Clinical trial NCT02234570
Conditions: Neurocysticercosis
Keywords: neurocysticercosis pork tapeworm Taenia solium
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2014-11-17; Completion date: 2015-11-24
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of the Phase I study are to evaluate the safety and tolerance of increasing single oral doses of oxfendazole in healthy volunteers.The secondary objectives assess the pharmacokinetic profile of oxfendazole and assess the metabolism of oxfendazole. The description of agent used is single oral dose of an aqueous suspension of oxfendazole, a benzimidazole carbamate antiparasitic drug. Each new cohort will be dosed only after the two week safety data for the preceding group have been reviewed. If a clinically significant AE is observed, and if this event is drug-related the safety monitoring committee will be convened to determine whether the study should continue.

Detailed description:
This Phase I study is a randomized, double-blind, placebo-controlled evaluation of the safety and pharmacokinetics of escalating single oral doses of oxfendazole (0.5 to 60 mg/kg) in healthy volunteers. Up to 70 healthy males and females (non-chldbearing potential), ages 18-45 volunteers recruited from one site will participate in this study. The study duration is approximately 18 months with subject participation of 2 weeks. The primary objective assess the safety and tolerability of oxfendazole in healthy adults. The secondary objectives assess the pharmacokinetic profile of oxfendazole and assess the metabolism of oxfendazole. Two sentinel subjects will receive the study product (1 drug/1 placebo) in each group and be monitored 48 hours for adverse events prior to completing enrollment of the remaining 8 subjects in the group.

Arms: arm 1: N=8 subjects receive single oral dose 0.5mg/kg of oxfendazole; N= 2 subjects receive single oral dose placebo arm 2: N=8 subjects receive single oral dose 1mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo arm 3: N=8 subjects receive single oral dose 3mg/kg of oxfendazole; N= 2 subjects receive single oral dose placebo arm 4: N=8 subjects receive single oral dose 7.5mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo arm 5: N=8 subjects receive single oral dose 15mg/kg of oxfendazole; N= 2 subjects receive single oral dose placebo arm 6: N=8 subjects receive single oral dose 30mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo arm 7: N=8 subjects receive single oral dose 60mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo
Interventions: intervention 1: Oxfendazole intervention 2: Placebo
Intervention descriptions: intervention 1: A benzimidazole carbamate antiparasitic drug. Oral Dose levels of 0.5,1, 3, 7.5, 15, 30, and 60 mg/kg will be evaluated sequentially, the dose increasing with each new cohort Group 1 to Group 7. intervention 2: Normal Saline administered with an oral dosing syringe. Group 1- Group 6

Protocol documents:
Prot_000.pdf: 
 
 ____________________________________________________________________________________________ 
A Randomized, Double-Blind Placebo-Controlled Phase I Trial 
Evaluating the Safety and Pharmacokinetics of Oxfendazole 
DMID Protocol Number:  12-0053 
DMID Funding Mechanism: Contract # HHSN272200800008C 
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 Scientific Lead: Gregory Deye, MD 
DMID Medical Monitor: Soju Chang, MD 
DMID Clinical Project Manager:  Effie Nomicos, RN, MSN 
DMID Regulatory Affairs Specialist: Blossom Smith, MS 
 
Version Number: 5.0 
September 1, 2015 
 
 


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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45CFR 
Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
• 
NIH 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 sub investigators 
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 Principal 
Investigator: 
 
Name/Title (Print) 
 
 
Signature: 
 
Date: ____________________________________________________ 
 
 


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TABLE OF CONTENTS 
 
 
Page 
STATEMENT OF COMPLIANCE ................................................................................................. i 
SIGNATURE PAGE .................................................................................................................... ii 
TABLE OF CONTENTS ............................................................................................................. iii 
LIST OF ABBREVIATIONS ........................................................................................................ vi 
PROTOCOL SUMMARY .......................................................................................................... viii 
1 
Key Roles ........................................................................................................................... 2 
2 
Background Information and Scientific Rationale................................................................ 4 
2.1 
Background Information .......................................................................................... 4 
2.1.1 
Oxfendazole ................................................................................................ 4 
2.1.2 
Human Cysticercosis ................................................................................... 7 
2.1.3 
Global Significance...................................................................................... 7 
2.2 
Rationale ................................................................................................................ 8 
2.3 
Potential Risks and Benefits ................................................................................... 9 
2.3.1 
Potential Risks ............................................................................................ 9 
2.3.2 
Known Potential Benefits........................................................................... 10 
3 
Objectives ........................................................................................................................ 11 
3.1 
Study Objectives ................................................................................................... 11 
3.2 
Study Outcome Measures .................................................................................... 11 
4 
Study Design .................................................................................................................... 12 
4.1 
Subject Inclusion Criteria ...................................................................................... 17 
4.2 
Subject Exclusion Criteria ..................................................................................... 18 
4.3 
Treatment Assignment Procedures ....................................................................... 20 
4.3.1 
Randomization Procedures ....................................................................... 20 
4.3.2 
Masking Procedures .................................................................................. 20 
4.3.3 
Reasons for Withdrawal ............................................................................ 20 
4.3.4 
Handling of Withdrawals ............................................................................ 21 
4.3.5 
Termination of Study ................................................................................. 22 
5 
Study Intervention/Investigational Product ........................................................................ 23 
5.1 
Study Product Description .................................................................................... 23 
5.1.1 
Acquisition ................................................................................................. 23 
5.1.2 
Formulation, Packaging, and Labeling....................................................... 23 
5.1.3 
Product Storage and Stability .................................................................... 24 
5.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 24 
5.3 
Modification of Study Intervention/Investigational Product for a Subject ................ 25 
5.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 25 
5.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 26 
5.6 
Concomitant Medications/Treatments ................................................................... 26 


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6 
Study Schedule (See Appendix A) ................................................................................... 27 
6.1 
Screening (Day -28 to -1): Clinic Visit 01............................................................... 27 
6.2 
Enrollment/Baseline (Day 1): Clinic Visit 02 .......................................................... 28 
6.3 
Follow-up (Days 2 – 8): Visits 03 through 07 ......................................................... 29 
6.4 
Final Study Visit, Clinic Visit 08 (Day 15) (+/-2 days): ........................................... 30 
6.5 
Early Termination Visit .......................................................................................... 30 
6.6 
Unscheduled Visit ................................................................................................. 31 
6.7 
Handling of Abnormal Liver Function or Hematological Tests ............................... 31 
7 
Study Procedures/Evaluations .......................................................................................... 32 
7.1 
Clinical Evaluations ............................................................................................... 32 
7.2 
Laboratory Evaluations ......................................................................................... 32 
7.2.1 
Clinical Laboratory Evaluations ................................................................. 32 
7.2.2 
Special Assays or Procedures ................................................................... 33 
7.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 34 
8 
Assessment of Safety ....................................................................................................... 35 
8.1 
Specification of Safety Parameters ....................................................................... 35 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 35 
8.2.1 
Adverse Events ......................................................................................... 35 
8.2.2 
Adverse Events ......................................................................................... 36 
8.2.3 
Serious Adverse Events ............................................................................ 36 
8.2.4 
Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ........................................................ 37 
8.3 
Reporting Procedures ........................................................................................... 38 
8.3.1 
Serious Adverse Events ............................................................................ 38 
8.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ............................................................................................................ 38 
8.3.3 
Reporting of Pregnancy ............................................................................. 39 
8.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 39 
8.5 
Halting Rules ........................................................................................................ 39 
8.6 
Safety Oversight (ISM, SRC, SMC) ...................................................................... 41 
8.6.1 
Independent Safety Monitor (ISM) ............................................................. 41 
8.6.2 
Safety Review Committee (SRC) .............................................................. 41 
8.6.3 
Safety Monitoring Committee (SMC) ......................................................... 41 
9 
Clinical Monitoring ............................................................................................................ 42 
9.1 
Site Monitoring Plan .............................................................................................. 42 
10 
Statistical Considerations ................................................................................................. 43 
10.1 
Study Hypotheses ................................................................................................. 43 
10.2 
Sample Size Considerations ................................................................................. 43 
10.3 
Planned Interim Analyses (if applicable) ............................................................... 44 
10.3.1 Safety Review ........................................................................................... 44 
10.3.2 Immunogenicity or Efficacy Review ........................................................... 44 
10.4 
Final Analysis Plan ............................................................................................... 44 


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11 
Source Documents and Access to Source Data/Documents ............................................ 46 
12 
Quality Control and Quality Assurance ............................................................................. 47 
13 
Ethics/Protection of Human Subjects ................................................................................ 48 
13.1 
Ethical Standard ................................................................................................... 48 
13.2 
Institutional Review Board .................................................................................... 48 
13.3 
Informed Consent Process ................................................................................... 49 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 49 
13.5 
Subject Confidentiality .......................................................................................... 49 
13.6 
Study Discontinuation ........................................................................................... 50 
13.7 
Future Use of Stored Specimens .......................................................................... 50 
13.8 
Data Management Responsibilities ....................................................................... 51 
13.9 
Data Capture Methods .......................................................................................... 51 
13.10 Types of Data ....................................................................................................... 52 
13.11 Timing/Reports ..................................................................................................... 52 
13.12 Study Records Retention ...................................................................................... 52 
13.13 Protocol Deviations ............................................................................................... 52 
14 
Literature References ....................................................................................................... 54 
Supplements/Appendices ......................................................................................................... 58 
Appendix A: Schedule of Events ............................................................................................... 59 
Appendix B: DMID Adult Toxicity Tables Non-Serious Adverse Events ..................................... 61 
Appendix C: GRADE THRESHOLDS FOR EKG ....................................................................... 65 
Appendix D: University of Iowa Normal Laboratory Values ....................................................... 66 
 
 


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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 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
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 
NIH 
National Institutes of Health 
NOEL 
No Observed Effect Level 


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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 
 
 


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PROTOCOL SUMMARY  
Title: 
A Randomized, Double-Blind Placebo-Controlled Phase I Trial 
Evaluating the Safety and Pharmacokinetics of Oxfendazole 
Phase: 
I 
Population: 
Up to 70 healthy males and females (non-childbearing 
potential), ages 18-45, recruited from around the University of 
Iowa 
Number of Sites: 
One site, the University of Iowa 
Study Duration: 
Approximately 18 months  
Subject Participation 
Duration: 
2 weeks 
Description of Agent or 
Intervention: 
Single oral dose of an aqueous suspension of oxfendazole, a 
benzimidazole carbamate antiparasitic drug. 
Objectives: 
 
Primary: 
• 
Assess the safety and tolerability of oxfendazole in healthy 
adults. 
 
 
 
Endpoints/Outcome 
Measures: 
Secondary: 
• 
Assess the pharmacokinetic profile of oxfendazole  
• 
Assess the metabolism of oxfendazole 
 
Primary endpoint: 
1. The rate of adverse events (AEs) related to oxfendazole 
within 14 days of receipt of a single oral dose. 
Secondary endpoints: 
1. Plasma Cmax, Tmax, AUC , t1/2 of oxfendazole for each 
dosage group. 
2. Plasma and urine concentrations of oxfendazole 
fenbendazole and oxfendazole sulfone at time points 
specified in Appendix A Schedule of Events and 
described in Section 4 Study Design relative to oral 


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dosing.  
Description of Study 
Design: 
 
This Phase I study is a randomized, double-blind, placebo-
controlled evaluation of the safety and pharmacokinetics of 
escalating single oral doses of oxfendazole (0.5 to 60 mg/kg) in 
healthy volunteers. Up to 70 volunteers will participate in this 
study. The dose will be increased approximately three-fold (one-
half log) at each increment, and each cohort will comprise 10 
volunteers (8 subjects will receive study drug and 2 will receive 
placebo). Two sentinel subjects (1 drug/1 placebo) in each 
cohort will be monitored for 48 hours after receiving the study 
drug prior to completing enrollment in the cohort.  Subjects will 
be monitored for two weeks after dosing, including monitoring 
the pharmacokinetics and metabolism of oxfendazole in blood 
and urine. Each new cohort will be dosed only after the two 
week safety data for the preceding group have been reviewed. If 
a clinically significant AE is observed, and if this event is drug-
related the safety monitoring committee will be convened to 
determine whether the study should continue.   
Estimated Time to 
Complete Enrollment: 
17 months 
 
 


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Schematic of Study Design: 
Note:  Two sentinel subjects will receive the study product (1 drug/1 placebo) in each group and 
be monitored 48 hours for adverse events prior to completing enrollment of the remaining 8 
subjects in the group.  Adverse events assessed as related to the study product and as defined 
in the Halting Rules may result in suspension of the study.  
 


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1 
KEY ROLES 
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 
Rockville,  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 
5601 Fishers Lane, 8A39 
Rockville,  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 
Rockville, MD  20892 
Tel. 240-627-3320 
Email: enomicos@mail.nih.gov 
 


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DMID Regulatory Affairs 
Specialist 
 
Blossom Smith, MS 
Office of Regulatory Affairs 
DMID/NIAID/NIH 
Office of Regulatory Affairs, DMID, NIAID, NIH 
5601 Fishers Lane, Room F745 
Bethesda, MD 20892 
Phone: 240-627-3376 
E-mail: smithbl@niaid.nih.gov 
 
DMID VTEU Project Officer 
 
Suzanne Murray, RN, BSN 
Office of the Associate Director of Clinical Research 
DMID/NIAID/NIH 
5601 Fishers Lane, 7G25 
Rockville,  MD   20852 
Phone: 240-627-3324 
E-mail: smurray@niaid.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 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
In humans, cerebral cysticercosis is the most common parasitosis of the central nervous system 
(CNS) (1, 2). On a worldwide basis, approximately 50,000 people die each year because of 
neurocysticercosis (3), and it is estimated that 1000 cases occur annually in the United States 
(US).(4) The current treatment for neurocysticercosis is far from ideal: complete cure is 
achieved in approximately 50% of cases, with regimens that require multiple doses of drug over 
several weeks (1, 5-7). Oxfendazole is currently marketed for use against lungworms and 
enteric helminths in beef livestock. In preliminary studies in pigs, single oral doses of 
oxfendazole appear to have substantial activity against the tissue stages of Taenia solium 
(cysticercosis) (8-10). These data suggest that oxfendazole has the potential to be useful as a 
single dose oral treatment for neurocysticercosis. The studies described in this protocol propose 
the first evaluation in humans of the safety, metabolism, and pharmacokinetics (PK) of 
oxfendazole. 
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 
properties against larval and adult forms of 
gastrointestinal cestodes and nematodes in various 
animal species (11). The structure consists of the benzimidazole carbamate characteristic of 
this group of drugs, with a phenylsulphinyl substituent in position 5 (12). The currently available 
formulation is an aqueous suspension of either 9.06% or 22.5% oxfendazole (Synanthic®), 
manufactured by Boehringer Ingelheim Animal Health.  Aliquots of the commercially available 
suspension will be used in the present study, as described in Table 3 below. Synanthic® should 
be stored at temperatures not to exceed 104°F (40°C) and protected from freezing and 
excessive heat (13, 14). 
2.1.1.2 
History 
The introduction of thiabendazole as the first benzimidazole anthelminthic in the early 1960s 
provided a significant advance in veterinary antiparasitic treatment (15). However, 
thiabendazole has a short biological half-life, due to rapid hydroxylation of the 5 (6) position of 
the benzimidazole ring and extensive urinary clearance (16). Further efforts were directed 


