RSV Infection
Conditions
Keywords
challenge study, RSV, antiviral, RSV-A Memphis 37b
Brief summary
A randomized, Phase 2a, double-blind, placebo-controlled study to evaluate the safety, pharmacokinetics and antiviral activity of multiple doses of orally administered EDP-323 in healthy subjects infected with RSV-A Memphis 37b. This study is designed to assess the antiviral effect of EDP-323 compared to a placebo control in the respiratory syncytial virus challenge model.
Interventions
DRUGEDP-323 Dose Regimen 1
EDP-323 capsule
DRUGEDP-323 Dose Regimen 2
EDP-323 capsule
DRUGPlacebo
Placebo capsule
Sponsors
hVIVO Services Limited
Enanta Pharmaceuticals, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* An informed consent document signed and dated by the subject. * Age 18 to 55 years, inclusive. * In good health with no history of major medical conditions. * A total body weight ≥ 50 kg and Body Mass Index (BMI) ≥ 18 kg/m2 and ≤ 35kg/m2.
Exclusion criteria
* Pregnant or nursing females * Acute or chronic medical illness * History of, or currently active, symptoms or signs suggestive of upper or lower respiratory tract (URT or LRT) infection within 4 weeks prior to the first study visit. * Abnormal lung function * Positive for HIV, active hepatitis B or C test * Nose or nasopharynx abnormalities * Receipt of any investigational drug within 3 months prior to the planned date of viral challenge/first dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quantitative Reverse Transcription-polymerase Chain Reaction (qRT-PCR): RSV Area Under the Viral Load-time Curve (VL-AUC) | Day 1 to Day 12 | Measured by qRT-PCR in nasal samples. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | Day 1 to Day 12 | Measured by qRT-PCR in nasal samples. |
| qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | Day 1 to Day 12 | The time from the assessment at the time of the first dose of IMP to qRT-viral load negativity was analyzed using the Kaplan-Meier method. Viral load negativity was reached at the first time when the viral load was undetectable (\< lower limit of detection \[LLOD\]) by qRT-PCR, after which no further detectable assessment appeared. Measured by qRT-PCR in nasal samples. |
| qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | Day 1 to Day 12 | Time to first negative slope = time of the timepoint after which there are two consecutive declines in viral load - time of the nearest viral load assessment to the first dose of IMP. Measured by qRT-PCR in nasal samples. |
| qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 High Dose | Up to Day 16 | Calculated as the slope of the RSV viral load over time from time of RSV VLPEAK to 1, 2, 3, and 4 days later. Estimates for fixed effects of a mixed linear model, modeling the viral load from peak up to the 4 following days, with time from VLPEAK, group and interaction between time and group as fixed effects and a random intercept within each participant. The model was a distinct analysis for the EDP-323 high dose and placebo groups where the estimates for both groups are model-dependent and impacted by the overall model. A negative slope indicated that the viral load decreased over time. Measured by qRT-PCR in nasal samples. |
| qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 Low Dose | Up to Day 16 | Calculated as the slope of the RSV viral load over time from time of RSV VLPEAK to 1, 2, 3, and 4 days later. Estimates for fixed effects of a mixed linear model, modeling the viral load from peak up to the 4 following days, with time from VLPEAK, group and interaction between time and group as fixed effects and a random intercept within each participant. The model was a distinct analysis for the EDP-323 low dose and placebo groups where the estimates for both groups are model-dependent and impacted by the overall model. A negative slope indicated that the viral load decreased over time. Measured by qRT-PCR in nasal samples. |
| Viral Culture: RSV VL-AUC | Day 1 to Day 12 | Measured by viral culture (plaque assay) in nasal samples. |
| Viral Culture: RSV VLPEAK | Day 1 to Day 12 | Measured by viral culture (plaque assay) in nasal samples. |
| Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | Day 1 to Day 12 | Measured by viral culture (plaque assay) in nasal samples. |
| Time to Resolution From Peak TSS | Day 1 to Day 12 | Time to resolution from peak TSS = time of the first 24-hour symptom-free time point - time of peak TSS. An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome. |
| Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | Day 1 to Day 12 | Measured by viral culture (plaque assay) in nasal samples. |
| Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | Day 1 to Day 12 | Measured by viral culture (plaque assay) in nasal samples. |
| Viral Culture: RSV Viral Load Clearance Rate | Up to Day 16 | Calculated as the slope of the RSV viral load over time from time of RSV VLPEAK to 1, 2, 3, and 4 days later. Estimates for fixed effects of a mixed linear model, modeling the viral load from peak up to the 4 following days, with time from VLPEAK, group and interaction between time and group as fixed effects and a random intercept within each participant. A negative slope indicated that the viral load decreased over time. Measured by viral culture in nasal samples. |
| Area Under the Total Symptom Score (TSS)-Time Curve (TSS-AUC) | Day 1 to Day 12 | An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome. The calculation of the TSS-AUC was performed on the TSS measured 3 times a day using the trapezoidal summation rule based on actual time intervals in hours. |
| Peak TSS | Day 1 to Day 12 | Defined as the highest recorded value of TSS. An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome. |
| qRT-PCR: RSV Peak Viral Load (VLPEAK) | Day 1 to Day 12 | Measured by qRT-PCR in nasal samples. |
