A Study to Evaluate Emapalumab in Japanese Healthy Volunteers.

Study Overview
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Brief Summary
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This is a randomized, placebo controlled and double-blinded study to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of a single dose (1 mg/kg) of emapalumab in adult healthy Japanese subjects.

Detailed Description
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This is a randomized, placebo-controlled and double-blinded study to evaluate the PK, PD and safety of a single dose (1 mg/kg) of emapalumab in adult healthy Japanese subjects, performed in Japan. The subjects, 8 in total, will be randomized to receive either emapalumab or matching placebo in a 3:1 ratio (emapalumab: placebo).

Official Title
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A Randomized, Double-blinded, Placebo-controlled, Single Center, Phase I Study to Evaluate Pharmacokinetics, Pharmacodynamics and Safety of Emapalumab After a Single Intravenous Dose in Japanese Healthy Volunteers.

Conditions
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Rare Diseases

Intervention / Treatment
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* Drug: NI-0501
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Japanese (male and female) subjects between 20 and 50 years (inclusive). Body weight greater than 45 kg (female) or 50 kg (male) and a body mass index (BMI) >18 kg/m2 and < 30 kg/m2 (BMI= weight (kg) / height (m)²) Vital signs in the following range: Axillary body temperature: 35.2 - 37.5℃ Heart rate (after at least 3 minutes of rest, measured in the supine position): 40-100 bpm BP < 140/80, mean of 3 readings after 15 minutes rest Haemoglobin level equal or above 11 g/dL in females and 13 g/dL in males. Subject having C-reactive protein (CRP) levels within the normal range (local laboratory range). Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant having agreed to use highly effective methods of contraception during dosing and for 6 months after receiving IMP. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient, otherwise highly effective methods to be applied. Use of oral (estrogen and progesterone) hormonal method of contraception, or placement of an intrauterine device (IUD) or intrauterine system (IUS) In case of use of oral contraception women should have been stable on the same brand (or generic equivalent) for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. Signed informed consent. Exclusion Criteria: Any clinically significant abnormality in the results of the safety laboratory tests. Subjects presenting a minor deviation from laboratory ranges could be enrolled if the investigator judge it to be non-clinically significant Any clinically significant abnormality on the screening electrocardiogram (ECG), as judged by the investigator History or clinical evidence of any disease and/or existence of any surgical or medical condition that might interfere with the absorption, distribution, metabolism or excretion of the study drugs Actual presence or occurrence of any bacterial, viral, parasitic or fungal infection within the 4 weeks preceding IMP infusion Positive results from serology examination for Hepatitis B surface antigen (HBsAg), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV), syphilis (TP-antigen and RPR) or pregnancy Positive stool test for Shigella or salmonella infection. Positive results from Sars-CoV-2 screening within 96 hours prior to randomization History or clinical evidence suggestive of active or latent tuberculosis at screening. (i.e. test positive to the interferon gamma (IFNγ)-release assay) History or presence of any severe allergic reactions History of hypersensitivity or allergy to any component of emapalumab and/or valaciclovir hydrochloride History or presence of any malignancy History or presence of drug or alcohol abuse Subject with a smoking history within the last 6 months prior to the time of screening Immunization with a live vaccine within 6 weeks prior to receiving IMP and 12 weeks after IMP infusion Experience of collected blood corresponding to any of the following Component blood donation within 2 weeks before the screening test and within 2 weeks before the first study drug administration Collection of 200 mL or more of blood (blood donation, etc.) from 4 weeks before the screening test until admission Male subject who has experience of collection of 400 mL or more of blood (blood donation, etc.) from 12weeks before the screening test until admission. Female subject who has experience of collection of 400 mL or more of blood (blood donation, etc.) from 16weeks before the screening test until admission. Usage of any prescription drugs within 2 weeks or over-the-counter medication including herbal supplements (with the exception of multi-vitamins) within 1 week before IMP administration without prior approval from the investigator Positive pregnancy test at screening or Day -1 Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol Enrollment in another concurrent clinical interventional study, or intake of another IMP, within four months or 5 half-lives (of the other IMP) prior to inclusion in this study

