A Study of ARC-520 at Varying Infusion Rates in Healthy Adult Volunteers

Study Overview
=================
Brief Summary
-----------------
Single doses of ARC-520 will be evaluated at varying infusion rates and by slow bolus push.

Detailed Description
-----------------
This is a single-center, open-label, sequential cohort, single-dose study of ARC-520 administered intravenously to healthy adult volunteers. Eligible subjects will receive a single intravenous injection of ARC-520. Up to 8 cohorts (a total of approximately 40 subjects) may be enrolled. ARC-520 (4.0 mg/kg) will be administered at increasing infusion rates up to a bolus push in cohort 5. In addition dose levels at 5.0 mg/kg and 6.0 mg/kg will be evaluated at an infusion rate of 0.9 mL/min. For each subject the duration of the study clinic visits is approximately 6 weeks; maximum study duration is approximately 17 weeks including follow-up telephone calls at Days 30, 60 and 90. Participants will undergo the following evaluations at regular intervals: medical history, physical examinations, bee venom allergy blood test, vital signs measurements, weight, adverse event monitoring, electrocardiograms (ECGs), telemetry, pregnancy test (females), concurrent medication, blood sample collection for hematology, coagulation, chemistry, pharmacokinetics, pharmacodynamics, and drug screens, and urinalysis.

Official Title
-----------------
A Phase 1, Open-Label Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ARC-520 at Varying Infusion Rates in Normal Adult Volunteers

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: ARC-520
* Drug: cetirizine
* Drug: diphenhydramine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, 18-55 years of age, inclusive Able to provide written informed consent BMI between 19.0 and 35.0 kg/m2, inclusive 12-lead ECG at Screening and pre-dose with no clinically significant abnormalities Highly effective, double barrier contraception (both male and female partners) during the study and for 3 months following the dose of ARC-520 Willing and able to comply with all study assessments Suitable venous access for blood sampling Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and creatinine levels in the normal range No abnormal finding of clinical relevance Exclusion Criteria: Pregnant/lactating Acute signs of hepatitis/other infection within 4 weeks of Screening Concurrent use of anticoagulants, corticosteroids, immunomodulators, or immunosuppressants. Use of prescription medication within 14 days prior to study treatment Depot injection/implant other than birth control within 3 months of study treatment Known diagnosis of diabetes mellitus History of autoimmune disease especially autoimmune hepatitis. Human immunodeficiency virus (HIV) infection Sero-positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) Uncontrolled hypertension: blood pressure (BP) > 150/100 mmHg History of cardiac rhythm disturbances Family history of congenital long QT syndrome, Brugada syndrome or unexplained sudden cardiac death. Currently uses medications known to prolong the corrected QT interval (QTc). Symptomatic heart failure (per New York Heart Association guidelines) Unstable angina, myocardial infarction, severe cardiovascular disease, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within past 6 months History of malignancy within last 5 years except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer Major surgery within 3 months of Screening History of alcohol and/or drug abuse < 12 months from Screening Regular use of alcohol within 6 months of Screening Evidence of systemic acute inflammation, sepsis or hemolysis. Clinically significant psychiatric disorder Use of recreational drugs within 3 months of Screening or drugs, such as cocaine, phencyclidine (PCP), and methamphetamines, within 1 year of Screening Positive urine drug screen History of allergy or hypersensitivity reaction to bee venom Positive reaction to the bee venom immunoglobulin E [IgE] test Use of investigational agents or devices within 30 days of study dosing or current participation in an investigational study. Clinically significant history/presence of any gastrointestinal pathology, unresolved gastrointestinal symptoms, liver or kidney disease Cholangitis, cholecystitis, cholestasis, or duct obstruction Clinically significant history/presence of neurological, endocrine, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease Blood donation or blood loss (500 mL) within 30 days prior to study treatment History of fever within 2 weeks of Screening. Excessive exercise/physical activity within 7 days of Screening or enrollment or planned during the study. History of coagulopathy, stroke within six (6) months of baseline, and/or concurrent anticoagulant medication(s)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARC-520 Cohort 1<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.6 mL/min + cetirizine | Drug: ARC-520<br> <br> Drug: cetirizine<br> <br> |
| Experimental: ARC-520 Cohort 2A<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.9 mL/min + cetirizine | Drug: ARC-520<br> <br> Drug: cetirizine<br> <br> |
| Experimental: ARC-520 Cohort 2<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.75 mL/min + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |
| Experimental: ARC-520 Cohort 3<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.9 mL/min + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |
| Experimental: ARC-520 Cohort 4<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 1.2 mL/min + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |
| Experimental: ARC-520 Cohort 5<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 1.5 mL/min + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |
| Experimental: ARC-520 Cohort 6<br>Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 5 minute slow bolus push + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |
| Experimental: ARC-520 Cohort 7<br>Single dose, intravenous administration of ARC-520 at 5.0 mg/kg 0.9 mL/min + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |
| Experimental: ARC-520 Cohort 8<br>Single dose, intravenous administration of ARC-520 at 6.0 mg/kg 0.9 mL/min + diphenhydramine | Drug: ARC-520<br> <br> Drug: diphenhydramine<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) is defined as any untoward medical occurrence that does not necessarily have a causal relationship with this treatment. TEAEs were defined as all AEs starting or worsening after commencement of treatment with investigational product. | post-dose through the end of study (Day 15 ± 1 day) plus 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours (AUC0-24) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting hepatitis B virus [HBV]) and melittin-like peptide (MLP). | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Quantifiable Plasma Concentration (AUClast) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Zero Extrapolated to Infinity (AUCinf) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Maximum Plasma Concentration (Cmax) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Clearance (CL) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Apparent Volume of Distribution (V) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Terminal Elimination Rate Constant (Lambda z) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose | 
| Pharmacokinetics: Half-Life (t1/2) of the Analytes of ARC-520 | Analytes include AD0009 and AD0010 (cholesterol-conjugated siRNA targeting HBV) and MLP. | Day 1 pre-dose through 48 hours post-dose |