This is a Phase 1, randomized, placebo-controlled, double-blinded study to assess the safety and pharmacokinetics of single IV administrations of EV68-228-N in healthy adult volunteers. Three doses (3, 10 and 30 mg/kg) of EV68-228-N will be evaluated in three separate, sequential cohorts in this single dose escalation study. The cohorts will be randomized in a 5:1 randomization scheme. The first two participants in each cohort will serve as sentinels. Sentinel participants may be located at different sites. Sentinel safety data will be collected through Day 3 before submitting to the Protocol Safety Review Team (PSRT) for review. The PSRT is comprised of the Principal Investigator (PI), the DMID Medical Monitor, and the DMID Medical Officer. Data to be reviewed will include clinical data collected from Visits 1, 2 and 3, the results of laboratory testing conducted at these visits, solicited adverse events (AEs) and the passive reporting of adverse events through Day 3. From the time of infusion of the sentinels to at least 48 hours after infusion, no new participants will be given study product or placebo, but screening may continue. If no safety signal is detected in the sentinel group, and after approval from the DMID Medical Monitor, the remaining 10 participants in the cohort will be dosed following the overall 5:1 randomization scheme. All participants will be actively monitored for AEs and safety laboratory data following dosing through Day 8. Data will be reviewed by the PSRT and discussed with the Safety Monitoring Committee (SMC) for their concurrence before advancing to the next cohort. Electronic review of the safety data by the SMC is required prior to the cohort dose escalation when halting rules are met or there are any safety concerns. The primary objective is to evaluate the safety of a single IV infusion of either 3, 10, or 30 mg/kg of EV68-228-N when administered to healthy adults.
This is a Phase 1, randomized, placebo-controlled, double-blinded study to assess the safety and pharmacokinetics of single IV administrations of EV68-228-N in healthy adult volunteers. Three doses (3, 10 and 30 mg/kg) of EV68-228-N will be evaluated in three separate, sequential cohorts in this single dose escalation study. The cohorts will be randomized in a 5:1 randomization scheme. The first two participants in each cohort will serve as sentinels. Sentinel participants may be located at different sites. Sentinel safety data will be collected through Day 3 before submitting to the Protocol Safety Review Team (PSRT) for review. The PSRT is comprised of the Principal Investigator (PI), the DMID Medical Monitor, and the DMID Medical Officer. Data to be reviewed will include clinical data collected from Visits 1, 2 and 3, the results of laboratory testing conducted at these visits, solicited adverse events (AEs) and the passive reporting of adverse events through Day 3. From the time of infusion of the sentinels to at least 48 hours after infusion, no new participants will be given study product or placebo, but screening may continue. If no safety signal is detected in the sentinel group, and after approval from the DMID Medical Monitor, the remaining 10 participants in the cohort will be dosed following the overall 5:1 randomization scheme. All participants will be actively monitored for adverse events (AEs) and safety laboratory data following dosing through Day 8. Data will be reviewed by the PSRT and discussed with the Safety Monitoring Committee (SMC) for their concurrence before advancing to the next cohort. Electronic review of the safety data by the SMC is required prior to the cohort dose escalation when halting rules are met or there are any safety concerns. Assuming no safety concerns are identified after review of the first cohort safety data through Day 8, enrollment of Cohort 2 will begin. The dose of EV68-228-N will be increased to 10 mg/kg for the second cohort. The same sentinel design and safety plan will be used to evaluate sentinel participants in Cohort 2 and determine whether to enroll the remaining participants in Cohort 2. In addition, the same sentinel design and safety plan will be used for Cohort 3, which will evaluate the 30 mg/kg dose. Following informed consent, participants will be screened for eligibility, including medical history, physical examination, weight and height measurements, vital signs, screening laboratory tests, and a 12-lead electrocardiogram (ECG). Within 28 days of screening, eligible participants will be seen at the clinical research unit (Day 1) and be randomized to receive either a single intravenous dose of EV68-228-N or placebo (formulation buffer alone). Participants will remain in the unit for at least 5 hours following infusion and return for assessments on Day 2 and Day 3. Participants will have subsequent follow-up clinic visits on Days 8, 15, 29, 61, 91, and 121. Participants will be monitored and assessed for safety and the incidence of adverse events (AEs) at all visits beginning with the dosing visit. An electronic memory aid will be utilized from Day 1 through Day 3 to assist with collecting solicited adverse events (AEs). Safety laboratory studies will be collected at screening and on Days 1, 2, 3, 8, and 29. Concomitant medications taken 28 days before and after dosing will be recorded. Pharmacokinetic (PK) samples will be collected prior to infusion, end of infusion, 1, 3, 5, 24 and 48 hours after end of infusion; and on Days 8, 15, 29, 61, 91, and 121. The single dose pharmacokinetic (PK) parameters to be estimated include maximum observed serum concentration (Cmax), time to Cmax (Tmax), area under the serum concentration-time curve (AUC) from time zero to time t (AUC0-t), from time zero to 48 hours post infusion \[AUC(0-48)\], from time zero to the last measurable concentration \[AUC(0-tlast)\] and extrapolated to infinity \[AUC(0-oo)\], apparent serum terminal elimination phase half-life (t\^1/2), total serum clearance (CL), and volume of distribution during the terminal phase (Vz). PK parameters will be calculated from serum EV68-228-N levels measured using an electrochemiluminescence (ECL) enzyme-linked immunosorbent assay (ELISA). Samples will be collected prior to infusion on Day 1 and on Days 8, 15, 29, 61, 91 and 121 for serum levels of anti-EV68-228-N antibodies. A sample will be collected pre-infusion on Day 1 for hypersensitivity testing in the event that the participant experiences an infusion reaction. These baseline samples will only be analyzed in the event of a hypersensitivity reaction related to the infusion. If a participant experiences anaphylaxis or an anaphylactoid event related to the infusion, three additional samples will be collected: 1) during onset, 2) 2 or more hours after onset, and 3) after resolution of symptoms. The primary objective is to evaluate the safety of a single IV infusion of either 3, 10, or 30 mg/kg of EV68-228-N when administered to healthy adults. The secondary objective is to: 1) characterize the PK of single ascending doses of EV68-228-N for approximately four months following the infusion and 2) measure the occurrence of anti-drug antibodies (ADAs) elicited following a single IV infusion of EV68-228-N in healthy adults.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
36
EV68-228-N is a recombinant human monoclonal IgG1 antibody which is produced by genetically engineered plasmids in Nicotiana benthamiana. This intervention is directed against enterovirus EV-D68 capsid protein potentially providing treatments for EV-D68 infection and AMF.
The placebo is a sterile buffer solution formulated to match the EV68-228-N Drug Product. The formulation is 20mM Citrate + 10 mM Glycine, 8% Sucrose, and 0.01% Polysorbate 80, with a target pH of 5.5. The placebo will be filled into glass vials at 10 mL per vial. The formulation buffer is a clear colorless liquid.
University of Maryland, School of Medicine, Center for Vaccine Development and Global Health
Baltimore, Maryland, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Number of Participants Experiencing Solicited Adverse Events (AEs) Through 48 Hours Post-infusion
Number of participants in each treatment group experiencing at least one solicited AE of any severity through 48 hours post-infusion
Time frame: Day 1 (post-infusion) through 48 hours post-infusion
Number of Participants Experiencing Unsolicited AEs - Including Clinical and Laboratory AEs - Through Day 29
Number of participants in each treatment group experiencing at least one unsolicited AE - including clinical and laboratory AEs - through Day 29
Time frame: Day 1 (post-infusion) through Day 29
Number of Participants Experiencing Unsolicited Serious Adverse Events (SAEs), Medically Attended Adverse Events (MAAEs), and New Onset Chronic Medical Conditions (NOCMCs) Through the End of the Study
Number of participants in each treatment group experiencing at least one SAE, MAAE, or NOCMC through the end of the study.