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: emapalumab<br>emapalumab i.v infusion | Drug: NI-0501<br>* emapalumab single i.v infusion (1 mg/kg)<br>* Other names: Gamifant;|
| Placebo Comparator: Placebo<br>Saline i.v. infusion | Drug: Saline<br>* Saline single i.v infusion<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Observed Concentration of Emapalumab | The maximum observed concentration of emapalumab (Cmax) | Day 1 preinfusion, 1hr, 2hrs, 4hrs, 8hrs, 10hrs post dose, day 2, 3, 5, 8, week 2, 4, 6, 8, 10, 12, study completion week 14 or Withdrawal | 
| The Time at Which the Maximum Concentration of Emapalumab is Observed | The time at which the maximum concentration of emapalumab is observed (Tmax) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 
| Concentration of Emapalumab at End of Infusion | Concentration of emapalumab at end of infusion (CEnd of inf)) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 
| Area Under the Plasma Concentration-time Curve | Area under the plasma concentration-time curve from emapalumab injection to time of last measurable concentration (AUClast) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 
| Area Under the Concentration-time Curve Extrapolated to Infinity | Area under the plasma concentration-time curve from emapalumab injection extrapolated to infinity (AUCinf) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 
| Emapalumab Elimination Half-life | Emapalumab elimination half-life (t1/2) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 
| Apparent Total Body Clearance of Emapalumab From Plasma | Apparent total body clearance of emapalumab from plasma (CL) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 
| Steady State Volume of Distribution | Apparent volume of distribution at steady state (Vss) | Day 1 preinfusion, 1hr, 2 hrs, 4hrs, 8hrs, 10hrs, Day 2, 3, 5, 8, Week 2, 4, 6, 8, 10, 12, study completion week 14 or at Withdrawal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Summary of Adverse Events | Total number of reported adverse events | Continuously from start of emapalumab infusion up to 14 weeks | 
| Change in Levels of Aspartate Aminotransferase | Change from baseline in levels of Aspartate aminotransferase (AST) | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Alanine Aminotransferase | Change from baseline in levels of Alanine aminotransferase (ALT) | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Direct Bilirubin | Change from baseline in levels of Direct Bilirubin | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Total Bilirubin | Change from baseline in levels of Total Bilirubin | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Uric Acid | Change from baseline in levels of Uric acid | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Alkaline Phosphatase | Change from baseline in levels of Alkaline phosphatase | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Total Protein | Change from baseline in levels of Total protein | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Albumin | Change from baseline in levels of Albumin | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Prothrombin Time/International Normalized Ratio | Change from baseline in levels of Prothrombin Time/International Normalized Ratio (PTINR) | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Fibrinogen | Change from baseline in levels of Fibrinogen | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Complement C3 | Change from baseline in levels of Complement C3 | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Creatinine | Change from baseline in levels of Creatinine | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of C-reactive Protein | Change from baseline in levels of C-reactive protein (CRP) | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Sodium | Change from baseline in levels of Sodium | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Potassium | Change from baseline in levels of Potassium | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Calcium | Change from baseline in levels of Calcium | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Glucose | Change from baseline in levels of Glucose | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of HDL | Change from baseline in levels of HDL | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of LDL | Change from baseline in levels of LDL | Baselilne, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of BUN/Urea Haematology | Change from baseline in levels of BUN/Urea haematology | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Hemoglobin | Change from baseline in levels of Hemoglobin | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Hematocrit | Change from baseline in levels of Hematocrit | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Platelet Count | Change from baseline in levels of Platelet count | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Neutrophils | Change from baseline in levels of Neutrophils | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Red Blood Cells | Change from baseline in levels of Red blood cells | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Immunoglobulin Levels | Change from baseline in levels of Immunoglobulin levels (IgG) | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Change in Levels of Coagulation Profile | Change from baseline in Activated Partial Thromboplastin Clotting Time (APTT) | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Presence of Anti-drug Antibodies and Neutralizing Antibodies | Presence of anti-drug antibodies (ADA) and neutralizing antibodies (nAb) | From Day 1 to Week 14 | 
| Change in Levels of Complement C4 | Change from baseline in levels of Complement C4 | Baseline, Days 1,2,3,5,8, Weeks 2,4,6,10, and Study Completion Visit (Week 14) | 
| Presence of Neutralizing Antibodies | Presence of neutralizing antibodies (nAb) | From Day 1 to Week 14 |