A Dose-Block Randomized, Placebo Controlled (Double-blind), Active Controlled(Open-label), Dose-escalation Study

A Dose-Block Randomized, Placebo Controlled (Double-blind), Active Controlled(Open-label), Dose-escalation Study to Investigate the Tolerability, and Pharmacokinetics/Pharmacodynamics of HL2351 After a Single Subcutaneous Administration in Healthy Male Subjects

The study design of this trial is a Dose-Block Randomized, Placebo controlled (Double-blind), Active Controlled(Open-label), Dose-escalation.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Biological: HL2351; Biological: Kineret(Anakinra)

Detailed Description

• Extended in vivo half-life of HL2351 is also anticipated to provide improved therapeutic efficacy based on sustained maintenance of an effective concentration.
• A safety concern may be addressed by utilizing IL-1Ra that is being used after getting approval by the EMA and the US FDA and known to be relatively safe, and the Fc fusion technology that has been already applied to various therapeutic agents.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • HANDOK Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. A healthy adult man aged between 20 and 45 years (inclusive) at screening

2. Weight between 55 and 90 kg (inclusive) and the body mass index(BMI) between 18.0 and 27.0 (inclusive)

   • BMI(kg/m2) = Body weight (kg)/{height (m)}2
3. Voluntary consent to participation in this study and signature on the IRB-approved informed consent form after being explained about characteristics of this clinical study, prior to any screening test

Exclusion Criteria:

1. Current or history of a clinically significant hepatic, renal, neurological, immunological, respiratory or endocrine disease or hematological or oncological disease, cardiovascular disease or psychiatric disease (mood disorder or compulsive disorder, etc.) (in case of a hepatic disease, a hepatitis virus-infected subject may be also included)
2. Hypersensitivity to a drug (aspirin or antibiotics, etc.) or past history of clinically significant hypersensitivity
3. In sitting vital signs measured after resting for 3 min or more, systolic blood pressure of <90mmHg or >150mmHg, or diastolic blood pressure of <60mmHg or >100 mmHg
4. Past history of drug abuse or positive urine drug screening results
5. Use of any prescription medicine or oriental medicine within 2 weeks or use of any over-the-counter(OTC) medication or vitamin preparation within 1 week prior to the scheduled first dose (however, a subject may be included if other conditions are satisfied, at the discretion of the investigator)
6. Participation in another clinical study and administration of a drug within 3 months prior to the scheduled first dose (from the dosing day)
7. Whole blood donation within 2 months or apheresis within 1 month prior to the scheduled first dose, or transfusion within 1 month prior to the first dose
8. A habitual drinker (>21 units/week, 1 unit = 10 g of pure alcohol) or a person who cannot abstain from alcohol consumption during hospitalization
9. A smoker of 10 cigarettes/day on average over the past 3 months or a person who cannot abstain from smoking during hospitalization
10. A person who is planning to get pregnant during the study or who cannot practice acceptable contraception (example: surgical sterilization of a subject or a partner, intrauterine device used by a partner, barrier contraception, diaphragm or condom used in combination) even if not planning to get pregnant
11. Notable prolongation of the QT/QTcb interval at screening (e.g., repeated confirmation of QTcb interval > 450 ms)
12. Confirmed history of a risk factor for TdP (e.g., heart failure, hypokalemia, family history of a long QT syndrome)
13. Chronic, uncontrolled or symptomatic inflammatory disease (e.g., rheumatoid arthritis, systemic lupus erythematosis)
14. Pyrexia of ≥38°C within 1 week prior to administration of the investigational product
15. Past history of tuberculosis infection and/or positive Quantiferon TB-Gold test results at screening
16. A person who had participated in this study and received the investigational product
17. A person who is otherwise determined as not eligible for clinical study participation by the investigator due to other reasons including clinical laboratory test results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HL2351; 1, 2, 4, 8, 12 mg/kg (SC) / Single-Dose	Biological: HL2351; Dose-escalation For 5 level dose groups A ~ E(each 1, 2, 4, 8, 12mg/kg), 10 subjects (8 for the study drug and 2 for placebo) are randomized to each dose group, and the study drug or placebo is subcutaneously administered for the relevant dose group.
Placebo Comparator: Placebo; 1, 2, 4, 8, 12 mg/kg (SC) / Single-Dose	Biological: HL2351; Dose-escalation For 5 level dose groups A ~ E(each 1, 2, 4, 8, 12mg/kg), 10 subjects (8 for the study drug and 2 for placebo) are randomized to each dose group, and the study drug or placebo is subcutaneously administered for the relevant dose group.
Active Comparator: Kineret(Anakinra); 100 mg (SC) / Single-Dose	Biological: Kineret(Anakinra); Active comparator(group F) is implemented in parallel with dose groups A~E in an open-label manner and 8 subjects subcutaneously administer Kineret® 100 mg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerability as measured by the occurrence of Adverse Events	Adverse Events after single subcutaneous dose of HL2351 : check Day -1, 1, 2, 3, 4, 5, 7, 11, 15, 22, 29	29 days
Tolerability as measured by Physical Examination, Vital Signs and Safety Laboratory Tests	Changes from baseline in physical examination, vital signs, ECG, clinical laboratory tests (routine hematology, routine chemistry, blood coagulation and urinalysis) after single subcutaneous dose of HL2351	29 days
Tolerability as measured by the occurrence of Local Toxicity	Local Toxicity after single subcutaneous dose of HL2351 : check Day 1, 2, 4	4 days
Tolerability as measured by Cytokine Laboratory Test	Cytokine Laboratory Test after single subcutaneous dose of HL2351 : check Day 1, 2, 4	4 days
Pharmacokinetics of HL2351: Maximum plasma concentration(Cmax)	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacokinetics of HL2351: Area under plasma drug concentration-time curve [AUC(0-last), AUCinf]	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacokinetics of HL2351: Time of maximum concentration(Tmax)	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacokinetics of HL2351: Elimination half-life(T1/2)	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacokinetics of HL2351: Apparent Clearance(CL/F)	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacokinetics of HL2351: Apparent Volume of Distribution(Vz/F)	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacokinetics of HL2351: Mean Residence Time (MRT)	To assess pharmacokinetics after single subcutaneous injection of HL2351	29 days
Pharmacodynamics of HL2351: IL-6 inhibition assay	To assess the pharmacodynamic dose-response relationship after single subcutaneous injection of HL2351 IL-6 inhibition assay: AUEClast, Emax	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunogenicity of HL2351: Anti-drug Antibody	To assess immunogenicity after single subcutaneous injection of HL2351	Day 1, Day 29
Tolerability in comparison with Kineret(Anakinra): measured by the occurrence of Adverse Events	To explore tolerability in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Tolerability in comparison with Kineret(Anakinra): measured by Physical Examination, Vital Signs and Safety Laboratory Tests	To explore tolerability in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Tolerability in comparison with Kineret(Anakinra): measured by the occurrence of Local Toxicity	To explore tolerability in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Tolerability in comparison with Kineret(Anakinra): measured by Cytokine Laboratory Test	To explore tolerability in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Maximum plasma concentration	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Area under plasma drug concentration-time curve [AUC(0-last), AUCinf]	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Time of maximum concentration(Tmax)	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Elimination half-life(T1/2)	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Apparent Clearance(CL/F)	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Apparent Volume of Distribution(Vz/F)	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacokinetics in comparison with Kineret(Anakinra): Mean Residence Time (MRT)	To explore pharmacokinetics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	3 days
Pharmacodynamics in comparison with Kineret(Anakinra): IL-6 inhibition assay	To explore pharmacodynamics in comparison with subcutaneous administration of a positive comparator, Kineret(Anakinra)	1 day

Collaborators and Investigators

• Sponsor: Handok Inc.
• Investigators: Principal Investigator: Hyeong Ki Lee, Professor, Clinical Trial Center, Seoul National University Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: June 17, 2014
• First Submitted That Met QC Criteria: June 24, 2014
• First Posted (Estimate): June 26, 2014

Study Record Updates

• Last Update Posted (Estimate): October 6, 2015
• Last Update Submitted That Met QC Criteria: October 5, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: First In Human; CAPS, SoJIA, AOSD, Bechet Disease, Rheumatoid arthritis
• Additional Relevant MeSH Terms: Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: HL_C101