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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 (17). 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 (18). Thiabendazole, mebendazole 
and albendazole are currently approved and marketed in the US for treatment of helminth 
infections in humans.  
2.1.1.3 
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 (18). They also alter the tubulin-microtubule 
equilibrium, by binding at the colchicine site in the tubulin dimer (19). Inhibition of tubulin 
polymerization induces disintegration of the microtubular network in parasites (20).  
2.1.1.4 
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 
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 


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Species 
Study 
No Effect Dose 
Dog 
Single dose 
 
1600 
 
864 
 
Selection of Starting Dose for Human Phase I study administering a single dose of oxfendazole  
Extrapolating (using a body surface area calculation) from the results of chronic oxfendazole 
toxicology studies conducted in animals, the most conservative estimate of a no-effect dose for 
humans (based on a no observed effect level NOEL] derived from a 1-year study) is 0.13 mg/kg 
(see Table 1 above).  Based on a standard 10-fold safety factor from the No Observed Adverse 
Effect Level (NOAEL) from single dose studies in the most sensitive species, starting doses up 
to 50 mg/kg would be supported. Because this exceeds the anticipated therapeutic dose, and 
due to the lower NOAEL human equivalent dose of 0.8 mg/kg/d seen in rats in the 14d repeat 
dose a significantly greater safety margin was incorporated.  Thus, 1.0 mg/kg has been selected 
as the starting point for the present single dose Phase I study. Furthermore, since the principal 
toxicology target organs appear to be the bone marrow and liver, safety monitoring for the 
proposed Phase I study includes clinical chemistry indicators of bone marrow and liver function. 
2.1.1.5 
Animal Safety  
The potential cardiovascular or toxicity effects of oxfendazole (OXF) were investigated after 
drug administration to beagle dogs (22).  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 (23).  There were no changes in feeding, behavior or 
physiological measurements (23).  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 
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and thymus.  Toxicology studies demonstrated mild hepatotoxicity in rats fed 2.1 or 7 mg/kg 
daily for a year (21).  Similar dog studies showed no toxicity (21).  Fetotoxicity was noted in rats 
and mice (21).  
2.1.2 Human 
Cysticercosis 
Cysticercosis in humans is caused 
by the larval stage of the cestode 
Taenia solium (pig tapeworm). The 
normal life cycle of this parasite 
includes the pig, which acts as an 
intermediate host with larval 
vesicles in its tissues, and the 
human, which is the definitive host, 
harboring the adult worm in the 
intestinal tract. The adult worm is 
relatively harmless; however, 
humans can also serve as an 
intermediate host by ingesting 
Taenia eggs and developing the 
cystic form of the infection in various tissues (24). The cysts, which may be up to several 
centimeters in diameter, may occur anywhere in the body, including subcutaneous tissue, 
muscle, eye, and most seriously, in the CNS. Neurocysticercosis, the presence of these cysts in 
the brain parenchyma, causes a variety of symptoms, the most common of which is seizures (5, 
6). Subarachnoidal or intraventricular cysts may also cause intracranial hypertension (25).  
2.1.3 Global Significance 
Neurocysticercosis is common in developing countries that practice pig husbandry. The disease 
is endemic throughout Latin America, Indonesia, Africa and parts of India. In Mexico, Ecuador, 
and Brazil, the prevalence of neurocysticercosis found at autopsy exceeds 1% (26, 27). In 
Mexico (28) and Peru (29), 12% of acute neurological hospital beds are occupied by patients 
with neurocysticercosis. Interestingly, epilepsy is more frequent in developing countries than it is 
in developed countries. In a community survey in Ecuador, the prevalence of epilepsy was 
12/1000 (30), and in Peru it was 16.6/1000 (31). These rates are 2-3 times those in 
industrialized countries (32).  It is assumed, based on serological studies in India (33), South 
Africa (34, 35), Mexico (36), and Peru (2), that the increased rates of epilepsy are due to 
neurocysticercosis. 
In the US, neurocysticercosis is diagnosed relatively commonly in hospitals that treat large 
Hispanic populations (e.g., hospitals in Los Angeles and San Diego) (37-39). The number of 
reported cases is increasing, probably as a result of better diagnosis and of increased 
immigration of T. solium-infected individuals. The number of indigenous cases is also rising, 


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even though pigs are not a source of infection in the US (38-41). A recent cluster of 
cysticercosis cases in orthodox Jews in Brooklyn, New York, was attributed to tapeworm 
infections in their Latin American domestic workers (36). 
 
2.1.3.1 Current Therapy 
For many years, therapeutic approaches to neurocysticercosis were limited to the use of 
steroids and surgery for the relief of intracranial hypertension (24). In 1978, praziquantel was 
recognized as the first antiparasitic drug with activity against neurocysticercosis (42-46). In 
1989, albendazole was reported to be effective (47), and it became widely used because of its 
efficacy and low cost (6, 47-50). Initially, the suggested duration of albendazole therapy was 30 
days (47), but shorter schedules of 8 or 15 days were successfully used (51, 52). We have 
reported the results of a prospective double blind trial, in which a seven-day course of 
albendazole decreased the number of parasites in 78% of patients, but complete cure was 
achieved in less than 40% of patients (53). The available therapy is clearly limited by marginal 
efficacy and the requirement for prolonged treatment (49, 53).  
2.1.3.2 
Oxfendazole for Porcine Cysticercosis 
No suitable single-dose therapy is currently available for porcine cysticercosis. Albendazole is 
effective when used in a 3-day treatment schedule, but not in a single dose (54). We performed 
two studies in Peru that suggest that in pigs, a single oral dose of oxfendazole is highly effective 
against the larval form of T. solium. In the first study, naturally parasitized pigs were divided into 
four groups and treated with single oral doses of oxfendazole (30 mg/kg; 1078 mg/m2), 
praziquantel (50 mg/kg), oxfendazole plus praziquantel, or placebo.(9) At necropsy 10-12 weeks 
later, the psoas and anconeal muscles, tongue, heart, and brain were dissected; cysts were 
removed, counted, and tested for viability. Importantly, oxfendazole treatment effected a 100% 
elimination of viable parasites in all four tissues, whereas praziquantel was ineffective. In a 
second, similarly designed study, the efficacies of single oral doses of 10, 20, or 30 mg/kg (359-
1078 mg/m2) oxfendazole were compared with placebo. All three doses eradicated parasites 
from the heart; there was a dose-dependent reduction in parasites from muscle (88.7-97.4%); 
and at all dose levels, there was a substantial reduction (83%) in parasites from brain and 
tongue,(8) effects that were confirmed in a third study (10). These studies demonstrate that 
single oral doses of oxfendazole are effective against T. solium in pigs, suggesting that in 
humans, comparable oral doses of 359 mg/m2 (9.49 mg/kg) oxfendazole might have substantial 
anti-cysticercosis activity.  
2.2 
Rationale 
With current treatment strategies for neurocysticercosis, cure is achieved in approximately 50% 
of patients despite multiple doses of drug (1, 5-7). In animal studies, single oral doses of 
oxfendazole appear to have substantial activity against the tissue stages of (Taenia solium)     
(8-10). Oxfendazole, as a single dose, might be efficacious against neurocysticercosis in 


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humans. A Phase I study is needed to evaluate its safety, metabolism, and pharmacokinetics 
(PK) in humans. 
2.3 Potential Risks and Benefits 
2.3.1 Potential Risks 
This study is the first time that oxfendazole will be evaluated in humans.  However, 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. It has 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 %.  We expect that oxfendazole may have similar 
gastrointestinal events and rare allergic reactions, though this will be the first study in humans.   
 
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 the present study, 
only a single dose of oxfendazole will be administered to each subject.  
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. 
 
This study will not recruit women of child bearing potential.  Men will be counseled to use 
condoms and avoid pregnancy attempts for 4 months following drug administration.   
 
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.  
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 
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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 will be no direct benefit to subjects.  


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3 
OBJECTIVES 
3.1 
Study Objectives 
Primary: 
• 
Assess the safety and tolerability of oxfendazole in healthy adults. 
Secondary: 
• 
Assess the pharmacokinetic profile of oxfendazole  
• 
Assess the metabolism of oxfendazole 
3.2 
Study Outcome Measures 
3.2.1 Primary endpoint: 
 
3.2.1.1 
The rate of adverse events (AEs) related to oxfendazole within 14 days of 
receipt of a single oral dose. 
 
3.2.2 Secondary endpoints: 
3.2.2.1 
Plasma Cmax, Tmax, AUC, t1/2 of oxfendazole for each dosage group. 
3.2.2.2 
Plasma and urine concentrations of oxfendazole fenbendazole and 
oxfendazole sulfone at time points specified in Appendix A Schedule of 
Events and described in Section 4 Study Design relative to oral dosing. 


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4 
STUDY DESIGN 
This Phase I study is a randomized, double-blind, placebo-controlled evaluation of the safety 
and PK of escalating single oral doses of oxfendazole (0.5, 1, 3, 7.5, 15, 30, 60 mg/kg) in 
healthy volunteers. The dose will be increased approximately three-fold (one-half log) at each 
increment, and each cohort will comprise 10 volunteers (8 drug, 2 placebo). Subjects will be 
monitored for 2 weeks after dosing, including monitoring the PK and metabolism of oxfendazole 
in blood and urine.  
 
Two sentinel subjects (one randomized to receive study drug and the other to receive placebo) 
will be dosed and monitored 48 hours for adverse events prior to enrolling the remaining 
subjects in each cohort.  If no drug-related serious adverse event or laboratory grade 3 study 
drug related events are observed within the 48 hour period, the remainder of the cohort will 
proceed with dosing. Each new cohort will be dosed only after the 2-week safety data for the 
preceding group have been analyzed.  A Safety Review Committee (SRC) composed of the 
Protocol Principal Investigator and Independent Safety Monitor will review blinded safety data 
for the completed cohort. If a clinically significant AE is observed that is possibly drug related, 
the SRC will determine if an ad hoc SMC meeting should be called. Up to 70 volunteers (56 
drug, 14 placebo) will complete the study.  The Safety Monitoring Committee (SMC) will review 
the safety data either when or if the final dose is reached.  
 
For the Phase I study, between 10 and 70 subjects (8:2 drug: placebo in each cohort receiving 
increasing doses) will be enrolled. This number should be small enough to perform the study 
safely and efficiently, yet large enough for an estimation of the PK, metabolism, and the 
identification of any common side effects of oxfendazole.  
 
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 2 week 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 18 months to finish the study.   
 
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 and 
eosinophil count, platelet count, creatinine, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, random glucose, urine dipstick for protein and glucose, 
hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus serology 
(HIV) will be conducted. Eligible subjects will be invited to join the study.  They will be advised to 


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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.  A 
brief interim medical history will be taken and review of medication history since screening visit. 
Vital signs, including oral temperature, blood pressure, and pulse will be obtained. A targeted 
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 and eosinophil 
count, platelet count, creatinine, Na, K, Cl, CO2, urea nitrogen, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), prothrombin time and partial thromboplastin time, total 
bilirubin, and urine dipstick for protein and glucose) and a spot urine sample will be obtained for 
PK baseline.  
 
Volunteers will be randomized using the EMMES web-based application to receive a single oral 
dose of oxfendazole or placebo.  The designated unblinded pharmacist will prepare the study 
product according to the treatment assignment for each subject. 
Subjects will be administered a single oral dose of coded oxfendazole/placebo by a blinded 
study nurse or investigator. Subjects will be fasting for 8 hours prior to, and for two hours after, 
the administration of drug/placebo.  On day of drug administration, lunch and dinner will be 
provided. Monitoring will start immediately after dosing and will continue for 2 weeks.  
 
On Day 1, subjects will be interviewed briefly to monitor for AEs and SAEs. Blood for 
oxfendazole and metabolites will be drawn at 0 (product administration), 1, 2, 4, 6, 8, 10, and 12 
hours.  Urine for oxfendazole and metabolites will be collected for 0-4, 4-8, 8-12, and subjects 
will be sent home with a 24 hour urine container to collect all urine between 12-24 hours. After 
12 hours, the 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 15).   
 
On Day 2, subjects will be interviewed briefly to review for concomitant medications, and any 
AEs or SAEs since the last visit.  Vital signs, including oral temperature, blood pressure, and 
pulse will be obtained.  A targeted physical exam will be performed if indicated by symptoms. 
Blood for oxfendazole and metabolites will be collected between 24-32 hours, and urine for 
oxfendazole and metabolites will be collected for the time frame 12–24 hours. A urine creatinine 
value will be tested on the 12-24 hours sample and used to calculate creatinine clearance.   
 
On Day 3, subjects will be interviewed briefly to review for concomitant medications, and any 
AEs or SAEs since the last visit.  Vital signs, including oral temperature, blood pressure, and 
pulse will be obtained.  A targeted physical exam will be performed if indicated by symptoms. 
Blood for oxfendazole and metabolites will be collected at a time point between 48-60 hours, 
and a spot urine for oxfendazole and metabolites will be collected between 48-60 hours.  Blood 
for safety laboratories (hemoglobin, white blood cell count with neutrophil and eosinophil count, 
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aspartate aminotransferase (AST), prothrombin time and partial thromboplastin time, total 
bilirubin) will be obtained for the two sentinel subjects only.   
 
On Day 4, subjects will be interviewed briefly to review for concomitant medications, and any 
AEs or SAEs since the last visit.  Vital signs, including oral temperature, blood pressure, and 
pulse will be obtained.  A targeted physical exam will be performed if indicated by symptoms.  
Blood and urine will be obtained for PK and safety studies (hemoglobin, white blood cell count 
with neutrophil and eosinophil count, platelet count, creatinine, Na, K, Cl, CO2, urea nitrogen, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, prothrombin 
time and partial thromboplastin time, , and urine dipstick for protein and glucose). An EKG will 
be performed.  
On Day 6, subjects will be interviewed briefly to review for concomitant medications, and any 
AEs, or SAEs since the last visit.  Vital signs, including oral temperature, blood pressure, and 
pulse will be obtained.  A targeted physical exam will be performed if indicated by symptoms.  
Blood for oxfendazole and metabolites will be collected. 
On Days 8 and 15, subjects will be interviewed briefly to review for concomitant medications, 
and any AEs, or SAEs since the last visit.  Vital signs, including oral temperature, blood 
pressure, and pulse will be obtained.  A targeted physical exam will be performed if indicated by 
symptoms.  Blood for oxfendazole and metabolites as well as safety panels (hemoglobin, white 
blood cell count with neutrophil and eosinophil count, platelet count, creatinine, Na, K, Cl, CO2, 
urea nitrogen, alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin 
time and partial thromboplastin time, total bilirubin, and urine dipstick for protein and glucose) 
will be collected. 
Clinical laboratory evaluations will be performed by the University of Iowa Clinical Pathology 
Laboratory. Samples for PK studies will be processed at Dr. Daryl Murry’s laboratory at the 
University of Iowa. The primary outcome measure in this study is: The rate of adverse events 
(AEs) related to oxfendazole within 14 days of receipt of a single oral dose. 


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Note:  Two sentinel subjects will receive the study product (1 drug/ 1 placebo) dose in each 
group and monitored 48 hours for adverse events prior to completing enrollment of the 
remaining 8 subjects in the group.  Adverse events assessed as related to the study product 
and as defined in the Halting Rules may result in suspension of the study.   
 
 
Safety oversight per DMID guidelines will be provided by an independent Safety Monitoring 
Committee (SMC) (Refer to http://www.niaid.nih.gov/dmid/clinresearch/). The committee will be 


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composed of individuals who are not directly involved in the study. A local independent safety 
monitor (ISM) from the University of Iowa who will provide local medical consultation for the 
study, but will not serve as a voting member of the SMC. The committee will meet to review 
cumulative safety data, adherence to the protocol and data relevant to proceeding. (Refer to 
Section 9.6) 


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Study Enrollment and Withdrawal 
Up to 70 males and females (non-childbearing potential), 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 17 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. 
4.1 
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 females of non-childbearing potential between the ages of 18 and 45 years, 
inclusive.*  
*Surgically sterile via tubal ligation, bilateral oophorectomy or hysterectomy or who have 
been postmenopausal for ≥1 year confirmed by LH and FSH levels.  
2. In good health, as judged by the investigator and determined by vital signs*  
*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. 


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3. Acceptable screening laboratories*  
 
*Hemoglobin, white blood cell (WBC) count, neutrophil, eosinophil and platelet counts within 
normal ranges. AST < 44 and ALT < 44 and total bilirubin, creatinine must be equal to or 
below the upper limit of normal (for eosinophil count, AST, ALT, creatinine, and total bilirubin 
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. 
4. Male participants must be willing to ensure use of condoms and spermicides for 4 months 
after study drug administration.  
5. Provide written informed consent before initiation of any study procedures.  
6. Willing to be available for all study-required procedures, and visits for the duration of the 
study. 
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. 
4.2 
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. History of residing for 6 or more months in regions with endemic cysticercosis as 
determined by the principal investigator or a designated study physician.   
2. Breastfeeding females. 
3. Body temperature ≥100.4°F (≥38.0°C) or acute illness within 3 days before administration 
of study drug (subject may be rescheduled).  
4. 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.  
5. Use of chronic systemic medications*   
*Intermittent use of over the counter medications such as acetaminophen, ibuprofen, cold 
and sinus medications are permitted for enrollment (please see section 5.6 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 5.6 for instructions on medication use 


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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.  
6. Has history of sensitivity to related benzimidazole compounds (e.g., albendazole, 
mebendazole). 
7. A diagnosis of schizophrenia, bipolar disease, or history of hospitalization for a psychiatric 
condition or previous suicide attempt.  
8. 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.   
9. Received an experimental agent* within 1 month before administration of study drug or 
expect to receive an experimental agent during the 15-day study period.  
*Vaccine, drug, biologic, device, blood product, or medication. 
10. Any condition that would, in the opinion of the investigator, 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.  
11. A history of alcohol consumption* or any illicit drug use†, or history of substance abuse#. 
Individuals must agree to abstain from drug or alcohol use for 48 hours prior to enrollment 
through day 15.  . 
*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.    
12.  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 15.   
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, AST, ALT, bilirubin and eosinophil 
count 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 
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for this study and will be followed with the standard safety laboratory follow-up outlined in the 
study.  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. 
4.3 
Treatment Assignment Procedures 
4.3.1 Randomization Procedures 
Randomized treatment assignments will be generated by a statistician at The EMMES 
Corporation, the statistical and data coordinating center (SDCC) for this study.  Subjects will be 
registered using a web-based application developed by The EMMES Corporation. Upon entry of 
demographic data and confirmation of eligibility for the trial, the subject will be enrolled.  After 
successful enrollment, a treatment assignment number will be displayed on the Enrollment 
Confirmation screen.  The treatment assignment number is referenced against a confidential 
randomization list provided to designated study personnel on-site to determine the study 
assignment.  The EMMES Corporation will monitor the implementation of this process. Two 
sentinel subjects in each cohort, one receiving study drug and one receiving placebo, will be 
dosed and monitored for safety for 48 hours prior to enrolling the remainder of the cohort. As 
further randomization in the group occurs, these two subjects will be incorporated into the 
subsequent randomization scheme. 
 
4.3.2 Masking Procedures 
This is a double-blinded, placebo controlled trial.  Aliquots of 22.5% or 9.6% Synanthic® 
suspension or placebo solution will be prepared by an unblinded clinical research pharmacist 
(See Section 6.2, Table 3) and administered orally by a blinded study nurse or investigator 
using an oral dosing syringe. Immediately following administration of the dose, the subject will 
drink 100 mL of water to ensure that the entire dose is taken. 
4.3.3 Reasons for Withdrawal 
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 


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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 7.5 for procedures 
to be followed if a subject withdraws from the study. 
4.3.4 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 
Termination Visit procedures are listed in Section 7.5.  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 study drug will not be 
replaced.  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 randomization but 
before receipt of study product may be replaced. 


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4.3.5 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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5 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
5.1 
Study Product Description 
5.1.1 Acquisition 
Oxfendazole suspension will be purchased through a commercial supplier of the over the 
counter product. 
 
Oxfendazole placebo solution will be obtained from SRI International.  The product was 
manufactured under cGMP conditions. 
 
5.1.2 Formulation, Packaging, and Labeling 
Oxfendazole suspension is currently available as a 9.06% and a 22.5% suspension.  Both 
strengths will be used in this study, as specified in Table 3 (Section 6.2).  Dose levels of 0.5, 1, 
3, 7.5, 15, 30, and 60 mg/kg will be evaluated sequentially, the dose increasing with each new 
cohort.   Doses will be administered orally using a syringe of a size appropriate to measure the 
needed volume.  A placebo will be prepared by SRI and will also be administered with an oral 
dosing syringe. 
 
The oxfendazole placebo formulation consists of polyethylene glycol, methyl paraben, and 
sterile water for injection. These excipients, widely used in pharmaceutical formulations, are NF 
(National Formulary) or USP (United States Pharmacopeia) grade listed in the FDA's inactive 
ingredient list.  The 15 mL of oxfendazole placebo solution is filled into pre-cleaned 22 mL screw 
thread vial with 20/400 PTFE (polytetrafluoroethylene) lined cap.  Table 2 describes the amount 
of each excipient in the formulation, container, and closure of oxfendazole placebo. 
 
Table 2: Oxfendazole Placebo Formulation and Packaging 
 
Item 
Material 
Amount  % (w/v) 
1 
Polyethylene Glycol, NF 
4.5%  
2 
Methyl Paraben, NF 
0.18%  
3 
Sterile Water For Injection, USP 
95.32%  
4 
22 mL Screw Thread Vial with 20/400 PTFE Lined Cap 
N/A 
Total 
100.00 
Corrugated box inserted with vials partition will be used to pack oxfendazole placebo vials. 


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Each vial has been affixed with a 2” x 4” open text label.  The label text is described in Figure 1. 
Figure 1: Oxfendazole placebo label text description 
 
 
 
 
 
5.1.3 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. 
Oxfendazole placebo is recommended to store at temperatures not to exceed 77°F ( 25°C). 
The stability of oxfendazole placebo is under evaluation.  The stability study at 25C/60% RH 
(testing at 3, 6, 9 and 12 months) and 40 C/75% RH (testing at 3 and 6 months) has been 
initiated. 
 
5.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Table 3.  Schema for administration of Synanthic® available product strengths 
 
Dose 
ID 
Synanthic® 
Dosing protocol 
Concentration of 
dosing suspension 
(mg/mL) 
Source of dosing 
suspension 
Protocol 
dose 
(mg/kg) 
mL to be 
administered 
Vol for 
80 kg 
subject 
(mL) 
A 
 
 
90.6 
 
 
9.06% Synanthic® 
0.5 
kg x 0.0055 
0.44 
B 
1.0 
kg x 0.011 
0.88 
C 
3.0 
kg x 0.033 
2.65 
D 
7.5 
kg x 0.083 
6.62 
E 
 
225 
 
22.5% Synanthic® 
15 
kg x 0.067 
5.32 
F 
30 
kg x 0.133 
10.66 
G 
60 
kg x 0.267 
21.33 
Oxfendazole Placebo, 15 mL  
Batch No.: 16146-10   Manufacture Date: Oct. 2013 
Store at temperature not exceeding  25°C (77°F) 
Caution: New Drug Limited by Federal (US) Law to 
Investigational Use Only. Keep out of the reach of 
children. 
Manufactured for the National Institute of Allergy and 
Infectious Disease (NIAID), Bethesda, MD 20817          
by SRI International, Menlo Park, CA 94025 


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Note:  Aliquots will be removed from the Synanthic® stock bottle immediately after mixing, as 
the marketed drug is a suspension. The content of the oral dosing syringe will be mixed in the 
pharmacy and transported to the clinical research for administration.  Administration must 
occur within 20 minutes after mixing in the pharmacy.   Immediately following administration 
of the dose, the subject will drink 100 mL of water to assure that the entire dose is taken.  If 
the dose is not administered within 20 minutes it should be discarded and a fresh dose mixed 
in the pharmacy. 
5.3 Modification of Study Intervention/Investigational Product 
for a Subject 
None as subjects will only receive a single dose. 
5.4 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
The investigator will sign that he has received the study medication, confirming the quantity 
received and registering its characteristics, including lot number and expiration date. Upon 
arrival, the drug will be stored locked in the facilities of each study center at appropriate 
temperature. The Study Pharmacist (as delegated by the Principal Investigator) will be 
responsible for appropriate handling and storage of the study medication and ensuring that it is 
dispensed to study subjects only in accordance with the protocol. A new bottle of Synanthic® will 
be opened for use on each day of drug administration. A record will be maintained of all study 
medication dispensed to each subject. Drug suspension not used will be retained in the original 
containers. 
The study products will be sent to the DMID central repository as directed by DHHS, and then 
will be supplied by the DMID central repository to the participating VTEU site prior to the start of 
the study. 
After receipt of study products, the site principal investigator is responsible for their distribution 
and disposition, and has ultimate responsibility for study product accountability.  Logs of receipt, 
temperature, maintenance, and disposal must be maintained in the study file.  The study 
product accountability records and dispensing logs will also capture time of preparation of the 
diluted study drug. IDS staff will develop a master Compounding Record for each product to be 
prepared and will follow the Departmental SOP for Compounding Procedures during the product 
preparation.   
Each item and volume/weight used in the preparation is double checked.  At least one person 
involved in the process must be a pharmacist. All doses of study drug whether administered or 
not must be documented on the appropriate study product accountability record or dispensing 


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log.  The sponsor's monitoring staff will verify the participating VTEU sites’ study product 
accountability records and dispensing logs per the site monitoring plan. 
 
Unused bottles of the study products will be retained until monitored and released for disposition 
as applicable.  Final disposition of the unused study drug will be determined by DMID and 
communicated to the participating VTEU sites by the DMID Clinical Project Manager. 
5.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
Oral intake of the study product by the subject will be observed by study personnel.  
Immediately following administration of the dose, the subject will drink 100 mL of water to 
assure the entire dose is taken.  If vomiting occurs at any time following ingestion of the study 
product, no further dosing will be provided and subject will continue to be followed for safety and 
pharmacokinetic analyses. Subjects who have vomiting after administration of the dose will not 
be replaced.   
5.6 
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 unless provided by an investigator or other licensed medical 
provider.  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 Day 15..  
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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6 
STUDY SCHEDULE (SEE APPENDIX A) 
6.1 
Screening (Day -28 to -1): Clinic Visit 01 
Informed Consent.  Written informed consent will be obtained prior to any other study 
procedures.  
History.  A complete medical history will be taken by a study nurse or study investigator.  
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 will be performed by a study clinician licensed to make 
medical 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 and eosinophil counts, 
platelet count. 
• 
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 
 
EKG.  Perform 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 15. 
• 
Abstain from tobacco use from the time of screening through Day 15. 
• 
Fasting 8 or more hours prior to receipt of study product. 


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6.2 
Enrollment/Baseline (Day 1): Clinic Visit 02  
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). 
• 
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. 
• 
A heparin lock will be inserted, blood will be drawn (10 mL) for baseline PK and (15 mL) 
for safety labs (hemoglobin, white blood cell count, including neutrophil and eosinophil 
counts, platelet count, prothrombin time, partial thromboplastin time, creatinine, Na, K, 
CL, CO2, urea nitrogen, ALT, AST, total bilirubin).   
• 
Collect urine sample for urine dipstick for protein and glucose and PK baseline. 
• 
Randomization. Randomized treatment assignments will be generated by a statistician 
at The EMMES Corporation, the statistical and data coordinating center (SDCC) for this 
study.  Subjects will be registered using a web-based application developed by The 
EMMES Corporation. Upon entry of demographic data and confirmation of eligibility for 
the trial, the subject will be enrolled.  After successful enrollment, a treatment 
assignment number will be displayed on the Enrollment Confirmation screen.  The 
treatment assignment number is referenced against a confidential randomization list 
provided to the designated unblinded study personnel on-site to determine the study 
assignment.  The EMMES Corporation will monitor the implementation of this process. 
 
Administration of Study Medication (drug/placebo).  
A blinded study nurse will administer a single oral dose of coded oxfendazole/placebo to the 
subject. Escalating dose levels of 0.5, 1, 3, 7.5, 15, 30, and 60 mg/kg will be evaluated 
sequentially.  
• 
Subjects will remain fasting for two hours after the administration of drug/placebo.  
• 
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 and metabolites will be drawn at at baseline ( prior to 
product administration), 1, 2, 4, 6, 8, 10, and 12 hours (all times have a window of +/- 15 
minutes except the 10 and 12 hour samples which have a window of +- 30 minutes- it is 
critical to record the exact time of blood draw).  


