A Study to Investigate the Safety, Tolerability, PK and PD of MG1113 in Healthy Subjects and Hemophilia Patients

Overview

The purpose of this study is to assess the safety and tolerability of MG1113 in the single ascending dose study (IV injection or SC injection) in healthy subjects and hemophiia patients.

Full Title of Study: “A Phase I, Randomized, Double-blind, Placebo-Controlled, Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MG1113 in Healthy Subjects and Hemophilia Patients”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Prevention
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: October 31, 2019

Detailed Description

This is a single-dose study that explore the safety, tolerability, PK, and PD of the study drug by sequentially increasing the study drug in 6 dose levels. The route of administration is either subcutaneous (SC) injection or intravenous (IV) injection. For healthy subjects, 6 subjects will be assigned to the study group and 2 subjects will be assigned to the placebo group to explore the safety and tolerability, and PK/PD of the study drug in comparison with placebo. Hemophilia patients will be assigned only to the study group with 3 subjects in each cohort. The investigator and subjects will know which cohort the healthy subjects have been assigned to, but they will be double-blinded as to whether the subjects are assigned to the study group (study drug) or the placebo group (placebo) within each cohort. The doses planned in healthy subjects are 0.5 mg/kg, 1.7 mg/kg, and 3.3 mg/kg by SC injection; 3.3 mg/kg and 6.6 mg/kg by IV injection. In hemophilia patients, 3.3 mg/kg will be administered by SC injection, and 6.6 mg/kg and 13.3 mg/kg will be administered by IV injection. The planned dose will be administered after checking the safety and tolerability at the previous dose to the extent not exceeding the criteria for discontinuation of dose escalation. The dose escalation will be decided by the Data Monitoring Committee (DMC) in the blinded evaluation of the safety and tolerability data obtained from each previous cohort for 7 days after administration. Both Cohort 4 and Cohort 3B can be proceeded after the evaluation for Cohort 3, and Cohort 5 and Cohort 5B will be proceeded independently after the evaluation for Cohort 4 and Cohort 3B, respectively. Before proceeding with Cohort 6, the safety, tolerability, PK, and PD data obtained from all healthy subjects and hemophilia patients up to Cohort 5 and Cohort 5B will be evaluated by the Data and Safety Monitoring Boards (DSMB) in a blinded manner. Then, the dose escalation and the modification of the highest dose will be determined.

Interventions

  • Biological: MG1113
    • MG1113
  • Other: Placebo of MG1113
    • Placebo of MG1113

Arms, Groups and Cohorts

  • Experimental: MG1113
    • Anti-tissue factor pathway inhibitor (TFPI) recombinant antibody Each vial contains 1mL of study drug The doses planned in healthy subjects are 0.5 mg/kg, 1.7 mg/kg, and 3.3 mg/kg by SC injection; 3.3 mg/kg and 6.6 mg/kg by IV injection. The highest dose will be 13.3 mg/kg administered to hemophilia patients. In hemophilia patients, 3.3 mg/kg will be administered by SC injection, and 6.6 mg/kg and 13.3 mg/kg (highest dose) will be administered by IV injection.
  • Placebo Comparator: Placebo of MG1113
    • Placebo of MG1113 Each vial contains 1mL of study drug

Clinical Trial Outcome Measures

Primary Measures

  • Adverse events
    • Time Frame: Through study completion (~50 day)
    • Adverse events such as subjective and objective symptoms

