Phase I Trial Evaluating the Safety and Pharmacokinetics of Oxfendazole

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double-Blind Placebo-Controlled Phase I Trial Evaluating the Safety and Pharmacokinetics of Oxfendazole

Conditions
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Neurocysticercosis

Intervention / Treatment
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* Drug: Oxfendazole
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 degrees Celsius, 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. 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. Exclusion Criteria: 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 degrees Fahrenheit (>/=38.0 degrees Celsius) 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 the prescription medications used less than once per week on average are permitted for enrollment (see section 5.6 for instructions on medication use during the study). If the subject has taken a short term prescription medication within the past 30 days (e.g. an antibiotic), they should be postponed from enrollment until 30 days have elapsed since the last dose 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>N=8 subjects receive single oral dose 0.5mg/kg of oxfendazole; N= 2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|
| Experimental: Group 2<br>N=8 subjects receive single oral dose 1mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|
| Experimental: Group 3<br>N=8 subjects receive single oral dose 3mg/kg of oxfendazole; N= 2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|
| Experimental: Group 4<br>N=8 subjects receive single oral dose 7.5mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|
| Experimental: Group 5<br>N=8 subjects receive single oral dose 15mg/kg of oxfendazole; N= 2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|
| Experimental: Group 6<br>N=8 subjects receive single oral dose 30mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|
| Experimental: Group 7<br>N=8 subjects receive single oral dose 60mg/kg of oxfendazole; N=2 subjects receive single oral dose placebo | Drug: Oxfendazole<br>* 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.<br>Other: Placebo<br>* Normal Saline administered with an oral dosing syringe. Group 1- Group 6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting Adverse Events Related to Oxfendazole Within 14 Days of Receipt of a Single Oral Dose. | All adverse events, defined as any untoward medical occurrence regardless of its causal relationship to the study treatment, were collected for 14 days after dosing. The PI then determined relatedness to the study drug. Related was defined as 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. | Within 14 Days of first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Time-curve From Time Zero to Infinity (AUC(0-infinity)) for Oxfendazole | AUC(0-infinity) was defined as the total area under the concentration-time curve from dosing (time 0) taken to the limit as the end time becomes arbitrarily large. AUC(0-infinity) and was calculated by adding AUC(0-last) to an extrapolated value equal to the last measured concentration greater than the lower limit of quantification of the bioanalytical assay divided by the terminal phase elimination rate constant (Ke) computed from concentrations that were measured using a validated HPLCMS/MS method | 0, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336 hours post-dose | 
| Maximum Observed Concentration (Cmax) of Oxfendazole in Plasma | Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations computed from concentrations that were measured using a validated HPLC-MS/MS method. | 0, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336 hours post-dose | 
| Plasma Concentrations of Oxfendazole Fenbendazole | Concentrations of oxfendazole fenbendazole in plasma were measured using a validated HPLCMS/MS method. Concentrations <LLOQ (2 ng/mL) set to LLOQ/2 if after 1st =LLOQ concentration or 0 otherwise for calculating summary statistics. | Day 1-Day15 | 
| Plasma Concentrations of Oxfendazole Sulfone | Concentrations of oxfendazole sulfone in plasma were measured using a validated HPLCMS/MS method. Concentrations <LLOQ (2 ng/mL) set to LLOQ/2 if after 1st =LLOQ concentration or 0 otherwise for calculating summary statistics. | Day 1-Day15 | 
| Terminal Elimination Half-life (t1/2) of Oxfendazole | The apparent terminal elimination half-life (t1/2) was defined as the time required for the drug concentration to decrease by a factor of one-half in the terminal phase computed from concentrations that were measured using a validated HPLCMS/MS method. | 0, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336 hours post-dose | 
| Time of Maximum Observed Concentration (Tmax) of Oxfendazole | Tmax was defined as the time at which the maximum concentration (Cmax) occurs in plasma computed from concentrations that were measured using a validated HPLCMS/MS method. | 0, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336 hours post-dose | 
| Urine Concentrations of Oxfendazole Fenbendazole | Concentrations of oxfendazole fenbendazole in urine were measured using a validated HPLCMS/MS method. Concentrations <LLOQ (2 ng/mL) set to LLOQ/2 if after 1st =LLOQ concentration or 0 otherwise for calculating summary statistics. | Day 1-Day 15 | 
| Urine Concentrations of Oxfendazole Sulfone | Concentrations of oxfendazole sulfone in urine were measured using a validated HPLCMS/MS method. Concentrations <LLOQ (2 ng/mL) set to LLOQ/2 if after 1st =LLOQ concentration or 0 otherwise for calculating summary statistics. | Day 1-Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurocysticercosis, pork tapeworm, Taenia solium