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

Hemophilia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03855696
• Other study ID #: MG1113_P1
• Status: Completed
• Phase: Phase 1
• Start date: January 21, 2019
• Est. completion date: August 31, 2021

Study information

• Verified date: October 2021
• Source: Green Cross Corporation
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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 4 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 and 6 subjects in each cohort, respectively.

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 by IV injection. In hemophilia patients, 1.7 mg/kg and 3.3 mg/kg will be administered by SC 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) and Data and Safety Monitoring Boards (DSMB) in the blinded evaluation of the safety and tolerability data obtained from each previous cohort for 7 days after administration. Before deciding dose escalation and proceeding to the next step, the safety, tolerability, PK, and PD data obtained from all healty subjects and hemophilia patients up to cohort 6 will be evaluated by the Data and Safety Monitoring Boards (DSMB) in an unblinded manner. In addition, if necessary, the analysis result of cohort that has completed all the scheduled visits can be reviewed in an unblinded manner.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: August 31, 2021
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 19 Years to 60 Years

Eligibility

<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 (If participating in a clinical trial after 12/06/2019, not within 90 days, but within 6 months is applied)

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

Related Conditions & MeSH terms

• Hemophilia
• Hemophilia A

Intervention

Biological:
• MG1113
MG1113

Other:
• Placebo of MG1113
Placebo of MG1113

Locations

Country	Name	City	State
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Yonsei Cancer Center, Yonsei University Severance Hospital	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Green Cross Corporation	Dream CIS, Inc.

Country where clinical trial is conducted

Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adverse events	Adverse events such as subjective and objective symptoms	Through study completion (~50 day)
Secondary	Immunogenicity assay	ADA [Anti-Drug Ab]	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - Cmax	Cmax	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - Tmax	Tmax	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - AUClast	AUClast	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - AUCinf	AUCinf	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - half-life	half-life	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - CL/F (for SC)	CL/F (for SC)	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - CL (for IV)	CL (for IV)	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - Vd/F (for SC)	Vd/F (for SC)	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - Vd (for IV)	Vd (for IV)	Through study completion (~50 day)
Secondary	Pharmacokinetic assessment - Bioavailability (F)	Bioavailability (F) Bioavailability (F) = AUCinf (at SC dosing [3.3 mg/kg])/AUCinf (at IV dosing [3.3 mg/kg])	Through study completion (~50 day)
Secondary	Pharmacodynamic assessment - Free TFPI in plasma	Free TFPI in plasma (ng/mL)	Through study completion (~50 day)
Secondary	Pharmacodynamic assessment - Diluted PT	Diluted PT (sec)	Through study completion (~50 day)
Secondary	Pharmacodynamic assessment - residual TFPI activity	residual TFPI activity	Through study completion (~50 day)
Secondary	Pharmacodynamic assessment - Thrombin generation	Thrombin generation (lag time, peak generation, Endogenous thrombin generation potential [ETP])	Through study completion (~50 day)
Secondary	Pharmacodynamic assessment - Pro-coagulant effect	Pro-coagulant effect (D-dimer, Fibrinogen, prothrombin fragments 1+2)	Through study completion (~50 day)
Secondary	Physical examination	Physical examination	Through study completion (~50 day)
Secondary	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	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	Through study completion (~50 day)
Secondary	Vital signs - blood pressure (Systolic, Diastolic)	Vital signs - blood pressure (Systolic, Diastolic)	Through study completion (~50 day)
Secondary	Vital signs - pulse rate	Vital signs - pulse rate	Through study completion (~50 day)
Secondary	Vital signs - body temperature	Vital signs - body temperature	Through study completion (~50 day)
Secondary	Frequency of Bleeding (only for hemophilia patients)	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)	Through study completion (~50 day)
Secondary	Local reaction in injection site	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).	Through study completion (~50 day)
Secondary	Incidence of participant abnormalities in laboratory tests by physiological parameter (Hematology, clinical chemistry, urinalysis, and blood coagulation test)	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, MCH in pg,MCHC in g/dL,Platelets 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,Creatinine Clearance),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%)	Through study completion (~50 day)