A Randomized, Double-blind, Placebo-controlled, Multiple Doses, Dose-escalation Phase 1 Clinical Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SRN001 in Healthy Korean and Caucasian Adult Males
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- siRNAgen Therapeutics Inc.
- Enrollment
- 30
- Locations
- 1
- Primary Endpoint
- Accumulation Ratio (R) of SRN001 at Steady State
Overview
Brief Summary
To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of SRN001 in healthy adult volunteers.
Detailed Description
SRN001 is a novel small interfering RNA (siRNA) drug being developed to treat fibrosis using Self Assembled Micelle inhibitory ribonucleic acid (SAMiRNA™) technology. Amphiregulin (AREG) is a growth factor involved in fibroblast proliferation and myofibroblast transformation which is the hallmark of fibrosis in lung and kidney tissues. AREG is a downstream gene overexpressed by Transforming growth factor-β (TGF-β) during fibrosis, promoting fibroblast to myofibroblast transition (FMT). SRN001 is designed to downregulate generating amphiregulin by RNA interference (RNAi). The goal of this clinical trial is to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics of SRN001 in healthy Korean and Caucasian adult males.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 19 Years to 60 Years (Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •Healthy Korean or Caucasian male volunteers aged 19 to 60 years at the time of screening.
- •Those who weighed 50.0 kg or more at the time of screening and had a body mass index (BMI) between 18.5 kg/m2 and 29.9 kg/m
- •Body mass index (BMI, kg/m2) = weight (kg) / {height (m2)} 2
- •Those whose screening results showed a serum amphiregulin concentration of 100 pg/mL or higher.
- •Those who voluntarily agreed to participate in this clinical trial after receiving a thorough explanation and fully understanding the clinical trial. Those who decided to participate and gave written consent to comply with the precautions.
Exclusion Criteria
- •Those with or have a history of clinically significant diseases of the hepatobiliary system (severe liver failure, viral hepatitis, etc.), kidney (severe renal failure, etc.), nervous system, immune system, respiratory system, digestive system, endocrine system, hematological/oncological system, cardiovascular system (heart failure, torsades de pointes, etc.), urinary system, psychiatric system (mood disorder, obsessive-compulsive disorder, etc.), or sexual dysfunction.
- •Those with a history of hypersensitivity to RNA drugs or other drugs (aspirin, antibiotics, etc.) or a history of clinically significant hypersensitivity reactions (atopy, asthma, etc.).
- •Those with a positive serum test result (hepatitis B test, hepatitis C test, human immunodeficiency virus (HIV) test, syphilis test).
- •Those with a history of drug abuse or a positive urine drug screening test for drugs of abuse.
- •Those who were screened in a sitting position after resting for at least 3 minutes. Those who exhibited the following values in measured vital signs:
- •Systolic blood pressure \< 80 mmHg or ≥ 140 mmHg
- •Diastolic blood pressure \< 45 mmHg or ≥ 90 mmHg
- •Pulse \< 45 bpm or \> 100 bpm
- •Body temperature \< 35.5 ℃ or \> 37.7 ℃
- •Those who exhibited the following values or clinically significant abnormal rhythm findings on the electrocardiogram (12-lead ECG) during the screening test:
Arms & Interventions
cohort1 Drug: SRN001 45mg
cohort1 Drug: SRN001 45mg
Intervention: SRN001 (Drug)
cohort2 Drug: SRN001 90mg
cohort2 Drug: SRN001 90mg
Intervention: SRN001 (Drug)
cohort3 Drug: SRN001 180mg
cohort3 Drug: SRN001 180mg
Intervention: SRN001 (Drug)
Placebo Comparator
Participants receive placebo (0.9% sodium chloride, normal saline)
Intervention: 0.9% sodium chloride (normal saline) (Drug)
Outcomes
Primary Outcomes
Accumulation Ratio (R) of SRN001 at Steady State
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Accumulation ratio (R) comparing exposure at steady state with that after the first dose (e.g., based on Cmax or AUC).
Incidence of Treatment-Emergent Adverse Events (TEAEs)
Time Frame: From first dose through end of study (up to 114 days)
Number of participants experiencing one or more TEAEs during the study period.
Number of participants with serious adverse events (SAEs)
Time Frame: From first dose through end of study (up to 114 days)
Number of participants with SAEs as defined in protocol.
Number of participants with clinically significant abnormal laboratory results
Time Frame: From first dose through end of study (up to 114 days)
Counts of clinically significant abnormal lab tests during study.
Maximum Observed Plasma Concentration (Cmax) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose)
Maximum observed plasma concentration (Cmax) following IV administration of SRN001.
Time to Maximum Plasma Concentration (Tmax) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Time to reach maximum observed plasma concentration following IV administration.
Area Under the Curve from time zero to last measurable concentration (AUClast)
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
AUClast of SRN001 plasma concentration versus time curve.
Area Under the Plasma Concentration-Time Curve over the Dosing Interval (AUCtau) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
AUCtau will be calculated as the area under the plasma concentration versus time curve over one complete dosing interval following multiple escalating intravenous doses of SRN001.
Terminal Half-Life (t½) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Terminal elimination half-life (t½) will be calculated from the plasma concentration-time profile at steady state following multiple doses.
Clearance (CL) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Systemic clearance (CL) will be determined from non-compartmental analysis of plasma concentrations at steady state after multiple dosing.
Apparent Volume of Distribution (Vz) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Apparent volume of distribution (Vz) will be calculated from plasma concentration data at steady state following multiple doses.
Time to Maximum Observed Plasma Concentration at Steady State (Tmax,ss) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Time to reach maximum observed plasma concentration at steady state following multiple intravenous doses.
Maximum Observed Plasma Concentration at Steady State (Cmax,ss) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Maximum observed plasma concentration at steady state following multiple intravenous doses.
Minimum Observed Plasma Concentration at Steady State (Cmin,ss) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Minimum observed plasma concentration at steady state following multiple doses.
Average Plasma Concentration at Steady State (Cavg,ss) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Average plasma concentration at steady state following multiple intravenous doses.
Trough Plasma Concentration at Steady State (Ctrough) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Plasma concentration just prior to the next dose at steady state following multiple dosing.
Area Under the Plasma Concentration-Time Curve over the Dosing Interval at Steady State (AUCtau,ss) of SRN001
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
AUCtau,ss will be calculated over one dosing interval at steady state following multiple intravenous doses.
Peak-to-Trough Fluctuation (PTF) of SRN001 at Steady State Description: Peak-to-trough fluctuation in plasma concentration at steady state, defined as (Cmax,ss - Cmin,ss)/Cavg,ss.
Time Frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose) Post-dose samples (Day 1 and Day 29): 0 (end of infusion), 10, 20, 30, and 45 minutes, and 1, 1.5, 2, 3, 6, 12, 24, and 48 hours after dosing
Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose)
Secondary Outcomes
No secondary outcomes reported