Clinical trial NCT06146374: Safety Study of SLV213 for the Treatment of COVID-19.
Official title: A Randomized, Double Blind, Placebo-Controlled, Multiple Ascending Dose, Phase 1 Study of SLV213 in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: COVID-19
Keywords: Coronavirus
Covid-19
Double Blind
Healthy Volunteers
Multiple Ascending Dose
Phase 1
Placebo Controlled
Randomized
SLV213
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2023-11-24
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated informed consent form.
2. Able to understand and willing to be available for all study visits and comply with all study procedures including Lifestyle Considerations throughout the study.
3. Male and Female individuals, age 18-65 inclusive at time of enrollment.
4. Good general health by medical history (MH), physical examination (PE), and vital signs (VS), clinical laboratory tests and Electrocardiogram (ECG) within normal reference range.

   Note 1: Lab exceptions include: lab test values that are within Grade 1 range per the Toxicity Table (Appendix A) 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 Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), alkaline phosphatase (AP), total and direct bilirubin, serum creatinine, estimated glomerular filtration rate (eGFR) per the CKD-EPI formula, and urine protein, which must be within the laboratory normal reference range.

   Note 2: Screening laboratory values that fall outside the laboratory normal reference ranges and the ranges are not listed within the Toxicity Table (Appendix A) (e.g., decrease activated partial thromboplastin time (aPTT)) that are deemed Not Clinically Significant by the PI will be acceptable.
5. Ability to take oral medication and be willing to adhere to the dosing regimen.
6. Women of childbearing potential1 must have practiced or use true abstinence2 or use at least one acceptable primary form of contraception3 for specified periods4 before, during and after dosing.

   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, tubal ligation, or Essure 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, non-hormonal, intrauterine device, (and if in a monogamous relationship with a male partner who uses a barrier method without spermicide) Note 4: Specified periods include 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.
7. Women of childbearing potential must have a negative serum Beta-human chorionic gonadotropin (HCG) pregnancy test at screening and a negative urine HCG pregnancy test at check-in (Day-1) within 24 hours before receiving the initial study product.
8. Male participants receiving the study product must use acceptable contraception and refrain from donating sperm from the day of first dose until 30 days after the last dose or be vasectomized.1 Note 1: Acceptable contraception includes abstinence from intercourse with a female of childbearing potential or use of a male condom without 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 for 180 days or more.
9. Willing to avoid excessive physical exercise starting within 48 h prior to dosing and until discharge from the CTU on Day 9.
10. No history of acute febrile or infectious illness for at least 7 days prior to the administration of study drug.

Exclusion Criteria:

1. Pregnant or lactating.
2. History of any chronic disease that may increase risk to subject or interfere with endpoint assessment1:

   Note 1: With the exception of stable chronic medical conditions that do not require prescribed oral or injectable medications (e.g., Type 2 diabetes managed by diet only).
3. History of bradycardia, orthostatic hypotension or orthostatic tachycardia, Long COVID or history of dysautonomia.1 Note 1: Exception is sinus bradycardia (HR \<60 bpm) in healthy participants (e.g., conditioned athletes) could be enrolled per investigator's clinical judgement.
4. Known history of a clinically significant food or drug allergy/hypersensitivity including known allergy/hypersensitivity to ingredients of the study drug or placebo.
5. Current seasonal allergies with ongoing symptoms for more than a week prior to dosing requiring glucocorticoids and/or frequent use of antihistamines for treatment.
6. History of any clinically significant disease or disorder, medical/surgical procedure, or trauma within 4 weeks prior to initiation of administration of study product(s).
7. History of any psychiatric condition that has required hospitalization in the last 12 months or subject is considered psychologically unstable by the investigator.
8. History of any substance use disorder or positive urine drug screening (UDS) test for illicit substances at Screening or Check-in (Day -1)1.

   Note 1: Any approved medical use of amphetamines, barbiturates, benzodiazepines, cannabis, tricyclic antidepressants and opiates will not be acceptable.
9. History of alcoholism or of binge1 or heavy alcohol drinking2 at any time in the 6 months before study product administration or positive urine alcohol test at Screening or Check-in (Day -1).

   Note 1: Binge drinking is defined as 5 or more drinks during a single occasion if male, or 4 or more if female.

   Note 2: 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.
10. History of \>/=10 pack-years of nicotine product1 consumption in the 5-year period before screening, or positive urine cotinine screen at Check-in (Day -1)2.

    Note 1: Nicotine products include cigarettes, e-cigarettes, pipe, cigar, chewing tobacco, nicotine patch.

    Note 2: Positive urine cotinine at Screening is allowed if negative at Check-in (Day -1).
11. Body mass index (BMI) \</= 18 kg/m2 or \>/= 32 kg/m2, or weight \</= 100 lbs at Screening.
12. Prior exposure to SLV213 or K777 or K11777.
13. Use of any prohibited prescription or non-prescription medication within 14 days or 5 half-lives of the drug, whichever is longer, prior to study Check-in.
14. Use of any investigational drug product within 30 days or 5 half-lives (whichever is longer) before investigational product administration in this study.
15. 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).
16. 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.
17. Positive viral serology tests for Human Immunodeficiency Virus (HIV), hepatitis B virus, or hepatitis C virus (HCV) at screening1 with one exception2:

    Note 1: Viral serology tests include HIV 1 and HIV 2 antibodies, Hepatitis B virus surface antigen (HBsAg), and HCV antibodies.