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• 
Urine will be collected (prior to product administration) and for the first 24 hours following 
drug administration.  Following drug administration, urine for oxfendazole, metabolites 
will be collected for 0-4, 4-8, 8-12, and subjects will be sent home with a 24 hour urine 
container to collect all urine between 12-24 hours.  A urine creatinine value will be tested 
on the 12-24 hours sample and used to calculate creatinine clearance. 
• 
Assess adverse events throughout the day and prior to discharge from the CRU. 
• 
Assess for AEs and SAEs 
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
6.3 
Follow-up (Days 2 – 8): Visits 03 through 07 
Clinic Visit 03, 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  
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
10 mL of blood for oxfendazole and metabolites will be drawn at 24 (+ 8) hours. 
• 
Spot urine for oxfendazole, metabolites will be collected at 24 (+8) hours. 
Clinic Visit 04, Day 3 
• 
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 and metabolites. 
• 
For the two sentinel subject only, collect 15 mL of blood for safety laboratory analysis 
(hemoglobin, white blood cell count with neutrophil and eosinophil count, platelet count, 
creatinine, Na, K, Cl, CO2, urea nitrogen, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), prothrombin time and partial thromboplastin time, total 
bilirubin). 
• 
Spot urine for oxfendazole, metabolites will be collected between 48-60 hours.  
Clinic Visit 05, 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  
• 
Counsel on need to avoid alcohol, drugs, tobacco and medications throughout the study. 
• 
Collect 10 mL of blood for oxfendazole and metabolites. 


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• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil and eosinophil counts, platelet count, prothrombin time, partial thromboplastin 
time, Na, K, Cl, CO2, urea nitrogen, creatinine, ALT, AST, total bilirubin, urine dipstick 
for protein and glucose) will be collected.  
• 
An EKG will be performed.  EKG will be reviewed by a cardiologist. 
Clinic Visit 06, Day 6 (+/- 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 and metabolites. 
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 and metabolites. 
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil and eosinophil counts, platelet count, prothrombin time, partial thromboplastin 
time, Na, K, Cl, CO2, urea nitrogen, creatinine, ALT, AST, total bilirubin, urine for 
dipstick testing for protein and glucose) will be collected.  
• 
An EKG will be performed and will be reviewed by a cardiologist. 
6.4 
Final Study Visit, Clinic Visit 08 (Day 15) (+/-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 and metabolites. 
• 
Collect 15 mL of blood for safety panels (hemoglobin, white blood cell count, including 
neutrophil and eosinophil counts, platelet count, prothrombin time, partial thromboplastin 
time, Na, K, Cl, CO2, urea nitrogen, creatinine, ALT, AST, total bilirubin, urine for 
dipstick testing for protein and glucose) will be collected.  
• 
An EKG will be performed and will be reviewed by a cardiologist. 
6.5 
Early Termination Visit 
If a subject withdraws from the study early, the following procedures should be performed at the 
early termination visit. 


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• 
Review current health status (interim medical history) and note any changes since the 
last visit 
• 
Review concomitant medications 
• 
Blood will be collected for safety laboratory tests  
• 
If early termination is prior to 72 hours after administration of the drug, urine 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. 
6.6 
Unscheduled Visit 
Unscheduled visits may occur at any time during the study. Unscheduled visits may occur after 
the scheduled final study visit (Day 15) 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. 
• 
A targeted physical exam, if indicated based on symptoms will be performed. 
• 
Adverse events and serious adverse events will be reviewed. 
6.7 
Handling of Abnormal Liver Function or Hematological Tests 
Preclinical tests demonstrated changes in liver function and hematological tests.  Subjects 
demonstrating a grade 3 or higher change in hematological parameters of absolute neutrophil 
count, hemoglobin, or platelet count or ALT or AST greater than 3 times the upper limit of 
normal or total bilirubin greater than 2 x the upper limit of normal will be asked to return for 
repeat testing within 72 hours of detection of the abnormal laboratory test.  Repeat testing of 
any change in the complete blood count or absolute neutrophil count will require a repeat CBC 
with differential.  Any change in the mentioned liver function tests (ALT, AST, or total bilirubin) 
will require repeat evaluation of all 4 liver tests.  Testing should be repeated 2-3x per week until 
the laboratory value stabilizes or has returned to normal.   All of the evaluations listed under 
“unscheduled visits” will apply for these return visits that require additional laboratory testing.   
 
 


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7 
STUDY PROCEDURES/EVALUATIONS 
7.1 
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.  
Concomitant Medications: All current medications and medications taken in the 30 days 
before enrollment (prescription and over-the-counter drugs) will be documented, as well as 
vitamins and supplements, through 14 days after receipt of study product. 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 2 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 study 
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. 
7.2 
Laboratory Evaluations 
7.2.1 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 with differential (eosinophils, 
neutrophils), platelets, prothrombin time and partial thromboplastin time 
 


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Clinical chemistry includes: Na, K, Cl, CO2, urea nitrogen, creatinine, ALT, AST, total 
bilirubin  
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 
should be deferred if a participant is menstruating, but should be performed as soon as 
possible. 
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. 
7.2.2 Special Assays or Procedures 
The following PK parameters will be analyzed at Dr. Daryl Murry’s lab at the University of Iowa.  
• 
Maximum plasma concentration (Cmax) 
• 
Time to Cmax (Tmax) 
• 
Elimination rate constant (λz) 
• 
Elimination half-life (t½)  
• 
Area under the curve to the final sample (AUC0-t) 
• 
Area under the curve to infinity (AUC) 
• 
Oral clearance (CL/F) 
• 
Oral volume of distribution (Vz/F) 
Blood samples for PK analysis will be collected in tubes containing sodium heparin as the 
anticoagulant at baseline (prior to product administration), at 1, 2, 4, 6, 8, 10, 12, 24 hrs, and 
Days 2, 3, 4, 6, 8 and 15 days after dosing. 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. Urine for oxfendazole, 
metabolites, and creatinine will be collected.   Urine for PK analysis will be collected at baseline 
(prior to product administration) and for the first 24 hours after product administration with 
specific collections times of urine for oxfendazole, 0-4, 4-8, 8-12, 12-24.  A urine creatinine 
value will be tested on the 12-24 hours sample and used to calculate creatinine clearance. Spot 
urine samples will be collected at 24 (+ 8 hrs) and on Day 3 after dosing; 10 mL will be saved, 
aliquoted and stored at -80°C until analyzed. After the study of each cohort is completed, the 
collected plasma and urine samples will be shipped to the analytical lab. Validated methods will 
be used to assay the oxfendazole concentration in each sample. 


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7.2.3 Specimen Preparation, Handling, and Shipping 
Instructions for specimen preparation, handling, storage, and shipping are included in the MOP. 


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8 
ASSESSMENT OF SAFETY 
8.1 
Specification of Safety Parameters 
Safety outcome measures are defined in Section 3.2 and include the rate of SAEs and non-
serious severe AEs. 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
8.2.1 Adverse Events 
Adverse Event (AE):  International Conference on Harmonisation (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 a 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 solicited systemic (subjective and quantitative) reactions, not meeting the 
protocol-defined criteria for SAEs will be captured on the appropriate data collection form and 
electronic case report form (eCRF).  Information to be collected for unsolicited AEs includes 
event description, date of onset, licensed study physician’s assessment of severity and 
relationship to study product and alternate etiology (if not related to study product) (assessed 
only by those with the training and authority to make a diagnosis and listed on the Form FDA 
1572 as the site principal investigator or sub-investigator), date of resolution of the event, 
seriousness and outcome.  All AEs occurring while on study will be documented appropriately 
regardless of relationship.  All AEs will be followed to resolution. 
Any medical condition that is present at the time that the subject is screened will be considered 
as baseline and not reported as an AE.  However, if the severity of any pre-existing medical 
condition increases at any time during the study, it will be recorded as an AE. 
All AEs must be graded for severity and assessed for relationship to study product (see 
definitions below).  Adverse events characterized as intermittent require documentation of onset 
and duration of each episode.  The start and stop date of each reported AE will be recorded on 
the appropriate data collection form and eCRF. 
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 a licensed study physician listed on the Form 
FDA 1572 as the site principal investigator or appropriate sub-investigator using a protocol-
defined grading system (see Section 9.2.2).  For events not included in the protocol-defined 
grading system, the following guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events require minimal or no treatment and do not interfere with the 
subject’s daily activities. 
• 
Moderate (Grade 2):  Events result in a low level of inconvenience or concern with the 
therapeutic measures.  Moderate events may cause some interference with functioning 
and daily activities. 
• 
Severe (Grade 3):  Events interrupt the subject’s usual daily activities and may require 
systemic drug therapy or other treatment.  Severe events are usually incapacitating. 
The severity of systemic and clinical laboratory adverse events will be assessed according to 
toxicity grading scales taken directly or adapted from the DMID Guidance for Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers.  ECG abnormalities will be assessed as per 
Appendix C.   
Relationship to Study Product:  The study clinician’s assessment of an AE's relationship to 
study product 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.  The relationship to study product must be assessed for all AEs 
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. 
8.2.2 Adverse Events 
Subjects will be queried at each visit as to whether they have experienced any new symptoms 
or adverse events.  Common events that may be encountered are listed below.  Vital signs 
including temperature, pulse and blood pressure will be recorded at each visit.  Please refer to 
the toxicity table in Appendix B for grading of adverse events.   
8.2.3 Serious Adverse Events 
Serious Adverse Event (SAE):  


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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 life functions, or, 
• 
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 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 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: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE form and eCRF. 
• 
Followed through resolution or stabilization by a study physician licensed to make 
medical diagnoses and listed on the Form FDA 1572 as the site principal investigator or 
sub-investigator. 
• 
Reviewed and evaluated by an Independent Safety Monitor (ISM), the SMC (periodic 
review unless related), DMID personnel including the medical monitor, and the IRB. 
8.2.4 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.  AE/SAEs, abnormal clinical laboratory test values, or abnormal clinical findings will be 
documented, reported, and followed appropriately. 


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8.3 
Reporting Procedures 
Reporting of Adverse Events: 
AEs will be documented from the time of receipt of study drug on Day 1 (Visit 02) through 
approximately 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 
approximately 14 days after receipt of study product. 
8.3.1 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 20814, 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.  
8.3.2 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 


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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 
information is available.  Upon request from FDA, DMID will submit to FDA any additional data 
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. 
8.3.3 Reporting of Pregnancy 
Not applicable.  Females of childbearing potential are excluded from enrollment in the study. 
8.4 
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. 
8.5 
Halting Rules 
Two sentinel subjects (1 study drug and 1 placebo) will be dosed and monitored 48 hours for 
adverse events prior to enrolling the remaining subjects in each cohort. If no drug-related SAE 
or grade 3 study drug related laboratory AE occurs in the sentinel subjects after 48 hours of 
observation, the remainder of the cohort may proceed with dosing.  


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An SRC composed of the Protocol Principal Investigator and Independent Safety Monitor will 
review blinded safety data for each completed cohort.   Each new cohort will be dosed only after 
the 2-week safety data for the preceding group have been reviewed for the following events: 
• 
The SRC will evaluate the safety data from each dose group and will allow continuation 
if there are no product related grade 3 AEs or if there are fewer than two product related 
grade 2 AEs identified.   
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 24 hours 
after administration of study product. 
• 
Any subject experiences a study drug-related Stevens Johnson Syndrome. 
• 
Two or more subjects experience generalized urticaria within 72 hours after 
administration of study product. 
• 
Any subject experiences a study drug-related SAE from the time of receipt of study drug 
through the subject’s last study visit. 
• 
Any subject develops new EKG changes that are deemed significant by a reviewing 
cardiologist.  
• 
 Any subject develops grade 3 laboratory abnormalities deemed related to the study 
drug. 
• 
The SRC members are not unanimous in their agreement to proceed to the next dosing 
group or cannot assess or do not unanimously agree on the relatedness of the adverse 
event to the study product. 
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. 


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8.6 
Safety Oversight (ISM, SRC, SMC) 
8.6.1 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. 
8.6.2 Safety Review Committee (SRC) 
An SRC composed of the Protocol Principal Investigator and Independent Safety Monitor will 
review blinded safety data for each completed cohort.  Each new cohort will be dosed only after 
the 2-week safety data for the preceding group have been analyzed. 
8.6.3 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 review the safety data at the request of the SRC and if any of the halting rules are 
met. 
 
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.  The SMC will have access to 
unblinded data during its closed session, if applicable. 
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. 


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9 
CLINICAL MONITORING 
9.1 
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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10 STATISTICAL CONSIDERATIONS 
10.1 Study Hypotheses 
The primary objective of the study is to assess the safety and tolerability of oxfendazole in 
healthy males and non-childbearing females adults aged 18-45 years. The secondary objectives 
of the study are to assess the pharmacokinetic profile of oxfendazole and to assess the 
metabolism of oxfendazole.  
Primary outcome measures include: 
• 
The rate of serious adverse events (SAEs) related to oxfendazole. 
• 
The rate of severe (Grade 3) adverse events within 7 days following study drug 
administration in each dosage group. 
• 
The rate of severe (Grade 3) adverse events within 14 days following study drug 
administration in each dosage group considered related to oxfendazole. 
Secondary outcome measures include: 
• 
Plasma Cmax, Tmax, AUC , t1/2 of oxfendazole for each dosage group. 
• 
Plasma and urine concentrations of oxfendazole fenbendazole and oxfendazole sulfone 
at time points specified in Appendix A Schedule of Events and described in Section 4 
Study Design relative to oral dosing. 
 
10.2 Sample Size Considerations 
Sample Size Calculations for Safety:  The goal of the safety evaluation for this dose-
escalation trial is to identify safety concerns associated with oxfendazole. The probability of 
detecting at least one event for a number of true underlying event rates for 3 potential sample 
sizes is listed in Table 4. A sample size of 8 will give at least an 80% probability of observing at 
least 1 event if the true underlying event rate is at least 18%. Sample sizes below 8 will have 
less than 80% probability of observing such events while a sample size of 10 can detect events 
with a true rate of 15% with the same probability. Additionally, a sample size of 8 subjects per 
trial will exclude events occurring in approximately more than 31% of subjects (i.e. the upper 
bound of an exact one-sided 95% confidence interval is 0.31). The sample of size 8 is 
consistent for the goals of this study, will provide an adequate basis for safety estimates of each 
dose and will allow only preliminary safety information relevant to progression to larger trials.  
Table 4: Probability of observing at least one event for several true event rates and the 
event rates which cannot be ruled out if no events are observed. 


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True Event Rate 
 
Probability of Observing 1 or more events 
N = 5 
N = 8 
N = 10 
0.05 
23% 
34% 
40% 
0.10 
41% 
57% 
65% 
0.18 
63% 
80% 
86% 
0.25 
76% 
90% 
94% 
 
Upper Bound for 95% CI if no event observed 
 
N = 5 
N = 8 
N = 10 
 
45% 
31% 
26% 
 
10.3 Planned Interim Data Review 
10.3.1 Safety Review  
Safety data will be reviewed by the SRC and SMC as outlined in Section 8. 
10.3.2 Pharmacokinetic Data Review 
 The study is a rising dose safety/tolerance study in which plasma is collected for analysis of 
oxfendazole, fenbendazole and oxfendazole sulfone levels.  The primary aim is to determine to 
what level single doses can be increased without causing limiting toxicity in normal volunteers.  
In order to facilitate planning for future product development activities without jeopardizing data 
integrity for this trial, pharmacokinetic data will be entered into the trial database as they 
become available. After PK data for a cohort is complete, locked and finalized, these group-level 
(mean and standard deviations) results can be distributed to the study team. These data may be 
distributed in limited fashion such as grant applications.  
 
10.4 Final Analysis Plan 
The primary analysis will be conducted on data and samples collected through study Day 15 of 
the last dosage cohort. This study, like other Phase I studies, is exploratory rather than 
confirmatory; its purpose is to estimate event rates and patterns of pharmacokinetic profiling 
and the metabolism of oxfendazole rather than to test formal statistical hypotheses. Estimates 
will be presented with their 95% confidence intervals for safety endpoints. Descriptive 
approaches will be used to meet the protocol objectives as stated in this protocol. Results will 
be presented in tabular format, as well as graphically when appropriate. Formal comparisons 
between dose groups will not be made. 
 
Statistical Analysis of PK 


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PK parameters for oxfendazole will be calculated using non-compartmental analysis. Only 
plasma concentrations greater than the respective lower limits of quantitation (LOQ) for the 
assay will be used in the PK analysis. 
The maximum plasma concentration (Cmax) and time to Cmax (Tmax) will be taken from the data 
description. The elimination rate constant, 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. Elimination half-life (t½) will be calculated according to the following equation: 
 
Area under the curve to the final sample with a concentration  LOQ (AUC0-t) will be calculated 
using the linear trapezoidal method and extrapolated to infinity using 
z
C
AUC
AUC
tf
t

+
=
−

0
 
where Ctf is the final concentration ≥ LOQ. 
 
Oral clearance (CL/F) and volume of distribution (Vz/F) will be calculated according to 
inf)
0
(
/
−
=
AUC
Dose
F
CL
 and 
inf)
0
(
/
−

=
AUC
z
Dose
F
Vz

. 
 
All PK calculations and graphs of individual subject data will be done using appropriate 
computer software, as determined by the sponsor. 
 
Listing of individual subject plasma concentrations, actual blood sampling times, PK 
parameters, and graphs of concentration vs. time will be prepared by dosing cohort. Plasma 
concentrations and PK parameters will be summarized by and compared among dosing cohorts 
using descriptive statistics. The relationship between Cmax and AUC and dose, i.e., dose 
proportionality, will be examined using the power model, i.e., 
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. 
 
z
t

693
.0
½ =


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11 SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
Data collection forms, most of which serve as source documents for this study, will be derived 
from the electronic CRF and provided by the Statistical and Data Coordinating Center (SDCC) 
to record and maintain data for each subject enrolled in the study. All data collection forms 
should be completed in a neat, legible manner to ensure accurate interpretation of data. Black 
or blue ink is required to ensure clarity of reproduced copies. When making a change or 
correction, 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. 
Data reported in the eCRF derived from the data collection forms should be consistent with the 
source documents or the discrepancies should be explained. 
The sponsor will provide guidance to investigators on making corrections to the data collection 
forms and eCRFs. 


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12 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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13 ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 Ethical Standard 
The study will be conducted according to ICH GCP, the Declaration of Helsinki and US 21 CFR 
Part 50 - Protection of Human Subjects, and Part 56 - Institutional Review Boards. An 
Independent Safety Monitoring Committee will be established prior to commencing the program. 
The principles of informed consent in the current edition of the Declaration of Helsinki and other 
related documents will be implemented before any protocol-specified procedure is carried out. 
Information will be provided to subjects in both oral and written form. Subjects will be given 
ample opportunity to inquire about details of the study and have all of their questions answered. 
The PI and the Co-Investigators have no financial interest in the drugs used in this study. 
 
Monitors under contract to the funding agency will visit the clinical research site to monitor all 
aspects of the study in accordance with the appropriate regulations. The objectives of a 
monitoring visit will be: to verify the prompt reporting of all data points, including reporting SAEs; 
to check availability of signed informed consent; to compare individual subject’s records to the 
source documents (supporting data, laboratory specimen records, and medical records, to 
include physician progress notes, nurse notes, subject’s hospital charts); to ensure protection of 
study subjects, compliance with the protocol, and to ensure accuracy and completeness of 
records. The monitors also will inspect the clinical site regulatory files to ensure that regulatory 
requirements are being followed. During the monitoring visits, the investigator (and/or designee) 
and other study personnel will be available to discuss the study progress and monitoring visit 
findings.  
 
The investigator (and/or designee) will make study documents (e.g., consent forms, clinical 
research forms) and pertinent hospital or clinical records readily available for inspection by the 
local IRB, the FDA, the site monitors, and the funding agency staff for verification of the study 
data.  
 
Any changes or additions to the protocol will be submitted to the local and funding agency IRBs 
for review. A copy of the written approval of the IRBs will be given to the monitor. These 
requirements for approval will not interfere with immediate action being taken, if needed, to 
preserve the safety of all subjects included in the study. 
 
Subject consent will be obtained by the study director or his designee. 
 
13.2 Institutional Review Board 
 


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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 sponsor and provided to the investigator for submission to 
the IRB. 
13.3 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.  Failure to obtain 
informed consent via a signed consent form from each subject before enrollment is a serious 
protocol violation. Before a potential subject is given the written consent form, a study nurse or 
licensed study clinician will discuss in detail with the individual the nature of the study, 
randomization, blinding, study procedures, the importance of compliance with study procedures, 
potential risks and benefits of participation, and the duration of the study. The subject will 
specifically be told of the risks of oxfendazole suggested by preclinical toxicology studies of 
oxfendazole or by known toxicity of other drugs of this class, which include risk of liver 
dysfunction, danger to an unborn child if pregnancy occurs, and effects on reproductive 
capabilities. The potential subject will be explicitly told that he/she is not obligated to participate 
and that there will be no penalty for declining to participate, and that he/she may withdraw from 
the study at any time.  
 
13.4 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. 
13.5 Subject Confidentiality 
Subjects will have code numbers and will not be identified by name.  Subject confidentiality is 
strictly held in trust by the participating site principal investigators, their study personnel, the 
sponsor(s), and their agents.  This confidentiality is extended to cover testing of biological 
samples, in addition to the clinical information relating to participating subjects. 


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The study protocol, documentation, data, and all other information generated will be held in 
strict confidence.  No information concerning the trial or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All information provided by the sponsor and all data and information generated by the 
participating VTEU site as part of the trial (other than a subject’s medical records) will be kept 
confidential by the site principal investigator and other study personnel to the extent permitted 
by law.  This information and data will not be used by the site principal investigator or other 
study personnel for any purpose other than conducting the trial.  These restrictions do not apply 
to: (1) information which becomes publicly available through no fault of the site principal 
investigator or other study personnel; (2) information which is necessary to disclose in 
confidence to an IRB solely for the evaluation of the trial (3) information which is necessary to 
disclose in order to provide appropriate medical care to a study subject; or (4) study results 
which may be published as described in Section 16.  If a written contract for the conduct of the 
trial which includes confidentiality provisions inconsistent with this statement is executed, that 
contract’s confidentiality provisions shall apply rather than this statement. 
The study monitor, the University of Iowa IRB, applicable regulatory authorities, such as the 
FDA, or other authorized representatives of the sponsor may inspect all documents and records 
required to be maintained by the site principal investigator.  This includes, but is not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the subjects in this trial.  
The participating VTEU sites will permit access to such records. 
13.6 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. 
13.7 Future Use of Stored Specimens 
 
No future uses of specimens collected during this study are planned.  Residual samples from 
safety laboratory evaluations and assays for PK analysis will be stored at the University of Iowa 
until all testing has been completed.  Each sample will be encoded (labeled) only with a barcode 
and a unique tracking number to protect subject’s confidentiality.  Samples will be destroyed 
after all study assays have been completed.  
 


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13.8 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. 
 
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. 
 
13.9 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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13.10 Types of Data 
Data for this study will include clinical, safety, and outcome measures (e.g., clinical laboratory 
values, adverse events, and pharmacokinetic and metabolic data). 
13.11 Timing/Reports 
A final report will be prepared following the availability of all the safety, adverse events, and 
pharmacokinetic data.  Interim statistical reports may be generated as deemed necessary and 
appropriate by DMID.  Safety and pharmacological summary reports may be generated for the 
SMC. 
13.12 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. 
13.13 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 
Management Support (CROMS) email (protocoldeviations@dmidcroms.com), web- 
(www.dmidctm.com) or fax-based system (1-215-699-6288).  


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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. 
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.gov55, 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 subject 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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14 LITERATURE REFERENCES 
1. 
Garcia HH, Gonzalez AE, Evans CA, Gilman RH. Taenia solium cysticercosis. Lancet. 
2003;362(9383):547-56. 
2. 
Garcia HH, Gilman R, Martinez M, Tsang VC, Pilcher JB, Herrera G, Diaz F, Alvarado 
M, Miranda E. Cysticercosis as a major cause of epilepsy in Peru. The Cysticercosis 
Working Group in Peru (CWG). Lancet. 1993;341(8839):197-200. 
3. 
Schantz PM, Cruz M, Sarti E, Pawlowski Z. Potential eradicability of taeniasis and 
cysticercosis. Bull Pan Am Health Organ. 1993;27(4):397-403. 
4. 
Shandera WX, White AC, Jr., Chen JC, Diaz P, Armstrong R. Neurocysticercosis in 
Houston, Texas. A report of 112 cases. Medicine (Baltimore). 1994;73(1):37-52. 
5. 
Garcia HH, Pretell EJ, Gilman RH, Martinez SM, Moulton LH, Del Brutto OH, Herrera G, 
Evans CA, Gonzalez AE. A trial of antiparasitic treatment to reduce the rate of seizures 
due to cerebral cysticercosis. N Engl J Med. 2004;350(3):249-58. 
6. 
Garcia HH, Gonzalez AE, Gilman RH. Diagnosis, treatment and control of Taenia solium 
cysticercosis. Curr Opin Infect Dis. 2003;16(5):411-9. 
7. 
White AC, Jr. Neurocysticercosis: updates on epidemiology, pathogenesis, diagnosis, 
and management. Annu Rev Med. 2000;51:187-206. 
8. 
Gonzalez AE, Falcon N, Gavidia C, Garcia HH, Tsang VC, Bernal T, Romero M, Gilman 
RH. Treatment of porcine cysticercosis with oxfendazole: a dose-response trial. Vet Rec. 
1997;141(16):420-2. 
9. 
Gonzales AE, Garcia HH, Gilman RH, Gavidia CM, Tsang VC, Bernal T, Falcon N, 
Romero M, Lopez-Urbina MT. Effective, single-dose treatment or porcine cysticercosis 
with oxfendazole. Am J Trop Med Hyg. 1996;54(4):391-4. 
10. 
Gonzalez AE, Falcon N, Gavidia C, Garcia HH, Tsang VC, Bernal T, Romero M, Gilman 
RH. Time-response curve of oxfendazole in the treatment of swine cysticercosis. Am J 
Trop Med Hyg. 1998;59(5):832-6. 
11. 
Review of Oxfendazole. Parasitology Today. 1991;6. 
12. 
Marriner SE, Bogan JA. Pharmacokinetics of oxfendazole in sheep. Am J Vet Res. 
1981;42(7):1143-5. 
13. 
Synanthic® 22.5% Label. St. Joseph, MO: Boehringer Ingelheim Vetmedica;  [December 
6, 2011]; 2010:[Available from: http://bi-vetmedica.com/products. 
14. 
Synanthic® 9.06% Label. St. Joseph, MO: Boehringer Ingelheim Vetmedica;  [December 
6, 2011]; 2010:[Available from: http://bi-vetmedica.com/products. 
15. 
Brown HD, Matzuk AR, Ilves IR, Peterson LH, Harris SA, Sarett LH, Egerton JR, Yakstis 
JJ, Campbell WC, AC. C. Antiparasitic Drugs  IV.  2-(4'thiazolyl)-benzimidazole, a new 
anthelminthic.  . J Am Chem Soc. 1961;83:1764-5. 
16. 
Tocco DJ, Buhs RP, Brown HD, Matzuk AR, Mertel HE, Harmon RE, NR. T. The 
metabolic phase of thiabendazole in sheep. J Med Chem. 1964;7:399-405. 


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55 
17. 
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. 1993;23(4):477-84. 
18. 
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. 1993;46(5-6):203-14. 
19. 
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. 1992;43(5):1095-100. 
20. 
Lubega GW, Prichard RK. Interaction of benzimidazole anthelmintics with Haemonchus 
contortus tubulin: binding affinity and anthelmintic efficacy. Exp Parasitol. 
1991;73(2):203-13. 
21. 
Freedom of Information Summary, NADA 140-854 Synanthic®-original approval. 1990 
[November 7, 2011]; Available from: 
http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrug
Summaries/ucm049983.html. 
22. 
Nash TE, Neva FA. Recent advances in the diagnosis and treatment of cerebral 
cysticercosis. N Engl J Med. 1984;311(23):1492-6. 
23. 
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. 
2001;345(12):879-85. 
24. 
Briceno P BF, Martinez J. Cisticercosis, Observaciones sobre 97 casos de autopsia. 
Prensa Medica Mexicana. 1961;193. 
25. 
Schenone H VF, Rojas A, Ramirez R. Cysticercosis: Present state of knowledge and 
perspectives In: Flisser A, Willms K, Laclette P, Larralde C.  (Eds.): New York: Academic 
Press; 1982. 25-38 p. 
26. 
Flisser A. Neurocysticercosis in Mexico. Parasitol Today. 1988;4:131-7. 
27. 
Garcia HH, Martinez M, Gilman R, Herrera G, Tsang VC, Pilcher JB, Diaz F, Verastegui 
M, Gallo C, Porras M, et al. Diagnosis of cysticercosis in endemic regions. The 
Cysticercosis Working Group in Peru. Lancet. 1991;338(8766):549-51. 
28. 
Placencia M, Sander JW, Roman M, Madera A, Crespo F, Cascante S, SD S. The 
characteristics of epilepsy in a largely untreated population in rural Ecuador. Neurol 
Neurosurg Psychiatry. 1994;57(3):320-5. 
29. 
Montano S, Villaran M, Ylquimiche L, Figueroa J, Rodriguez S, Bautista C, Gonzalez A, 
Tsang V, Gilman R, Garcia H. Neurocysticercosis: association between seizures, 
serology and brain CT in rural Peru. Neurology. 2005;65:229-33. 
30. 
Davis A. Drug and vaccine development. Trop Med Parasitol. 1987;38(3):215-21. 
31. 
Chopra JS, Kaur U, Mahajan RC. Cysticerciasis and epilepsy: a clinical and serological 
study. Trans R Soc Trop Med Hyg. 1981;75(4):518-20. 
32. 
Powell SJ, Proctor EM, Wilmot AJ, Barnett AM. Neurological complications of 
cysticercosis in Africans: a clinical and serological study. Ann Trop Med Parasitol. 
1966;60(2):159-64. 