Secondary Measures

  • Immunogenicity assay
    • Time Frame: Through study completion (~50 day)
    • ADA [Anti-Drug Ab]
  • Pharmacokinetic assessment – Cmax
    • Time Frame: Through study completion (~50 day)
    • Cmax
  • Pharmacokinetic assessment – Tmax
    • Time Frame: Through study completion (~50 day)
    • Tmax
  • Pharmacokinetic assessment – AUClast
    • Time Frame: Through study completion (~50 day)
    • AUClast
  • Pharmacokinetic assessment – AUCinf
    • Time Frame: Through study completion (~50 day)
    • AUCinf
  • Pharmacokinetic assessment – half-life
    • Time Frame: Through study completion (~50 day)
    • half-life
  • Pharmacokinetic assessment – CL/F (for SC)
    • Time Frame: Through study completion (~50 day)
    • CL/F (for SC)
  • Pharmacokinetic assessment – CL (for IV)
    • Time Frame: Through study completion (~50 day)
    • CL (for IV)
  • Pharmacokinetic assessment – Vd/F (for SC)
    • Time Frame: Through study completion (~50 day)
    • Vd/F (for SC)
  • Pharmacokinetic assessment – Vd (for IV)
    • Time Frame: Through study completion (~50 day)
    • Vd (for IV)
  • Pharmacokinetic assessment – Bioavailability (F)
    • Time Frame: Through study completion (~50 day)
    • Bioavailability (F) Bioavailability (F) = AUCinf (at SC dosing [3.3 mg/kg])/AUCinf (at IV dosing [3.3 mg/kg])
  • Pharmacodynamic assessment – Free TFPI in plasma
    • Time Frame: Through study completion (~50 day)
    • Free TFPI in plasma (ng/mL)
  • Pharmacodynamic assessment – Diluted PT
    • Time Frame: Through study completion (~50 day)
    • Diluted PT (sec)
  • Pharmacodynamic assessment – FXa activity
    • Time Frame: Through study completion (~50 day)
    • FXa activity
  • Pharmacodynamic assessment – Thrombin generation
    • Time Frame: Through study completion (~50 day)
    • Thrombin generation (lag time, peak generation, Endogenous thrombin generation potential [ETP])
  • Pharmacodynamic assessment – Pro-coagulant effect
    • Time Frame: Through study completion (~50 day)
    • Pro-coagulant effect (D-dimer, Fibrinogen, prothrombin fragments 1+2)
  • Physical examination
    • Time Frame: Through study completion (~50 day)
    • Physical examination
  • Incidence of participant abnormalities in 12-lead ECG (Ventricular rate in beat/min, Interval for PR in msec, QRS in msec, QTc in msec) for physiological parameter
    • Time Frame: Through study completion (~50 day)
    • The result for 12-lead ECG will be reported as Clinical Significant or Not-Clinical Significant. Ventricular rate in beat/min Interval for PR in msec QRS in msec QTc in msec
  • Vital signs – blood pressure (Systolic, Diastolic)
    • Time Frame: Through study completion (~50 day)
    • Vital signs – blood pressure (Systolic, Diastolic)
  • Vital signs – pulse rate
    • Time Frame: Through study completion (~50 day)
    • Vital signs – pulse rate
  • Vital signs – body temperature
    • Time Frame: Through study completion (~50 day)
    • Vital signs – body temperature
  • Frequency of Bleeding (only for hemophilia patients)
    • Time Frame: Through study completion (~50 day)
    • Bleeding evaluation (only for hemophilia patients) by questionnaire; Occurrence date, Persistence in yes or no questionnaire, Causes (blood in naturally occurring/Traumatic bleeding), Severity (mild/moderate/Severe)
  • Local reaction in injection site
    • Time Frame: Through study completion (~50 day)
    • Pain or tenderness, itching, rash, redness (in mm), and induration (in mm) will be reported. Local stimulation test in injection site: Occurrence date, Persistence, Causes, Severity (mild/moderate/Severe) The occurrence of pain or tenderness, itching and rash will be reported by Yes or No questionnaire. The size of redness and induration will be measured in millmeters(mm).
  • Incidence of participant abnormalities in laboratory tests by physiological parameter (Hematology, clinical chemistry, urinalysis, and blood)
    • Time Frame: Through study completion (~50 day)
    • Parameters for laboratory tests include Hematology(WBC in 10**3/mcL, Neutrophils in %, ANC in mcL, Lymphosyte in %, Monocyte in %, Eosinophils in %, Basophils in %, RBC in 10**6/mcL, Hemoglobin in g/dL, Hematocrit in %, MCV in fL, MCHin pg, MCHC in g/dL, Plstelets in 10**3/mcL, MPV in fL), Clinical chemistry(Glucose in mg/dL, BUN in mg/dL, Uric adic in mg/dL, Total cholesterol in mg/dL, Triglyceride in mg/dL, Protein, Albumin in g/dL, Total bilirubin in mg/dL, Alkaline phosphatase in IU/L, AST in IU/L, ALT in IU/L, r-GT in IU/L, LDH in IU/L, Serum creatinine in mg/dL, Na in mmol/L, K in mmol/L, Cl in mmol/L, CPK in IU/L, Troponin I in ng/mL, Troponin T in ng/mL), Urinalysis(These values are reported only as a number; Specific garavity, Color, pH, Protein, Glucose, Ketone, Bilirubin, Blood, Urobilinogen, Nitrite, WBC, Squma EP cell, Casts, Crystal, Clarity, RBC) Blood coagulation test (aPTT in sec, PT in sec, Fibronogen in mg/dL, Antithrombon III in %, Protein C in %, Protein S in %)

Participating in This Clinical Trial

<Healthy adult subjects> Inclusion Criteria:

1. Healthy male adult subjects aged 19-60 years (both inclusive) at screening 2. 50 to 90 kg in weight with calculated BMI between 18.5 and 29.9 kg/m2 3. Agree to use medically acceptable adequate dual contraceptive methods (condom, vasectomy, spermicide, oral contraceptives, intrauterine device, and complete sexual abstinence, etc.) and not to donate sperm until 3 months after administration of the investigational product 4. Voluntarily decided to participate in the study and provided written consent to follow precautions after receiving a detailed explanation on this study and fully understanding the information Exclusion Criteria:

1. Presence or history of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immune, skin, nervous, or psychiatric disease 2. Symptoms of acute disease within 28 days of investigational product administration 3. Medical history that may affect absorption, distribution, metabolism and excretion of drugs 4. Clinically significant active chronic disease 5. Clinically significant allergic disease (however, mild allergic rhinitis or allergic dermatitis not requiring any medication is allowed) or history of any anaphylactic reaction 6. Any of the following results from laboratory tests: 1) AST (sGOT) or ALT (sGPT) >2 x UNL 2) Hb < 9.0 g/dL 3) Absolute Neutrophil Count < 1500 mm2 4) Platelet count < 100 x 103 mm2 5) aPTT, PT > 1.5 x UNL 6) Have hepatitis B (HBsAg positive) or C (anti-HCV positive), or have positive HIV test result 7) Creatinine clearance ≤80 mL/min (calculated by the Cockcroft-Gault formula) 7. Have a family history or be considered to be at risk of thromboembolic events, or have the following test results: 1) Antithrombin level ≤LNL 2) Protein C or S activity ≤LNL 3) Factor V Leiden mutation 4) Prothrombin G20210A mutation 8. Used ethical drugs including prescription drugs within 14 days of investigational product administration 9. Used drugs (over-the-counter drugs, herbal medicines, and nutritional agents and vitamins for the purpose of same efficacy) within 7 days of investigational product administration 10. Cannot have standard meals provided at the hospital 11. Donated whole blood within 60 days of investigational product administration, or donated blood components within 20 days of investigational product administration, or received blood transfusion within 1 month before administration 12. Participated in another clinical trial or bioequivalence study within 90 days of investigational product administration 13. Individuals who consume caffeine (caffeine >5 cups/day) or alcohol (alcohol >30 g/day) continuously, who cannot abstain from drinking during the study, or heavy smoker (>10 cigarettes/day) 14. Determined to be ineligible to participate in the study per investigator's judgment due to other reasons including the laboratory test results 15. History of drug abuse or positive urine drug screen results <Hemophilia patients> Inclusion criteria 1. Male hemophilia A or B patients aged 19-60 years (both inclusive) at screening 2. ≥50 kg in weight with calculated BMI between 18.5 and 29.9 kg/m2 3. Agree to use medically acceptable adequate dual contraceptive methods (condom, vasectomy, spermicide, oral contraceptives, intrauterine device, and complete sexual abstinence, etc.) and not to donate sperm until 60 days after administration of the investigational product 4. Voluntarily decided to participate in the study and provided written consent to follow precautions after receiving a detailed explanation on this study and fully understanding the information Exclusion criteria 1. Symptoms of acute disease within 28 days of investigational product administration or any surgery planned during the study period 2. Medical history that may affect absorption, distribution, metabolism and excretion of drugs 3. Clinically significant active chronic disease 4. Clinically significant allergic disease (however, mild allergic rhinitis or allergic dermatitis not requiring any medication is allowed) or history of any anaphylactic reaction 5. Patients having current human factor VIII or IX with an inhibitor titer of >5 Bethesda units or patients requiring treatment with bypassing agent 6. Patients who has a history of confirmed human factor VIII or IX with an inhibitor titer of >5 Bethesda units at any time 7. History of ≥6 bleeding episodes despite temporary bypassing agent administered for 24 weeks before screening, or ≥2 bleeding episodes despite the bypassing agent administered prophylactically 8. Received factor VIII or factor IX within 48 hours prior to administration of the investigational product 9. Hemostatic agent, etc. prescribed to control bleeding within 5 days prior to administration of the investigational product 10. Immune tolerance induction prescribed within 30 days prior to administration of the investigational product 11. Currently using systemic immunomodulator (e.g., interferon or rituximab) 12. Be at risk of thrombotic microangiopathy per investigator's judgment or have related medical history or family history 13. Congenital or acquired anticoagulant disorders other than hemophilia A or B, or conditions of other diseases that increase the risk of bleeding or thrombus (e.g., autoimmune disease) 14. Any of the following results from laboratory tests: 1) AST (sGOT) or ALT (sGPT) >3 x UNL 2) Hb < 9.0 g/dL 3) Absolute Neutrophil Count < 1500 mm2 4) Platelet count < 100 x 103 mm2 5) Have hepatitis B (HBs Ag positive) or C (anti-HCV positive), or have HIV positive test result 6) Creatinine clearance ≤80 mL/min (calculated by the Cockcroft-Gault formula) 15. Cannot have standard meals provided at the hospital 16. Participated in another clinical trial within 90 days of investigational product administration 17. Individuals who consume caffeine (caffeine >5 cups/day) or alcohol (alcohol >30 g/day) continuously, who cannot abstain from drinking during the study, or heavy smoker (>10 cigarettes/day) 18. Determined to be ineligible to participate in the study per investigator's judgment due to other reasons including the laboratory test results 19. History of drug abuse or positive urine drug screen results

Gender Eligibility: Male

Minimum Age: 19 Years

Maximum Age: 60 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Green Cross Corporation
  • Collaborator
    • Dream CIS, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Ji-Young Park, MD, Principal Investigator, Korea University Anam Hospital
  • Overall Contact(s)
    • Hyun Jin Yoon, 82-31-260-1993, yoonchoco@greencross.com

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