    Note 2: 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.
18. Positive SARS-CoV-2 (COVID-19) molecular diagnostic test (Cue Care™ test) at Check-in (Day -1).

Primary outcomes:
measure: Incidence of ECG adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Incidence of ECG serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Incidence of laboratory adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Incidence of laboratory serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Incidence of treatment-emergent systemic adverse events (TEAEs)
timeFrame: Day 1 - Day 28
measure: Incidence of treatment-emergent systemic serious adverse events (TESAEs)
timeFrame: Day 1 - Day 28
measure: Number and percentage of participants terminated early or withdrawn due to treatment-emergent adverse events (TEAEs)
timeFrame: Day 1 - Day 28
measure: Number and percentage of participants that have at least 1 treatment-emergent adverse event (TEAE)
timeFrame: Day 1 - Day 28
measure: Number and percentage of participants that meet Grade 3 abnormal criteria for safety laboratory tests at least once post-dose
timeFrame: Day 1 - Day 28
measure: Number and percentage of participants that meet Grade 3 abnormal criteria for vital sign measurements at least once post-dose
timeFrame: Day 1 - Day 28
measure: Number and percentage of participants that meet Grade 3 criteria for safety electrocardiogram (ECG) parameters at least once post-dose
timeFrame: Day 1 - Day 28
measure: Proportion of oral medication doses completed
timeFrame: Day 1 - Day 28
measure: Relatedness to study drug of all ECG serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Relatedness to study drug of all electrocardiographic (ECG) adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Relatedness to study drug of all laboratory adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Relatedness to study drug of all laboratory serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Relatedness to study drug of all treatment-emergent systemic adverse events (TEAEs)
timeFrame: Day 1 - Day 28
measure: Relatedness to study drug of all treatment-emergent systemic serious adverse events (TESAEs)
timeFrame: Day 1 - Day 28
measure: Severity of ECG serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Severity of electrocardiographic (ECG) adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Severity of laboratory adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Severity of laboratory serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Severity of treatment-emergent systemic adverse events (TEAEs)
timeFrame: Day 1 - Day 28
measure: Severity of treatment-emergent systemic serious adverse events (TESAEs)
timeFrame: Day 1 - Day 28
measure: Type of ECG serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Type of electrocardiographic (ECG) adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Type of laboratory adverse events (AEs)
timeFrame: Day 1 - Day 28
measure: Type of laboratory serious adverse events (SAEs)
timeFrame: Day 1 - Day 28
measure: Type of treatment-emergent systemic adverse events (TEAEs)
timeFrame: Day 1 - Day 28
measure: Type of treatment-emergent systemic serious adverse events (TESAEs)
timeFrame: Day 1 - Day 28
Secondary outcomes:
measure: Accumulation ratio for area under the plasma concentration-time curve (RAUC) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Accumulation ratio for maximum observed plasma concentration (RCmax) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Area under the plasma concentration-time curve (AUC) from 0h (pre-dose) to 12h after dosing (AUC0-12) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Area under the plasma concentration-time curve (AUC) from 0h (pre-dose) to 48h after dosing (AUC0-48,ss) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Area under the plasma concentration-time curve (AUC) from 0h (pre-dose) to the end of the dosing interval at a steady state (AUC0-tau,ss) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUC0-inf) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: 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
timeFrame: Day 1 - Day 7
measure: Area under the plasma concentration-time curve (AUC) to the end of the dosing interval (AUC0-tau) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: 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
timeFrame: Day 1 - Day 7
measure: Calculate trough plasma concentrations of total SLV213
timeFrame: Day 1 - Day 7
measure: Calculated average concentration (Cavg) during the dosing interval following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Maximum observed plasma concentration (Cmax) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Maximum observed plasma concentration at a steady state (Cmax,ss) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Minimum observed plasma concentration (Cmin) at the end of the dosing interval following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Minimum observed plasma concentration at a steady state (Cmin,ss) at the end of the dosing interval following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Pharmacokinetics (PK) of multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Ratio of dose-normalized exposure parameters (AUC0-tau/Dose) and (Cmax/Dose) following multiple-dose of SLV213.
timeFrame: Day 1 - Day 7
measure: Ratio of dose-normalized exposure parameters (AUC0-tau/Dose) and (Cmax/Dose) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Terminal half-life (t1/2) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Terminal half-life (t1/2) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Terminal phase elimination rate constant (Ke) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Time (h) of maximum plasma concentration (Tmax) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Time of maximum plasma concentration (Cmax) at a steady state (Tmax,ss) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Time of minimum plasma concentration (Tmin) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Total clearance (CLT) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Total clearance (CLT) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Volume of distribution (Vd) following single-dose of SLV213
timeFrame: Day 1 - Day 7
measure: Volume of distribution at a steady state (Vd,ss) following multiple-dose of SLV213
timeFrame: Day 1 - Day 7
Other outcomes:
Locations:
city: Overland Park
country: United States
facility: Altasciences Inc - Kansas City
state: Kansas
Study officials:
References: