 – 1.5 
1.1 – 1.2 
<1.1 
Phosphorous – hypophosphatemia 
mg/dL 
2.3 – 2.5 
2.0 – 2.2 
<2.0 
CPK – mg/dL 
400-1000 
1001-1500 
>1500 
Albumin – Hypoalbuminemia g/dL 
2.8 – 3.0 
2.5 – 2.7 
< 2.5 
Total Protein – Hypoproteinemia 
g/dL 
5.5 – <LLN 
5.0 – 5.4 
< 5.0 
Alkaline phosphate – U/L 
132-240 
241– 360 
>360 
AST U/L 
44 – 105 
106-175 
>175 
ALT U/L 
44 – 105 
106-175 
>175 
Bilirubin (serum total) mg/dL 
1.3 – 2.0 
2.1 – 2.5 
> 2.5  
Bilirubin – when ALT >105 (Hy’s 
law) 
1.3 -1.5 
1.6 – 2.0  
> 2.0  
Amylase- U/L 
200-270 
271-360 
>360 
Lipase- U/L 
176-270 
271-360 
>360 
Hemoglobin (Female) – g/dL 
11.0 – 11.5 
9.5 – 10.9 
< 9.5  
Hemoglobin (Male) – g/dL 
12.0 – 12.5 
10.0 – 11.9 
<10.0 
WBC Increase – cell/mm3 
11,001 – 
15,000 
15,001 – 
20,000 
> 20,000 


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WBC Decrease – cell/mm3 2,500 – 3,500 
1,500 – 2,499 
< 1500 
Lymphocytes Decrease – cell/mm3 
750 – 1,000 
500 – 749 
< 500 
Neutrophils Decrease – cell/mm3 1,500 – 2,000 
1,000 – 1,499 
< 1000 
Eosinophils – cell/mm3 
500-750 
751-1500 
> 1500 
Platelets Decreased – cell/mm3 
120,000 – 
130,000 
100,000 – 
119,999 
<100,000 
INR –(International Normalized 
Ratio of the prothrombin time) 
1.3 to <1.7  
1.8- <2.3  
≥ 2.4  
PTT – seconds (partial 
thromboplastin time) 
>ULN-42.1 
42.2– 50.0 
> 50.0 
Fibrinogen increase – mg/dL 
>ULN – 500 
501 – 600 
> 600 
Fibrinogen decrease – mg/dL 
<LLN – 140 
125 – 139 
<125  
   
 
  
Urine * 
 Grade 1  
 Grade 2  
 Grade 3  
Protein 
1+ 
2+ 
>2+ 
Glucose 
1+ 
2+ 
>2+ 
Blood (microscopic) – red blood 
cells per high power field (rbc/hpf) 
5-10 
11-50  
> 50 and/or 
gross blood 
 
* The laboratory values provided in the tables serve as guidelines and are dependent 
upon institutional normal parameters.  
* Institutional normal reference ranges should be provided to demonstrate that they 
are appropriate. 


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APPENDIX C: GRADE THRESHOLDS FOR EKG 
 
 
Grades 
Parameter 
Origin 
1 
2 
3 
PR interval increase (ms)* 
CPI 
220 to 250 and 
increase exceeding 
20 ms 
>250 
Mobitz 2 or syncope  
 
 
 
 
 
QTc interval increase (young 
male) using the most 
accurate QTc formula (ms)* 
 
ULNR to 475 ms 
and increase 
exceeding 40 ms 
476 to 
499 
>499 ms, or QTC 
over 460 and 
increase exceeding 
60 ms 
 
 
 
 
 
QTc interval increase 
(women)* 
 
Same as male plus 
20 ms 
 
 
*Assuming supine position, 10 min at rest conditions, not sleeping subjects and several 
concordant results. ULNR, Upper limit of normal range; LLNR, Lower limit of normal 
range; CPI, Club phase I task force. 
 


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APPENDIX D: UNIVERSITY OF IOWA NORMAL LABORATORY VALUES 
 
Male 
Female 
Complete Blood Count 
 
 
WBC 
3.7-10.5 k/mm³ 
3.7-10.5 k/mm³ 
 
 
 
Hemoglobin 
13.2-17.7 g/dl 
11.9-15.5 g/dl 
Platelets 
150-400 k/mm³ 
150-400 k/mm³ 
Hemogram plus Automated Differential 
 
 
Neutrophils 
2188-7800/mm³  
Same 
 
 
 
BUN  
10-20 mg/dl 
Same 
Creatinine 
0.6-1.2 mg/dl 
0.5-1.0 mg/dl 
Alanine Aminotransferase (ALT) 
0-41 u/l 
0-33 u/l 
Aspartate Aminotransaminase (AST) 
0-40 u/l 
0-32 u/l 
Chloride 
95-107 
Same 
CO2 
22-29 mEq/L 
Same 
Potassium 
3.5-5.0 
Same 
Sodium 
135-145 
Same 
Total Bilirubin 
<=1.2 mg/dL 
Same 
Prothrombin Time 
9-12 seconds 
Same 
Partial Thromboplastin Time 
22-31 seconds 
Same 
INR 
0.9-1.2 
Same 
Glucose (random) 
<140 
Same 
Urinalysis, Routine Screen (using 
Reflectance Spectrophotometry) 
Specific gravity: 1.000-1.029; pH: 5.0-
9.0, Dipstick negative for protein, 
hemoglobin, bilirubin, urobilinogen, 
ketones, glucose, leukocyte esterase 
and nitrite 
Same 
Urine Microscopy 
0-5 WBC, 0-2 RBC 
Same 
Pregnancy Test 
 
Positive = pregnant  
Negative = not pregnant 
Hepatitis B Surface Antigen 
Negative 
Same 
HIV Types 1&2 Antibody 
Non-Reactive 
Same 
Hepatitis C Virus Antibody, Version 2.0 
Negative 
Same 
 
 

SAP_001.pdf: 
 CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
Clinical Pharmacokinetic Noncompartmental 
Data Analysis Plan 
 
 
For 
 
DMID Protocol: 16-0005 
 
Study Title: A Phase 1 Open Label, Multiple 
Ascending Dose Study of Oxfendazole in Healthy 
Adult Volunteers 
 
 
 
Version 1.0 
 
DATE: 09 October 2018 
 
 
 
 
 
 
Prepared and Distributed by: 
The Emmes Corporation 
Rockville, Maryland USA 
 
 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
- ii- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
SIGNATURE PAGE 
SPONSOR: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
STUDY TITLE: 
A Phase 1 Open Label, Multiple Ascending Dose Study of 
Oxfendazole in Healthy Adult Volunteers 
PROTOCOL NUMBER: 
DMID 16-0005 
Principal Investigator: Patricia Winokur, M.D. 
Signed: 
 
Date: 
 
 
 
 
 
DMID Scientific Lead: Greg Deye, M.D. 
Signed:   
Date:  
 
 
 
 
 
The Emmes Corporation: Shirley Galbiati 
Signed: 
 
Date: 
 
 
Title: Statistician 
 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
ACRONYMS AND ABBREVIATIONS ..................................................................................... IV 
1. 
PREFACE .....................................................................................................................1 
2. 
CLINICAL STUDY METHODS .................................................................................2 
2.1. 
Treatment Groups .........................................................................................................2 
2.2. 
Dose Administration .....................................................................................................3 
2.3. 
PK Sampling Schedule Treatment Groups ...................................................................3 
2.4. 
Analytical Methods .......................................................................................................4 
2.5. 
Collection of Pharmacodynamic or Clinical Endpoints ...............................................4 
3. 
PHARMACOKINETIC ANALYSIS METHODS.......................................................5 
3.1. 
Analysis Populations and Handling of Missing Time Points .......................................5 
3.2. 
Demographic and Baseline Characteristics ..................................................................5 
3.3. 
Dosing and Pharmacokinetic Sampling Summary .......................................................5 
3.4. 
Definition and Estimation of Individual PK Parameters ..............................................6 
3.5. 
Descriptive Statistics and Inference of PK Parameters ................................................9 
3.6. 
Comparison of Current Pharmacokinetic Results to Pharmacokinetic Results 
from Previous Studies .................................................................................................13 
4. 
REFERENCES ...........................................................................................................14 
5. 
LISTING OF PROPOSED TABLES, FIGURES, AND LISTINGS .........................15 
6. 
APPENDICES ............................................................................................................16 
Appendix I: List of Proposed Tables .............................................................................................16 
Appendix II: List of Proposed Figures...........................................................................................36 
Appendix III: List of Proposed Listings ........................................................................................51 
 


