This Phase 1 double blind, placebo-controlled study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses (MAD) of SLV213 in healthy male and female participants, 18-65 years of age. This study will help to select the most likely suitable dose (e.g., at Maximum Tolerated Dose \[MTD\]) for the treatment of patients with COVID-19 in a pivotal study. This phase 1 double blind, placebo-controlled study will consist of three sequential cohorts of 12 participants each (8 SLV213 and 4 placebo), at doses of 400 mg every 12 hours (Q12h), 600 mg Q12h, and 800 mg Q12h administered orally (PO) for 7 days. After each cohort, a Safety Review Committee (SRC) will evaluate the safety of the regimen before proceeding to dose the next cohort. Randomization will occur into the respective cohorts as above. Upon meeting the Inclusion/Exclusion criteria, subjects will begin treatment with SLV213 or placebo per their assigned cohort. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SLV213 for 7 days in healthy participants.
This Phase 1 double blind, placebo-controlled study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses (MAD) of SLV213 in healthy male and female participants, 18-65 years of age. This study will help to select the most likely suitable dose (e.g., at Maximum Tolerated Dose \[MTD\]) for the treatment of patients with COVID-19 in a pivotal study. This phase 1 double blind, placebo-controlled study will consist of three sequential cohorts of 12 participants each (8 SLV213 and 4 placebo), at doses of 400 mg every 12 hours (Q12h), 600 mg Q12h, and 800 mg Q12h administered orally (PO) for 7 days. After each cohort, a Safety Review Committee (SRC) will evaluate the safety of the regimen before proceeding to dose the next cohort. Randomization will occur into the respective cohorts as above. Upon meeting the Inclusion/Exclusion criteria, subjects will begin treatment with SLV213 or placebo per their assigned cohort. Participants will take their study drug in the fasted state prior to morning and evening meals and will remain as in-patient in the clinical trial unit (CTU) during all treatments and for approximately 48 hours (h) after the last dose for monitoring. After discharge from the CTU, participants will be monitored by CTU staff by telephone to assess for new adverse events and use of concomitant medication since the last visit or contact, approximately weekly for three weeks. Participants will be asked to return to the CTU for further assessment of moderate or severe adverse events (AEs) use of concomitant medications (ConMeds) since the last visit or contact, approximately weekly for three weeks. The primary objective is to evaluate the safety and tolerability of multiple ascending doses of SLV213 for 7 days in healthy participants. The secondary objective is to characterize the multiple dose PK of SLV213 in healthy participants.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
16
Microcrystalline cellulose in a size 1 orange hard gelatin capsule.
SLV213 drug substance (K777) is 4-methylpiperazine-1-carboxylic acid, a vinyl sulfone cysteine protease inhibitor for the treatment of subjects infected with SARS-CoV-2. SLV213 is a white powder substance without excipients or stabilizer that will be packed into gelatin capsules which has been demonstrated to exhibit broad inhibitory properties against host cathepsins (e.g., Cathepsin L).
Altasciences Inc - Kansas City
Overland Park, Kansas, United States
Frequency of Treatment-Emergent Adverse Events (TEAEs) by Maximum Severity
The number of participants who experienced at least one unsolicited TEAE of any relatedness are summarized by the maximum severity recorded. A TEAE is defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. A TEAE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal (investigational) product. Any medical condition that was present at screening was considered a baseline finding and not reported as a TEAE. However, if the severity (i.e., grade) of any pre-existing medical condition increases, it was recorded as a TEAE.
Time frame: Day 1 through Day 28
Frequency of Related Treatment-Related TEAEs
The number of participants who experienced at least one related unsolicited TEAE of any severity. A TEAE is defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. A TEAE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of medicinal (investigational) product. Any medical condition that was present at screening was considered a baseline finding and not reported as a TEAE. However, if the severity (i.e., grade) of any pre-existing medical condition increases, it was recorded as a TEAE. A TEAE is considered related if there is a reasonable possibility that the study intervention caused the TEAE, or there is a temporal relationship between the study intervention and event.
Time frame: Day 1 through Day 28
Frequency of Serious Adverse Events (SAEs)
The number of participants who experienced at least one SAE throughout the course of the study. An AE is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the following outcomes: * Death * A life-threatening adverse event * Inpatient hospitalization or prolongation of existing hospitalization * A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or * A congenital anomaly/birth defect.
Time frame: Day 1 through Day 28
Frequency of Laboratory AEs by Maximum Severity
The number of participants who experienced at least one laboratory AE of any relatedness are summarized by the maximum severity recorded. Graded chemistry measurements include sodium, potassium, carbon dioxide, calcium, creatinine, blood urea nitrogen, fasting glucose, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, amylase, lipase, magnesium, and inorganic phosphorous. Graded hematology measurements include hemoglobin, platelets, white blood cells, neutrophils, lymphocytes, monocytes, basophils, and eosinophils. Graded coagulation measurements include prothrombin time and activated partial thromboplastin time. Graded urinalysis measurements include nitrite, urine protein, urine glucose, white blood cells, red blood cells, and bacteria. If a laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time frame: Day 1 through Day 28
Frequency of Treatment-Related Laboratory AEs
The number of participants who experienced at least one related laboratory AE of any severity. Graded chemistry measurements include sodium, potassium, carbon dioxide, calcium, creatinine, blood urea nitrogen, fasting glucose, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, amylase, lipase, magnesium, and inorganic phosphorous. Graded hematology measurements include hemoglobin, platelets, white blood cells, neutrophils, lymphocytes, monocytes, basophils, and eosinophils. Graded coagulation measurements include prothrombin time and activated partial thromboplastin time. Graded urinalysis measurements include nitrite, urine protein, urine glucose, white blood cells, red blood cells, and bacteria. If a laboratory value met the threshold for an AE at baseline, subsequent safety laboratory results were only considered to be an AE if the grading worsened in severity.
Time frame: Day 1 through Day 28
Frequency of Electrocardiogram (ECG) AEs by Maximum Severity
The number of participants who experienced at least one ECG AE of any relatedness are summarized by the maximum severity recorded. Graded ECG parameters include PR Internal and QTcF Interval.
Time frame: Day 1 through Day 28
Frequency of Treatment-Related ECG AEs
The number of participants who experienced at least one related ECG AE of any severity. Graded ECG parameters include PR Internal and QTcF Interval.
Time frame: Day 1 through Day 28
Frequency of Early Terminations or Withdrawals Due to Treatment-Related TEAEs
The number of participants who terminated early or were withdrawn due to a treatment-related TEAE. This outcome is used to assess the tolerability of the study treatment.
Time frame: Day 1 through Day 28
Frequency of TEAEs
The number of participants who experienced at least one TEAE of any severity. This outcome is used to assess the tolerability of the study treatment.
Time frame: Day 1 through Day 28
Frequency of Grade 3 or Higher Laboratory AEs
The number of participants who experienced at least one Grade 3 (severe) or higher laboratory AE. This outcome is used to assess the tolerability of the study treatment.
Time frame: Day 1 through Day 28
Frequency of Grade 3 or Higher Vital Signs AEs
The number of participants who experienced at least one Grade 3 (severe) or higher vital signs AE. This outcome is used to assess the tolerability of the study treatment.
Time frame: Day 1 through Day 28
Frequency of Grade 3 or Higher ECG AEs
The number of participants who experienced at least one Grade 3 (severe) or higher ECG AE. This outcome is used to assess the tolerability of the study treatment.
Time frame: Day 1 through Day 28
Frequency of Participants Who Received All Oral Medication Doses
The number of participants who received all doses of study product. This outcome is used to assess the tolerability of the study treatment.
Time frame: Day 1 through Day 28
Maximum Concentration (Cmax) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Minimum Concentration (Cmin) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Time of Maximum Concentration (Tmax) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Time of Minimum Concentration (Tmin) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to Infinity (AUC0-inf) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis. AUC0-inf was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: 0 h through 12 h post dose 1
Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to 12 h (AUC0-12) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
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Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to the Last Concentration Above the Lower Limit of Quantitation (AUC0-last) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to the End of the Dosing Interval (AUC0-tau) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Terminal Half-Life (t1/2) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis. t1/2 was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: 0 h through 12 h post dose 1
Total Clearance (CLT) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis. CLT was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: 0 h through 12 h post dose 1
Terminal Phase Elimination Rate Constant (Ke) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis. Ke was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: 0 h through 12 h post dose 1
Volume of Distribution (Vd) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis. Vd was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: 0 h through 12 h post dose 1
Dose-normalized AUC0-Tau (AUC0-tau/Dose) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Dose-normalized Cmax (Cmax/Dose) of SLV213 in Plasma After Dose 1
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1
Cmax at Steady State (Cmax,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Cmin at Steady State (Cmin,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Average Concentration During the Dosing Interval (Cavg) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Tmax at Steady State (Tmax,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Tmin at Steady State (Tmin,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Area Under the Concentration-Time Curve From 0 h (Pre-Dose) to 48 h at Steady State (AUC0-48,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
AUC0-tau at Steady State (AUC0-tau,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
t1/2 of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. t1/2 was estimated for parameters meeting the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) \>= 0.90 and includes at least 3 time points after Tmax.
Time frame: 0 h through 48 h post dose 14
CLT at Steady State (CLT,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Vd at Steady State (Vd,ss) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Dose-Normalized AUC0-tau,ss (AUC0-tau,ss/Dose) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Dose-Normalized Cmax,ss (Cmax,ss/Dose) of SLV213 in Plasma After Dose 14
PK parameters were estimated from the SLV213 plasma concentration-time data after dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved.
Time frame: 0 h through 48 h post dose 14
Linearity Index of SLV213 in Plasma
Linearity index is estimated as AUC0-tau,ss (Dose 14)/AUC0-inf (Dose 1). PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 and dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1, 0 h through 48 h post dose 14
Accumulation Ratio for AUC (RAUC) of SLV213 in Plasma
RAUC is estimated as AUC0-tau,ss (Dose 14)/AUC0-tau (Dose 1). PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 and dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1, 0 h through 48 h post dose 14
Accumulation Ratio for Cmax (RCmax) of SLV213 in Plasma
RCmax is estimated as Cmax,ss (Dose 14)/Cmax (Dose 1). PK parameters were estimated from the SLV213 plasma concentration-time data after dose 1 and dose 14 (the last dose) using Phoenix WinNonlin Non-compartmental analysis.
Time frame: 0 h through 12 h post dose 1, 0 h through 48 h post dose 14