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A dose-block randomized, double-blind, placebo-controlled, single dosing, dose-escalation phase I clinical trial to investigate the safety/tolerability and pharmacokinetics of HNP-2006 after intravenous administration in healthy adult volunteers

Status Approved

  • First Submitted Date

    2020/05/07

  • Registered Date

    2020/07/28

  • Last Updated Date

    2020/11/06

CRIS Required

WHO ICTRP (International Clinical Trial Registry Platform) Required

  • 1. Background

    Background - CRIS Registration Number, Unique Protocol ID, Public/Brief Title, Scientific Title, Acronym, MFDS Regulated Study, IND/IDE Protocol, Registered at Other Registry, Name of Registry/Registration Number
    CRIS
    Registration Number
    KCT0005257
    Unique Protocol ID H-1903-057-1017
    Public/Brief Title A dose-block randomized, double-blind, placebo-controlled, single dosing, dose-escalation phase I clinical trial to investigate the safety/tolerability and pharmacokinetics of HNP-2006 after intravenous administration in healthy adult volunteers
    Scientific Title A dose-block randomized, double-blind, placebo-controlled, single dosing, dose-escalation phase I clinical trial to investigate the safety/tolerability and pharmacokinetics of HNP-2006 after intravenous administration in healthy adult volunteers
    Acronym
    MFDS Regulated Study Yes
    IND/IDE Protocol Yes
    Registered at Other Registry No
    Healthcare Benefit Approval Status Not applicable
  • 2. Institutional Review Board / Ethics Committee

    Institutional Review Board Information
    Board Approval Status Submitted approval
    Board Approval Number H-1903-057-1017
    Approval Date 2019-03-27
    Institutional Review Board Name Seoul National University Hospital Institutional Review Board
    Institutional Review Board Address 101, Daehak-ro, Jongno-gu, Seoul
    Institutional Review Board Telephone 02-2072-0694
    Data Monitoring Committee No
  • 3. Contact Details

    Contact Details Information - Contact Person for Principal Investigator / Scientific Queries, Contact Person for Public Queries, Contact Person for Updating Information의 Name, Title, Email, Telephone, Cellular Phone, Affiliation, Address
    Contact Person for Principal Investigator / Scientific Queries
    Name SeungHwan Lee
    Title Associate Professor
    Telephone +82-2-2072-2343
    Affiliation Seoul National University Hospital
    Address 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
    Contact Person for Public Queries
    Name KiYoung Huh
    Title Resident
    Telephone +82-2-2072-1666
    Affiliation Seoul National University Hospital
    Address 101 Daehak-ro, Jongno-gu, Seoul, Republic of Korea
    Contact Person for Updating Information
    Name MinAh Choi
    Title Study Manager
    Telephone +82-2-559-5780
    Affiliation Hana Pharm
    Address 10F, EK tower, 407 Teheran-ro, Gangnam-gu, Seoul, Republic of Korea
  • 4. Status

    Status Information - Study Site, Overall Recruitment Status, Date of First Enrollment, Status of First Enrollment, Target Number of Participant, Primary Completion Date, Recruitment Status by Participating Study Site, Name of Study Site, Recruitment Status, Date of First Enrollment, Status of First Enrollemnt
    Study Site Single
    Overall Recruitment Status Completed
    Date of First Enrollment 2020-01-13 Actual
    Target Number of Participant 40
    Primary Completion Date 2020-08-18 , Actual
    Study Completion Date 2020-09-15 , Actual
    Recruitment Status by Participating Study Site 1
    Name of Study Seoul National University Hospital
    Recruitment Status Completed
    Date of First Enrollment 2020-01-13 ,
  • 5. Source of Monetary / Material Support

    Source of Monetary / Material Support Information - Organization Name, Organization Type, Project ID
    1. Source of Monetary/Material Support
    Organization Name Hana Pharm
    Organization Type Pharmaceutical Company
    Project ID HNP-2006-CS-101
  • 6. Sponsor Organization

    Sponsor Organization Information - Organization Name, Organization Type
    1. Sponsor Organization
    Organization Name Hana Pharm
    Organization Type Pharmaceutical Company
  • 7. Study Summary

    Study Summary Information
    Lay Summary
    1) Purpose
      This study aims to evaluate the safety, tolerability and pharmacokinetics of HNP-2006 after a single intravenous administration in healthy adults. 
    