DMID Protocol 16-0005 
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ACRONYMS AND ABBREVIATIONS 
Standard acronyms and abbreviations are listed below. 
Abbreviation 
Definition 
AIC 
Akaike Information Criterion 
AUC 
Area Under the Concentration-Time Curve 
AUClast 
AUC to the Last Measurable Concentration 
AUC0-∞ 
AUC Extrapolated to Infinity  
AUCτ 
AUC of Dosing Interval 
BA 
Bioavailability  
BE 
Bioequivalence 
BMI 
Body Mass Index 
BQL 
Below the Quantification Limit 
Clast 
Last measurable concentration (above the quantification limit) 
CL 
Clearance 
CL/F 
Apparent Oral Clearance 
Cmax 
Maximum Concentration 
Ctrough 
Pre-dose Trough Concentration 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
F 
Bioavailability 
FDA 
Food and Drug Administration 
GM 
Geometric Mean 
hr 
Hour 
λz 
Terminal Phase Elimination Rate Constant 
LC/MS/MS 
Liquid Chromatography-tandem Mass Spectrometry 
LOD 
Limit of Detection 
LLOQ 
Lower Limit of Quantification 
Max 
Maximum 
Min 
Minimum 
NCA 
Noncompartmental Analysis 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
AR 
Accumulation Ratio 
SD 
Standard Deviation 
SS 
Steady State 
τ 
Length of the Dosing Interval 
t1/2 
Apparent Terminal Elimination Half-Life 
Tlast 
Time of Last Measurable Concentration 
Tmax 
Time to Obtain Maximum Concentration (Cmax) 
Vd/F 
Apparent Volume of Distribution 


DMID Protocol 16-0005 
 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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1. 
PREFACE 
DMID Protocol 16-0005 is a Phase I study of oxfendazole in healthy adult volunteers. The 
pharmacokinetic (PK)-related objectives of the study are: 
• To define the multi-dose pharmacokinetics of oxfendazole 
• To determine the effect of food on the pharmacokinetics of oxfendazole 
This document reiterates key PK elements in the study design of 16-0005 and thoroughly 
describes the presentations and summaries of PK data as well as the noncompartmental analysis 
(NCA) to be included in a PK Report or in the clinical study report (CSR). Shells and mockups 
are given for all tables, figures, and listings planned for inclusion in the report. 
Any deviation from this statistical plan will be described and justified in protocol amendments 
and/or in the report, as appropriate. The reader of this SAP is encouraged to also review the 
clinical protocol for details on conduct of the study and the operational aspects of clinical 
assessments. 
Some minor modifications may be necessary to the planned design of tables, figures, and listings 
to accommodate data collected during the actual study conduct. 


DMID Protocol 16-0005 
 
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2. 
CLINICAL STUDY METHODS 
2.1. 
Treatment Groups 
This Phase I study is an open label multiple ascending dose evaluation of the safety and PK of 
oxfendazole (3, 7.5, or 15 mg/kg) in healthy adult men and nonpregnant women aged 18-45 
(inclusive) followed by a single dose crossover trial evaluating the safety and pharmacokinetics 
of a single dose of oxfendazole (3 mg/kg) given following an 8 hour fast or following a high fat 
meal. 
In the multiple ascending dose trial, each dose group will be comprised of 8 subjects, all of 
whom will receive study product once daily for 5 days. To enhance safety, 1 sentinel subject will 
be enrolled and followed for 7 days for defined safety events. A second sentinel subject will then 
be enrolled and followed for 7 days. If no predefined safety events are identified, the remaining 6 
subjects in this group will be enrolled. All volunteers will be followed for 10 days and PK, safety 
laboratory and EKG studies will be performed. If no predefined safety events occur after all 8 
subjects have completed the Day 10 visit, the DMID Medical Monitor will issue approval to 
proceed with enrollment of the second group of 8 subjects, who will receive 5 days of 7.5 mg/kg 
of oxfendazole using the same enrollment plan as outlined above. If no predefined safety events 
are encountered, the third group of 8 subjects will be enrolled to receive 5 days of 15 mg/kg 
using the same enrollment plan.  
In the second phase of the study evaluating the effects of food on drug absorption, 12 subjects 
will be enrolled into a randomized, single dose, two-period, two-treatment (2x2) crossover trial. 
In the first period of this trial, half of the subjects will initially receive a single dose of 3 mg/kg 
of oxfendazole following an 8 hour fast, and the other half will receive a single dose of 3 mg/kg 
of oxfendazole following a high fat breakfast. After a one-week wash-out period, subjects will 
cross over in the second period to receive a single dose following a high fat breakfast or 8 hour 
fast. The order of conditions, Sequence A (fasted condition first) and Sequence B (fed condition 
first), will be randomly assigned upon enrollment in a 1:1 ratio. 
Subjects who withdraw, or are withdrawn or terminated from the study, or are lost to follow-up 
after signing the informed consent form, randomization, and receipt of 3 or more doses of study 
drug will not be replaced. If the subject has only received two or fewer doses of study drug prior 
to termination from the study, the subject will be replaced. If a subject vomits more than two 
doses (i.e. if vomiting occurs within 1 hour of study drug administration and the subject vomits 
on two days or more), the subject will be replaced. Additionally, if the subject vomits within 1 
hour after the receipt of the dose on day 1, the subject will be replaced. No more than two 
subjects will be replaced in any group. Unless prohibited by the volunteer, data and samples 
obtained prior to withdrawal will be included in study analysis. Subjects who withdraw, or are 
withdrawn or terminated from the study, or are lost to follow-up after signing the informed 
consent form and enrollment but before receipt of study product may be replaced. If a subject in 


DMID Protocol 16-0005 
 
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Group 4 is lost to follow up after the first dose, a replacement subject will be enrolled and 
randomized. 
2.2. 
Dose Administration 
In the first phase of the study, subjects will be administered oxfendazole q24 hours via oral 
syringe by a study nurse or investigator on Days 1, 2, 3, 4 and 5. Subjects will be fasting (water 
is permitted) for 8 hours prior to, and for 2 hours after, the administration of drug 
In the second phase, half of the subjects will receive a single dose of 3 mg/kg of oxfendazole 
following an 8 hour fast and the other half will receive a single dose following a high fat meal. 
After 7 days, each subject will cross over to receive a single dose of oxfendazole (3mg/kg) 
following either a high fat meal or following an 8 hour fast. Subjects receiving a high fat meal 
will be administered study product approximately 30 minutes (+/- 15 minutes) following 
completion of the meal. Subjects who fasted prior to receiving study product will remain fasting 
for 2 hours after administration of drug. Lunch and dinner will be provided. Subjects will be 
allowed to eat snacks but will be asked to avoid drinking grapefruit juice and excessive (>2 cups) 
coffee. 
Subjects in both phases of the study will be provided lunch and dinner on day of dosing. If vomiting 
occurs following ingestion of the study product, that dose will not be replaced. All subjects will 
be counseled to avoid drug, alcohol, and tobacco use through the end of the study. 
Additional details regarding study product administration can be found in the protocol and Manual 
of Procedures (MOP). 
2.3. 
PK Sampling Schedule Treatment Groups 
For the first phase of the study (Groups 1-3), 10 mL of blood for oxfendazole level will be drawn 
pre-dose and at 30 minutes, 1, 2, 3, 4, 6, 9, and 12 hours following the first dose. All times have 
a window of +/- 15 minutes except the 9 and 12 hour samples which have a window of +/- 30 
minutes. On Days 2, 3, and 4, blood will be sampled for oxfendazole level approximately 24 
hours (+/- 4 hours for Day 2, +/- 2 hours for Days 3 and 4) after the prior dose, but before the 
current study day dose. On Days 2, 3, and 4, approximately 2 hours (+/- 20 minutes) after 
administration of study drug, blood will be drawn for oxfendazole level. On Day 5, blood will be 
sampled pre-dose (24 hours +/- 2 hours after the prior dose) and at 30 minutes, 1, 2, 3, 4, 6, 9, 
and 12 hours (all times have a window of +/- 15 minutes except the 9 and 12 hour samples which 
have a window of +/- 30 minutes). Blood will also be sampled for oxfendazole level on Day 6, 
approximately 24 hours after dosing on Day 5 (+/- 6 hours) and Days 8 (+/- 1 day) and 10 (+/- 2 
days). 
In the second phase of the study (Group 4), blood sampling for oxfendazole level will be 
performed pre-dose and at 30 minutes, 1, 2, 3, 4, 5, 9, 12 and 24 hours following each dose on 
Day 1 and Day 8 (+/- 1 day). All times have a window of +/- 15 minutes except the 9 and 12 


DMID Protocol 16-0005 
 
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hour samples which have a window of +/- 30 minutes and the 24-hour sample which has a 
window of +/- 4 hours. Blood will also be sampled for oxfendazole level on Day 14 (+/- 2 days). 
The exact time for all blood draws for oxfendazole level will be recorded and used for 
pharmacokinetic noncompartmental analysis (NCA). 
2.4. 
Analytical Methods 
Measurement of oxfendazole plasma concentrations will be performed by the Dr. Guohua An's 
Pharmacokinetics & Pharmacodynamics laboratory at the University of Iowa using a validated 
liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for quantification of 
oxfendazole in human plasma with sodium heparin with lower limit of quantification (LLOQ) of 
0.5 ng/mL.  
Blood samples for PK analysis will be collected in tubes containing sodium heparin as the 
anticoagulant at baseline. The blood samples (10 mL) will be placed on ice after draw, and 
centrifuged within 1 hour at 4-8°C at approximately 3000 rpm for 15 minutes. The plasma will 
then be collected and stored frozen at –80°C until analyzed. Plasma samples will be shipped to 
the analytical lab frozen.  
2.5. 
Collection of Pharmacodynamic or Clinical Endpoints 
Not applicable. 


DMID Protocol 16-0005 
 
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3. 
PHARMACOKINETIC ANALYSIS METHODS 
3.1. 
Analysis Populations and Handling of Missing Time Points 
All subjects receiving study drug and having at least 1 measurable drug concentration will be 
included in the multiple ascending dose study PK population or the food effect study PK 
population, as appropriate. If there are subjects who do not have sufficient samples for a 
complete analysis, a modified analysis will be conducted in which some or all PK parameters 
may not be estimated for those subjects, but available PK concentrations will still be tabulated 
and graphed.  
If any subjects are found to be noncompliant with respect to dosing, have incomplete data, or 
experience an event that is likely to affect PK, the Sponsor, the Investigator, and the Statistician 
will determine their inclusion into the population on a case-by-case basis. Subjects excluded 
from the PK analyses and their reasons for exclusion will be denoted and detailed. 
PK sample concentrations identified as laboratory errors will be indicated as such in the report 
and may be excluded from analyses. Time points below the lower limit of quantification (LLOQ) 
preceding the first PK concentration above the LLOQ will be imputed as 0. Pharmacokinetically 
plausible concentration value(s) below LLOQ at time points between two measurable 
concentration values (e.g., at trough timepoints) will be replaced by the LLOQ/2 value for 
graphing purposes only, and treated as missing for analyses. All other PK sample concentrations 
below the LLOQ will be treated as missing for analyses. Missing PK sample concentrations will 
not be imputed for the NCA. A geometric mean of concentrations will be treated as missing for 
sets of data points containing a below the quantification limit (BQL) value. 
3.2. 
Demographic and Baseline Characteristics 
Sex, race, age, weight, height, and body mass index (BMI) of subjects in the PK population will 
be listed and summarized by treatment group (Listing 1, Table 1, and Table 2). 
3.3. 
Dosing and Pharmacokinetic Sampling Summary 
Subject dose administration times will be presented (Listing 2). Special cases that potentially 
affect the analysis will be discussed. Drug plasma concentrations will be listed by group and 
subject, with BQL, out of sample time window, and PK analyses-excluded samples indicated 
(Listing 3). The listings will also indicate, for each sample, the associated dose number, nominal 
and actual time since first dose, and actual time since the preceding dose.  
Important protocol deviations related to dosing or PK sampling will be discussed. Potentially 
important bioanalytical errors and their effect on the PK analysis will also be discussed. 
For Groups 1-3, Table 3, Table 4, and Table 5 will list and summarize drug concentrations for 
Dose 1 and Table 6, Table 7, and Table 8 will summarize drug concentrations for Dose 5. As 
only peak and trough concentrations are measured for doses 2-4, these concentrations will be 


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displayed in Table 9, Table 10, and Table 11. For Group 4, Table 12, Table 13, Table 14, and 
Table 15 will list and summarize drug concentrations by sequence and period. 
The following figures will display concentration data for the multiple ascending dose phase 
(Groups 1-3): 
• Linear scale concentration profiles of all subjects, color-coded by dose group 
(Figure 1) 
• Linear plot of mean concentration for each dose group over time, with error bars 
representing standard deviation, color-coded by dose group (Figure 3) 
• Linear scale concentration profile for each subject individually, repeated for all 
subjects (Figure 5) 
• Data from Figures 1, 3 and 5 will be presented on a semi-log scale in Figure 2, 
Figure 4, and Figure 6. 
The following figures will display concentration data for the second phase evaluating food 
effects (Group 4): 
• Linear scale concentration profiles of all subjects, displayed by sequence and period 
(Figure 7) 
• Linear plot of mean concentration for each condition over time, with error bars 
representing standard deviation, color-coded by condition (Figure 9) 
• Linear scale concentration profile of each condition for each subject individually, 
repeated for all subjects (Figure 11) 
• Data from Figure 7, Figure 9, and Figure 11 will be presented on a semi-log scale in 
Figure 8, Figure 10 and Figure 12. 
3.4. 
Definition and Estimation of Individual PK Parameters 
The PK parameters listed below will be estimated through a NCA using version 8.0 of Phoenix 
WinNonlin (Pharsight Corporation, Cary, NC). Actual post-dose time will be used for the 
estimation of PK parameters instead of nominal time. Subject-specific PK parameters will be 
presented (Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22  Table 27 , 
Listing 3, Listing 4, and Listing 5). 
Phoenix WinNonlin NCA will use the following settings to compute parameters from plasma PK 
data: 
• Linear Up Log Down calculation method 
• Uniform weighting 
• Extravascular dose 
• Lambda Z Acceptance Criteria 
o Rsq_adjusted ≥ 0.85 
o Span ≥ 1.5 half-lives 
 
 


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Cmax 
Maximum concentration (Cmax) is defined as the maximum observed drug concentration 
observed over all PK sample concentrations for a given dose, and will be obtained from the 
Cmax parameter calculated by Phoenix WinNonlin. 
Ctrough 
Pre-dose trough concentration (Ctrough) is defined as the drug concentration observed at the last 
planned timepoint prior to dosing. Since there is no dose following Day 5, Ctrough for that day is 
defined as the concentration 24 hours (nominal time) after dosing. 
Tmax 
Time of maximum concentration (Tmax) is defined as the time at which the maximum 
concentration occurs within the given dosing interval and will be obtained from the Tmax 
parameter calculated by Phoenix WinNonlin. 
λz 
The terminal phase elimination rate constant (λz) is defined as the first-order rate constant 
describing the rate of decrease of drug concentration in the terminal phase (defined as the 
terminal region of the PK curve where drug concentration follows first-order elimination 
kinetics), and will be obtained from the Lambda_z parameter calculated by Phoenix WinNonlin. 
λz will be computed as the slope of a terminal region consisting of at least 3 successive points in 
the plot of log-transformed concentration data versus time. λz will be estimated using uniform 
weighting. Time points used in the estimation of λz will be initially selected using the Phoenix 
WinNonlin automatic algorithm. The set of points chosen must contain only timepoints after 
Tmax, include at least 3 timepoints, and satisfy the Lambda Z Acceptance Criteria described 
above.  The range of concentrations used to estimate λz for each profile will be inspected by the 
PK analyst, and the PK analyst may adjust the set of concentrations used to estimate λz if deemed 
necessary, but manually selected ranges must satisfy the same acceptance criteria as those chosen 
automatically by the Phoenix WinNonlin algorithm.  
Drug concentrations used to calculate λz will be indicated in Listing 3. 
λz will be estimated for Doses 1 and 5 in Groups 1, 2, and 3, and for Group 4. 
t½  
The apparent terminal elimination half-life (t½) is defined as the time required for the drug 
concentration to decrease by a factor of one-half in the terminal phase. The apparent terminal 
elimination half-life (t½) will be estimated as ln (2) / λz and will be obtained from the 
HL_Lambda_z parameter calculated by Phoenix WinNonlin.  t½ will be estimated for Doses 1 
and 5 in Groups 1, 2, and 3, and for Group 4, when λz is estimable. 
 
 


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AUC 
AUC is defined as the area under the concentration-time curve. AUC will be estimated using the 
Linear Up Log Down calculation method. 
AUCτ 
AUCτ is defined as AUC of a single dosing period. In groups 1-3, AUCτ for a given dose will be 
calculated as AUC from time of dosing to the end of the 24-hour dosing interval for Dose 1 and 
Dose 5.  AUCτ will be obtained in Phoenix WinNonlin using the Partial Area functionality. 
AUClast 
AUClast is defined as the AUC from dosing to the time of the last measured concentration ≥ 
LLOQ (Clast) of that dosing period and will be obtained from the AUClast parameter calculated 
by Phoenix WinNonlin. 
AUC (0-∞) 
AUC (0-∞) is defined as the AUC from dosing taken to the limit as the end time becomes 
arbitrarily large. AUC(0-∞) for a given dose will be estimated by adding AUClast for that dose to 
an extrapolated value equal to the last measured concentration greater than the LLOQ divided by 
λz: 
AUC(0-∞) = AUClast + Clast
λZ
, 
where Clast is the last measured concentration ≥ LLOQ. AUC(0-∞) will be obtained from the 
AUCINF_obs parameter calculated by Phoenix WinNonlin If the amount extrapolated portion of 
AUC(0-∞) is >25%, the estimated AUC(0-∞) value will be flagged when listed in the report and will 
be excluded from downstream statistical analyses, but included in the calculation of summary 
statistics. 
AUCτ, will be estimated for Dose 1 and Dose 5 in Groups 1, 2, and 3. AUClast will be estimated for 
Dose 5 in Groups 1, 2 and 3, and for Group 4. AUC(0-∞) will be estimated for Group 4 when λz is 
estimable. 
CL/F 
For Group 4, apparent oral clearance (CL/F) will be calculated as Dose/AUC(0-∞) and will be 
obtained from the CL_F parameter in Phoenix WinNonlin. If the amount extrapolated portion of 
AUC(0-∞) is >25%, the estimated CL/F value will be flagged when listed in the report, but 
included in the calculation of summary statistics. 
CLSS/F 
For Groups 1, 2 and 3, apparent oral clearance at steady state (CLSS/F) will be calculated as the 
dose in mg/kg divided by the AUCτ for Dose 5 (expected steady state) and will be obtained from 
the Clss_F parameter calculated by Phoenix WinNonlin. 


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CLSS/F = 
Dose
AUCτ,  Dose 5
 
Vd/F 
For Group 4, apparent volume of distribution (Vd/F) will be calculated as (CL/F)/ λz and will be 
obtained from the Vz_F parameter in Phoenix WinNonlin. If the amount extrapolated portion of 
AUC(0-∞) is >25%, the estimated Vd/F value will be flagged when listed in the report, but 
included in the calculation of summary statistics. 
AR 
For Groups 1, 2 and 3, the observed accumulation ratio (AR) is defined as the ratio of exposure 
parameters following multiple and single dosing. AR will be calculated using AUCτ and Cmax: 
AR = AUCτ,  Dose 5
AUCτ, Dose 1
, 
AR = Cmax,  Dose 5
Cmax, Dose 1
 
When λZ is estimable, AR will also be estimated using the elimination rate λz from Dose 5: 
AR = 
1
1-e-λZτ , 
where τ is the length of the dosing interval, 24 hours. 
3.5. 
Descriptive Statistics and Inference of PK Parameters 
3.5.1. 
Pharmacokinetic Parameter Summaries 
All PK parameters will be summarized using descriptive statistics: N, Mean, standard deviation 
(SD), Min, Max, Median, coefficient of variation as a percent (CV %), and geometric mean 
(GM). A subset of PK parameters will be summarized by dose and dose group where appropriate 
(Table 16, Table 17, Table 18, Table 19, Table 20, and Table 21). Group 4 parameters will be 
summarized by condition (Table 22). 
3.5.2. 
Analysis of Sex Differences in PK 
This study was not designed to formally assess differences in PK by sex. During the course of 
this study, preclinical evidence suggestive of sex-based differences in PK became available 
(communication with Sponsor). To facilitate a descriptive comparison of PK by sex, select PK 
parameters will be summarized by dose, dose group, and sex (Table 24 and Table 25). Group 4 
parameters will be summarized by condition and sex (Table 25). AUCτ, Cmax and Ctrough will also 
be presented graphically by dose, dose group, and sex in box plots for Groups 1, 2 and 3 
(Figure 13, Figure 14, and Figure 15). Box plots of AUClast and Cmax will be presented by sex and 
fed/fasted condition for Group 4 (Figure 16). Scatter plots of AUCτ, Cmax and Ctrough by dose, 
dose group, weight, and sex will also be presented for Groups 1, 2, and 3 (Figure 17, Figure 18 , 


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and Figure 19). Scatter plots of AUClast and Cmax will be presented by weight, sex, and fed/fasted 
condition for Group 4 (Figure 20). 
For the statistical models described in Sections 3.5.3 and 3.5.5, sex will be added as a covariate. 
The models with and without the additional covariate for sex will be compared, and the final 
model will be chosen based on Akaike Information Criterion (AIC) and graphical diagnostics of 
model assumptions and fit. 
3.5.3. 
Attainment of Steady State 
Attainment of steady state by Dose 5 will be assessed by visual examination of the concentration 
versus time plots (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, and Figure 6).  
Graphical findings will be supported by statistical comparison of Cmax and Ctrough values on Day 
5 with the corresponding values on Day 4 and Day 3. Cmax and Ctrough will be log-transformed 
and analyzed using the following mixed effects model for Yijk, the log-transformed exposure 
parameter observed on the kth subject on day j of dose group i: 
Yijk= μ+ πj+λ𝑖𝑖+τd[i,j]+sik+𝜀𝜀ijk 
where µ is the intercept; πj is a fixed effect associated with day j; λi is a fixed effect associated 
with dose group i, τd[i,j] is a fixed effect associated with the interaction of day j and dose group i; 
sik is a random effect associated with the kth subject in dose group i, and eijk is a random error 
term with mean 0 and variance 𝜎𝜎𝑒𝑒
2. This model will be fit using restricted maximum likelihood 
estimation (REML) in SAS PROC MIXED, with the Kenward and Roger denominator degrees 
of freedom.1 Covariance structure will be selected based on AIC, from the following candidate 
structures: variance components, first-order autoregressive, compound symmetry, Toeplitz, and 
unstructured. SAS code will be similar to: 
PROC MIXED; 
 
CLASS DAY DOSEGROUP SUBJECT; 
 
MODEL LCMAX = DAY DOSEGROUP DAY*DOSEGROUP / DDFM=KR; 
 
RANDOM SUBJECT / TYPE = VC; 
 
LSMEANS DAY*DOSEGROUP / PDIFF CL; 
RUN; 
The mean difference in log-transformed parameter (Cmax or Ctrough) between Day 5 and each of 
Days 4 and 3 at each dose level will be back transformed to obtain the geometric mean ratio. 
Contrasts of model parameters will be used to generate 95% confidence intervals for the 
geometric mean ratios. The geometric mean ratios and corresponding confidence intervals will 
be graphically depicted in Figure 25 and reported in Table 26, alongside the p-value for the 
hypothesis test of no difference in log-transformed Cmax and Ctrough between Day 5 and each of 
Days 4 and 3 at each dose level.  
 


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3.5.4. 
Summary of Accumulation upon Multiple Dosing 
Accumulation ratio will be summarized for each dose group in Groups 1-3 (Table 27). 
3.5.5. 
Analysis of Dose Proportionality 
The presence of dose proportionality over the range of studied dose levels for Groups 1-3 will be 
assessed using the exposure parameters AUCτ, Cmax, and Ctrough of Dose 1 and at expected 
steady-state (Dose 5).  Analysis will be conducted with the power model as described by Smith 
et al2: 
AUCτ = eα × doseβ. 
Let 𝜌𝜌 be the ratio (highest dose studied / lowest dose studied) and let (L, U) represent the 90% 
confidence interval for 𝛽𝛽̂. In the presence of dose proportionality, 𝜌𝜌𝛽𝛽෡−1 = 1. Accordingly, using 
the bioequivalence criteria of the current FDA guidance3, dose proportionality across the studied 
dose range is concluded when: 
Θl = 0.8 ≤ ρL-1 < ρU-1 ≤ 1.25 = Θh. 
Or, equivalently, 
1 + ln 0.8
ln ρ  ≤ L < U ≤ 1 + ln 1.25
ln ρ . 
Dose proportionality using Cmax and Ctrough will also be assessed using the same approach. Point 
estimates and 90% confidence intervals for 𝛽𝛽̂ will be presented (Table 28). Predicted values from 
the power model including 90% prediction bands will be overlaid on plots of exposure data 
(AUCτ, Cmax) by dose in mg/kg (Figure 21, Figure 22). Additionally, ANOVA on the log-
transformed parameters will be used to construct confidence intervals of the geometric means of 
dose-adjusted AUCτ and Cmax by dose, which will be displayed in Table 29 and plotted side-by-
side in order of increasing dosage (Figure 23, Figure 24).  
3.5.6. 
Analysis of Changes in Tmax by Dose Number and Dose Level 
Shift in Tmax between Dose 1 and Dose 5 for Groups 1, 2 and 3 will be tested using the Wilcoxon 
signed-rank test procedure. Point estimates of the shift (the Hodges-Lehmann estimator) and 
associated 90% confidence intervals will be provided (Table 30). A test for any difference in 
Tmax among the three studied dose levels will be performed using the Kruskal-Wallis one-way 
ANOVA on ranks. 
3.5.7. 
Analysis of Food Effect 
Determination of the effect of food on the kinetics of oxfendazole in Group 4 will be conducted 
in accordance with current FDA guidance3,4. Key exposure parameters (AUC(0−∞), AUC(0−last), 
and Cmax) will be log-transformed and analyzed using the following mixed effects model for Yijk, 
the log-transformed exposure parameter observed for the ith condition (fed/fasted) for the kth 
subject in period j: 


