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A randomized, participant and investigator-blinded, placebo-controlled, single ascending intravenous and single subcutaneous dose study to assess the safety, tolerability and pharmacokinetics of CMK389 in Japanese healthy participants

A randomized, participant and investigator-blinded, placebo-controlled, single ascending intravenous and single subcutaneous dose study to assess the safety, tolerability and pharmacokinetics of CMK389 in Japanese healthy participants

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This study was conducted with Japanese healthy participants and all 32 randomized participants were Asian and not of Hispanic or Latino ethnicity. The demographic characteristics were generally well balanced across the CMK389 Cohorts and pooled placebo group. The median age of total population was 28.5 years (range: 20 - 49) and all participants were male. The median weight of participants was 64.4 kg (range: 52 - 83) and median BMI was 22.0 kg/m2 (range: 19 - 28).

All 32 subjects completed the study period.

- No deaths or SAEs or AEs leading to discontinuation or dose adjustment were reported in this study. - Overall, AEs by PT were reported in 5 participants, 3 participants in the CMK389 treatment groups (10 mg/kg i.v., 30 mg/kg i.v. and 300 mg s.c. dose groups) and 2 participants in the pooled placebo group. No grade >=3 AEs were reported in the CMK389 treatment groups, while a grade 3 AE of blood creatine phosphokinase increased was reported in 1 participant in the pooled placebo group. - In the CMK389 treatment groups, the AEs reported were increased blood creatinine phosphokinase and COVID-19 in 1 participant in the 10 mg/kg i.v., dose group; lymphocyte count decreased, neutrophil count increased, and white blood cell count increased in 1 participant in 30 mg/kg i.v. group (suspected to be treatment related); and back pain in 1 participant in the 300 mg s.c. dose group. No AEs were reported in 3 mg/kg i.v. dose group. - In the pooled placebo group, the AEs reported were blood creatinine phosphokinase increased, alanine aminotransferase increased and aspartate aminotransferase increased in 1 participant and periodontal disease in 1 participant.

Primary endpoint The CMK389 treatment at single 3 mg/kg i.v., 10 mg/kg i.v., 300 mg/kg i.v., and 300 mg s.c. doses was generally well tolerated and safe in this study on healthy Japanese volunteers. Secondary endpoint The PK properties of CMK389 were in line with expectations for a typical human IgG-type immunoglobulin in healthy volunteers. The PK properties of CMK389 were in line with expectations for a typical human IgG-type immunoglobulin in healthy volunteers.

Treatment with single ascending dose of i.v. CMK389 at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg and a single s.c. CMK389 at a dose of 300 mg was safe and well tolerated in Japanese healthy participants. CMK389 showed dose-proportional increases in exposure (Cmax and AUC) with increasing dose, and constant clearance irrespective of dose with i.v. administration.

Dec. 22, 2023

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071210115

Yamada Hiroyuki

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

rinshoshiken.toroku@novartis.com

Yamada Hiroyuki

Novartis Pharma. K.K.

Toranomon Hills Mori Tower 23-1, Toranomon 1-chome Minato-ku, Tokyo 105-6333, Japan

+81-120-003-293

rinshoshiken.toroku@novartis.com

Complete

Feb. 11, 2022

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Written informed consent must be obtained before any assessment is performed.
2. Japanese healthy participants 20 to 65 years of age included, and in good health as determined by past medical history, physical examination, vital signs, ECG, and laboratory tests at screening and baseline.
3. Able to communicate well with the investigator, to understand and comply with the requirements of the study.
4. Participants must weigh at least 45 kg (female) or 50 kg (male) to participate in the study, and must have a BMI within the range of 18-30 kg/m2 at screening.
5. At screening and baseline, vital signs (body temperature, systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the participant has rested at least 3 minutes. Sitting vital signs should be within the following ranges:
- Axillary body temperature between 35.0-37.5 degree Celsius
- Systolic blood pressure, 90-139 mm Hg
- Diastolic blood pressure, 40-89 mm Hg
- Pulse rate, 40-90 bpm

1. Participants who are not capable of giving consent, persons depending on the sponsor, investigator or site as well as persons who have been committed to an institution by way of official or judicial order.
2. Use of any prescription drugs or herbal supplements within 4 weeks prior to initial dosing, and/or over-the-counter (OTC) medication or dietary supplements (vitamins included) within 2 weeks prior to initial dosing.
3. Use of other investigational drugs at the time of screening, or within a period corresponding to less than 5 half-lives of the drug before screening, or within 30 days, whichever is longer.
4. Significant illness, including infectious diseases that has not resolved within 2 weeks prior to baseline, or positive SARS-CoV-2 test result at screening, or contact with a known case of COVID-19 infection in the 2 weeks prior to baseline.
5. COVID-19 vaccination in progress (plan to receive or in between the first and second dose) at baseline, or within 3 weeks of the last dose (i.e. completion of the vaccination).
6. Receipt of live/attenuated vaccine within a 1 month period before dose of CMK389 (Day 1).
7. History of hepatitis B or hepatitis C or serologic evidence for viral hepatitis. A positive Hepatitis B virus surface antigen (HBsAg) test at screening excludes a participant. Participants with a positive Hepatitis C virus (HCV) antibody test should be excluded.
8. History of immunodeficiency diseases, including a positive Human immunodeficiency virus (HIV) (antibodies to HIV Type 1 and/or Type 2 and confirmatory test) test result at screening
9. A positive syphilis test result at Screening.
10. Any clinically relevant abnormalities on hematology and clinical chemistry at screening or baseline.
11. Any history or presence of significant hematological abnormalities or immunodeficiency or any condition that might compromise the immune system (e.g., immunosuppressive treatment)
12. Any history of drug or alcohol abuse or history of recreational cannabis use within 4 weeks prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during screening.
13. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin) within 5 years of screening, regardless of whether there is evidence of local recurrence or metastases.
14. Lifetime history of hypersensitivity or allergy to any of the study treatments or excipients or to drugs of similar chemical classes.
15. Smokers (use of tobacco/nicotine products within 3 months of dosing). Urine cotinine levels will be measured during screening and at baseline for all participants.
16. Any surgical or medical condition which might put the participant at risk in case of participation in the study. The Investigator should make this determination in consideration of the participant's medical history and/or clinical or laboratory evidence of any of the following: At screening or baseline
- Lipase and/or amylase must not exceed the 1.5 x upper limit of normal (ULN)
- Liver disease or liver injury as indicated by abnormal liver function tests (LFT) (as defined below):
- Any of the following single parameters in serum of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), gamma-GT, alkaline phosphatase (ALP) or bilirubin must not exceed 1.5 x ULN.
- Any elevation above ULN of more than one parameter of ALT, AST, gamma-GT, ALP or serum bilirubin will exclude a participant from participation in the study.
- History of renal injury / renal disease or presence of impaired renal function as indicated by any elevation above ULN of creatinine and/or BUN values, or the presence of abnormal urinary constituents (e.g., albuminuria)
- Evidence of urinary obstruction or difficulty in voiding
17. Lifetime history or current diagnosis of cardiac or cardiac repolarization abnormalities indicating significant risk of safety for participating in the study
18. The ECG abnormalities at screening or baseline
19. Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the giving birth, confirmed by a positive hCG laboratory test
21. Women of child-bearing potential (WOCBP) (see definition below), unless they are using highly effective methods of contraception until EOS.

Both

Japanese healthy participants

Cohort 1
- Single i.v. infusion of 3 mg/kg CMK389
- Single i.v. infusion of CMK389 placebo arm
Cohort 2
- Single i.v. infusion of 10 mg/kg CMK389
- Single i.v. infusion of CMK389 placebo arm
Cohort 3
- Single i.v. infusion of 30 mg/kg CMK389
- Single i.v. infusion of CMK389 placebo arm
Cohort 4
- Single s.c. injection of 300 mg CMK389
- Single s.c. injection of CMK389 placebo arm

All safety endpoints [i.e., vital signs, ECG parameters, clinical laboratories, and AEs, including SAEs] up to and including the End of Study (EOS) visit

+81-92-283-7701

Dec. 17, 2021

none