Safety Study of SLV213 for the Treatment of COVID-19.

Study Overview
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Brief Summary
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The proposed study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses (MAD) of SLV213 administered orally (PO) every 12 hours (Q12h) daily for 7 days 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 Q12h, 600 mg Q12h, and 800 mg Q12h administered orally 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.

Detailed Description
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The proposed study will evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses (MAD) of SLV213 administered orally (PO) every 12 hours (Q12h) daily for 7 days 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 Q12h, 600 mg Q12h, and 800 mg Q12h administered orally 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 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 AEs. 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.

Official Title
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A Randomized, Double Blind, Placebo-Controlled, Multiple Ascending Dose, Phase 1 Study of SLV213 in Healthy Volunteers

Conditions
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COVID-19

Intervention / Treatment
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* Other: Placebo for SLV213
* Drug: SLV213


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form. Be able to understand and stated willingness to be available for all study visits and comply with all study procedures throughout the duration of the study, including adherence to Lifestyle Considerations. Male and Female individuals, age 18-65 inclusive at time of enrollment. In good general health as evidenced by medical history (MH), physical examination (PE), and vital signs (VS), Clinical Laboratory Tests and electrocardiogram (ECG) within normal reference ranges at Screening and Check-in (Day -1), with the following exceptions: Note 1: VS exceptions include: (1) Resting blood pressure (BP) in Grade 1 range (or up to 140/90 if otherwise healthy), (2) resting heart rate (HR) 45 <HR< 90 bpm if otherwise healthy adults with known history of asymptomatic bradycardia or tachycardia, (3) resting respiratory rate (RR) in Grade 1 (or up to 22 BPM), and (4) temperature (T) up to 100.4 degrees Fahrenheit without symptoms of intercurrent illness . Note 2: Lab exceptions include: lab test values that are in Grade 1 range per the Toxicity Table (Appendix A, Table 4) are acceptable if not considered to be clinically significant by the investigator (PI, sub-investigator, or authorized clinician) , with the exception of liver function tests (LFT) (transaminases (ALT, AST, alkaline phosphatase (AP), total and direct bilirubin), serum creatinine, and estimated glomerular filtration rate (eGFR) per the CKD-EPI formula. Normal or stable baseline electrocardiogram (ECG) without cardiovascular symptoms or signs on PE. Ability to take oral medication and be willing to adhere to the dosing regimen. Women of childbearing potential must agree to use or have practiced true abstinence or use at least one acceptable primary form of contraception for at least 30 days prior to screening, during the period between screening and completion of dosing, and until at least 30 days following receipt of the last dose of study product. Note 1: Not of childbearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, salpingectomy, or Essure (R) placement with a history of documented radiological confirmation test at least 90 days after the procedure). Note 2: True abstinence is 100% of the time without sexual intercourse (the male's penis enters the female's vagina). (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception). Note 3: Acceptable forms of primary contraception include a monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more before the participant receiving the study product, tubal ligation, intrauterine device, birth control pills, and injectable/implantable/insertable hormonal birth control products. Women of childbearing potential must have a negative serum Human Chorionic Gonadotropin (HCG) pregnancy test at screening and a negative urine HCG pregnancy test within 24 hours before receiving the initial study product. Male participants receiving the study product must agree to refrain from donating sperm and to use contraception from the day receiving the study product until Day 30 after dosing or be vasectomized. Note 4: Acceptable contraception includes abstinence from intercourse with a female of childbearing potential or use of a male condom with spermicide when engaging in any activity that allows for the passage of ejaculate to a female during the intervention period and for at least 30 days after ending study dosing, or surgical sterilization. Willing to avoid excessive physical exercise starting within 48h prior to dosing and until discharge from the Clinical Trial Unit (CTU) on Day 9. No history of acute febrile or infectious illness for at least 7 days prior to the administration of study drug. Exclusion Criteria: Pregnant or lactating. Any history unstable chronic disease or of one or more of the following chronic conditions that may increase risk to subject or interfere with endpoint assessment, or any: Unstable chronic disease is defined by need for frequent medical interventions that lead to a change in medications and/or required hospitalization, surgery or an invasive procedure or emergency department/urgent care visit, as determined by the Site Principal Investigator (PI). Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, emphysema, cystic fibrosis. Diabetes mellitus (type 1 or 2), requiring oral medication or insulin for treatment. Cardiovascular disease, including hypertension, requiring at least 1 oral medication for treatment; congestive heart failure; coronary artery disease; cardiomyopathy; pulmonary hypertension. Chronic renal disease. Chronic liver disease (alcoholic, cirrhotic, etc.). Chronic gastrointestinal, biliary or pancreatic disease. Hemoglobin disorders, (e.g., sickle cell disease or trait, thalassemia). Dementia or other chronic neurological conditions or known history of past or current epilepsy or seizure disorders, excluding febrile seizures of childhood. Down syndrome. Any other gastrointestinal (GI), renal, or hepatic disease that may impact Absorption, Distribution, Metabolism and Excretion (ADME) of the investigational compound per the discretion of the Principal Investigator (PI). Known history of a clinically significant food or drug allergy/hypersensitivity including known allergy/hypersensitivity to ingredients of the study drug or placebo. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing requiring glucocorticoids and/or frequent use of antihistamines for treatment. History of any clinically significant (CS) disease or disorder, medical/surgical procedure, or trauma within 4 weeks prior to initiation of administration of study product(s). History of any psychiatric condition that has required hospitalization in the last 12 months or subject is considered psychologically unstable by the investigator. History of any substance use disorder or positive urine drug screening test (UDS) for illicit substances at Screening or Day -1. Note 1: Any approved medical use of amphetamines, barbiturates, benzodiazepines, cannabis, and opiates will not be acceptable. History of alcoholism or of binge alcohol drinking or heavy drinking of alcohol at any time in the 6 months before study product administration or positive urine alcohol test at Screening or Check-in (Day -1). Note 2: Binge drinking is defined as 5 or more drinks during a single occasion if male, or 4 or more if female. Note 3: Heavy drinking of alcohol is defined as consumption of more than 14 drinks of alcohol per week if male, or more than 7 drinks if female. History of >/=10 pack-years of nicotine product consumption in the 5-year period before screening, or positive urine cotinine screen at Check-in (Day -1). Note 4: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, nicotine patch. Note 5: Positive urine cotinine at Screening is allowed if negative at Check-in (Day -1). Body mass index (BMI) </= 18 kg/m2 or >/=32 kg/m2 at Screening or weight </= 100 lbs. Prior exposure to SLV213 or K777 or K11777. Use of any prohibited prescription or non-prescription medication within 14 days prior to the first dose of study drug(s). Use of any investigational drug product within 30 days or 5 half-lives (whichever is longer) before investigational product administration in this study. Planned participation in a clinical research study that requires treatment with a study drug, blood draws or other invasive assessments during the study period (screening until final visit). Blood or plasma donation of 500 mL within 3 months or more than 100 mL within 30 days before signing informed consent or planned donation prior to completion of this trial. Positive test for Human Immunodeficiency Virus (HIV) antibodies (HIV1 and HIV2), hepatitis B virus surface antigen (HBsAg), or Hepatitis C virus (HCV) antibodies at screening with the following exception: Note 6: Do not exclude participants with HCV antibodies who have been successfully treated for Hepatitis C, do not take any treatment medications currently, do not use prohibited medications, have normal transaminases and are generally healthy. Positive COVID-19 rapid antigen test at Screening or Check-in (Day -1).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 2<br>600mg (6x 100mg capsules) of SLV213 (N=8) or placebo (N=4) administered orally every 12 hours for 7 days to healthy male and female participants 18-65 years of age. | Other: Placebo for SLV213<br>* Microcrystalline cellulose in a size 1 orange hard gelatin capsule.<br>Drug: SLV213<br>* 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).<br>|
| Experimental: Group 3<br>800mg (8x 100mg capsules) of SLV213 (N=8) or placebo (N=4) administered orally every 12 hours for 7 days to healthy male and female participants 18-65 years of age. | Other: Placebo for SLV213<br>* Microcrystalline cellulose in a size 1 orange hard gelatin capsule.<br>Drug: SLV213<br>* 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).<br>|
| Experimental: Group1<br>400mg (4x 100mg capsules) of SLV213 (N=8) or placebo (N=4) administered orally every 12 hours for 7 days to healthy male and female participants 18-65 years of age. | Other: Placebo for SLV213<br>* Microcrystalline cellulose in a size 1 orange hard gelatin capsule.<br>Drug: SLV213<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of ECG adverse events (AEs) |  | Day 1 - Day 28 | 
