Clinical trial NCT06607484: Study Investigating the Safety, Tolerability and Blood Concentration of the Substance SR-878
Official title: Single Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Effects of SR-878 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Healthy Volunteers
Lead sponsor: SciRhom GmbH
Sponsor class: INDUSTRY
First posted: 2024-09-23
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

24 hours after the study medication infusion, participants in the 3rd-6th cohorts, will be injected with a product, called lipopolysaccharide (LPS). It has the ability to boost the body's immune response, even without causing an actual infection. LPS might trigger slight flu-like symptoms (i.e. uneasiness, little fever). Participants will be requested to stay an additional 8 hours in the hospital, and they will undergo several blood samplings and their body's reaction will be monitored. In the first 6 hours, they will receive a saline infusion to keep them hydrated, and in case they find the potential symptoms of the provoked inflammation unbearable, the study doctor will provide a medication (paracetamol) to relieve them.

In the following 12 weeks, participants will be requested to return regularly to the hospital, 10 times in total. During these visits, their medical status will be examined, and blood will be collected. For participants in the 3rd-6th cohorts, 12 weeks after their study medication dose, the LPS injection and the saline infusion will be repeated, and they will stay 8 hours again on the site. They will undergo several blood draws, and their medical condition will be monitored. They will also be requested to return to the site on the next day to repeat these assessments.

Interventions:

* Participants will receive SR-878 in a 1-hour long infusion once. The dose will depend on the cohort;
* Participants in the 3rd-6th cohorts will receive LPS injections twice, in a dose of 2 ng/kg body weight.

Eligibility criteria: Inclusion Criteria:

1. 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;
2. 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;
3. Has adequate venous access for blood collection;
4. In female subjects of childbearing potential, a negative serum pregnancy test at screening;
5. 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.

Exclusion Criteria:

1. Treatment with an investigational drug within one month or two half-lives prior to screening, whichever is longer;
2. Abnormal findings in medical history and physical examination that the investigator considers to be a clinically relevant abnormality;
3. 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
4. Subjects infected with human immunodeficiency virus (HIV), hepatitis B and C viruses (HBV and HCV);
5. Clinically relevant ECG (12 leads) abnormalities;
6. Subjects with acute infectious diseases within 2 weeks prior to screening;
7. History of any autoimmune diseases or any chronic inflammation;
8. Relevant history of other renal, hepatic, gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine, inflammatory, chronic infectious, or neurological diseases;
9. 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;
10. Known hypersensitivity to the active substance or to any of the excipients of the investigational medicinal products or auxiliary medicinal products;
11. Drug abuse, alcohol \>1 drink/day, defined according to the Food-based Dietary Guidelines in Europe;
12. Females who are pregnant, breastfeeding, or planning to become pregnant during the study.

Primary outcomes:
measure: Occurrence of treatment-emergent adverse event (TEAE)
timeFrame: Day 1 to Day 85 in Cohorts 1-2 and Day 1 to 86 in Cohorts 3-6
Secondary outcomes:
measure: Terminal half-life (T1/2) of SR-878
timeFrame: Day 1 until Day 85
measure: Area under the blood concentration-time curve 0-85 days (AUC0-85)
timeFrame: Day 1 until Day 85
measure: AUC0-inf
timeFrame: Day 1 until Day 85
measure: Maximum concentration (Cmax)
timeFrame: Day 1 until Day 85
measure: Reference-adjusted area under the effect curve 0-24 hours (AUEC0-24)
timeFrame: 0-24 hours
measure: Maximum effect (Emax) for tumour necrosis factor-alpha (TNF-alpha) after lipopolysaccharide (LPS) challenges
timeFrame: Day 2-3 and Day 85-86
measure: Safety Measurement Assessment - Adverse Events, including Serious Adverse Events
timeFrame: Day 1 until Day 85 or until day 85 (cohorts 3-6)
measure: Safety Measurement Assessment - Physical Examination
timeFrame: Day 1 until Day 85 or until day 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Vital signs - Respiratory rate
timeFrame: Screening, Day 1 to day 85 (cohorts 1-2) or to day 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Vital signs - Blood pressure
timeFrame: Screening, Day 1 to day 85 (cohorts 1-2) or to day 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Vital signs - Heart rate
timeFrame: Screening, Day 1 to day 85 (cohorts 1-2) or to day 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Vital signs - Body temperature
timeFrame: Screening, Day 1, 2, 3, 4, 8, 11, and 86 (cohorts 3-6).
measure: Safety Measurement Assessment - Vital signs - Oxygen saturation
timeFrame: Day 2, day 85
measure: Safety Measurement Assessment - Electrocardiogram (ECG) recording
timeFrame: Screening, Day 1, 2, 3, 11, 85, and 86 (cohorts 3-6).
measure: Safety Measurement Assessment - Urinalysis - Protein concentration
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Urinalysis - Blood
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Urinalysis - Glucose concentration
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and 86 (cohorts 3-6)
measure: Safety Measurement Assessment - Monitoring of local tolerability
timeFrame: Day 1, 2 and 85
measure: Safety Measurement Assessment - Coagulation parameters - INR
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3-6).
measure: Safety Measurement Assessment - Coagulation parameters - aPTT
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3-6).
measure: Safety Measurement Assessment - Coagulation parameters - Fibrinogen
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3-6).
measure: Safety Measurement Assessment - Haematology - Haemoglobin
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Haematology - Haematocrit
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Haematology - Red blood cell count
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Haematology - White blood cell count
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Haematology - Platelets
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Haematology - Differential blood cell count
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85, and 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Potassium
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Calcium
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Chloride
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Sodium
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Uric acid
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Urea
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Creatinine
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Total bilirubin
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Total protein
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Lactate dehydrogenase
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Glucose
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - CRP
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Alkaline Phosphatase
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Gamma-glutamyl Transferase
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Alanine Aminotransferase
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
measure: Safety Measurement Assessment - Blood chemistry - Aspartate Aminotransferase
timeFrame: Screening, Day 1, 2, 3, 11, 29, 85 and day 86 (cohorts 3 - 6)
Other outcomes:
measure: Levels of tumour necrosis factor-alpha, and their ratios to baseline after SR-878 administration in Cohorts 1-6
timeFrame: Day 1 until Day 22
measure: Development of anti-drug antibodies
timeFrame: Day 1 - Day 85
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
affiliation: SciRhom GmbH
name: Jürgen Reeß, Dr.
role: STUDY_CHAIR
References: