To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of SRN001 in healthy adult volunteers.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
30
SRN001 is an investigational drug administered at doses of 45 mg, 90 mg, or 180 mg depending on cohort.
0.9% sodium chloride solution administered as placebo control.
Seoul National University Hospital
Seoul, South Korea
RECRUITINGIncidence of Treatment-Emergent Adverse Events (TEAEs)
Number of participants experiencing one or more TEAEs during the study period.
Time frame: From first dose through end of study (up to 114 days)
Number of participants with serious adverse events (SAEs)
Number of participants with SAEs as defined in protocol.
Time frame: From first dose through end of study (up to 114 days)
Number of participants with clinically significant abnormal laboratory results
Counts of clinically significant abnormal lab tests during study.
Time frame: From first dose through end of study (up to 114 days)
Maximum Observed Plasma Concentration (Cmax) of SRN001
Maximum observed plasma concentration (Cmax) following IV administration of SRN001.
Time frame: Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose)
Time to Maximum Plasma Concentration (Tmax) of SRN001
Time to reach maximum observed plasma concentration following IV administration.
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
Area Under the Curve from time zero to last measurable concentration (AUClast)
AUClast of SRN001 plasma concentration versus time curve.
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
Area Under the Plasma Concentration-Time Curve over the Dosing Interval (AUCtau) of SRN001
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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.
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 Half-Life (t½) of SRN001
Terminal elimination half-life (t½) will be calculated from the plasma concentration-time profile at steady state following multiple doses.
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
Clearance (CL) of SRN001
Systemic clearance (CL) will be determined from non-compartmental analysis of plasma concentrations at steady state after multiple dosing.
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) of SRN001
Apparent volume of distribution (Vz) will be calculated from plasma concentration data at steady state following multiple doses.
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 Maximum Observed Plasma Concentration at Steady State (Tmax,ss) of SRN001
Time to reach maximum observed plasma concentration at steady state following multiple intravenous doses.
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 (Cmax,ss) of SRN001
Maximum observed plasma concentration at steady state following multiple intravenous doses.
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 (Cmin,ss) of SRN001
Minimum observed plasma concentration at steady state following multiple doses.
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 (Cavg,ss) of SRN001
Average plasma concentration at steady state following multiple intravenous doses.
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
Trough Plasma Concentration at Steady State (Ctrough) of SRN001
Plasma concentration just prior to the next dose at steady state following multiple dosing.
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
Area Under the Plasma Concentration-Time Curve over the Dosing Interval at Steady State (AUCtau,ss) of SRN001
AUCtau,ss will be calculated over one dosing interval at steady state following multiple intravenous doses.
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
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.
Pre-dose samples: Day 1, Day 15, and Day 29 (pre-dose)
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) of SRN001 at Steady State
Accumulation ratio (R) comparing exposure at steady state with that after the first dose (e.g., based on Cmax or AUC).
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