A Study to Evaluate Emapalumab in Japanese Healthy Volunteers.

Phase 1

Completed

• Conditions: Rare Diseases
• Interventions: Drug: NI-0501; Drug: Saline

• Registration Number: NCT04765553
• Lead Sponsor: Swedish Orphan Biovitrum

Brief Summary

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

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).

Study Timeline

• Study Start: 2021-01-14
• Study First Submitted: 2021-01-18
• Study First Submitted QC: 2021-02-19
• Study First Posted: 2021-02-21
• Primary Completion: 2021-06-25
• Study Completion: 2021-07-25
• Results First Submitted: 2022-01-10
• Results First Submitted QC: 2023-02-13
• Status Verified: 2023-11
• Results First Posted: 2023-11-24
• Last Update Submitted: 2023-11-28
• Last Update Posted: 2023-11-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

1. Healthy Japanese (male and female) subjects between 20 and 50 years (inclusive).

2. 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)

3. 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

4. Haemoglobin level equal or above 11 g/dL in females and 13 g/dL in males.

5. Subject having C-reactive protein (CRP) levels within the normal range (local laboratory range).

6. 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.

7. Signed informed consent.

Exclusion Criteria

1. 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

2. Any clinically significant abnormality on the screening electrocardiogram (ECG), as judged by the investigator

3. 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

4. Actual presence or occurrence of any bacterial, viral, parasitic or fungal infection within the 4 weeks preceding IMP infusion

5. 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

6. Positive stool test for Shigella or salmonella infection.

7. Positive results from Sars-CoV-2 screening within 96 hours prior to randomization

8. History or clinical evidence suggestive of active or latent tuberculosis at screening. (i.e. test positive to the interferon gamma (IFNγ)-release assay)

9. History or presence of any severe allergic reactions

10. History of hypersensitivity or allergy to any component of emapalumab and/or valaciclovir hydrochloride

11. History or presence of any malignancy

12. History or presence of drug or alcohol abuse

13. Subject with a smoking history within the last 6 months prior to the time of screening

14. Immunization with a live vaccine within 6 weeks prior to receiving IMP and 12 weeks after IMP infusion

15. 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.

16. 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

17. Positive pregnancy test at screening or Day -1

18. 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

19. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
emapalumab	NI-0501	emapalumab i.v infusion
Placebo	Saline	Saline i.v. infusion

Primary Outcome Measures

Name	Time	Method
The Maximum Observed Concentration of Emapalumab	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 maximum observed concentration of emapalumab (Cmax)
The Time at Which the Maximum Concentration of Emapalumab is Observed	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	The time at which the maximum concentration of emapalumab is observed (Tmax)
Concentration of Emapalumab at End of Infusion	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 (CEnd of inf))
Area Under the Plasma Concentration-time Curve	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 from emapalumab injection to time of last measurable concentration (AUClast)
Area Under the Concentration-time Curve Extrapolated to Infinity	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 from emapalumab injection extrapolated to infinity (AUCinf)
Emapalumab Elimination Half-life	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 (t1/2)
Apparent Total Body Clearance of Emapalumab From Plasma	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 (CL)
Steady State Volume of Distribution	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 volume of distribution at steady state (Vss)

Secondary Outcome Measures

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

Trial Locations

Locations (1)

P-One Clinic; 🇯🇵 Tokyo, Japan