| Total Weight of Nasal Discharge (Mucus) Produced | Day 1 to Day 12 | Each participant was given pre-weighed packets of paper tissues. Participants were asked to place single tissues used for nose blowing or sneezing into a specified collection bag (for that participant only). |
| Total Number of Tissues Used | Day 1 to Day 12 | Each participant was given pre-weighed packets of paper tissues. Participants were asked to place single tissues used for nose blowing or sneezing into a specified collection bag (for that participant only). |
| Maximum Plasma Concentration (Cmax) | First Dose: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose) and Day 2 pre-dose; Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma pharmacokinetic (PK) parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, below the limit of quantification (BQL) values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Time to Cmax (Tmax) | First Dose: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose) and Day 2 pre-dose; Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Terminal Half-life (t1/2) | Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Apparent Systemic Clearance at Steady-state (CLss/F) | Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Terminal Elimination Rate Constant (λz) | Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Apparent Volume of Distribution at Steady-state (Vss/F) | Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose: Day 1, 12 and 24 hours post-dose; Last Dose: Day 5, 12 and 24 hours post-dose | In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose) and Day 2 pre-dose; Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The AUCs were calculated using linear up/log down method. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose) | Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The AUCs were calculated using linear up/log down method. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table. |
| Number of Participants With Adverse Events (AEs) up to Discharge | Day -2 to Day 12 | An AE was defined as any untoward medical occurrence in clinical study participants administered a pharmaceutical (investigational or non-investigation) product. An AE does not necessarily have a causal relationship with the study intervention. A serious AE (SAE) was defined as any untoward medical occurrence that, at any dose: * Resulted in death * Was life threatening * Required inpatient hospitalization or prolongation of existing hospitalization * Resulted in persistent disability/incapacity * Was a congenital anomaly/birth defect * Was an important medical event |
| Number of Participants With Treatment-emergent Adverse Events | Day 1 to Day 28 | An AE was defined as any untoward medical occurrence in clinical study participants administered a pharmaceutical (investigational or non-investigation) product. An AE does not necessarily have a causal relationship with the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: * Resulted in death * Was life threatening * Required inpatient hospitalization or prolongation of existing hospitalization * Resulted in persistent disability/incapacity * Was a congenital anomaly/birth defect * Was an important medical event |
| Time to Peak TSS | Day 1 to Day 12 | Time to peak TSS = time of peak TSS - time of the nearest TSS assessment to the first dose of IMP. An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome. |
Countries
United Kingdom
Participant flow
Recruitment details
A total of 142 participants were enrolled and inoculated with challenge virus (Respiratory Syncytial Virus \[RSV\]-A Memphis 37b) of which 141 participants were randomized 1:1:1 into one of three treatment groups to receive EDP-323 (at two different doses) or placebo at one site in the United Kingdom between November 2023 and July 2024.
Pre-assignment details
One participant was enrolled and received RSV-A Memphis 37b virus inoculation on Day 0 but was not randomized to receive EDP-323 or matched placebo.
Participants by arm
| Arm | Count |
|---|---|
| EDP-323 High Dose Participants received RSV-A Memphis 37b virus inoculation on Day 0 then orally administered 600 mg EDP-323 QD for 5 days. | 47 |
| EDP-323 Low Dose Participants received RSV-A Memphis 37b virus inoculation on Day 0 then orally administered loading dose 600 mg EDP-323 on Day 1 followed by 200 mg EDP-323 QD for the remaining 4 days. | 47 |
| Placebo Participants received RSV-A Memphis 37b virus inoculation on Day 0 then orally administered matching placebo QD for 5 days. | 47 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | EDP-323 High Dose | EDP-323 Low Dose | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 29.09 years STANDARD_DEVIATION 6.372 | 27.62 years STANDARD_DEVIATION 5.98 | 27.91 years STANDARD_DEVIATION 6.223 | 28.21 years STANDARD_DEVIATION 6.182 |
| Race/Ethnicity, Customized Asian | 2 Participants | 3 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 7 Participants | 5 Participants | 15 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 46 Participants | 45 Participants | 46 Participants | 137 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 2 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized White | 39 Participants | 35 Participants | 38 Participants | 112 Participants |
| Sex: Female, Male Female | 15 Participants | 17 Participants | 19 Participants | 51 Participants |
| Sex: Female, Male Male | 32 Participants | 30 Participants | 28 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 47 | 0 / 47 | 0 / 1 |
| other Total, other adverse events | 13 / 47 | 15 / 47 | 15 / 47 | 0 / 0 |
| serious Total, serious adverse events | 0 / 47 | 0 / 47 | 0 / 47 | 0 / 0 |
Outcome results
Primary
Quantitative Reverse Transcription-polymerase Chain Reaction (qRT-PCR): RSV Area Under the Viral Load-time Curve (VL-AUC)
Measured by qRT-PCR in nasal samples.
Time frame: Day 1 to Day 12
Population: Intent-to-treat infected (ITT-I) Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Quantitative Reverse Transcription-polymerase Chain Reaction (qRT-PCR): RSV Area Under the Viral Load-time Curve (VL-AUC) | 99.05 log10 copies/mL*hours | Standard Deviation 133.325 |
| EDP-323 Low Dose | Quantitative Reverse Transcription-polymerase Chain Reaction (qRT-PCR): RSV Area Under the Viral Load-time Curve (VL-AUC) | 82.28 log10 copies/mL*hours | Standard Deviation 158.033 |
| Placebo | Quantitative Reverse Transcription-polymerase Chain Reaction (qRT-PCR): RSV Area Under the Viral Load-time Curve (VL-AUC) | 657.45 log10 copies/mL*hours | Standard Deviation 396.743 |
Comparison: High Dose versus (vs) Placebop-value: <0.000195% CI: [-680.8, -400.33]ANCOVA
Comparison: Low Dose vs Placebop-value: <0.000195% CI: [-674.46, -371.78]ANCOVA
Comparison: Pooled EDP-323 vs Placebop-value: <0.000195% CI: [-641.71, -430.89]ANCOVA
Secondary
Apparent Systemic Clearance at Steady-state (CLss/F)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint. No participants in the EDP-323 high dose and EDP-323 low dose groups had quantifiable samples for EP-038725 and EP-039082 (BLQ) for the analysis of this PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Apparent Systemic Clearance at Steady-state (CLss/F) | EDP-323 | 32.39 L/h | Standard Deviation 13.648 |
| EDP-323 Low Dose | Apparent Systemic Clearance at Steady-state (CLss/F) | EDP-323 | 24.51 L/h | Standard Deviation 11.383 |
Secondary
Apparent Volume of Distribution at Steady-state (Vss/F)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint. No participants in the EDP-323 high dose and EDP-323 low dose groups had quantifiable samples for EP-038725 and EP-039082 (BLQ) for the analysis of this PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Apparent Volume of Distribution at Steady-state (Vss/F) | EDP-323 | 569.26 liters | Standard Deviation 208.202 |
| EDP-323 Low Dose | Apparent Volume of Distribution at Steady-state (Vss/F) | EDP-323 | 402.73 liters | Standard Deviation 143.305 |
Secondary
Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The AUCs were calculated using linear up/log down method. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: First Dose: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose) and Day 2 pre-dose; Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | Last Dose: EP-039082 | 35.35 h*ng/mL | Standard Deviation 28.171 |
| EDP-323 High Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: EP-039082 | 26.11 h*ng/mL | Standard Deviation 21.928 |
| EDP-323 High Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: EDP-323 | 15626.46 h*ng/mL | Standard Deviation 5982.746 |
| EDP-323 High Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | Last Dose: EDP-323 | 31084.37 h*ng/mL | Standard Deviation 13945.732 |
| EDP-323 High Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: EP-038725 | 7181.42 h*ng/mL | Standard Deviation 3848.438 |
| EDP-323 High Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | Last Dose: EP-038725 | 10814.63 h*ng/mL | Standard Deviation 5619.005 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: EDP-323 | 16703.77 h*ng/mL | Standard Deviation 7268.939 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: EP-038725 | 8319.19 h*ng/mL | Standard Deviation 3563.734 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | Last Dose: EDP-323 | 13816.76 h*ng/mL | Standard Deviation 7801.297 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | First Dose: EP-039082 | 31.34 h*ng/mL | Standard Deviation 28.251 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | Last Dose: EP-039082 | 4.77 h*ng/mL | Standard Deviation 4.119 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-last) | Last Dose: EP-038725 | 3174.73 h*ng/mL | Standard Deviation 1641.754 |
Secondary
Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The AUCs were calculated using linear up/log down method. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: EDP-323 | 21585.30 h*ng/mL | Standard Deviation 7915.479 |
| EDP-323 High Dose | Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: EP-038725 | 8944.82 h*ng/mL | Standard Deviation 4528.012 |
| EDP-323 High Dose | Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: EP-039082 | 48.21 h*ng/mL | Standard Deviation 26.6 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: EP-039082 | 7.31 h*ng/mL | Standard Deviation 10.464 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: EDP-323 | 9653.80 h*ng/mL | Standard Deviation 4245.794 |
| EDP-323 Low Dose | Area Under the Concentration-time Curve Over the Dosing Interval (AUC0-tau) | Last Dose: EP-038725 | 2588.19 h*ng/mL | Standard Deviation 1379.765 |
Secondary
Area Under the Total Symptom Score (TSS)-Time Curve (TSS-AUC)
An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome. The calculation of the TSS-AUC was performed on the TSS measured 3 times a day using the trapezoidal summation rule based on actual time intervals in hours.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Area Under the Total Symptom Score (TSS)-Time Curve (TSS-AUC) | 127.31 score*hours | Standard Deviation 149.221 |
| EDP-323 Low Dose | Area Under the Total Symptom Score (TSS)-Time Curve (TSS-AUC) | 82.67 score*hours | Standard Deviation 100.412 |
| Placebo | Area Under the Total Symptom Score (TSS)-Time Curve (TSS-AUC) | 369.10 score*hours | Standard Deviation 330.397 |
Comparison: High Dose vs Placebop-value: <0.000195% CI: [-404.44, -156.77]ANCOVA
Comparison: Low Dose vs Placebop-value: <0.000195% CI: [-428.53, -173.76]ANCOVA
Secondary
Maximum Plasma Concentration (Cmax)
Plasma pharmacokinetic (PK) parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, below the limit of quantification (BQL) values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: First Dose: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose) and Day 2 pre-dose; Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Maximum Plasma Concentration (Cmax) | First Dose: EP-038725 | 1225.02 ng/mL | Standard Deviation 753.882 |
| EDP-323 High Dose | Maximum Plasma Concentration (Cmax) | Last Dose: EP-039082 | 6.41 ng/mL | Standard Deviation 5.131 |
| EDP-323 High Dose | Maximum Plasma Concentration (Cmax) | Last Dose: EP-038725 | 1294.19 ng/mL | Standard Deviation 772.921 |
| EDP-323 High Dose | Maximum Plasma Concentration (Cmax) | Last Dose: EDP-323 | 1703.09 ng/mL | Standard Deviation 746.73 |
| EDP-323 High Dose | Maximum Plasma Concentration (Cmax) | First Dose: EP-039082 | 5.40 ng/mL | Standard Deviation 5.265 |
| EDP-323 High Dose | Maximum Plasma Concentration (Cmax) | First Dose: EDP-323 | 1358.47 ng/mL | Standard Deviation 590.191 |
| EDP-323 Low Dose | Maximum Plasma Concentration (Cmax) | First Dose: EP-039082 | 6.59 ng/mL | Standard Deviation 4.923 |
| EDP-323 Low Dose | Maximum Plasma Concentration (Cmax) | First Dose: EDP-323 | 1453.70 ng/mL | Standard Deviation 627.552 |
| EDP-323 Low Dose | Maximum Plasma Concentration (Cmax) | Last Dose: EDP-323 | 759.38 ng/mL | Standard Deviation 322.938 |
| EDP-323 Low Dose | Maximum Plasma Concentration (Cmax) | First Dose: EP-038725 | 1501.55 ng/mL | Standard Deviation 776.02 |
| EDP-323 Low Dose | Maximum Plasma Concentration (Cmax) | Last Dose: EP-038725 | 381.94 ng/mL | Standard Deviation 266.839 |
| EDP-323 Low Dose | Maximum Plasma Concentration (Cmax) | Last Dose: EP-039082 | 1.40 ng/mL | Standard Deviation 1.346 |
Secondary
Number of Participants With Adverse Events (AEs) up to Discharge
An AE was defined as any untoward medical occurrence in clinical study participants administered a pharmaceutical (investigational or non-investigation) product. An AE does not necessarily have a causal relationship with the study intervention. A serious AE (SAE) was defined as any untoward medical occurrence that, at any dose: * Resulted in death * Was life threatening * Required inpatient hospitalization or prolongation of existing hospitalization * Resulted in persistent disability/incapacity * Was a congenital anomaly/birth defect * Was an important medical event
Time frame: Day -2 to Day 12
Population: Safety Analysis Set (Treated Participants): All participants having received challenge virus and IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EDP-323 High Dose | Number of Participants With Adverse Events (AEs) up to Discharge | Any SAE | 0 Participants |
| EDP-323 High Dose | Number of Participants With Adverse Events (AEs) up to Discharge | Any AE | 13 Participants |
| EDP-323 Low Dose | Number of Participants With Adverse Events (AEs) up to Discharge | Any AE | 15 Participants |
| EDP-323 Low Dose | Number of Participants With Adverse Events (AEs) up to Discharge | Any SAE | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) up to Discharge | Any AE | 15 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) up to Discharge | Any SAE | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events
An AE was defined as any untoward medical occurrence in clinical study participants administered a pharmaceutical (investigational or non-investigation) product. An AE does not necessarily have a causal relationship with the study intervention. An SAE was defined as any untoward medical occurrence that, at any dose: * Resulted in death * Was life threatening * Required inpatient hospitalization or prolongation of existing hospitalization * Resulted in persistent disability/incapacity * Was a congenital anomaly/birth defect * Was an important medical event
Time frame: Day 1 to Day 28
Population: Safety Analysis Set (Treated Participants): All participants having received challenge virus and IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| EDP-323 High Dose | Number of Participants With Treatment-emergent Adverse Events | Any TEAEs | 11 Participants |
| EDP-323 High Dose | Number of Participants With Treatment-emergent Adverse Events | Any Treatment-emergent SAEs | 0 Participants |
| EDP-323 Low Dose | Number of Participants With Treatment-emergent Adverse Events | Any TEAEs | 14 Participants |
| EDP-323 Low Dose | Number of Participants With Treatment-emergent Adverse Events | Any Treatment-emergent SAEs | 0 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Any TEAEs | 13 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events | Any Treatment-emergent SAEs | 0 Participants |
Secondary
Peak TSS
Defined as the highest recorded value of TSS. An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Peak TSS | 2.65 score on a scale | Standard Deviation 1.765 |
| EDP-323 Low Dose | Peak TSS | 2.35 score on a scale | Standard Deviation 2.673 |
| Placebo | Peak TSS | 5.77 score on a scale | Standard Deviation 4.439 |
Comparison: High Dose vs Placebop-value: <0.000195% CI: [-5.26, -2.02]ANCOVA
Comparison: Low Dose vs Placebop-value: <0.000195% CI: [-5.35, -2.05]ANCOVA
Secondary
Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h)
In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: First Dose: Day 1, 12 and 24 hours post-dose; Last Dose: Day 5, 12 and 24 hours post-dose
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C24h: EDP-323 | 351.45 ng/mL | Standard Deviation 166.086 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C12h: EP-039082 | 1.28 ng/mL | Standard Deviation 0.493 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C24h: EDP-323 | 493.16 ng/mL | Standard Deviation 250.229 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C12h: EP-039082 | 1.60 ng/mL | Standard Deviation 0.739 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C12h: EDP-323 | 711.96 ng/mL | Standard Deviation 265.557 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C12h: EP-038725 | 189.71 ng/mL | Standard Deviation 94.962 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C24h: EP-038725 | 52.47 ng/mL | Standard Deviation 27.362 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C12h: EDP-323 | 935.04 ng/mL | Standard Deviation 318.005 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C24h: EP-039082 | 1.00 ng/mL | Standard Deviation 0 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C12h: EP-038725 | 281.01 ng/mL | Standard Deviation 168.564 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C24h: EP-039082 | 1.04 ng/mL | Standard Deviation 0.166 |
| EDP-323 High Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C24h: EP-038725 | 96.78 ng/mL | Standard Deviation 59.546 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C24h: EP-039082 | 1.00 ng/mL | Standard Deviation 0 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C24h: EDP-323 | 368.54 ng/mL | Standard Deviation 216.14 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C12h: EDP-323 | 423.38 ng/mL | Standard Deviation 203.294 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C12h: EP-038725 | 221.48 ng/mL | Standard Deviation 162.256 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C24h: EP-038725 | 56.57 ng/mL | Standard Deviation 23.845 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C24h: EP-038725 | 30.29 ng/mL | Standard Deviation 14.62 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C24h: EP-039082 | 1.01 ng/mL | Standard Deviation 0.041 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C24h: EDP-323 | 220.69 ng/mL | Standard Deviation 141.715 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C12h: EP-038725 | 78.22 ng/mL | Standard Deviation 39.056 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C12h: EP-039082 | 1.44 ng/mL | Standard Deviation 0.775 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | Last Dose C12h: EP-039082 | 1.00 ng/mL | Standard Deviation 0.014 |
| EDP-323 Low Dose | Plasma Concentration at 12 Hours (C12h) and 24 Hours (C24h) | First Dose C12h: EDP-323 | 756.02 ng/mL | Standard Deviation 345.633 |
Secondary
qRT-PCR: RSV Peak Viral Load (VLPEAK)
Measured by qRT-PCR in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | qRT-PCR: RSV Peak Viral Load (VLPEAK) | 2.52 log10 copies/mL | Standard Deviation 2.173 |
| EDP-323 Low Dose | qRT-PCR: RSV Peak Viral Load (VLPEAK) | 1.99 log10 copies/mL | Standard Deviation 2.711 |
| Placebo | qRT-PCR: RSV Peak Viral Load (VLPEAK) | 6.48 log10 copies/mL | Standard Deviation 2.311 |
Comparison: High Dose vs Placebop-value: <0.000195% CI: [-4.85, -2.81]ANCOVA
Comparison: Low Dose vs Placebop-value: <0.000195% CI: [-5.44, -2.89]ANCOVA
Secondary
qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 High Dose
Calculated as the slope of the RSV viral load over time from time of RSV VLPEAK to 1, 2, 3, and 4 days later. Estimates for fixed effects of a mixed linear model, modeling the viral load from peak up to the 4 following days, with time from VLPEAK, group and interaction between time and group as fixed effects and a random intercept within each participant. The model was a distinct analysis for the EDP-323 high dose and placebo groups where the estimates for both groups are model-dependent and impacted by the overall model. A negative slope indicated that the viral load decreased over time. Measured by qRT-PCR in nasal samples.