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56 
33. 
Naidoo DV, Pammenter MD, Moosa A, van Dellen JR, Cosnett JE. Seventy black 
epileptics. Cysticercosis, computed tomography and electro-encephalography. S Afr 
Med J. 1987;72(12):837-8. 
34. 
Schantz PM, Moore AC, Munoz JL, Hartman BJ, Schaefer JA, Aron AM, Persaud D, 
Sarti E, Wilson M, Flisser A. Neurocysticercosis in an Orthodox Jewish community in 
New York City. N Engl J Med. 1992;327(10):692-5. 
35. 
Shanley JD, Jordan MC. Clinical aspects of CNS cysticercosis. Arch Intern Med. 
1980;140(10):1309-13. 
36. 
Loo L, Braude A. Cerebral cysticercosis in San Diego. A report of 23 cases and a review 
of the literature. Medicine (Baltimore). 1982;61(6):341-59. 
37. 
McCormick GF. Cysticercosis--review of 230 patients. Bull Clin Neurosci. 1985;50:76-
101. 
38. 
Earnest MP, Reller LB, Filley CM, Grek AJ. Neurocysticercosis in the United States: 35 
cases and a review. Rev Infect Dis. 1987;9(5):961-79. 
39. 
Scharf D. Neurocysticercosis. Two hundred thirty-eight cases from a California hospital. 
Arch Neurol. 1988;45(7):777-80. 
40. 
Robles Castillo C. [Medical treatment of cerebral cysticercosis]. Salud Publica Mex. 
1981;23(5):443-50. 
41. 
deGhetaldi LD, Norman RM, Douville AW, Jr. Cerebral cysticercosis treated biphasically 
with dexamethasone and praziquantel. Ann Intern Med. 1983;99(2):179-81. 
42. 
Sotelo J, Escobedo F, Rodriguez-Carbajal J, Torres B, Rubio-Donnadieu F. Therapy of 
parenchymal brain cysticercosis with praziquantel. N Engl J Med. 1984;310(16):1001-7. 
43. 
Sotelo J, Torres B, Rubio-Donnadieu F, Escobedo F, Rodriguez-Carbajal J. Praziquantel 
in the treatment of neurocysticercosis: long-term follow- up. Neurology. 1985;35(5):752-
5. 
44. 
Joubert J, Jenni WK. Treatment of neurocysticercosis. S Afr Med J. 1990;77(1):27-30. 
45. 
Escobedo F, Penagos P, Rodriguez J, Sotelo J. Albendazole therapy for 
neurocysticercosis. Arch Intern Med. 1987;147(4):738-41. 
46. 
Sotelo J, del Brutto OH, Penagos P, Escobedo F, Torres B, Rodriguez-Carbajal J, 
Rubio-Donnadieu F. Comparison of therapeutic regimen of anticysticercal drugs for 
parenchymal brain cysticercosis. J Neurol. 1990;237(2):69-72. 
47. 
Botero D, Uribe CS, Sanchez JL, Alzate T, Velasquez G, Ocampo NE, Villa LA. Short 
course albendazole treatment for neurocysticercosis in Columbia. Trans R Soc Trop 
Med Hyg. 1993;87(5):576-7. 
48. 
Takayanagui OM, Jardim E. Therapy for neurocysticercosis. Comparison between 
albendazole and praziquantel. Arch Neurol. 1992;49(3):290-4. 
49. 
Sotelo J, Escobedo F, Penagos P. Albendazole vs praziquantel for therapy for 
neurocysticercosis. A controlled trial. Arch Neurol. 1988;45(5):532-4. 
50. 
Sotelo J, Penagos P, Escobedo F, Del Brutto OH. Short course of albendazole therapy 
for neurocysticercosis. Arch Neurol. 1988;45(10):1130-3. 


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51. 
Garcia HH, Gilman RH, Horton J, Martinez M, Herrera G, Altamirano J, Cuba JM, Rios-
Saavedra N, Verastegui M, Boero J, Gonzalez AE. Albendazole therapy for 
neurocysticercosis: a prospective double-blind trial comparing 7 versus 14 days of 
treatment. Cysticercosis Working Group in Peru. Neurology. 1997;48(5):1421-7. 
52. 
Gonzalez AE, Garcia HH, Gilman RH, Lopez MT, Gavidia C, McDonald J, Pilcher JB, 
Tsang VC. Treatment of porcine cysticercosis with albendazole. Am J Trop Med Hyg. 
1995;53(5):571-4. 
53. 
Metropolitan Height and Weight Tables. Stat Bull. 1983;64:2-9. 
54. 
CDER, CBER. Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation. 2009. p. 28. 
55. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351:1250-1. 
 
 


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SUPPLEMENTS/APPENDICES 
 


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APPENDIX A: SCHEDULE OF EVENTS  
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Study Day (post 
administration) 
D-28 
to -1 
D1 
D2 
D3 
D4 
D6 
D8 
D15 
Visit/Contact Window 
(Days) 
NA 
NA 
NA 
NA 
NA 
+/- 1 
+/- 1 
+/- 2 
Informed Consent 
x 
 
 
 
 
 
 
 
Inclusion/Exclusion 
x 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
Interim Medical History 
 
x 
 
 
 
 
 
 
Concomitant 
Medications 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs1 
x 
x 
x 
x 
x 
x 
x 
x 
Physical Examination 
x 
x 
 
 
 
 
 
 
HIV, HBC, HCV Testing 
x 
 
 
 
 
 
 
 
Administration of 
oxfendazole/placebo2 
 
x 
 
 
 
 
 
 
Counseling on 
avoidance of 
medications, 
recreational drugs and 
alcohol intake 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 


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Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
Study Day (post 
administration) 
D-28 
to -1 
D1 
D2 
D3 
D4 
D6 
D8 
D15 
Visit/Contact Window 
(Days) 
NA 
NA 
NA 
NA 
NA 
+/- 1 
+/- 1 
+/- 2 
Targeted physical exam 
 
 
x 
x 
x 
x 
x 
x 
Screening  and  Safety 
Labs (CBC, Blood 
Chemistry, 
Urinalysis)1,3,4,7 
x7 
x4 
 
X8 
x4 
 
x4 
x4 
EKG 
x 
 
 
 
x 
 
x 
x 
Blood draw for 
oxfendazole and 
metabolites5 
 
x 
x 
x 
x 
x 
x 
x 
Urine collection for 
oxfendazole,  
metabolites and 
creatinine6 
 
x 
x 
x 
 
 
 
 
Assess/review for AEs 
and SAEs 
 
x 
x 
x 
x 
x 
x 
x 
Blood Volume for Day 
(Total Blood Volume for 
Study) 
15 mL 
(15mL) 
105 mL 
(120mL) 
10 mL 
(130 
mL) 
10 mL 
(140 
mL) 
25 mL 
(165 
mL) 
10 mL 
(175 
mL) 
25 mL 
(200 
mL) 
25 mL 
(225 
mL) 
1 Vital signs and laboratory values will be evaluated using the FDA Guidance for Industry “Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials,” September 2007.  
2 Volunteers will remain fasting for 2 hours after administration of drug/placebo. 
3   Any abnormal laboratory result arising after administration of oxfendazole, and of moderate or greater severity, will be 
followed until results return to baseline value or for the duration of safety follow-up. 
4   Safety laboratories include:  WBC, absolute neutrophil count, eosinophil count, total platelet count, hemoglobin, sodium, 
potassium, chloride, bicarbonate, urea nitrogen, creatinine, prothrombin time, partial thromboplastin time, ALT, AST, total 
bilirubin, urine dipstick for protein and glucose   
5  Blood will be drawn prior to dosing for baseline PK data, and then at, 1, 2, 4, 6, 8, 10, 12, 24 (+ 8 hours), and on Day 3, 
followed by the indicated visit days.  Blood will also be drawn at the final study visit (Day 15). 
6  Urine will be obtained on admission for baseline PK data, and all urine will be collected for the first 24 hours following the 
schedule of urine collections at  0-4, 4-8, 8-12, 12-24 hours.  Spot urine samples will be collected on Days 2 and 3 
following drug administration.  A urine creatinine value will be tested on the 12-24 hours sample only. 
7 Screening labs include WBC, absolute neutrophil count, eosinophil count, total platelet count, hemoglobin, creatinine, 
ALT, AST, total bilirubin, random glucose,  urine dipstick for protein and glucose 
8 Blood for safety laboratory analysis will be obtained for the two sentinel subjects in each dose group. (WBC, absolute 
neutrophil count, eosinophil count, total platelet count, hemoglobin, sodium, potassium, chloride, bicarbonate, urea 
nitrogen, creatinine, prothrombin time, partial thromboplastin time, ALT, AST, total bilirubin)  
   


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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 
>102.1  
** 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 2 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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 Arrythmia 
 
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 
 
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 – 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 


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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 
5.2 – <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 
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 
PT – seconds (prothrombin time) 
> ULN-14.4 
14.5 – 15.7 
> 15.7 
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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65 
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 
[21] 
 
 
 
 
 
QTc interval increase (young 
male) using the most accurate 
QTc formula (ms)* 
 
ULNR to 475 ms and 
increase exceeding 40 
ms 
476 to 
499 
>500 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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66 
 
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 
RBC 
4.5-6.2 millions/mm³ 
4.0-5.2 
millions/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 
Eosinophils 
40-390/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 
Glucose (fasting) 
65-99 
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 
 
DMID Protocol 12-0053: A Randomized, Double-Blind Placebo-Controlled Phase I Trial 
Evaluating the Safety and Pharmacokinetics of Oxfendazole 
 
 
PK STATISTICAL ANALYSIS PLAN 
Principal Investigator: 
Patricia Winokur, MD 
University of Iowa University of Iowa Hospitals and Clinics 
Iowa City, Iowa  52242 
USA 
 
 
Version 1.0 
 
15 September 2015 
 
Prepared and Distributed by: 
Statistical and Data Coordinating Center (SDCC) 
The EMMES Corporation 
Rockville, Maryland USA 
 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL 


 
Statistical Analysis Plan 
 Version 1.0 
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15 September 2015 
 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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STATISTICAL ANALYSIS PLAN 
 
Trial Number Code: 
DMID Protocol: 12-0053 
Development Phase: 
Phase I 
Product: 
Oxfendazole suspension 
Form/Route: 
Tablet/Oral  
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
6610 Rockledge Drive 
Bethesda, Maryland 20892-6603 
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 
Rockville,  MD   20852 
Phone: 240-292-4178 
E-Mail: changsoju@niaid.nih.gov 
 
Clinical/Medical Monitor: 
Greg Deye, MD 
Parasitology and International Programs Branch 
Division of Microbiology and Infectious Diseases  
National Institute of Allergy and Infectious Diseases  
National Institutes of Health  
6610 Rockledge Drive, Room 5067  
Bethesda, Maryland 20892-6603 
Tel: 301-443-9383 
Fax: 301-402-0659 
Email: gregory.deye@nih.gov 
 
 


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STATISTICAL ANALYSIS PLAN – (Continued) 
 
 
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PREPARED BY THE EMMES CORPORATION 
Biostatistician: 
Tina J.T. Dube, PhD 
The Emmes Corporation 
401 North Washington Street, Suite 700 
Rockville, MD 20850 
Email: tdube@emmes.com 
Clinical Trial Initiation Date: 
17 November 2014 
Clinical Trial Completion Date: 
October 2015 (Anticipated) 
Date of the Analysis Plan: 
15 September 2015 
Version Number: 
Version 1.0 
 
Information contained in this publication is the property of Division of Microbiology and Infectious 
Diseases and is confidential. This information may not be disclosed to third parties without written 
authorization from Division of Microbiology and Infectious Diseases.  This report may not be reproduced, 
stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording 
or otherwise - without the prior authorization from Division of Microbiology and Infectious Diseases.  This 
document must be returned to Division of Microbiology and Infectious Diseases upon request. 
 


 
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PROTOCOL SYNOPSIS 
Title of the Trial 
A Randomized, Double-Blind Placebo-Controlled Phase I Trial Evaluating the 
Safety and Pharmacokinetics of Oxfendazole 
Investigators 
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 
 
Trial Center 
 The University of Iowa  
Trial Period 
First Subject First Visit: 17 November 2014  
Last Subject Last Visit: October 2015 (anticipated) 
Development Phase 
Phase I 
Objectives 
Primary: 
• 
Assess the safety and tolerability of oxfendazole in healthy 
adults. 
Secondary: 
• 
Assess the pharmacokinetic profile of oxfendazole  
• 
Assess the metabolism of oxfendazole 
 
Sample Size 
70 (10  subjects in each of 7 dose groups) 
Investigational product  Single oral dose of an aqueous suspension of oxfendazole, a benzimidazole 
carbamate antiparasitic drug. 
Duration of Follow-up 
2 weeks 
Endpoints for Analysis 
Primary Endpoint 
The rate of adverse events (AEs) related to oxfendazole within 14 days of 
receipt of a single oral dose. 
 
Secondary Endpoints 
Plasma Cmax, Tmax, AUC, t1/2 of oxfendazole for each dosage group. 
Plasma and urine concentrations of oxfendazole fenbendazole and 
oxfendazole sulfone at time points specified in Appendix A Schedule of 
Events and described in Section 4 Study Design relative to oral dosing. 
 


 
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PHARMACOKINETIC ANALYSIS PLAN SIGNATURE PAGE: 
Sponsor:  
Division of Microbiology and Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
 
Protocol Number: 
DMID 12-0053 
 
Study Title: 
A Randomized, Double-Blind Placebo-Controlled Phase I Trial Evaluating 
the Safety and Pharmacokinetics of Oxfendazole  
 
Principal Investigator:  Patricia Winokur, M.D. 
Signed: 
 
 
Date: 
 
 
Title:   
 
 
DMID Scientific Lead:  Greg Deye, M.D. 
Signed: 
 
 
Date: 
 
 
Title:   
 
 
The Emmes Corporation:  Tina J.T. Dube, Ph.D. 
Signed:  
 
Date: 
 
 
Title:  Statistician 
 
 
 


 
Statistical Analysis Plan 
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TABLE OF CONTENTS 
 
Page 
PROTOCOL SYNOPSIS .............................................................................................................. iii 
PHARMACOKINETIC ANALYSIS PLAN SIGNATURE PAGE: ............................................ iv 
TABLE OF CONTENTS ................................................................................................................ v 
LISTING OF ABBREVIATIONS .................................................................................................. 1 
1 
PREFACE ........................................................................................................................... 3 
2 
INTRODUCTION .............................................................................................................. 3 
2.1 
Purpose of the Pharmacokinetic Analyses ................................................................... 4 
3 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS ..................................................... 4 
3.1 
Study Design ................................................................................................................ 4 
3.2 
Study Objectives (Pharmacokinetic Only) .................................................................. 5 
3.3 
Study Outcome Measures (Pharmacokinetic Only) .................................................... 5 
4 
PHARMACOKINETIC ANALYSES ................................................................................ 5 
4.1 
General Considerations ................................................................................................ 5 
4.2 
PK Analysis Population ............................................................................................... 5 
4.3 
Demographics and Other Subject Characteristics ....................................................... 6 
4.4 
Summary of Pharmacokinetic Sampling and Sample Properties ................................ 6 
4.4.1 
Handling of Special Cases in Analyses ..................................................................... 6 
4.5 
Interim Pharmacokinetic Analyses .............................................................................. 6 
4.6 
Primary Pharmacokinetic Analysis .............................................................................. 6 
4.6.1 
Concentration Summaries ......................................................................................... 6 
4.6.2 
Pharmacokinetic Parameters ..................................................................................... 7 
4.6.3 
Pharmacokinetic Parameter Estimation .................................................................... 8 
4.7 
Additional Analyses ..................................................................................................... 8 
5 
REPORTING CONVENTIONS ......................................................................................... 8 
6 
TECHNICAL DETAILS .................................................................................................... 8 
7 
REFERENCES ................................................................................................................... 9 
8 
LIST OF PROPOSED TABLES, AND FIGURES .......................................................... 10 
EXHIBIT 1: Summary Statistics of Baseline Characteristics........................................... 11 
EXHIBIT 2: Individual and Summary Statistics for Oxfendazole (Plasma) Concentrations 
by Nominal Time (hours)*................................................................................................ 12 


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TABLE OF CONTENTS – (Continued) 
 
 
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EXHIBIT 3:  Individual and Summary Statistics for Fenbendazole (Plasma)  
Concentrations by Nominal Time (hours)* ...................................................................... 13 
EXHIBIT 4:  Individual and Summary Statistics for Sulfone (Plasma)  Concentrations by 
Nominal Time (hours)*..................................................................................................... 14 
EXHIBIT 5:  Concentrations Profiles by Nominal Time (hours)* ................................... 15 
EXHIBIT 7:  Line Plots of Mean Oxfendazole (Plasma) Concentration by Nominal 
Time* ................................................................................................................................ 17 
EXHIBIT 8:  Line Plots of Mean Fenbendazole (Plasma) Concentration by Nominal 
Time* ................................................................................................................................ 18 
EXHIBIT 9:  Line Plots of Mean Sulfone (Plasma) Concentration by Nominal Time* .. 19 
EXHIBIT 10:  Summary Statistics for Cumulative Amount of Oxfendazole  Excreted 
Unchanged in Urine by Nominal Time* ........................................................................... 20 
EXHIBIT 11: Summary Statistics for Cumulative Amount of  Fenbendazole  Excreted 
Unchanged in Urine by Nominal Time* ........................................................................... 20 
EXHIBIT 12:  Summary Statistics for Cumulative Amount of Sulfone  Excreted 
Unchanged Urine by Nominal Time* ............................................................................... 21 
EXHIBIT 13:  Cumulative Amount of Oxfendazole  Excreted Unchanged in Urine by 
Nominal Time* ................................................................................................................. 22 
EXHIBIT 14:  Cumulative Amount of Fenbendazole  Excreted in Urine by Nominal 
Time* ................................................................................................................................ 23 
EXHIBIT 15:  Summary Statistics for Cumulative Amount of Sulfone  Excreted in Urine 
by Nominal Time* ............................................................................................................ 24 
EXHIBIT 16: Individual and Summary Statistics for Oxfendazole Noncompartmental PK 
Parameters* ....................................................................................................................... 25 
EXHIBIT 17: Individual and Summary Statistics for Fenbendazole Noncompartmental 
PK Parameters* ................................................................................................................. 26 
EXHIBIT 18: Individual and Summary Statistics for Sulfone Noncompartmental PK 
Parameters* ....................................................................................................................... 27 
LISTING 1: Subject Level Demographic and Baseline Characteristics ........................... 28 
LISTING 2: Subject Level Amount Excreted in Urine and Urine Concentrations by 
Treatment Group and Analyte .......................................................................................... 29 
 


 
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LISTING OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
AUC0-t 
Area Under the Curve to the Final Sample 
AUC0-∞ 
AUC Extrapolated to Infinity 
BQL 
Below the Quantification Limit 
Clast 
Last measurable (non-zero) concentration 
CL 
Clearance 
CL/F 
Oral Clearance 
CLR 
Renal Clearance 
Cmax 
Maximum Plasma Concentration 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
F 
Bioavailability 
FDA 
Food and Drug Administration 
fe 
Fraction Excreted Unchanged in Urine 
fu 
Fraction Unbound in Plasma 
GM 
Geometric Mean 
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 
LLOQ 
Lower Limit of Quantification 
LLN 
Lower Limit of Normal 
MedDRA 
Medical Dictionary for Regulatory Activities 


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LISTINGS OF ABBREVIATIONS – (Continued) 
 
 
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MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NCA 
Noncompartmental Analysis 
NF 
National Formulary 
NEJM 
New England Journal of Medicine 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
NOEL 
No Observed Effect Level 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
OXF 
Oxfendazole 
PD 
Pharmacodynamic 
PG 
Pharmacogenomic 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PKAR 
Pharmacokinetics Analysis Report 
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 of 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 
 


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1 
PREFACE 
The Statistical Analysis Plan (SAP) for “DMID Protocol 12-0053: A Randomized, Double-Blind 
Placebo-Controlled Phase I Trial Evaluating the Safety and Pharmacokinetics of Oxfendazole” describes 
and expands upon the statistical information presented in the protocol.   
 
This document describes all planned pharmacokinetic analyses, and provides reasons and justifications 
for these analyses as well as all planned sample tables, listings and figures. Regarding the final analysis 
and final integrated Clinical/Statistical Report (CSR), this SAP follows the International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) 
Guidelines, as indicated in Topic E3 (Structure and Content of Clinical Study Reports), and more 
generally is consistent with Topic E8 (General Considerations for Clinical Trials) and Topic E9 
(Statistical Principles for Clinical Trials). The structure and content of the SAP provides sufficient detail 
to meet the requirements identified by the FDA and ICH, while all work planned and reported for this 
SAP will follow internationally accepted guidelines published by the American Statistical Association 
and the Royal Statistical Society for statistical practice. 
 
This document contains four sections: (1) a review of the study design, (2) general statistical 
considerations, (3) comprehensive statistical analysis methods for pharmacokinetic outcomes, and (4) a 
list of proposed tables and figures. Any deviation from this statistical plan will be described and justified 
in protocol amendments and/or in the final study 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. 
 
IMPORTANT NOTES: 
 
Tables, indicated by footnote, presented in this statistical analysis plan will be presented by dose 
group. 
 
This SAP relies on simulated (fake) sample data to illustrate the statistical methods, tables, and 
graphical displays that will be used in analyzing the study data. These simulated data are for 
illustrative purposes only and no inferences should be drawn regarding pharmacokinetic profiles.  
Appropriate scales and units will be added to all figures for the final analysis. 
2 
INTRODUCTION 
With current treatment strategies for neurocysticercosis, cure is achieved in approximately 50% of 
patients despite multiple doses of drug. In animal studies, single oral doses of oxfendazole appear to have 
substantial activity against the tissue stages of Taenia solium. Oxfendazole, as a single dose, might be 
efficacious against neurocysticercosis in humans. A Phase I study is needed to evaluate its safety, 
metabolism, and pharmacokinetics (PK) in humans. As a result, this Phase I randomized, double-blind, 
placebo-controlled evaluation of the safety and PK of escalating single oral doses of oxfendazole (0.5, 1, 


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3, 7.5, 15, 30, 60 mg/kg) in healthy volunteers is designed to assess safety, metabolism and PK in 
humans. 
2.1 
Purpose of the Pharmacokinetic Analyses 
The study is a rising dose safety/tolerance study in which plasma is collected for analysis of oxfendazole, 
fenbendazole and sulfone levels.  The primary aim is to determine to what level single doses can be 
increased without causing limiting toxicity in normal volunteers.  
 
The analyses described will assess the pharmacokinetics of a single dose of oxfendazole (0.5, 1, 3, 7.5, 
15, 30, 60 mg/kg) in healthy volunteers and will be included in the Interim PK Analysis Report (PKAR) 
and also may be distributed in limited fashion such as for grant applications.  
 
Subject level results will be included in the clinical study report (CSR).  Dose group-level (mean and 
standard deviations) results will be presented at each interim look. This PK analysis plan describes the 
analyses that will be performed. 
 
3 STUDY DESIGN, OBJECTIVES AND ENDPOINTS 
3.1 
Study Design 
This Phase I study is a randomized, double-blind, placebo-controlled evaluation of the safety and PK of 
escalating single oral doses of oxfendazole (0.5, 1, 3, 7.5, 15, 30, 60 mg/kg) in healthy volunteers. Each 
cohort will comprise 10 volunteers (8 drug, 2 placebo). Subjects will be monitored for 2 weeks after 
dosing, including monitoring the PK and metabolism of oxfendazole in blood and urine. 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 18 months to finish the study.   
 
Two sentinel subjects (one randomized to receive study drug and the other to receive placebo) will be 
dosed and monitored 48 hours for adverse events prior to enrolling the remaining subjects in each cohort.  
If no drug-related serious adverse event or laboratory grade 3 study drug related events are observed 
within the 48 hour period, the remainder of the cohort will proceed with dosing. Each new cohort will be 
dosed only after the 2-week safety data for the preceding group have been analyzed.  A Safety Review 
Committee (SRC) composed of the Protocol Principal Investigator and Independent Safety Monitor will 
review blinded safety data for the completed cohort. If a clinically significant AE is observed that is 
possibly drug related, the SRC will determine if an ad hoc SMC meeting should be called. Up to 70 
volunteers (56 drug, 14 placebo) will complete the study.  The Safety Monitoring Committee (SMC) will 
review the safety data either when or if the final dose is reached.  
 
Sample Collection: 
Blood and urine will be obtained for PK analysis. Blood samples for PK analysis are collected at 14 time 
points: baseline (prior to product administration); 1, 2, 4, 6, 8, 10, 12 (all times have a window of +/- 15 
minutes except the 10 and 12 hour samples which have a window of +/- 30 minutes), and 24 (+8) hours; 
and Days 3, 4, 6, 8 and 15 after dosing. Urine for oxfendazole, metabolites, and creatinine will be 


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collected. Urine for PK analysis will be collected at baseline (prior to product administration) and for the 
first 24 hours after product administration with specific collections times of urine for oxfendazole, 0-4, 4-
8, 8-12, 12-24. Spot urine samples will be collected at 24 (+ 8 hrs) and on Day 3 after dosing.  
 
Samples for PK studies will be processed at Dr. Daryl Murry’s laboratory at the University of Iowa. 
3.2 
Study Objectives (Pharmacokinetic Only) 
• 
Assess the pharmacokinetic profile of oxfendazole  
• 
Assess the metabolism of oxfendazole 
3.3 
Study Outcome Measures (Pharmacokinetic Only) 
• 
Plasma Cmax, Tmax, AUC, t1/2 of oxfendazole for each dosage group. 
• 
Plasma and urine concentrations of oxfendazole fenbendazole and oxfendazole sulfone at 
the following time points: 
o 
Blood- prior to dosing for baseline PK data, and then at, 1, 2, 4, 6, 8, 10, 12, 24 (+ 8) 
hours, Day 3 and Day 15. 
o 
Urine- prior to dosing for baseline PK data, and then for the first 24 hours following the 
schedule of urine collections at  0-4, 4-8, 8-12, 12-24 hours.  Spot urine samples will be 
collected on Days 2 and 3 following drug administration.    
 
4 PHARMACOKINETIC ANALYSES 
4.1 
General Considerations 
Subject characteristics will be summarized overall and by dose group. PK parameters determined by 
noncompartmental approaches will be summarized by dose group. Statistics include the arithmetic mean, 
geometric mean, standard deviation (SD), coefficient of variation (CV), minimum (min), maximum 
(max), and median. 
4.2 
PK Analysis Population  
All subjects who receive active study drug and have at least 1 measured oxfendazole concentration at a 
scheduled PK time point after start of dosing are eligible for the PK population.  If any subjects are found 
to be noncompliant with respect to dosing, have incomplete data, or an event that is likely to affect PK, a 
decision will be made on a case-by-case basis as to their inclusion in the population. Subjects excluded 
from the PK analyses and their reasons for exclusion will be denoted and detailed in the PKAR. 
 
 


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4.3 
Demographics and Other Subject Characteristics 
The following variables will be summarized for the PK analysis population: 
• 
Demographic variables: gender, age, race, and ethnicity. 
• 
Physical characteristics: height and weight recorded at the PK dosing visits or carried 
forward from a previous study visit. 
• 
Clinical laboratory parameters:  Creatinine, AST, ALT 
4.4 
Summary of Pharmacokinetic Sampling and Sample Properties 
4.4.1 
Handling of Special Cases in Analyses 
Key protocol violations and deviations related to PK sample collection or storage that could potentially 
impact PK results will be summarized.  Samples with bioanalytical errors reported by the laboratory will 
be excluded.  Collection times of samples missing the actual collection time will be imputed using the 
nominal collection time.  Such samples will be identified in the PKAR. 
4.5 
Interim Pharmacokinetic Analyses 
This study is a rising dose safety/tolerance study in which plasma is collected for analysis of oxfendazole, 
fenbendazole and sulfone levels. The primary aim is to determine to what level single doses can be 
increased without causing limiting toxicity in normal volunteers. 
  
In order to assess safety of rising dose levels and to facilitate planning for future product development 
activities without jeopardizing data integrity for this trial, pharmacokinetic data will be entered into the 
trial database as they become available and reviewed after each dose group. After PK data for a cohort is 
complete, locked and finalized, group-level results will be distributed to the study team. These data may 
be distributed in limited fashion such as grant applications.   
 
Subject baseline characteristics will be summarized and presented by Dose group. Dose group-level 
summary statistics as well as line plots for of oxfendazole, fenbendazole and sulfone levels will be 
presented.  
 
