Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Effects of SR-878 in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- SciRhom GmbH
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Occurrence of treatment-emergent adverse event (TEAE)
研究概览
简要总结
SR-878 is a newly developed medicine that aims to treat autoimmune disorders. It inhibits a protein (iRhom2), that regulates enzymes that are involved in the production of cytokines (small proteins that are crucial in controlling the activity of immune system cells). This is the first study in humans, and SR-878 will be administered once to each participant in 6 different doses to establish a safe dosage and investigate, what are potential side effects.
This clinical trial includes six study groups, called cohorts, and each cohort includes 8 participants. In each cohort, 6 participants will receive SR-878 and 2 participants will receive a placebo, a dummy drug with no active ingredients that looks identical. The comparison with placebo will be used to better assess the side effects of SR-878. The dose of SR-878 will be gradually increased between cohorts. Participants in the first cohort will receive the lowest dose, and if this is considered safe 10 days after dosing, the next cohort will be initiated at a higher dose. Participants visit the hospital regularly over the next 12 weeks after receiving SR-878 or placebo. During these visits, medical condition will be checked and blood will be taken.
Participants in the third to sixth cohort will be injected with a product called LPS 24 hours after the infusion of the investigational product, which may stimulate the immune system and cause a temporary inflammatory response in the body. During this time, participants may have mild "flu-like" symptoms. 12 weeks after dose of investigational product, the LPS injection and saline infusion will be repeated.
详细描述
Rationale: SR-878 is a newly developed medicine that aims to treat autoimmune disorders. It works by blocking a protein called iRhom2, which controls the production of small proteins called cytokines. Cytokines are the drivers that keep the inflammatory process ongoing in autoimmune diseases important for regulating the activity of cells in the immune system. This is the first study in humans, and SR-878 will be administered once to each participant in 6 different doses to investigate potential side effects.
Objectives:
- To assess the safety and tolerability of a single dose of SR-878;
- To select the optimal dose that is safe and tolerable;
- To explore any effects of a single dose of SR-878 in the human body;
- To investigate the connection between the concentration of SR-878 and potential side effects;
- To assess the amount of immune response against SR-878. Trial design: This clinical study will have six treatment groups, so called cohorts, and each cohort will include 8 participants. In each cohort 6 participants will receive SR-878, and 2 participants will receive a placebo, that is a dummy treatment without active ingredients. The comparison with the placebo is used to better assess the side effects of SR-878. The dose of SR-878 will be gradually increased between cohorts.
After the screening period, participants will be randomly assigned to receive SR-878 or placebo. This is a double-blind study, which means neither the participant nor the study staff, including the study doctor, will know which study medication was used.
The study medication will be administered in a 1-hour long infusion. The participants will be requested to stay 24 hours in the hospital after the infusion, and their medical condition will be monitored, and they will undergo several blood draws.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy male or female subjects aged 18 to 40 years inclusive on the day of informed fonsent form (ICF) signature and with a body weight ≥ 45 kg and body mass index (BMI) ≤ 30 kg/m2;
- •Subjects willing to sign a written informed consent and able to comply with the study protocol for the duration of the study, including the inpatient confinement for about 24 or 32 hours;
- •Has adequate venous access for blood collection;
- •In female subjects of childbearing potential, a negative serum pregnancy test at screening;
- •Females of childbearing potential agreeing to use highly effective methods of contraception for the duration of the study; Males agreeing to use highly effective methods of contraception and not to donate sperm until 90 days after the study drug administration.
排除标准
- •Treatment with an investigational drug within one month or two half-lives prior to screening, whichever is longer;
- •Abnormal findings in medical history and physical examination that the investigator considers to be a clinically relevant abnormality;
- •Clinically significant abnormal screening laboratory tests, including but not limited to:
- •Haemoglobin (HGB) < 120 g/L for males or < 110 g/L for females
- •White Blood Cells (WBC) > 1.5 upper limit of normal (ULN)
- •C-reactive Protein (CRP) > 1.5 ULN
- •Serum Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) or Alkaline Phosphatase (ALP) > 1.5 ULN
- •Estimated Glomerular Filtration Rate (eGFR) < 55 mL/min/1.73 m2
- •Subjects infected with human immunodeficiency virus (HIV), hepatitis B and C viruses (HBV and HCV);
- •Clinically relevant ECG (12 leads) abnormalities;
- •Subjects with acute infectious diseases within 2 weeks prior to screening;
- •History of any autoimmune diseases or any chronic inflammation;
- •Relevant history of other renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine, inflammatory, chronic infectious, or neurological diseases;
- •History of anaphylaxis to drugs or major allergic reactions in general, which in the view of the investigator may compromise the safety of the subjects;
- •Known hypersensitivity to the active substance or to any of the excipients of the investigational medicinal products or auxiliary medicinal products;
- •Drug abuse, alcohol >1 drink/day, defined according to the Food-based Dietary Guidelines in Europe;
- •Females who are pregnant, breastfeeding, or planning to become pregnant during the study.
研究组 & 干预措施
SR-878
Solution for infusion, administered intravenously once
干预措施: SR-878 (Drug)
Placebo
Solution for infusion, administered intravenously once
干预措施: Placebo (Drug)
结局指标
主要结局
Occurrence of treatment-emergent adverse event (TEAE)
时间窗: Day 1 to Day 85 in Cohorts 1-2 and Day 1 to 86 in Cohorts 3-6
The number and proportion of subjects with TEAE overall and before the LPS challenge will be calculated by cohort and by arm.
次要结局
- Terminal half-life (T1/2) of SR-878(Day 1 until Day 85)
- Area under the blood concentration-time curve 0-85 days (AUC0-85)(Day 1 until Day 85)
- AUC0-inf(Day 1 until Day 85)
- Maximum concentration (Cmax)(Day 1 until Day 85)
- Reference-adjusted area under the effect curve 0-24 hours (AUEC0-24)(0-24 hours)
- Maximum effect (Emax) for tumour necrosis factor-alpha (TNF-alpha) after lipopolysaccharide (LPS) challenges(Day 2-3 and Day 85-86)
- Safety Measurement Assessment - Adverse Events, including Serious Adverse Events(Day 1 until Day 85 or until day 85 (cohorts 3-6))
- Safety Measurement Assessment - Physical Examination(Day 1 until Day 85 or until day 86 (cohorts 3-6))
- Safety Measurement Assessment - Vital signs - Respiratory rate(Screening, Day 1 to day 85 (cohorts 1-2) or to day 86 (cohorts 3-6))
- Safety Measurement Assessment - Vital signs - Blood pressure(Screening, Day 1 to day 85 (cohorts 1-2) or to day 86 (cohorts 3-6))
- Safety Measurement Assessment - Vital signs - Heart rate(Screening, Day 1 to day 85 (cohorts 1-2) or to day 86 (cohorts 3-6))
- Safety Measurement Assessment - Vital signs - Body temperature(Screening, Day 1, 2, 3, 4, 8, 11, and 86 (cohorts 3-6).)
- Safety Measurement Assessment - Vital signs - Oxygen saturation(Day 2, day 85)
- Safety Measurement Assessment - Electrocardiogram (ECG) recording(Screening, Day 1, 2, 3, 11, 85, and 86 (cohorts 3-6).)
- Safety Measurement Assessment - Urinalysis - Protein concentration(Screening, Day 1, 2, 3, 11, 29, 85 and 86 (cohorts 3-6))
- Safety Measurement Assessment - Urinalysis - Blood(Screening, Day 1, 2, 3, 11, 29, 85 and 86 (cohorts 3-6))
- Safety Measurement Assessment - Urinalysis - Glucose concentration(Screening, Day 1, 2, 3, 11, 29, 85 and 86 (cohorts 3-6))
- Safety Measurement Assessment - Monitoring of local tolerability(Day 1, 2 and 85)
- Safety Measurement Assessment - Coagulation parameters - INR(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3-6).)
- Safety Measurement Assessment - Coagulation parameters - aPTT(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3-6).)
- Safety Measurement Assessment - Coagulation parameters - Fibrinogen(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3-6).)
- Safety Measurement Assessment - Haematology - Haemoglobin(Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Haematology - Haematocrit(Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Haematology - Red blood cell count(Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Haematology - White blood cell count(Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Haematology - Platelets(Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Haematology - Differential blood cell count(Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Potassium(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Calcium(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Chloride(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Sodium(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Uric acid(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Urea(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Creatinine(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Total bilirubin(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Total protein(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Lactate dehydrogenase(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Glucose(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - CRP(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Alkaline Phosphatase(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Gamma-glutamyl Transferase(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Alanine Aminotransferase(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))
- Safety Measurement Assessment - Blood chemistry - Aspartate Aminotransferase(Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6))