Time frame: Up to Day 16
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with at least one detectable viral load during qRT-PCR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EDP-323 High Dose | qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 High Dose | -0.5650 log10 copies/mL/day |
| EDP-323 Low Dose | qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 High Dose | -1.3299 log10 copies/mL/day |
Secondary
qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 Low Dose
Calculated as the slope of the RSV viral load over time from time of RSV VLPEAK to 1, 2, 3, and 4 days later. Estimates for fixed effects of a mixed linear model, modeling the viral load from peak up to the 4 following days, with time from VLPEAK, group and interaction between time and group as fixed effects and a random intercept within each participant. The model was a distinct analysis for the EDP-323 low dose and placebo groups where the estimates for both groups are model-dependent and impacted by the overall model. A negative slope indicated that the viral load decreased over time. Measured by qRT-PCR in nasal samples.
Time frame: Up to Day 16
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with at least one detectable viral load during qRT-PCR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EDP-323 High Dose | qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 Low Dose | -0.5480 log10 copies/mL/day |
| EDP-323 Low Dose | qRT-PCR: RSV Viral Load Clearance Rate - EDP-323 Low Dose | -1.3298 log10 copies/mL/day |
Secondary
qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load
Time to first negative slope = time of the timepoint after which there are two consecutive declines in viral load - time of the nearest viral load assessment to the first dose of IMP. Measured by qRT-PCR in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with at least one detectable viral load during qRT-PCR.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | 0.77 days | Standard Deviation 0.954 |
| EDP-323 Low Dose | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | 1.33 days | Standard Deviation 2.36 |
| Placebo | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | 2.60 days | Standard Deviation 1.632 |
Comparison: High Dose vs Placebo.p-value: 0.002195% CI: [-2.53, -0.61]ANCOVA
Comparison: Lose Dose vs Placebop-value: 0.090595% CI: [-2.35, 0.18]ANCOVA
Secondary
qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity
The time from the assessment at the time of the first dose of IMP to qRT-viral load negativity was analyzed using the Kaplan-Meier method. Viral load negativity was reached at the first time when the viral load was undetectable (\< lower limit of detection \[LLOD\]) by qRT-PCR, after which no further detectable assessment appeared. Measured by qRT-PCR in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with available data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDP-323 High Dose | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | 2.3 days |
| EDP-323 Low Dose | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | 1.5 days |
| Placebo | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | 8.5 days |
Secondary
qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK
Measured by qRT-PCR in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | 2.89 days | Standard Deviation 2.922 |
| EDP-323 Low Dose | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | 3.12 days | Standard Deviation 3.113 |
| Placebo | qRT-PCR: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | 3.12 days | Standard Deviation 1.555 |
Comparison: High Dose vs Placebop-value: 0.63395% CI: [-1.5, 0.92]ANCOVA
Comparison: Lose Dose vs Placebop-value: 0.830995% CI: [-1.46, 1.17]ANCOVA
Secondary
Terminal Elimination Rate Constant (λz)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint. No participants in the EDP-323 low dose group had quantifiable samples for EP-039082 (BLQ) for the analysis of this PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Terminal Elimination Rate Constant (λz) | EDP-323 | 0.06 per hour | Standard Deviation 0.018 |
| EDP-323 High Dose | Terminal Elimination Rate Constant (λz) | EP-038725 | 0.04 per hour | Standard Deviation 0.009 |
| EDP-323 High Dose | Terminal Elimination Rate Constant (λz) | EP-039082 | 0.17 per hour | Standard Deviation 0.061 |
| EDP-323 Low Dose | Terminal Elimination Rate Constant (λz) | EDP-323 | 0.06 per hour | Standard Deviation 0.019 |
| EDP-323 Low Dose | Terminal Elimination Rate Constant (λz) | EP-038725 | 0.04 per hour | Standard Deviation 0.008 |
Secondary
Terminal Half-life (t1/2)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose), Day 2 pre-dose, Day 3 pre-dose, Day 4 pre-dose, Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint. No participants in the EDP-323 low dose group had quantifiable samples for EP-039082 (below limit of quantification \[BLQ\]) for the analysis of this PK parameter.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| EDP-323 High Dose | Terminal Half-life (t1/2) | EP-038725 | 16.56 hours | Standard Deviation 3.049 |
| EDP-323 High Dose | Terminal Half-life (t1/2) | EDP-323 | 13.07 hours | Standard Deviation 4.793 |
| EDP-323 High Dose | Terminal Half-life (t1/2) | EP-039082 | 3.89 hours | Standard Deviation 1.346 |
| EDP-323 Low Dose | Terminal Half-life (t1/2) | EDP-323 | 12.55 hours | Standard Deviation 4.621 |
| EDP-323 Low Dose | Terminal Half-life (t1/2) | EP-038725 | 17.16 hours | Standard Deviation 3.103 |
Secondary
Time to Cmax (Tmax)
Plasma PK parameters for EDP-323 and metabolites (EP-038725 and EP-039082) were estimated using non-compartmental methods. The plasma PK parameters were estimated from the concentration-time profiles. In estimating the PK parameters, BQL values were set to zero. Actual sampling times, rather than scheduled sampling times, were used in all computations involving sampling times. If the actual time or dose time was missing, the scheduled time could be substituted in order to calculate the PK parameter. In case of an actual sampling time deviating by \>20% from the scheduled (nominal) time, this plasma concentration was excluded from descriptive statistics in the plasma concentration-time table.
