A Randomized, Double Blind, Placebo-Controlled, Multiple Ascending Dose, Phase 1 Study of SLV213 in Healthy Volunteers
Overview
- Phase
- Phase 1
- Intervention
- Placebo for SLV213
- Conditions
- COVID-19
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 16
- Locations
- 1
- Primary Endpoint
- Frequency of Treatment-Emergent Adverse Events (TEAEs) by Maximum Severity
- Status
- Terminated
- Last Updated
- 9 months ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of signed and dated informed consent form.
- •Able to understand and willing to be available for all study visits and comply with all study procedures including Lifestyle Considerations throughout the study.
- •Male and Female individuals, age 18-65 inclusive at time of enrollment.
- •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.
- •Ability to take oral medication and be willing to adhere to the dosing regimen.
- •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).
Exclusion Criteria
- •Pregnant or lactating.
- •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).
- •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.
- •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 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 (UDS) test for illicit substances at Screening or Check-in (Day -1)
- •Note 1: Any approved medical use of amphetamines, barbiturates, benzodiazepines, cannabis, tricyclic antidepressants and opiates will not be acceptable.
Arms & Interventions
Group 2
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.
Intervention: Placebo for SLV213
Group 2
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.
Intervention: SLV213
Group 3
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.
Intervention: Placebo for SLV213
Group 3
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.
Intervention: SLV213
Group1
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.
Intervention: Placebo for SLV213
Group1
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.
Intervention: SLV213
Outcomes
Primary Outcomes
Frequency of Treatment-Emergent Adverse Events (TEAEs) by Maximum Severity
Time Frame: Day 1 through Day 28
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.
Frequency of Related Treatment-Related TEAEs
Time Frame: Day 1 through Day 28
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.
Frequency of Serious Adverse Events (SAEs)
Time Frame: Day 1 through Day 28
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.
Frequency of Laboratory AEs by Maximum Severity
Time Frame: Day 1 through Day 28
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.
Frequency of Treatment-Related Laboratory AEs
Time Frame: Day 1 through Day 28
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.
Frequency of Electrocardiogram (ECG) AEs by Maximum Severity
Time Frame: Day 1 through Day 28
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.
Frequency of Treatment-Related ECG AEs
Time Frame: Day 1 through Day 28
The number of participants who experienced at least one related ECG AE of any severity. Graded ECG parameters include PR Internal and QTcF Interval.
Frequency of Early Terminations or Withdrawals Due to Treatment-Related TEAEs
Time Frame: Day 1 through Day 28
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.
Frequency of TEAEs
Time Frame: Day 1 through Day 28
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.
Frequency of Grade 3 or Higher Laboratory AEs
Time Frame: Day 1 through Day 28
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.
Frequency of Grade 3 or Higher Vital Signs AEs
Time Frame: Day 1 through Day 28
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.
Frequency of Grade 3 or Higher ECG AEs
Time Frame: Day 1 through Day 28
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.
Frequency of Participants Who Received All Oral Medication Doses
Time Frame: Day 1 through Day 28
The number of participants who received all doses of study product. This outcome is used to assess the tolerability of the study treatment.
Secondary Outcomes
- Maximum Concentration (Cmax) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Minimum Concentration (Cmin) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Time of Maximum Concentration (Tmax) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Time of Minimum Concentration (Tmin) of SLV213 in Plasma After Dose 1(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(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(0 h through 12 h post dose 1)
- 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(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(0 h through 12 h post dose 1)
- Terminal Half-Life (t1/2) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Total Clearance (CLT) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Terminal Phase Elimination Rate Constant (Ke) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Volume of Distribution (Vd) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Dose-normalized AUC0-Tau (AUC0-tau/Dose) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Dose-normalized Cmax (Cmax/Dose) of SLV213 in Plasma After Dose 1(0 h through 12 h post dose 1)
- Cmax at Steady State (Cmax,ss) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Cmin at Steady State (Cmin,ss) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Average Concentration During the Dosing Interval (Cavg) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Tmax at Steady State (Tmax,ss) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Tmin at Steady State (Tmin,ss) of SLV213 in Plasma After Dose 14(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(0 h through 48 h post dose 14)
- AUC0-tau at Steady State (AUC0-tau,ss) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- t1/2 of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- CLT at Steady State (CLT,ss) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Vd at Steady State (Vd,ss) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Dose-Normalized AUC0-tau,ss (AUC0-tau,ss/Dose) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Dose-Normalized Cmax,ss (Cmax,ss/Dose) of SLV213 in Plasma After Dose 14(0 h through 48 h post dose 14)
- Linearity Index of SLV213 in Plasma(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(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(0 h through 12 h post dose 1, 0 h through 48 h post dose 14)