| Incidence of ECG serious adverse events (SAEs) |  | Day 1 - Day 28 | 
| Incidence of laboratory adverse events (AEs) |  | Day 1 - Day 28 | 
| Incidence of laboratory serious adverse events (SAEs) |  | Day 1 - Day 28 | 
| Incidence of treatment-emergent systemic adverse events (TEAEs) |  | Day 1 - Day 28 | 
| Incidence of treatment-emergent systemic serious adverse events (TESAEs) |  | Day 1 - Day 28 | 
| Number and percentage of oral medication doses completed |  | Day 1 - Day 28 | 
| Number and percentage of participants terminated early or withdrawn due to treatment-emergent adverse events (TEAEs) | Assessed as related to intake of study medication | Day 1 - Day 28 | 
| Number and percentage of participants that have at least 1 treatment-emergent adverse event (TEAE) | Total and per dose level | Day 1 - Day 28 | 
| Number and percentage of participants that meet Grade 3 abnormal criteria for safety laboratory tests at least once post-dose |  | Day 1 - Day 28 | 
| Number and percentage of participants that meet Grade 3 abnormal criteria for vital sign measurements at least once post-dose |  | Day 1 - Day 28 | 
| Number and percentage of participants that meet Grade 3 criteria for safety electrocardiogram (ECG) parameters at least once post-dose |  | Day 1 - Day 28 | 
| Severity of ECG adverse events (AEs) |  | Day 1 - Day 28 | 
| Severity of ECG serious adverse events (SAEs) |  | Day 1 - Day 28 | 
| Severity of laboratory adverse events (AEs) |  | Day 1 - Day 28 | 
| Severity of laboratory serious adverse events (SAEs) |  | Day 1 - Day 28 | 
| Severity of treatment-emergent systemic adverse events (TEAEs) |  | Day 1 - Day 28 | 
| Severity of treatment-emergent systemic serious adverse events (TESAEs) |  | Day 1 - Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accumulation ratio for area under the plasma concentration-time curve (RAUC) following multiple-dose of SLV213 | Estimated as (AUC0-tau) (Day 7) / (AUC0-24) (Day 1) | Day 1 - Day 7 | 
| Accumulation ratio for maximum observed plasma concentration (Cmax) following multiple-dose of SLV213 | Estimated as (Cmax) (Day 7) / (Cmax) (Day 1) | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) from 0h (pre-dose) to 12h after dosing (AUC0-12) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) from 0h (predose) to 48h after dosing (AUC0-48,ss) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-inf) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) from time 0 to the last concentration above the lower limit of quantitation (AUC0-last) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) to the end of the dosing interval (AUC0-tau) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) to the end of the dosing interval at a steady state (AUC0-tau,ss) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Area under the plasma concentration-time curve (AUC) to the last time with a concentration greater than or equal to the validated limit of quantitation of the assay (AUC0-t) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Calculated average concentration (Cavg) during the dosing interval following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Maximum observed plasma concentration (Cmax) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Maximum observed plasma concentration at a steady state (Cmax,ss) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Minimum observed plasma concentration (Cmin) at the end of the dosing interval following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Minimum observed plasma concentration at a steady state (Cmin,ss) at the end of the dosing interval following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Pharmacokinetics (PK) of multiple-dose of SLV213 | Linearity Index: (AUC0-tau,ss (Day 7) / (AUC0-inf)(Day 1) | Day 1 - Day 7 | 
| Ratio of dose-normalized exposure parameters (AUC0-tau/Dose) and (Cmax/Dose) following multiple-dose of SLV213. |  | Day 1 - Day 7 | 
| Ratio of dose-normalized exposure parameters (AUC0-tau/Dose) and (Cmax/Dose) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Terminal half-life (t1/2) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Terminal half-life (t1/2) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Terminal phase elimination rate constant (Ke) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Time (h) of maximum plasma concentration (Tmax) |  | Day 1 - Day 7 | 
| Time of maximum plasma concentration (Cmax) at a steady state (Tmax,ss) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Time of minimum plasma concentration (Tmin) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Total clearance (CLT) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 
| Total clearance (CLT) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Volume of distribution (Vd) following single-dose of SLV213 |  | Day 1 - Day 7 | 
| Volume of distribution at a steady state (Vd,ss) following multiple-dose of SLV213 |  | Day 1 - Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus, Covid-19, Double Blind, Healthy Volunteers, Multiple Ascending Dose, Phase 1, Placebo Controlled, Randomized, SLV213