Time frame: First Dose: Day 1 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, and 15 hours post-dose) and Day 2 pre-dose; Last Dose: Day 5 (pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 24, 30, 36, 48, 60, and 72 hours post-dose)
Population: PK Analysis Set: All ITT analysis set participants with at least one post-dose PK result. Inclusive only of participants with available data for each analyte and timepoint.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| EDP-323 High Dose | Time to Cmax (Tmax) | Last Dose: EDP-323 | 4.82 hours |
| EDP-323 High Dose | Time to Cmax (Tmax) | Last Dose: EP-038725 | 4.92 hours |
| EDP-323 High Dose | Time to Cmax (Tmax) | First Dose: EP-039082 | 3.00 hours |
| EDP-323 High Dose | Time to Cmax (Tmax) | First Dose: EDP-323 | 3.98 hours |
| EDP-323 High Dose | Time to Cmax (Tmax) | First Dose: EP-038725 | 3.97 hours |
| EDP-323 High Dose | Time to Cmax (Tmax) | Last Dose: EP-039082 | 3.82 hours |
| EDP-323 Low Dose | Time to Cmax (Tmax) | Last Dose: EP-038725 | 3.98 hours |
| EDP-323 Low Dose | Time to Cmax (Tmax) | Last Dose: EDP-323 | 4.10 hours |
| EDP-323 Low Dose | Time to Cmax (Tmax) | First Dose: EP-038725 | 3.85 hours |
| EDP-323 Low Dose | Time to Cmax (Tmax) | First Dose: EDP-323 | 3.92 hours |
| EDP-323 Low Dose | Time to Cmax (Tmax) | Last Dose: EP-039082 | 2.00 hours |
| EDP-323 Low Dose | Time to Cmax (Tmax) | First Dose: EP-039082 | 2.97 hours |
Secondary
Time to Peak TSS
Time to peak TSS = time of peak TSS - time of the nearest TSS assessment to the first dose of IMP. An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Time to Peak TSS | 2.00 days | Standard Deviation 2.403 |
| EDP-323 Low Dose | Time to Peak TSS | 2.84 days | Standard Deviation 3.125 |
| Placebo | Time to Peak TSS | 3.36 days | Standard Deviation 2.065 |
Comparison: High Dose vs Placebop-value: 0.055295% CI: [-2.19, 0.03]ANCOVA
Comparison: Low Dose vs Placebop-value: 0.559995% CI: [-1.69, 0.92]ANCOVA
Secondary
Time to Resolution From Peak TSS
Time to resolution from peak TSS = time of the first 24-hour symptom-free time point - time of peak TSS. An individual TSS (10-items) was derived at each assessment of the diary card as the sum of the scores given to the 10 following symptoms on that symptom score card, giving a score between 0 and 3: * Runny nose * Stuffy nose * Sneezing * Sore throat * Earache * Malaise/Tiredness * Headache * Muscle and/or Joint Ache * Cough * Shortness of breath TSS ranged from 0 to 30 with higher TSS indicating a higher disease burden and thus a worse outcome.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive of participants with at least one TSS \>0 only.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Time to Resolution From Peak TSS | 2.16 days | Standard Deviation 1.922 |
| EDP-323 Low Dose | Time to Resolution From Peak TSS | 2.58 days | Standard Deviation 2.415 |
| Placebo | Time to Resolution From Peak TSS | 2.93 days | Standard Deviation 1.789 |
Comparison: High Dose vs Placebop-value: 0.030795% CI: [-1.97, -0.1]ANCOVA
p-value: 0.411995% CI: [-1.81, 0.76]ANCOVA
Secondary
Total Number of Tissues Used
Each participant was given pre-weighed packets of paper tissues. Participants were asked to place single tissues used for nose blowing or sneezing into a specified collection bag (for that participant only).
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Total Number of Tissues Used | 17.62 tissues | Standard Deviation 23.329 |
| EDP-323 Low Dose | Total Number of Tissues Used | 16.22 tissues | Standard Deviation 21.457 |
| Placebo | Total Number of Tissues Used | 28.79 tissues | Standard Deviation 27.58 |
Comparison: High Dose vs Placebop-value: 0.002695% CI: [-30.61, -6.84]ANCOVA
p-value: 0.002295% CI: [-31.3, -7.26]ANCOVA
Secondary
Total Weight of Nasal Discharge (Mucus) Produced
Each participant was given pre-weighed packets of paper tissues. Participants were asked to place single tissues used for nose blowing or sneezing into a specified collection bag (for that participant only).
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Total Weight of Nasal Discharge (Mucus) Produced | 6.12 grams | Standard Deviation 6.564 |
| EDP-323 Low Dose | Total Weight of Nasal Discharge (Mucus) Produced | 9.49 grams | Standard Deviation 20.537 |
| Placebo | Total Weight of Nasal Discharge (Mucus) Produced | 16.44 grams | Standard Deviation 22.152 |
Comparison: High Dose vs Placebop-value: 0.004295% CI: [-22.34, -4.4]ANCOVA
Comparison: Low Dose vs Placebop-value: 0.005895% CI: [-22.38, -4]ANCOVA
Secondary
Viral Culture: RSV Viral Load Clearance Rate
Calculated as the slope of the RSV viral load over time from time of RSV VLPEAK to 1, 2, 3, and 4 days later. Estimates for fixed effects of a mixed linear model, modeling the viral load from peak up to the 4 following days, with time from VLPEAK, group and interaction between time and group as fixed effects and a random intercept within each participant. A negative slope indicated that the viral load decreased over time. Measured by viral culture in nasal samples.
Time frame: Up to Day 16
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with at least one detectable viral load during plaque assay.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| EDP-323 High Dose | Viral Culture: RSV Viral Load Clearance Rate | -0.1336 log10 PFU/mL/day |
| EDP-323 Low Dose | Viral Culture: RSV Viral Load Clearance Rate | -0.2565 log10 PFU/mL/day |
| Placebo | Viral Culture: RSV Viral Load Clearance Rate | -1.1124 log10 PFU/mL/day |
Secondary
Viral Culture: RSV VL-AUC
Measured by viral culture (plaque assay) in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Viral Culture: RSV VL-AUC | 3.82 log10 plaque-forming units (PFU)/mL*h | Standard Deviation 9.333 |
| EDP-323 Low Dose | Viral Culture: RSV VL-AUC | 6.21 log10 plaque-forming units (PFU)/mL*h | Standard Deviation 15.448 |
| Placebo | Viral Culture: RSV VL-AUC | 227.04 log10 plaque-forming units (PFU)/mL*h | Standard Deviation 189.998 |
Comparison: High Dose vs Placebop-value: <0.000195% CI: [-272.18, -135.07]ANCOVA
Comparison: Low Dose vs Placebop-value: <0.000195% CI: [-288.84, -141.22]ANCOVA
Secondary
Viral Culture: RSV VLPEAK
Measured by viral culture (plaque assay) in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Viral Culture: RSV VLPEAK | 0.04 log10 PFU/mL | Standard Deviation 0.198 |
| EDP-323 Low Dose | Viral Culture: RSV VLPEAK | 0.16 log10 PFU/mL | Standard Deviation 0.569 |
| Placebo | Viral Culture: RSV VLPEAK | 3.45 log10 PFU/mL | Standard Deviation 2.191 |
Comparison: High Dose vs Placebop-value: <0.000195% CI: [-4.05, -2.4]ANCOVA
Comparison: Low Dose vs Placebop-value: <0.000195% CI: [-4.11, -2.34]ANCOVA
Secondary
Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load
Measured by viral culture (plaque assay) in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with at least one detectable viral load during plaque assay.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | 0.00 days | Standard Deviation 0 |
| EDP-323 Low Dose | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | 0.00 days | Standard Deviation 0 |
| Placebo | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to First Negative Slope of RSV Viral Load | 2.92 days | Standard Deviation 1.739 |
Comparison: High Dose vs Placebop-value: 0.038995% CI: [-4.23, -0.12]ANCOVA
Comparison: Low Dose vs Placebop-value: 0.271395% CI: [-3.73, 1.1]ANCOVA
Secondary
Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity
Measured by viral culture (plaque assay) in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection. Inclusive only of participants with available data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| EDP-323 High Dose | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | 0.5 days |
| EDP-323 Low Dose | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | 0.5 days |
| Placebo | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV Viral Load Negativity | 4.5 days |
Secondary
Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK
Measured by viral culture (plaque assay) in nasal samples.
Time frame: Day 1 to Day 12
Population: ITT-I Analysis Set: All participants having received challenge virus, randomized, and having received at least one dose of IMP, and meeting the criterion for laboratory-confirmed RSV infection.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| EDP-323 High Dose | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | 5.82 days | Standard Deviation 2.98 |
| EDP-323 Low Dose | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | 5.78 days | Standard Deviation 3.304 |
| Placebo | Viral Culture: Time From the Assessment at the Time of the First Dose of IMP to RSV VLPEAK | 3.95 days | Standard Deviation 2.29 |
Comparison: High Dose vs Placebop-value: 0.023895% CI: [0.2, 2.68]ANCOVA
Comparison: Low Dose vs Placebop-value: 0.013495% CI: [0.36, 2.99]ANCOVA