All PK parameters will be presented by group and specimen type. No individual subject summaries will 
be presented in interim pharmacokinetic report.   
4.6 
Primary Pharmacokinetic Analysis 
4.6.1 
Concentration Summaries 
Dose group-level summary plots will be produced by plotting plasma concentrations (mean ± SD) versus 
nominal time to explore average trends and variability.  Dose group-level summary plots of the amount 
excreted in urine will be produced by plotting the cumulative amount excreted in each collection interval 
versus the midpoint of the collection interval.  
 
 


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4.6.2 
Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated using actual post-dose time. All PK parameters will also 
be summarized by dose group and specimen type using descriptive statistics.  Additionally, subject-level 
PK parameters will be presented by subject in data listings in the final PKAR.   
 
The following parameters will be calculated from the concentration-time profiles: 
 
Maximum plasma concentration (Cmax) is defined as: the maximum observed drug concentration in 
blood plasma for a particular dose interval.  
 
Time of maximum plasma concentration (Tmax) is defined as: the time at which the maximum plasma 
concentration occurs. 
 
AUC0-t is defined as: the area under the concentration-time curve from administration (time 0) to the time 
of the last quantifiable concentration at time =t. 
 
The following parameters will be estimated when the elimination rate constant is estimable: 
 
Elimination rate constant (λz) is defined as: the first-order rate constant describing rate of elimination 
from plasma.   
 
Elimination half-life (t1/2) is defined as: the time required for a drug concentration to be reduced by half 
during the elimination phase.  The terminal half-life will be estimated by ln(2) divided by λz. 
 
  
 
AUC0-∞ is defined as: the total area under the concentration-time curve and is computed by adding AUC0-t 
to an extrapolated value equal to the last measured concentration greater than limits of quantitation 
divided by λz and will be calculated using 
Z
tf
t
C
AUC
AUC
λ
+
=
−
∞
−
0
0
,  
where Ctf is the last measurable concentration ≥ LLOQ  
 
Oral clearance (CL/F) is calculated as: the dose divided by the AUC0-∞.  
 
Apparent volume of distribution (Vz/F) is defined as: the theoretical volume that the total amount of 
administered drug would occupy to provide the same concentration as it currently is in blood plasma 
divided by the bioavailability.  
∞
−
×
=
0
/
AUC
z
Dose
F
Vz
λ
  
Amount of drug excreted in urine (Ae) is defined as: the cumulative amount of drug excreted in urine. 
Ae will be used to calculate the fraction of dose excreted in urine (fe) and estimate renal clearance (CLR). 
 


Statistical Analysis Plan 
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Additional parameters may be estimated, if appropriate. 
4.6.3 
Pharmacokinetic Parameter Estimation 
Samples with concentrations greater than the LLOQ will be considered for the estimation of λz.  This 
slope will be computed from log-transformed concentration data.  The correlation between time and 
concentration in the time points used to estimate λz should be sufficiently high (|r|>0.8) for λz. to be 
estimated reliably.  At least three samples will be used for the calculation of λz. The observation collected 
at Tmax may be considered to be used in the calculation if the concentration at that time point is not 
strongly affected by drug absorption. The range of selected time points should be >1.5 half-lives. 
 
Samples used to calculate λz along with the number of samples used for the calculation will be included in 
subject listings. 
 
The AUC will be computed using the linear-up log-down (linear-log) trapezoidal method in WinNonlin 
(Pharsight Corporation, Cary, NC).  
4.7 
Additional Analyses 
In order to assess dose proportionality and linearity across the range of administered doses, plots of dose 
versus exposure (AUC0-∞ or Cmax) will be presented with corresponding descriptive statistics such as R2. 
Parameter estimates for an appropriate (simple least squares, weighted least squares, or power) regression 
model will also be provided [2, 3]. Model selection will be guided by graphical diagnostics to assess 
model fit. 
5 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported 
as “<0.001”; p-values greater than 0.999 will be reported as “>0.999”.  Parameters directly derived from 
source data (e.g., Cmax and Cmin) will be reported and analyzed with the same precision as the source 
data.  Parameters derived from actual sample collection times (e.g., Tmax and Tmin) will be reported with 
the same precision as the actual elapsed sampling time value of the source data.  The mean, standard 
deviation, and any other statistics other than quantiles, will be reported to one decimal place greater than 
the original data.  Quantiles such as the minimum and maximum will use the same number of decimal 
places as the original data. Proportions will be presented as two decimal places; proportions <0.01 will be 
presented as “<0.01”. Percentages will be reported to the nearest whole number; values < 1% will be 
presented as “<1”. Estimated parameters, not on the same scale as raw observations (e.g. regression 
coefficients) will be reported to 3 significant figures. 
6 
TECHNICAL DETAILS 
Estimation of pharmacokinetic parameters will be performed in a validated version of WinNonlin  version 
6.3 or later, or a similar software package. WinNonlin or SAS version 9.3 or later will be used to generate 
all tables, figures, and listings 
 


Statistical Analysis Plan 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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7 
REFERENCES 
1. Cawello W (ed). Parameters of Compartment-free Pharmacokinetics: Standardisation of Study 
Design, Data Analysis and Reporting. Shaker Verlag; Aachen, Germany, 1999. 
2. Hummel J, McKendrick S, Brindley C, and French R. Exploratory Assessment of Dose 
Proportionality: Review of Current Approaches and Proposal for a Practical Criterion. 
Pharmaceut. Statist., Vol. 8, No. 1, January-March 2009. DOI: 10.1002/pst.326. 
3. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, and Forgue ST. 
Confidence Interval Criteria for Assessment of Dose Proportionality. Pharm Res 2000; 17:1278-
1283. 
 


 
Statistical Analysis Plan 
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8 
LIST OF PROPOSED TABLES, AND FIGURES 
 


Statistical Analysis Plan 
Version 1.0 
DMID Protocol 12-0053 
15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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EXHIBIT 1: 
Summary Statistics of Baseline Characteristics 
Characteristic 
Dose Group 
1 
(N=) 
Dose Group 
2 
(N=) 
All Groups 
(N=) 
Dose (mg) 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
Min, Max 
 
 
 
Gender– n (%) 
 
 
 
Male 
 
 
 
Female 
 
 
 
Age (Years) 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
Min, Max 
 
 
 
Height (cm) 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
Min, Max 
 
 
 
Weight (kg) 
 
 
 
Mean (SD) 
 
 
 
Median 
 
 
 
Min, Max 
 
 
 
 


Statistical Analysis Plan 
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15 September 2015 
 
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EXHIBIT 2: 
Individual and Summary Statistics for Oxfendazole (Plasma) Concentrations by Nominal Time (hours)* 
Subject ID 
Nominal Time (hrs) 
Pre-
Dose 
1 
2 
4 
6 
8 
10 
12 
24 
48 
72 
120 
168 
336 
001 
 
 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
Number > 
LLOQ 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
*This table will be repeated for each dose group.  
LLOQ = 2 ng/ml 
LLOD = 1 ng/ml 
 
 


Statistical Analysis Plan 
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EXHIBIT 3:  
Individual and Summary Statistics for Fenbendazole (Plasma)  
Concentrations by Nominal Time (hours)* 
Subject ID 
Nominal time (hrs) 
Pre-
Dose 
1 
2 
4 
6 
8 
10 
12 
24 
48 
72 
120 
168 
336 
001 
 
 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
Number > 
LLOQ 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
*This table will be repeated for each dose group.  
LLOQ = 2 ng/ml 
LLOD = 1 ng/ml 
 
 


Statistical Analysis Plan 
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EXHIBIT 4:  
Individual and Summary Statistics for Sulfone (Plasma) 
 Concentrations by Nominal Time (hours)* 
Subject ID 
Nominal time (hrs) 
Pre-
Dose 
1 
2 
4 
6 
8 
10 
12 
24 
48 
72 
120 
168 
336 
001 
 
 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
 
Number > 
LLOQ 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
* This table will be repeated for each dose group.  
LLOQ = 2 ng/ml 
LLOD = 1 ng/ml 
 
 


Statistical Analysis Plan 
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EXHIBIT 5:  
Concentrations Profiles by Nominal Time (hours)* 
 
*This figure will be repeated for each subject. 


Statistical Analysis Plan 
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EXHIBIT 6:  
 Semilogarithmic Individual Concentration Profiles* 
 
*This figure will be repeated for each subject. 
 


Statistical Analysis Plan 
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15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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EXHIBIT 7:  
Line Plots of Mean Oxfendazole (Plasma) Concentration by Nominal Time* 
 
*Error bars give +/- standard deviation.  
 


Statistical Analysis Plan 
 Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
EXHIBIT 8:  
Line Plots of Mean Fenbendazole (Plasma) Concentration by Nominal Time*  
 
*Error bars give +/- standard deviation.  
 
 


Statistical Analysis Plan 
 Version 1.0 
DMID Protocol 12-0053 
15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
EXHIBIT 9:  
Line Plots of Mean Sulfone (Plasma) Concentration by Nominal Time* 
 
*Error bars give +/- standard deviation.  
 
 


Statistical Analysis Plan 
 Version 1.0 
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15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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EXHIBIT 10:  
Summary Statistics for Cumulative Amount of Oxfendazole 
 Excreted Unchanged in Urine by Nominal Time* 
Pre-Dose 
0-4 hours 
4-8 hours 
8-12 hours 
12-24 hours 
Statistic 
 
 
N 
 
 
Mean 
 
 
SD 
 
 
Min 
 
 
Median 
 
 
Max 
 
 
* This table will be repeated for each dose group.  
Subject level data is presented in Listing 2. 
EXHIBIT 11: 
Summary Statistics for Cumulative Amount of  Fenbendazole  
Excreted Unchanged in Urine by Nominal Time* 
Pre-Dose 
0-4 hours 
4-8 hours 
8-12 hours 
12-24 hours 
Statistic 
 
 
N 
 
 
Mean 
 
 
SD 
 
 
Min 
 
 
Median 
 
 
Max 
 
 
* This table will be repeated for each dose group. 
Subject level data is presented in Listing 2. 
 
 


Statistical Analysis Plan 
 Version 1.0 
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15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
EXHIBIT 12:  
Summary Statistics for Cumulative Amount of Sulfone 
 Excreted Unchanged Urine by Nominal Time*  
Pre-Dose 
0-4 hours 
4-8 hours 
8-12 hours 
12-24 hours 
Statistic 
 
 
N 
 
 
Mean 
 
 
SD 
 
 
Min 
 
 
Median 
 
 
Max 
 
 
This table will be repeated for each dose group.  
Subject level data is presented in Listing 2. 


Statistical Analysis Plan 
 Version 1.0 
DMID Protocol 12-0053 
15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
EXHIBIT 13:  
Cumulative Amount of Oxfendazole 
 Excreted Unchanged in Urine by Nominal Time* 
 
This figure will be repeated for each dose group.  
 
 


Statistical Analysis Plan 
 Version 1.0 
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15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
EXHIBIT 14:  
Cumulative Amount of Fenbendazole 
 Excreted in Urine by Nominal Time* 
 
This figure will be repeated for each dose group.  
 


Statistical Analysis Plan 
 Version 1.0 
DMID Protocol 12-0053 
15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
PREPARED BY THE EMMES CORPORATION 
EXHIBIT 15:  
Summary Statistics for Cumulative Amount of Sulfone 
 Excreted in Urine by Nominal Time*  
 
This figure will be repeated for each dose group. 
  
 


Statistical Analysis Plan 
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15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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EXHIBIT 16: 
Individual and Summary Statistics for Oxfendazole Noncompartmental PK Parameters* 
Subject ID 
AUC0-t  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Tmax (hr) 
Cmax 
(ng/mL) 
N for λz 
λz (hr-1) 
t1/2 (hr) 
CL/F 
(L/hr) 
Vz/F 
(L) 
CLR (L/hr) 
fe 
001 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
CV % 
 
 
 
 
 
 
 
GM 
 
 
 
 
 
 
 
* This table will be repeated for each dose group. 
LLOQ = 2 ng/ml 
LLOD = 1 ng/ml 
N= number of time points used to calculate λz 
 
 


Statistical Analysis Plan 
 Version 1.0 
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15 September 2015 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
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EXHIBIT 17: 
Individual and Summary Statistics for Fenbendazole Noncompartmental PK Parameters* 
Subject ID 
AUC0-t  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Tmax (hr) 
Cmax 
(ng/mL) 
N for λz 
λz (hr-1) 
t1/2 (hr) 
CL/F 
(L/hr) 
Vz/F 
(L) 
CLR (L/hr) 
fe 
001 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
CV % 
 
 
 
 
 
 
 
GM 
 
 
 
 
 
 
 
* This table will be repeated for each dose group. 
LLOQ = 2 ng/ml 
LLOD = 1 ng/ml 
N= number of time points used to calculate λz 
 
 


Statistical Analysis Plan 
 Version 1.0 
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15 September 2015 
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EXHIBIT 18: 
Individual and Summary Statistics for Sulfone Noncompartmental PK Parameters* 
Subject ID 
AUC0-t  
(ng·hr/mL) 
AUC0-∞ 
(ng·hr/mL) 
Tmax (hr) 
Cmax 
(ng/mL) 
N for λz 
λz (hr-1) 
t1/2 (hr) 
CL/F 
(L/hr) 
Vz/F 
(L) 
CLR (L/hr) 
fe 
001 
 
 
 
 
 
 
 
002 
 
 
 
 
 
 
 
003 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
CV % 
 
 
 
 
 
 
 
GM 
 
 
 
 
 
 
 
* This table will be repeated for each dose group. 
LLOQ = 2 ng/ml 
LLOD = 1 ng/ml 
N= number of time points used to calculate λz 
 
 


Statistical Analysis Plan 
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LISTING 1: 
Subject Level Demographic and Baseline Characteristics 
Dose Group 
Subject 
ID 
Dose (mg) 
Sex 
Age 
(Years) 
Weight 
(kg) 
Height 
(cm) 
 
 
 
 
 
 


Statistical Analysis Plan 
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LISTING 2: 
Subject Level Amount Excreted in Urine and Urine Concentrations by Treatment Group and Analyte 
Dose 
Group 
Subject 
ID 
Visit 
Number 
(Study 
Day) 
Scheduled 
Collection 
Interval 
(hr) 
 
 
 
 
Date 
(Time) 
 of Sample 
Collection 
Oxfendazole 
Fenbendazole 
Sulfone 
Actual 
Collectio
n 
Interval 
(hr) 
Start Date 
(Time) 
 of Urine 
Collection 
Stop 
Date 
(Time) 
 of Urine 
Collectio
n 
Collected 
Urine 
Volume 
(mL) 
Concentration 
(ng/mL) 
Amount 
Excrete
d (mg) 
Concentratio
n (ng/mL) 
Amount 
Excreted 
(mg) 
Concentratio
n (ng/mL) 
Amount 
Excreted 
(mg)