    2) Backgroud
    Contrast agent is a drug injected into a human body to make a specific organ, tissue, or blood vessel look clear by improving contrast of structures in the body and body fluids during diagnostic imaging, including radiography, ultrasonography, and magnetic resonance imaging (MRI), or procedures. Use of contrast agent is a noninvasive and innovative way to diagnose a disease, but long-term, potential results of use of contrast agent can never be ignored. 
      MRI contrast agent is classified into positive and negative, or T1 and T2 contrast agent, and the disadvantage of contrast agent is that a broader area than an actual area is exposed for imaging. In Korea, T2 contrast agent (Feridex and Resovist) were marketed, but the marketing has been stopped due to inconvenience and side effects experienced by patients (The most common side effects was low back pain and the incidence of side effects was approximately 10 - 15 %). The most commonly used T1 contrast agent in clinical settings is Gd-DOTA and Gd-DO3A. Gadolinium contrast agent is mostly removed through a kidney, but trace amounts of gadolinium may remain in the body, bones, skin, and organs, and it is known that more gadolinium remains when a linear agent rather than a macrocyclic agent is used. In this regard, nephrogenic systemic fibrosis, a disease where fibrosis is caused when gadolinium ion (Gd3+) is separated, may occur as a serious side effect. In 2010, the US Food and Drug Administration (FDA) recommended that gadodiamide and gadopentetate should not be used in patients with severe renal impairment (eGFR < 30mL/min/1.73m2), and Korea also distributed a safety letter. In addition, in 2017, the European Commission announced withdrawal of marketing approval for drugs containing any of the three components (gadodiamide, gadopentetate meglumine, and gadoversetamide) of linear gadolinium contrast agents as a result of reviewing benefit-risk of accumulation of gadolinium in the brain. In August 2018, Korea also announced that approval and supply were maintained only for gadoterate, gadoteridol, and gadobutrol and that supply of drugs containing any of gadodiamide, gadopentetate meglumine, or gadoversetamide would be gradually discontinued by the end of 2018. As shown above, safety of contrast agent is a continuously discussed issue, and development of an alternative drug that is safer than existing contrast agents is required. Therefore, to resolve safety issues related to release of gadolinium ion, a new drug <HNP-2006> has been developed as a contrast agent that has high water solubility, ensures safety by reducing toxicity compared to existing MRI contrast agents, and shows great contrast enhancement. HNP-2006 is a new functional cyclic contrast agent that has high water solubility by using ligand DO3A- acetamide and shows a higher relaxation rate and thermodynamic and pharmacokinetic stability compared to existing gadolinium.
    This study aims to evaluate the safety, tolerability and pharmacokinetics of HNP-2006 after a single intravenous administration in healthy adults.
    
     3) Design
      A dose-block randomized, double-blind, placebo-controlled, single dosing, dose-escalation phase I clinical trial 
      This study will sequentially increase the dose from the lowest dose for Cohort 1 (0.02 mmol/kg). Upon the completion of each cohort, the investigator and sponsor will review blinded safety data and if necessary, PK data obtained, and determine whether to proceed to the subsequent cohort. When determining whether to proceed from Cohort 3 (0.1 mmol/kg) to Cohort 4 (0.2 mmol/kg), 2 independent experts (1 clinical pharmacologist and 1 radiologist) will review blinded data prior to a decision on dose escalation.
  • 8. Study Design

    Study Design Information - Study Type, Study Purpose, Phase, Intervention Model, Blinding/Masking, Blinded Subject, Allocation, Intervention Type, Intervention Description, Number of Arms, Arm Label, Target Number of Participant, Arm Type, Arm Description
    Study Type Interventional Study
    Study Purpose
    Treatment
    Phase Phase1
    Intervention Model Parallel  
    Blinding/Masking Double
    Blinded Subject Subject, Investigator
    Allocation RCT
    Intervention Type Drug  
    Intervention Description
    A dose-block randomized, single dosing, intravenous administration 
    1) 1Cohort: 0.02mmol/kg HNP-2006(6) or placebo(2) 
    2) 2Cohort: 0.05mmol/kg HNP-2006(6) or placebo(2) 
    3) 3Cohort: 0.10mmol/kg HNP-2006(6) or placebo(2) 
    4) 4Cohort: 0.20mmol/kg HNP-2006(6) or placebo(2) 
    5) 5Cohort: 0.30mmol/kg HNP-2006(6) or placebo(2)
    Number of Arms 2
    Arm 1

    Arm Label

    HNP-2006

    Target Number of Participant

    30

    Arm Type

    Experimental

    Arm Description

    A dose-block randomized, single dosing, intravenous administration 
    1) 1Cohort: 0.02mmol/kg HNP-2006(6) 
    2) 2Cohort: 0.05mmol/kg HNP-2006(6) 
    3) 3Cohort: 0.10mmol/kg HNP-2006(6) 
    4) 4Cohort: 0.20mmol/kg HNP-2006(6) 
    5) 5Cohort: 0.30mmol/kg HNP-2006(6)
    Arm 2

    Arm Label

    Placebo of HNP-2006 injection

    Target Number of Participant

    10

    Arm Type

    Placebo comparator

    Arm Description

    A dose-block randomized, single dosing, intravenous administration 
    1) 1Cohort: 0.04ml/kg placebo(2) 
    2) 2Cohort: 0.10ml/kg placebo(2) 
    3) 3Cohort: 0.20ml/kg placebo(2) 
    4) 4Cohort: 0.40ml/kg placebo(2) 
    5) 5Cohort: 0.60ml/kg placebo(2)
  • 9. Subject Eligibility

