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

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: ARC-520
Drug: diphenhydramine
Drug: cetirizine

Registration Number: NCT02535416

Lead Sponsor: Arrowhead Pharmaceuticals

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ARC-520 Cohort 2A	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.9 mL/min + cetirizine
ARC-520 Cohort 8	ARC-520	Single dose, intravenous administration of ARC-520 at 6.0 mg/kg 0.9 mL/min + diphenhydramine
ARC-520 Cohort 4	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 1.2 mL/min + diphenhydramine
ARC-520 Cohort 3	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.9 mL/min + diphenhydramine
ARC-520 Cohort 1	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.6 mL/min + cetirizine
ARC-520 Cohort 2	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.75 mL/min + diphenhydramine
ARC-520 Cohort 5	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 1.5 mL/min + diphenhydramine
ARC-520 Cohort 6	ARC-520	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 5 minute slow bolus push + diphenhydramine
ARC-520 Cohort 7	ARC-520	Single dose, intravenous administration of ARC-520 at 5.0 mg/kg 0.9 mL/min + diphenhydramine
ARC-520 Cohort 2	diphenhydramine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.75 mL/min + diphenhydramine
ARC-520 Cohort 6	diphenhydramine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 5 minute slow bolus push + diphenhydramine
ARC-520 Cohort 1	cetirizine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.6 mL/min + cetirizine
ARC-520 Cohort 2A	cetirizine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.9 mL/min + cetirizine
ARC-520 Cohort 3	diphenhydramine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 0.9 mL/min + diphenhydramine
ARC-520 Cohort 4	diphenhydramine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 1.2 mL/min + diphenhydramine
ARC-520 Cohort 5	diphenhydramine	Single dose, intravenous administration of ARC-520 at 4.0 mg/kg 1.5 mL/min + diphenhydramine
ARC-520 Cohort 7	diphenhydramine	Single dose, intravenous administration of ARC-520 at 5.0 mg/kg 0.9 mL/min + diphenhydramine
ARC-520 Cohort 8	diphenhydramine	Single dose, intravenous administration of ARC-520 at 6.0 mg/kg 0.9 mL/min + diphenhydramine

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	post-dose through the end of study (Day 15 ± 1 day) plus 30 days	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.

Secondary Outcome Measures

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