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Yijk= μ+ πj+λd[i,j]+τd[i,j]+sk+𝜀𝜀ijk 
where µ is an intercept; πj is a fixed effect associated with period j; λi is a fixed effect associated 
with the condition i, τd[i,j] is a fixed effect associated with the interaction of period j and condition 
i; and sik is a random effect associated with the kth subject with mean 0 and variance 𝜎𝜎𝑠𝑠
2, and eijk 
is a random error term with mean 0 and variance 𝜎𝜎𝑒𝑒
2. 
The model will be fit using REML in SAS PROC MIXED. Point estimates and 90% confidence 
intervals for the mean difference between fed and fasted conditions will be constructed for each 
log-transformed exposure parameter. SAS code will be similar to: 
PROC MIXED; 
 
CLASS PERIOD CONDITION SUBJECT; 
 
MODEL LCMAX = PERIOD CONDITION PERIOD*CONDITION / DDFM=KR; 
 
RANDOM SUBJECT; 
 
LSMEANS CONDITION / ALPHA=0.1 PDIFF CL; 
RUN; 
Point and interval estimates of the mean difference in log-transformed exposure parameters will 
then be back-transformed to obtain point estimates and 90% confidence intervals for the ratio of 
geometric means of the parameters. Equivalence between the fasting and fed conditions will be 
based on whether the 90% confidence interval for the ratio of the population geometric mean of 
the parameter measured from the 2 conditions is contained in the interval [0.80, 1.25].  
In addition, for each exposure parameter, the intrasubject coefficient of variation (CVW ) will be 
calculated to provide an estimate of the variability in exposure within the same subject, when the 
subject is administered one dose of study product on two separate occasions.  
For normally distributed data with mean µ and variance σ2, coefficient of variation is defined as: 
CV  = ඨVar ൬ X - μ 
μ
൰= σ
𝜇𝜇= ඥVar(X)
E(X)
 
If X is instead distributed log-normally (i.e., Y = log(X) is normally distributed with mean µ and 
variance σ2), then: 
E(X) = exp ቆμ + σ2
2 ቇ 
Var(X) =[exp(σ2) −1] exp൫2μ + σ2൯ 
The coefficient of variation can be written in terms of σ2 as: 
CV = ඥVar(X)
E(X)
=
ቂඥexp(σ2) - 1ቃ exp ൬μ + σ2
2 ൰
 exp ൬μ + σ2
2 ൰
= ඥexp(σ2) - 1 


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Thus, the intrasubject coefficient of variation can be estimated from the model on log-transformed 
data as:  
CVW 
෣= ඥexp(MSE) - 1 
where MSE is the residual mean squared error from the model. Results from the statistical 
analysis of food effect will be shown in Table 31. 
Distributional assumptions and homoscedasticity will be assessed by residual plots and/or other 
graphical diagnostics. Alternative analyses will be considered if assumptions are violated. 
Food effect on Tmax will be assessed with the Wilcoxon signed-rank test procedure. The Hodges-
Lehmann estimator (pseudomedian) for the difference in Tmax between fed and fasted conditions 
will be reported, as well as the associated 90% confidence interval will be displayed in Table 32. 
Potential differences in Tmax due to sequence effects will be explored graphically. 
3.6. 
Comparison of Current Pharmacokinetic Results to Pharmacokinetic Results 
from Previous Studies 
Not applicable. 


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4. 
REFERENCES 
1. Kenward, M. G. and Roger, J. H. Small sample inference for fixed effects estimators 
from restricted maximum likelihood. Biometrics 53 (1997): 983-997.  
2. Smith, Brian P., et al. Confidence interval criteria for assessment of dose proportionality. 
Pharmaceutical Research 17.10 (2000): 1278-1283. 
3. Food and Drug Administration. Guidance for Industry: Statistical Approaches to 
Establishing Bioequivalence, January 2001.  
4. Food and Drug Administration. Guidance for Industry: Food-Effect Bioavailability and 
Fed Bioequivalence Studies, December 2002. 
5. Food and Drug Administration. Guidance for Industry: Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products – General 
Considerations, March 2003. 
 


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5. 
LISTING OF PROPOSED TABLES, FIGURES, AND LISTINGS 
Proposed table, figure, and listing shells are presented in Appendices I, II, and III. 
 


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6. APPENDICES 
Appendix I: List of Proposed Tables 
LIST OF TABLES 
Table 1: 
Summary of Demographic and Baseline Characteristics of Subjects Included 
in the Multiple Ascending Dose Trial PK Analysis ...................................................18 
Table 2: 
Summary of Demographic and Baseline Characteristics of Subjects Included 
in the Food Effect Trial PK Analysis .........................................................................19 
Table 3: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
1 (3 mg/kg), Dose 1 ....................................................................................................20 
Table 4: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
2 (7.5 mg/kg), Dose 1 .................................................................................................20 
Table 5: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
3 (15 mg/kg), Dose 1 ..................................................................................................20 
Table 6: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
1 (3 mg/kg), Dose 5 ....................................................................................................21 
Table 7: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
2 (7.5 mg/kg), Dose 5 .................................................................................................21 
Table 8: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
3 (15 mg/kg), Dose 5 ..................................................................................................21 
Table 9: 
Peak and Trough Concentrations by Dose: Group 1 (3 mg/kg) .................................22 
Table 10: Peak and Trough Concentrations by Dose: Group 2 (7.5 mg/kg) ..............................22 
Table 11: Peak and Trough Concentrations by Dose: Group 3 (15 mg/kg) ...............................22 
Table 12: Individual Concentrations and Summary Statistics by Nominal Time: Group 
4 Sequence A, Period 1 (3mg/kg, Fasted) ..................................................................23 
Table 13: Individual Concentrations and Summary Statistics by Nominal Time: Group 
4 Sequence A, Period 2 (3mg/kg, Fed) .......................................................................24 
Table 14: Individual Concentrations and Summary Statistics by Nominal Time: Group 
4 Sequence B, Period 1 (3mg/kg, Fed) .......................................................................24 
Table 15: Individual Concentrations and Summary Statistics by Nominal Time: Group 
4 Sequence B, Period 2 (3mg/kg, Fasted) ...................................................................24 
Table 16: Individual PK Parameters and Summary Statistics: Group 1 (3 mg/kg),  Dose 
1 ..................................................................................................................................25 
Table 17: Individual PK Parameters and Summary Statistics: Group 1 (3 mg/kg),  Dose 
5 ..................................................................................................................................26 


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Table 18: Individual PK Parameters and Summary Statistics: Group 2 (7.5 mg/kg),  
Dose 1 .........................................................................................................................26 
Table 19: Individual PK Parameters and Summary Statistics: Group 2 (7.5 mg/kg),  
Dose 5 .........................................................................................................................26 
Table 20: Individual PK Parameters and Summary Statistics: Group 3 (15 mg/kg),  
Dose 1 .........................................................................................................................26 
Table 21: Individual PK Parameters and Summary Statistics: Group 3 (15 mg/kg),  
Dose 5 .........................................................................................................................26 
Table 22: Individual PK Parameters and Summary Statistics: Group 4 .....................................27 
Table 23: Summary Statistics of PK Parameters by Group and Sex: Groups 1, 2 and 3, 
Dose 1 .........................................................................................................................28 
Table 24: Summary Statistics of PK Parameters by Group and Sex: Groups 1, 2 and 3, 
Dose 5 .........................................................................................................................29 
Table 25: Summary Statistics of PK Parameters by Group and Sex: Group 4 ...........................30 
Table 26: Statistical Analysis of Attainment of Steady State .....................................................31 
Table 27: Population Summary Statistics for Accumulation Ratio ............................................32 
Table 28: Dose Proportionality Power Model Estimates: Groups 1-3 .......................................33 
Table 29: Geometric Mean Dose-adjusted Exposure by Dose Group ........................................34 
Table 30: Summary of Shift in Tmax following Multiple Dosing ................................................35 
Table 31: Statistical Analysis of Food Effect on Exposure ........................................................35 
Table 32: Statistical Analysis of Food Effect on Tmax ................................................................35 
 


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Table 1: Summary of Demographic and Baseline Characteristics of Subjects Included in 
the Multiple Ascending Dose Trial PK Analysis 
Note: Racial categories will be expanded as appropriate. 
Parameter 
Group 1  
(3 mg/kg) 
(N=) 
Group 2  
(7.5 mg/kg) 
(N=) 
Group 3  
(15 mg/kg) 
(N=) 
All Groups 
(N=) 
Sex – N (%) 
 
 
 
 
Male 
x (x) 
x (x) 
x (x) 
x (x) 
Female 
x (x) 
x (x) 
x (x) 
x (x) 
Age (Years) 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x  
x, x  
x, x  
Height (cm) 
 
 
 
 
Mean (SD) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
Median 
x 
x 
x 
x 
Min, Max 
x, x 
x, x  
x, x  
x, x  
Weight (kg) 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
BMI (kg/m2) 
 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
Race – N (%) 
 
 
 
 
Black or African 
American 
x (x) 
x (x) 
x (x) 
x (x) 
White 
x (x) 
x (x) 
x (x) 
x (x) 
 
 


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Table 2: Summary of Demographic and Baseline Characteristics of Subjects Included in 
the Food Effect Trial PK Analysis 
Note: Racial categories will be expanded as appropriate. 
Parameter 
Group 4, Sequence A 
(N=) 
Group 4, 
Sequence B 
(N=) 
All Groups 
(N=) 
Sex – N (%) 
 
 
 
Male 
x (x) 
x (x) 
x (x) 
Female 
x (x) 
x (x) 
x (x) 
Age (Years) 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
Height (cm) 
 
 
 
Mean (SD) 
x (x.x) 
x (x.x) 
x (x.x) 
Median 
x 
x 
x 
Min, Max 
x, x 
x, x 
x, x 
Weight (kg) 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
Min, Max 
x.x, x.x 
x.x, x.x 
x.x, x.x 
BMI (kg/m2) 
 
 
 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median 
x.x 
x.x 
x.x 
Min, Max 
x.x, x.x 
x.x, x.x 
x.x, x.x 
Race – N (%) 
 
 
 
Black or African American 
x (x) 
x (x) 
x (x) 
White 
x (x) 
x (x) 
x (x) 
 


DMID Protocol 16-0005  
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan 
09 October 2018 
-20- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 3: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 1 (3 mg/kg), Dose 1 
Subject ID 
Nominal Time After Dose 1(hours) 
Pre-dose 
0.5 
1 
2 
3 
4 
6 
9 
12 
24 
99ZZZ001 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ002 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ003 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Statistic 
 
 
 
 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
(Min, Max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come after a PK sample concentration that is 
above the LLOQ and treated as missing otherwise. 
Table 4: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 2 (7.5 mg/kg), Dose 1 
Table 5: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 3 (15 mg/kg), Dose 1 
Table 4 and Table 5 will use the form of Table 3 to display corresponding data for Groups 2 and 3. 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan 
09 October 2018 
-21- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 6: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
1 (3 mg/kg), Dose 5 
Subject ID 
Nominal Time After Dose 5 (hours) 
Pre-dose 
.5 
1 
2 
3 
4 
6 
9 
12 
24 
72 
120 
99ZZZ001 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ002 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ003 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Statistic 
 
 
 
 
 
 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
(Min, Max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) (x, x) 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
Table 7: Individual Concentrations and Summary Statistics by Nominal Time: Group 2 
(7.5 mg/kg), Dose 5 
Table 8: Individual Concentrations and Summary Statistics by Nominal Time: Group 3 
(15 mg/kg), Dose 5 
Table 7 and Table 8 will use the form of Table 6 to display corresponding data for Group 2 
 and Group 3. 
 
 


DMID Protocol 16- 0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan 
09 October 2018 
-22- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 9: 
Peak and Trough Concentrations by Dose: Group 1 (3 mg/kg) 
 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
Peak1 
Trough2 
Peak 
Trough 
Peak 
Trough 
Peak 
Trough 
Peak 
Trough 
99ZZZ001 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ002 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ003 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Statistic 
 
 
 
 
 
 
 
 
 
 
N3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
(Min, Max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
1 Peak concentration is shown in this table as concentration at 2 hours (nominal time) after the corresponding dose. 
2 Trough concentration is shown in this table as concentration at 24 hours (nominal time) after the corresponding 
dose. 
3 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
Table 10: Peak and Trough Concentrations by Dose: Group 2 (7.5 mg/kg) 
Table 11: Peak and Trough Concentrations by Dose: Group 3 (15 mg/kg) 
Table 10 and Table 11 will use the form of Table 9 to display corresponding data for Group 2 
and Group 3. 
 
 


DMID Protocol 16- 0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan 
09 October 2018 
-23- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 12: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
4 Sequence A, Period 1 (3mg/kg, Fasted) 
Subject ID 
Nominal Time After Dose (hours) 
Pre-
dose 
0.5 
1 
2 
3 
4 
6 
9 
12 
24 
99ZZZ001 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ002 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ003 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Statistic 
 
 
 
 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
(Min, Max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
 
 


DMID Protocol 16- 0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan 
09 October 2018 
-24- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 13: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 
4 Sequence A, Period 2 (3mg/kg, Fed) 
Subject ID 
Nominal Time After Dose (hours) 
Pre-
dose 
.5 
1 
2 
3 
4 
6 
9 
12 
24 
144 
99ZZZ001 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ002 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
99ZZZ003 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
… 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Statistics 
 
 
 
 
 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
(Min, Max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
Table 14: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 4 
Sequence B, Period 1 (3mg/kg, Fed) 
Table 15: 
Individual Concentrations and Summary Statistics by Nominal Time: Group 4 
Sequence B, Period 2 (3mg/kg, Fasted) 
Table 14 and Table 15 will use the forms of Table 12 and Table 13 to display corresponding 
data for Group 4, Sequence B. 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
-25- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 16: 
Individual PK Parameters and Summary Statistics: Group 1 (3 mg/kg),  
Dose 1 
Subject ID 
AUCτ  
(ng·hr/mL) 
Tmax  
(hr) 
Cmax 
(ng/mL) 
Ctrough 
(ng/mL) 
λz 
 (hr-1) 
t1/2  
(hr) 
99ZZZ001 
x 
x.x 
x 
x 
x.x 
x.x 
99ZZZ002 
x 
x.x 
x 
x 
x.x 
x.x 
99ZZZ003 
x 
x.x 
x 
x 
x.x 
x.x 
… 
 
 
 
 
 
 
Statistic 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x.x 
x 
x 
x.x 
x.x 
Median 
x 
x.x 
x 
x 
x.x 
x.x 
Max 
x 
x.x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
-26- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 17: 
Individual PK Parameters and Summary Statistics: Group 1 (3 mg/kg),  
Dose 5 
Subject ID 
AUCτ 
(ng·hr/mL) 
AUClast 
(ng·hr/mL) 
Tmax  
(hr) 
Cmax 
(ng/mL) 
Ctrough 
(ng/mL) 
t1/2  
(hr) 
CLss/F 
(L/hr/kg) 
99ZZZ001 
x 
x 
x.x 
x 
x 
x.x 
x.x 
99ZZZ002 
x 
x 
x.x 
x 
x 
x.x 
x.x 
99ZZZ003 
x 
x 
x.x 
x 
x 
x.x 
x.x 
… 
 
 
 
 
 
 
 
Statistic 
 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x 
x 
x.x 
x 
Median 
x 
x 
x.x 
x 
x 
x.x 
x 
Max 
x 
x 
x.x 
x 
x 
x.x 
x 
CV % 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
Table 18: 
Individual PK Parameters and Summary Statistics: Group 2 (7.5 mg/kg),  
Dose 1 
Table 19: 
Individual PK Parameters and Summary Statistics: Group 2 (7.5 mg/kg),  
Dose 5 
Table 20: 
Individual PK Parameters and Summary Statistics: Group 3 (15 mg/kg),  
Dose 1 
Table 21: 
Individual PK Parameters and Summary Statistics: Group 3 (15 mg/kg),  
Dose 5  
Table 18, Table 19, Table 20, and Table 21 will use the forms of Table 16 and Table 17 to 
display corresponding data for Groups 2 and 3. 
 


DMID Protocol 16-0005 
 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
 
09 October 2018 
-27- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 22: 
Individual PK Parameters and Summary Statistics: Group 4 
Subject ID 
AUClast  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Tmax  
(hr) 
Cmax 
(ng/mL) 
t1/2  
(hr) 
CL/F 
(L/hr/kg) 
Vd/F 
(L/kg) 
 
Fed 
Fasted 
Fed 
Fasted 
Fed 
Fasted 
Fed 
Fasted 
Fed 
Fasted 
Fed 
Fasted 
Fed Fasted 
99ZZZ001 
x 
x 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
99ZZZ002 
x 
x 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
99ZZZ003 
x 
x 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Median 
x 
x 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Max 
x 
x 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come after a PK sample concentration that is 
above the LLOQ and treated as missing otherwise. 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
-28- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 23: 
Summary Statistics of PK Parameters by Group and Sex: Groups 1, 2 and 3, 
Dose 1 
Statistics 
AUCτ 
(ng·hr/mL) 
Tmax  
(hr) 
Cmax 
(ng/mL) 
Ctrough 
(ng/mL) 
t1/2  
(hr) 
 
Male 
Female 
Male 
Female 
Male 
Female 
Male 
Female Male 
Female 
Group 1 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Group 2 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Group 3 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
-29- 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
Table 24: 
Summary Statistics of PK Parameters by Group and Sex: Groups 1, 2 and 3, 
Dose 5 
Statistics 
AUCτ 
(ng·hr/mL) 
Tmax  
(hr) 
Cmax 
(ng/mL) 
Ctrough 
(ng/mL) 
t1/2  
(hr) 
 
Male 
Female 
Male 
Female 
Male 
Female 
Male 
Female Male 
Female 
Group 1 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Group 2 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Group 3 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Table 25: 
Summary Statistics of PK Parameters by Group and Sex: Group 4 
Statistics 
AUClast  
(ng·hr/mL) 
Tmax  
(hr) 
Cmax 
(ng/mL) 
t1/2  
(hr) 
 
Male 
Female 
Male 
Female 
Male 
Female 
Male 
Female 
Fed 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Fasted 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
Median 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
Max 
x 
x 
x.x 
x.x 
x 
x 
x.x 
x.x 
CV % 
x 
x 
x 
x 
x 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
1 Number of data points used to compute the summary statistics. BQL values were imputed as 0 if they did not come 
after a PK sample concentration that is above the LLOQ and treated as missing otherwise. 
 
 


DMID Protocol 16-0005 
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Table 26: 
Statistical Analysis of Attainment of Steady State 
Exposure 
Parameter 
Dose 
Level 
Day 3 vs. Day 5 Comparison1 
Day 4 vs. Day 5 Comparison1 
Geometric Mean Ratio 
(95% CI) 
p-value 
Geometric Mean Ratio 
(95% CI) 
p-value 
Cmax (ng/mL) 
3 mg/kg 
x.xxx (x.xxx, x.xxx) 
x.xxx 
x.xxx (x.xxx, x.xxx) 
x.xxx 
7.5 mg/kg 
x.xxx (x.xxx, x.xxx) 
x.xxx 
x.xxx (x.xxx, x.xxx) 
x.xxx 
15 mg/kg 
x.xxx (x.xxx, x.xxx) 
x.xxx 
x.xxx (x.xxx, x.xxx) 
x.xxx 
Ctrough(ng/mL) 
3 mg/kg 
x.xxx (x.xxx, x.xxx) 
x.xxx 
x.xxx (x.xxx, x.xxx) 
x.xxx 
7.5 mg/kg 
x.xxx (x.xxx, x.xxx) 
x.xxx 
x.xxx (x.xxx, x.xxx) 
x.xxx 
15 mg/kg 
x.xxx (x.xxx, x.xxx) 
x.xxx 
x.xxx (x.xxx, x.xxx) 
x.xxx 
1 Based on a mixed effects model with fixed effects of day, dose group, and day*dose group interaction, and random 
effect of subject. 
 
 


DMID Protocol 16-0005 
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Table 27: 
Population Summary Statistics for Accumulation Ratio 
AR Estimation Method 
 
Group 1  
(3 mg/kg) 
Group 2 
(7.5 mg/kg) 
Group 3 
(15 mg/kg) 
AR = AUCτ,  Dose 5
AUCτ, Dose 1
 
 
N 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
Min 
x.x 
x.x 
x.x 
Median 
x.x 
x.x 
x.x 
Max 
x.x 
x.x 
x.x 
CV % 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
AR = Cmax,  Dose 5
Cmax, Dose 1
 
N 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
Min 
x.x 
x.x 
x.x 
Median 
x.x 
x.x 
x.x 
Max 
x.x 
x.x 
x.x 
CV % 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
AR = 
1
1-e-λZτ 
 
N 
x 
x 
x 
Mean 
x.x 
x.x 
x.x 
SD 
x.x 
x.x 
x.x 
Min 
x.x 
x.x 
x.x 
Median 
x.x 
x.x 
x.x 
Max 
x.x 
x.x 
x.x 
CV % 
x 
x 
x 
GM 
x.x 
x.x 
x.x 
Note: λZ from Dose 5 is used to estimate AR. 
 


DMID Protocol 16-0005 
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Table 28: 
Dose Proportionality Power Model Estimates: Groups 1-3 
 
Exposure Parameter 
𝜷𝜷෡ 
90% CI 
Conclusion1 
Dose 1 
Cmax (ng/mL) 
x.xxx 
(x.xxx, x.xxx) 
Proportional 
Ctrough(ng/mL) 
x.xxx 
(x.xxx, x.xxx) 
Proportional 
AUCτ (ng ∙hr
mL) 
x.xxx 
(x.xxx, x.xxx) 
Proportional 
Dose 5 
Cmax (ng/mL) 
x.xxx 
(x.xxx, x.xxx) 
Not Proportional 
Ctrough(ng/mL) 
x.xxx 
(x.xxx, x.xxx) 
Not Proportional 
AUCτ (ng ∙hr
mL) 
x.xxx 
(x.xxx, x.xxx) 
Inconclusive 
1Based on comparison of 90% CI to limits of (x.xxx, x.xxx) in accordance with FDA-recommended bioequivalence 
criteria 
 
 


DMID Protocol 16-0005 
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Table 29: 
Geometric Mean Dose-adjusted Exposure by Dose Group 
 
 
Geometric Mean of Dose-adjusted Exposure (95% CI) 
 
Exposure Parameter 
Group 1 (3 mg/kg) 
Group 2 (7.5 mg/kg) 
Group 3 (15 mg/kg) 
Dose 1 
Cmax ൬ng/mL
mg/kg൰ 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Ctrough ൬ng/mL
mg/kg൰ 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
AUCτ ൬ng ∙hr/mL
mg/kg
൰ 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Dose 5 
Cmax ൬ng/mL
mg/kg൰ 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Ctrough ൬ng/mL
mg/kg൰ 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
AUCτ ൬ng ∙hr/mL
mg/kg
൰ 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Table 30: 
Summary of Shift in Tmax following Multiple Dosing 
 
Median Tmax (hr) 
Estimated Median 
Difference (hr) 
90% CI of Estimated 
Median Difference (hr) 
Dose 1 
Dose 5 
Group 1 (3 mg/kg) 
x.x 
x.x 
x.x 
x.x, x.x 
Group 2 (7.5 mg/kg) 
x.x 
x.x 
x.x 
x.x, x.x 
Group 3 (15 mg/kg) 
x.x 
x.x 
x.x 
x.x, x.x 
Table 31: 
Statistical Analysis of Food Effect on Exposure 
Parameter 
Fed GM 
Fasted GM 
Ratio  
(Fed / Fasted)  
90% CI of Ratio 
𝐂𝐂𝐂𝐂𝐖𝐖 (%) 
𝐀𝐀𝐀𝐀𝐀𝐀𝛕𝛕 
x.x 
x.x 
x.xxx 
(x.xxx, x.xxx) 
xx.xx 
𝐀𝐀𝐀𝐀𝐀𝐀(𝟎𝟎−∞) 
x.x 
x.x 
x.xxx 
(x.xxx, x.xxx) 
xx.xx 
𝐂𝐂𝐦𝐦𝐦𝐦𝐦𝐦 
x.x 
x.x 
x.xxx 
(x.xxx, x.xxx) 
xx.xx 
Table 32: Statistical Analysis of Food Effect on Tmax 
 
Fed Median 
Fasted 
Median 
Estimated 
Median 
Difference 
90% CI of Estimated 
Median Difference 
Wilcoxon Signed 
Rank Test P-Value 
Tmax 
x.x 
x.x 
x.xxx 
(x.xxx, x.xxx) 
x.xxx 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Appendix II: List of Proposed Figures 
LIST OF FIGURES 
Figure 1: 
Concentration Profiles for All Subjects, Groups 1-3 ..................................................37 
Figure 2: 
Semi-log Concentration Profiles for All Subjects, Groups 1-3 ..................................38 
Figure 3:  Mean Concentration Profiles, Groups 1-3 ..................................................................39 
Figure 4: 
Semi-log Geometric Mean Concentration Profiles, Groups 1-3 ................................40 
Figure 5: 
Subject Concentration Profile by Time, Group 1, Subject 99ZZZ001 .......................41 
Figure 6: 
Semi-log Plot of Concentration by Nominal Time, Group 1, Subject 
99ZZZ001 ...................................................................................................................42 
Figure 7:  Concentration Profiles for Group 4 by Sequence and Period .....................................43 
Figure 8:  Semi-log Concentration Profiles for Group 4 by Sequence and Period .....................43 
Figure 9:  Mean Concentration Profile, Group 4 ........................................................................44 
Figure 10:  Semi-log Geometric Mean Concentration Profile, Group 4 .......................................44 
Figure 11: Subject Concentration Profile by Time, Group 4, Subject 99ZZZ001 .......................45 
Figure 12: Semi-log Subject Concentration Profile by Time, Group 4, Subject 
99ZZZ001 ...................................................................................................................45 
Figure 13:  PK Parameters by Dose Number and Sex, Group 1 ..................................................46 
Figure 14:  PK Parameters by Dose Number and Sex, Group 2 ..................................................46 
Figure 15:  PK Parameters by Dose Number and Sex, Group 3 ..................................................46 
Figure 16:  PK Parameters by Condition and Sex, Group 4 ........................................................46 
Figure 17:  PK Parameters by Weight, Dose Number, and Sex, Group 1 ...................................47 
Figure 18:  PK Parameters by Weight, Dose Number, and Sex, Group 2 ...................................47 
Figure 19:  PK Parameters by Weight, Dose Number, and Sex, Group 3 ...................................47 
Figure 20:  PK Parameters by Weight, Condition, and Sex, Group 4 ..........................................47 
Figure 21:  Oxfendazole Exposure by Dose, Groups 1-3, Dose 1 ...............................................48 
Figure 22:  Oxfendazole Exposure by Dose, Groups 1-3, Dose 5 ...............................................48 
Figure 23: Dose-Adjusted Exposure by Dose, Groups 1-3, Dose 1 .............................................49 
Figure 24: Dose-Adjusted Exposure by Dose, Groups 1-3, Dose 5 .............................................49 
Figure 25: Assessment of Steady State – Geometric Mean Ratio and 95% CI for Cmax 
and Ctrough on Day 3 and Day 4 Relative to Day 5 by Dose Level .............................50 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 1: 
Concentration Profiles for All Subjects, Groups 1-3 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 2: 
Semi-log Concentration Profiles for All Subjects, Groups 1-3 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 3:  
Mean Concentration Profiles, Groups 1-3 
 
Note: Error bars show 1 standard deviation. 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 4: 
Semi-log Geometric Mean Concentration Profiles, Groups 1-3 
 
Note: Error bars show 1 geometric standard deviation. 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
09 October 2018 
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Figure 5: 
Subject Concentration Profile by Time, Group 1, Subject 99ZZZ001 
The following figure will be repeated for each subject in Groups 1-3. 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 6: 
Semi-log Plot of Concentration by Nominal Time, Group 1, Subject 
99ZZZ001 
The following figure will be repeated for each subject in Groups 1-3. 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 7:  
Concentration Profiles for Group 4 by Sequence and Period 
 
Figure 8:  
Semi-log Concentration Profiles for Group 4 by Sequence and Period 
 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 9:  
Mean Concentration Profile, Group 4 
 
Note: Error bars show 1 standard deviation. 
Figure 10:  
Semi-log Geometric Mean Concentration Profile, Group 4 
 
Note: Error bars show 1 geometric standard deviation. 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 11: Subject Concentration Profile by Time, Group 4, Subject 99ZZZ001 
The following figure will be repeated for each subject in Group 4. 
 
Figure 12: 
Semi-log Subject Concentration Profile by Time, Group 4, Subject 
99ZZZ001 
The following figure will be repeated for each subject in Group 4. 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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 Figure 13: 
 PK Parameters by Dose Number and Sex, Group 1 
 
Figure 14: 
 PK Parameters by Dose Number and Sex, Group 2 
Figure 15: 
 PK Parameters by Dose Number and Sex, Group 3 
Figure 14 and Figure 15 will use the form of Figure 13 to present analogous data for Group 2 
and Group 3. 
Figure 16: 
 PK Parameters by Condition and Sex, Group 4 
Figure 16 will use the form of Figure 13 to present AUClast and Cmax by fed/fasted condition 
instead of dose number for Group 4. 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 17: 
 PK Parameters by Weight, Dose Number, and Sex, Group 1 
 
Figure 18: 
 PK Parameters by Weight, Dose Number, and Sex, Group 2 
Figure 19: 
 PK Parameters by Weight, Dose Number, and Sex, Group 3 
Figure 18 and Figure 19 will use the form of Figure 17 to present analogous data for Group 2 
and Group 3. 
Figure 20: 
 PK Parameters by Weight, Condition, and Sex, Group 4 
Figure 20 will use the form of Figure 17 to present AUClast and Cmax by fed/fasted condition 
instead of dose number for Group 4. 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 21: 
 Oxfendazole Exposure by Dose, Groups 1-3, Dose 1 
 
Note: Blue line represents predicted values from power model. Blue region shows 90% pointwise prediction interval 
around the power model curve. Black dashed line shows the best fit straight line through the origin. 
 
Figure 22:  Oxfendazole Exposure by Dose, Groups 1-3, Dose 5 
This figure will use the form of Figure 21 to display Dose 5 data. 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 23: 
Dose-Adjusted Exposure by Dose, Groups 1-3, Dose 1 
 
Figure 24: 
Dose-Adjusted Exposure by Dose, Groups 1-3, Dose 5 
This figure will use the form of Figure 23 to display Dose 5 data. 
 
 


DMID Protocol 16-0005 
Version 1.0 
Noncompartmental Pharmacokinetic Analysis Plan  
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Figure 25: 
Assessment of Steady State – Geometric Mean Ratio and 95% CI for Cmax 
and Ctrough on Day 3 and Day 4 Relative to Day 5 by Dose Level 
 
 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Appendix III: List of Proposed Listings 
TABLE OF LISTINGS 
Listing 1: Subject Level Demographic and Baseline Characteristics ............................................52 
Listing 2: Dosing............................................................................................................................53 
Listing 3: Subject Level Drug Concentrations...............................................................................54 
Listing 4: Group 1-3 Subject Level Accumulation Ratios and Shift in Tmax .................................55 
Listing 5: Group 4 Subject Level Exposure Parameters ................................................................56 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Listing 1: Subject Level Demographic and Baseline Characteristics 
[Implementation note: Treatment Group will list one of the following, according to Group: “Group 1 (3 mg/kg),” “Group 2 (7.5 mg/kg),” “Group 3 
(10 mg/kg),” “Group 4 Sequence A,” “Group 4 Sequence B.”] 
Subject ID  
Treatment Group 
Sex 
Race 
Age (years) 
Weight (kg) 
Height (cm) 
BMI (kg/m2) 
 
 
 
 
 
 
 
 
 


DMID Protocol 16-0005 
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Listing 2: Dosing 
Subject ID 
Treatment 
Group 
Dose 
(mg)1 
Dose 
Number 
Nominal Time Since 
First Dose 
(day:hour:minute) 
Actual Time Since 
First Dose 
(day:hour:minute) 
Actual Time Since 
Preceding Dose2 
(day:hour:minute) 
Dose Within Time 
Window 
 
 
 
 
yes/no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Dose in milligrams calculated as (volume in mL administered) * (concentration of formulation in mg/mL) 
2 Out of window times are indicated by an asterisk 
 


DMID Protocol 16-0005 
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Noncompartmental Pharmacokinetic Analysis Plan  
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Listing 3: Subject Level Drug Concentrations 
Subject 
ID 
Treatment 
Group 
Dose 
Number 
Nominal 
Time Since 
First Dose 
(day:hour: 
minute) 
Actual Time 
Since First 
Dose 
(day:hour: 
minute) 
Actual Time 
Since 
Preceding 
Dose1 
(day:hour: 
minute) 
Drug 
Concentrations 
(ng/mL) 
Sample 
Within 
Time 
Window 
Used in λz 
Calculations 
Excluded 
from NCA 
Reason for 
Exclusion 
from NCA 
 
 
 
 
yes/no 
yes/no 
yes/no 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Out of window times are indicated by an asterisk 
 


DMID Protocol 16-0005 
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Listing 4: Group 1-3 Subject Level Accumulation Ratios and Shift in Tmax 
Subject ID 
Treatment Group 
𝐀𝐀𝐀𝐀= 𝐀𝐀𝐀𝐀𝐀𝐀𝝉𝝉,𝐃𝐃𝐃𝐃𝐃𝐃𝐃𝐃 𝟓𝟓
𝐀𝐀𝐀𝐀𝐀𝐀𝝉𝝉,𝐃𝐃𝐃𝐃𝐃𝐃𝐃𝐃 𝟏𝟏
 
𝐀𝐀𝐀𝐀= 𝐂𝐂𝐦𝐦𝐦𝐦𝐦𝐦,𝐃𝐃𝐃𝐃𝐃𝐃𝐃𝐃 𝟓𝟓
𝐂𝐂𝐦𝐦𝐦𝐦𝐦𝐦,𝐃𝐃𝐃𝐃𝐃𝐃𝐃𝐃 𝟏𝟏
 
𝐀𝐀𝐀𝐀= 
𝟏𝟏
𝟏𝟏−𝒆𝒆−𝝀𝝀𝒁𝒁𝛕𝛕 
Tmax, Dose 5 - Tmax, Dose 1  
(hr) 
 
 
 
 
 
 
 
 
 
 
 
 
 


DMID Protocol 16-0005 
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Listing 5: Group 4 Subject Level Exposure Parameters 
Subject ID 
Sequence 
𝐀𝐀𝐀𝐀𝐀𝐀(𝟎𝟎−∞) (ng∙hr/mL) 𝐀𝐀𝐀𝐀𝐀𝐀(𝟎𝟎−𝐥𝐥𝐥𝐥𝐥𝐥𝐥𝐥) (ng∙hr/mL) 
Cmax (ng/mL) 
Tmax (hr) 
Fed 
Fasted 
Ratio  
Fed: 
Fasted 
Fed 
Fasted 
Ratio  
Fed: 
Fasted 
Fed 
Fasted 
Ratio  
Fed: 
Fasted 
Fed 
Fasted 
Difference 
Fed- 
Fasted