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

• ClinicalTrials.gov Identifier: NCT02535416
• Recruitment Status: Completed
• First Posted: August 28, 2015
• Results First Posted: February 26, 2018
• Last Update Posted: February 26, 2018
• Sponsor: Arrowhead Pharmaceuticals
• Information provided by (Responsible Party): Arrowhead Pharmaceuticals

Study Description

Brief Summary:

Single doses of ARC-520 will be evaluated at varying infusion rates and by slow bolus push.

Condition or disease	Intervention/treatment	Phase
Healthy	Drug: ARC-520; Drug: cetirizine; Drug: diphenhydramine	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: September 2015
• Actual Primary Completion Date: August 2016
• Actual Study Completion Date: August 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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)

Contacts and Locations

Locations

Australia, Queensland

QPharm, Pty Limited, Royal Brisbane Hospital

Herston, Queensland, Australia, 4029

Sponsors and Collaborators

Arrowhead Pharmaceuticals

More Information

• Responsible Party: Arrowhead Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02535416
• Other Study ID Numbers: Heparc-1002
• First Posted: August 28, 2015
• Results First Posted: February 26, 2018
• Last Update Posted: February 26, 2018
• Last Verified: August 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Additional relevant MeSH terms:

Diphenhydramine; Promethazine; Cetirizine; Sleep Aids, Pharmaceutical; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anesthetics, Local; Anesthetics; Sensory System Agents; Peripheral Nervous System Agents; Antiemetics; Autonomic Agents; Gastrointestinal Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Allergic Agents; Antipruritics; Dermatologic Agents; Histamine H1 Antagonists, Non-Sedating