Relative Bioavailability of CE-Iohexol (Captisol-enabled™ Iohexol) Injection and Omnipaque™ Injection

Study Overview
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Brief Summary
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This study is designed to compare the bioavailability of the test Product(CE-Iohexol Injection) and the reference product Iohexol Injection (Omnipaque™) following intravenous injection in normal healthy volunteers. The secondary objective is to assess the safety and tolerability of the treatments administered. Captisol® is present to improve stability and to potentially reduce the risk of contrast-induced acute kidney injury(CI-AKI) associated with iohexol administration.

Detailed Description
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This is a single center, randomized, double-blind, 2-period, crossover study. A total of 24 subjects will be enrolled in the study; subjects will be dosed as 2 groups of 12 subjects each. Additional subjects may be enrolled into the study to obtain the statistical power of 90%. Subjects will attend a screening visit within 28 days prior to Period 1, and eligible subjects will then return to the clinic on the evening prior to Day -1. On Day 1, prior to dosing, subjects will be randomized to receive either CE-Iohexol Injection or the reference product during the first treatment period and the alternate product during the second treatment period. In each period, the study drug will be administered after a fasting period ≥8 hours. Each dose of intravenous iohexol will be separated by a minimum of a 7-day washout period. The test or reference product (iohexol 350 mg Iodine/mL, 80 mL) will be infused at a high flow rate of 4 mL/second for a dose of 400 mgI/kg for 70 kg subject. The test or reference product will be administered using a power injector. Plasma samples for determination of iohexol concentrations will be obtained from arm #2 (the arm not used for dosing) at 0 (pre-dose), 30 seconds, 5, 10, 15, 20, 30 and 45 minutes, and 1, 2, 3, 4, 6, 8, 12, 24, and 48 hours after infusion start; the 30-second sample obtained at the end of infusion. Subjects will be discharged from the clinic on Day 3 following collection of the 48-hour blood sample.

Official Title
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A Randomized, Double-Blind, 2-Period Crossover Trial to Determine the Relative Bioavailability of CE-Iohexol (Iohexol/Sulfobutylether-β-Cyclodextrin ( Captisol®)) Injection and Omnipaque™ (Iohexol) Injection in Healthy Adult Volunteers

Conditions
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Contrast-induced Nephropathy, Coronary Angiography

Intervention / Treatment
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* Other: Omnipaque™ (iohexol) Injection
* Other: CE-Iohexol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women of childbearing potential who are sexually active with a non-sterile male partner must be using a medically acceptable form of birth control for the duration of the trial and for 30 days after the last dose of study drug BMI within the range of 18.5-35 kg/m2, inclusive, and body weight > 45 kg No significant disease or abnormal laboratory values Normal vital signs, without any clinically significant abnormalities Normal 12-lead electrocardiogram, without any clinically significant abnormalities of rate, rhythm or conduction Nonsmokers defined as not having smoked in the past 3 months prior to dosing Estimated glomerular filtration rate (eGFR) of > 60 mL/min/1.73 m2 Exclusion Criteria: Known hypersensitivity or allergy to iohexol, CAPTISOL®, Omnipaque™ or its excipients Known hypersensitivity or allergy to iodine or radio-opaque dyes Women who are pregnant or breast feeding History or presence of asthma or other pulmonary disease, thyroid disease (hypo- or hyperthyroidism), hepatitis or other liver disease Any disease or condition (medical or surgical) which, in the opinion of the investigator, might compromise a major system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk Abnormal laboratory values which are considered clinically significant Positive screen for Hepatitis B (HbsAg, Hepatitis B Surface Antigen), Hepatitis C (anti HCV, Hepatitis C Antibody), or HIV (anti-HIV 1/2) Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to the first dose Use of medication other than topical products without significant systemic absorption, hormonal contraceptives and hormone replacement therapy Unwilling to refrain from consumption of alcohol within 48 hours prior to each dose administration and during any in-patient period. Positive urine drug screen, positive alcohol breath test or positive cotinine test at screening and upon check-in to the study facility History of significant alcohol abuse within one year prior to screening or regular use of alcohol within six months prior to the screening visit Illicit drug use,significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction A history of difficulty with donating blood or with the insertion of large-calibre catheter Donation of plasma (500 mL) within 7 days prior to drug administration. Hemoglobin < 128 g/L (males) and < 115 g/L (females) and hematocrit < 0.36 L/L (males) and < 0.32 L/L (females) at screening Any history of photosensitivity

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Single center, randomized, double-blind, 2-period, crossover study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator<br>Omnipaque™ (iohexol) Injection, 755 mg/mL iohexol (350 mgI/mL) | Other: Omnipaque™ (iohexol) Injection<br>* 755 mg/mL iohexol (350 mgI/mL), 80 mL infused intravenously over approximately 20 seconds<br>|
| Experimental: Experimental<br>CE-Iohexol Injection, 755 mg/mL iohexol (350 mgI/mL)/50 mg CAPTISOL®/mL | Other: CE-Iohexol<br>* 755 mg/mL iohexol (350 mgI/mL)/50 mg CAPTISOL®/mL, 80 mL infused intravenously over approximately 20 seconds<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Iohexol Area Under the Concentration-Time Curve (AUC) [ Time Frame: At designated time points up to 48 hours per Period ] | Blood samples are to be collected at designated time points for the determination of the iohexol AUC. (Time points for CE-Iohexol Injection: Pre-dose, 30 seconds, 5, 10, 15, 20, 30 and 45 minutes, and 1, 2, 3, 4, 6, 8, 12, 24 and 48 hrs post dose. Time points for Omnipaque™ (iohexol) Injection: Pre-dose, 30 seconds, 5, 10, 15, 20, 30 and 45 minutes, and 1, 2, 3, 4, 6, 8, 12, 24 and 48 hrs post dose). | 48 hours | 
| Iohexol Maximum Plasma Concentration (Cmax) [ Time Frame: At designated time points up to 48 hours per Period ] | Blood samples are to be collected at designated time points for the determination of the iohexol Cmax. (Time points for CE-Iohexol Injection: Pre-dose, 30 seconds, 5, 10, 15, 20, 30 and 45 minutes, and 1, 2, 3, 4, 6, 8, 12, 24 and 48 hrs post dose. Time points for Omnipaque™ (iohexol) Injection: Pre-dose, 30 seconds, 5, 10, 15, 20, 30 and 45 minutes, and 1, 2, 3, 4, 6, 8, 12, 24 and 48 hrs post dose). | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of all Adverse Events graded according to the Common Terminology Criteria for Adverse Events (CTCAE) [Time Frame: Day -1, 24h and 48h post dose]. | An adverse event is defined as any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. The severity of all adverse events will be graded according to the CTCAE version 4.0 from dosing until 30 days post-dose | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Iohexol, Captisol®, cyclodextrin, radiographic, iodinated contrast medium, Omnipaque™