    Subject Eligibility Information
    Condition(s)/Problem(s)    Not Applicable-Etc 

    Healthy adult/Contrast Media [D27.505.259.500]
    Rare Disease No
    Inclusion Criteria

    Gender

    Both

    Age

    19Year~55Year

    Description

    1.Healthy adults aged ≥ 19 to < 55 years at the time of screening test 
    2.Body mass index (BMI) of ≥ 18.5 to < 27.0 ※ BMI = Body weight (kg)/[height (m)2] 
    3.For females, one of the following must be met: 
    - Menopause (no spontaneous menses for at least 2 years) 
    - Surgical sterilization (being sterile by hysterectomy or bilateral oophorectomy, tubal ligation, or other methods) 
    4.For males who are sexually active with females of childbearing potential, agreed to use contraception (use of double barrier contraceptive methods such as condom with diaphragm or cervical cap) and not to donate sperm during the study period and for at least 8 weeks after the last dose of the investigational product (if male subjects or their female partners are infertile, the above contraceptive methods are not needed) 
    5.Voluntarily decided to participate in the study and provided written consent to follow precautions after receiving a sufficient explanation on this study and fully understanding the information
    Exclusion Criteria
    1.Presence or history of clinically significant hepatobiliary (e.g., severe hepatic impairment), renal (e.g., acute or chronic severe renal impairment, acute renal failure due to hepatorenal syndrome, and acute renal failure before and after liver transplantation), nervous (e.g., spastic disorders such as epilepsy), immune, respiratory, endocrine, and cardiovascular (e.g., congenital long QT syndrome and heart failure) diseases, malignant tumor, or mental diseases 
    2.Family history of long QT syndrome or dysrhythmia after administration of a drug prolonging the repolarization cycle of action potential 
    3.Medical history of hypersensitivity to contrast agents or any components of contrast agents, bronchial asthma or allergy, and clinically significant hypersensitivity 
    4.Subjects who met any of the following in the screening test 
    - AST, ALT in blood > 1.5 x the upper limit of normal 
    - Total bilirubin in blood > 1.5 x the upper limit of normal 
    - eGFR < 90 mL/min/1.73m2 based on CKD-EPI formula 
    5.Systolic blood pressure > 150 mmHg or < 90 mmHg or diastolic blood pressure > 100 mmHg or < 60 mmHg in the vital signs measured in the sitting position after at least 5 minutes rest. 
    6.Positive serologic test result (hepatitis B, hepatitis C, human immunodeficiency virus, and syphilis) 
    7.History of drug abuse or positive result in urine drug screening test 
    8.Gadolinium-based contrast agents (e.g., Gadovist and Dotarem) administered within 30 days prior to the administration of the investigational product 
    9.Use of any prescribed drugs or herbal medicines within 14 days, or any over-the-counter (OTC) drugs including dietary supplement and vitamins within 7 days prior to the administration of the investigational product, which is considered to affect this study or the safety of the subjects in the opinion of the investigator 
    10.Participated in another clinical study (including bioequivalence study) and received an investigational product within 90 days [6 months as of 12 Jun 2019] prior to the administration of this investigational product (The period may be extended for biological products considering a half-life) 
    11.Donated whole blood within 60 days, or donated blood components within 30 days prior to the administration of the investigational product 
    12.Received a blood transfusion within 30 days prior to the administration of the investigational product 
    13.Determined to be ineligible to participate in the study by the investigator due to other reasons
    Healthy Volunteers Yes
  • 10. Outcome Measure(s)

    Outcome Measure(s) Information - Type of Primary Outcome, Primary Outcome, Outcome, Timepoint, Secondary Outcome, Outcome, Timepoint
    Type of Primary Outcome Pharmacokinetics
    Primary Outcome(s) 1
    Outcome
    AUClast, AUCinf, Cmax, Tmax, t1/2, CL, Vd, MRT of HNP-2006
    Timepoint
    Before administration of investigational product, up to 72 hours
    Secondary Outcome(s) 1
    Outcome
    Safety and tolerability evaluation (Adverse Events, Physical Examination, Vital Signs, Clinical Laboratory Test 12-lead ECG, etc.)
    Timepoint
    Up to 14 days
  • 11. Study Results and Publication

    Study Results and Publication Information - Result Registered, Final Enrollment Number, Number of Publication, Publications, Results Upload, Date of Posting Results, Protocol URL or File Upload, Brief Summary
    Result Registered No
  • 12. Sharing of Study Data(Deidentified Individual-Patient Data, IPD)

    Sharing of Study Data Information - Sharing Statement, Time of Sharing, Way of Sharing
    Sharing Statement No
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