Time frame: Day 1 (post-infusion) through Day 121
Area Under the Concentration-time Curve From Time 0 (Time of Infusion Start, t=0 Hours) to the Last Quantifiable Concentration (AUC0-last) of EV68-228-N in Serum
Pharmacokinetics (PK) parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. AUC0-last is defined as the area under the concentration time-curve from time of infusion start (t=0 hours) to the last quantifiable concentration above the lower limit of quantitation (LLOQ)
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Area Under the Concentration-time Curve From Time 0 (Time of Infusion Start, t=0 Hours) to Infinity (AUC0-infinity) of EV68-228-N in Serum
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. AUC0-infinity is defined as the area under the concentration time-curve from time of infusion start (t=0 hours) extrapolated to infinity based on the last observed concentration (Clast) and the elimination rate constant (lambda-z), where Clast is defined as the last observed positive concentration above the lower limit of quantitation (LLOQ) and lambda-z is defined as the first-order rate constant associated with the terminal (log-linear) portion of the concentration versus time curve describing the rate of elimination from serum. Estimated by linear regression of time vs. log concentration, AUC0-infinity was computed by adding AUC0-last to an area extrapolated by Clast divided by lambda-z.
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Area Under the Concentration-time Curve From Time 0 (Time of Infusion Start, t=0 Hours) to 48 Hours Post-dose (AUC0-48) of EV68-228-N in Serum
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. AUC0-48 is defined as the area under the concentration time-curve from time of infusion start (t=0 hours) to 48 hours post-infusion start.
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion
Maximum Observed Serum Concentration (Cmax) of EV68-228-N in Serum
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. Cmax is defined as the maximum observed serum concentration.
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Time of Maximum Observed Serum Concentration (Tmax) of EV68-228-N in Serum
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. Tmax is defined at the time of at which Cmax occurs. Because non-steady state data was collected, the entire curve was considered. If the maximum observed concentration was not unique, then the first maximum was used.
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Apparent Terminal Elimination Half-life (t1/2) of EV68-228-N in Serum
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. t1/2 is defined as the time it takes serum concentrations to reduce by 50% during the terminal elimination phase and was estimated by the natural logarithm of 2 (ln(2)) divided by the elimination rate constant (lambda-z).
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Total Clearance (CL) of EV68-228-N in Serum
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. CL is defined as the total clearance and represents a volume that is cleared of the molecule of interest per hour. It was calculated as the dose divided by the area under the concentration-time curve from time 0 (time of infusion start, t=0 hours) to infinity (AUC0-infinity).
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Volume of Distribution (Vz) of EV68-228-N in Serum During the Terminal Phase
PK parameters were estimated from the EV68-228-N serum concentration-time data using Phoenix WinNonlin Non-compartmental analysis. Vz is defined as the theoretical volume that the total amount of the molecule of interest would occupy if uniformly distributed at the concentration observed in serum. If the terminal phase was adequately captured, this value should approximate the volume of distribution at steady state and was calculated as the total clearance (CL) divided by elimination rate constant (lambda-z).
Time frame: Prior to infusion; end of infusion; 1, 3, 5, 24, and 48 hours after end of infusion; Days 8, 15, 29, 61, 91, and 121
Number of Participants With Detectable Anti-EV68-228-N Antibodies in Serum
Anti-EV68-228-N antibodies were assessed utilizing a Meso Scale Discovery (MSD) Electrochemiluminescent (ECL) assay. Detectable anti-EV68-228-N is defined as having a positive screening MSD ECL assay result AND a positive confirmatory MSD ECL assay result.
Time frame: Day 1 (pre-dose), Days 8, 15, 29, 61, 91, and 121
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