Respiratory Syncytial Virus Infection
Conditions
Brief summary
The primary objective of this study is to evaluate the effects of presatovir on respiratory syncytial virus (RSV) viral load in RSV-positive adults who have been hospitalized with acute respiratory infectious symptoms. Participants will receive 1 dose of presatovir on Day 1 and followed for 27 days postdose. Nasal swabs will be collected at each study visit (excluding Day 28) and assayed for change in viral load as the primary endpoint.
Interventions
DRUGPresatovir
Presatovir 200 mg (4 x 50 mg tablets) administered orally
DRUGPresatovir placebo
Presatovir placebo tablets administered orally
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Current inpatient * New onset of acute respiratory infectious symptoms, or acute worsening of chronic symptoms related to ongoing respiratory disease for ≤ 5 days prior to screening: * Upper respiratory tract symptoms: nasal congestion, runny nose, sore throat, or earache * Lower respiratory tract symptoms: cough, sputum production, wheezing, dyspnea, or chest tightness * Documented to be RSV-positive at the current admission within 72 hours of screening, or as evaluated at screening Key
Exclusion criteria
* Related to concomitant or previous medication use: * Use of oral prednisone or other corticosteroid equivalent to: * \> 20 mg/day for \> 14 days prior to screening is not permitted. * \> 20 mg/day for ≤ 14 days, including corticosteroids received during current hospitalization (ie, bolus doses), is permitted. * ≤ 20 mg/day, regardless of duration, is permitted. * Individuals taking a moderate or strong cytochrome P450 enzyme (CYP) inducer including but not limited to rifampin, St John's Wort, carbamazepine, phenytoin, efavirenz, bosentan, etracirine, modafinil, and nafcillin within 2 weeks prior to the first dose of study drug * Related to medical history: * Pregnant, breastfeeding, or lactating females * Individuals requiring \> 50% supplemental oxygen (while the individual is awake) at screening * Individuals with a Clinical Frailty Scale (CFS) \> 7 at Baseline * Known significant abnormality altering the anatomy of the nose or nasopharynx that in, the opinion of the investigator, will preclude obtaining adequate nasal swab sampling in either nasal passage * Waiting for or recently (within the past 12 months) received a bone marrow, stem cell, or solid organ transplant, or who have received radiation or chemotherapy within 12 months prior to Screening * Individuals with HIV/AIDS and a known CD4 count \< 200 cells/uL * History of severe dementia or Alzheimer's disease * History of drug and/or alcohol abuse that, in the opinion of the investigator, may prevent adherence to study activities * Related to medical condition at screening: * Influenza-positive as determined by local diagnostic test * Known Middle East Respiratory Syndrome coronavirus (MERS-CoV) infection or known coinfection with other coronavirus * Use of mechanical ventilation during the current admission, not including noninvasive ventilation * Clinically significant bacteremia or fungemia that has not been adequately treated prior to Screening, as determined by the investigator * Inadequate treatment of confirmed bacterial, fungal, or non-RSV pneumonia, as determined by the investigator * Excessive nausea/vomiting at admission, as determined by the investigator, that precludes administration of an orally administered study drug * Related to allergies: * Known allergy to components of the study drug (microcrystalline cellulose, mannitol, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol and talc) * Documented history of acute (anaphylaxis) or delayed (Stevens-Johnson syndrome or epidermal necrolysis) allergy to sulfa drugs Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change in Respiratory Syncytial Viral (RSV) Load From Baseline to Day 5 | Baseline to Day 5 | The time-weighted average change, often referred to as the DAVG, provides the average viral burden change from baseline. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-weighted Average Change in the Flu-PRO Score From Baseline to Day 5 | Baseline to Day 5 | The Flu-PRO is a patient-reported outcome questionnaire utilized as a standardized method for evaluating symptoms of influenza. Flu-PRO Score was calculated as the mean of 38 individual scores. Individual scores ranged from 0 (no symptoms) to 4 (worst symptoms). The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor. |
| Number of Hospitalization-Free Days Following Presatovir Administration | Up to Day 28 | — |
| Rate of Unplanned Medical Encounters | Up to Day 28 | The adjusted rate of unplanned medical encounters (clinic visits, emergency room visits, urgent care visits, and rehospitalizations) related to a respiratory illness after initial hospital discharge through Day 28 will be assessed. Event rate was calculated as the total number of unplanned medical encounters divided by the total number of participants. The mean values presented were adjusted for stratification factor. |
Countries
Australia, Belgium, France, Israel, Italy, Netherlands, New Zealand, Poland, South Korea, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Australia, Europe, Asia, New Zealand, and the United States. The first participant was screened on 09 June 2014. The last study visit occurred on 12 April 2017.
Pre-assignment details
833 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Presatovir Single dose of presatovir 200 mg (4 x 50 mg tablets) | 92 |
| Placebo Single dose of placebo tablets | 94 |
| Total | 186 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Investigator's Discretion | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Randomized but Not Treated | 2 | 1 |
| Overall Study | Withdrew Consent | 2 | 2 |
Baseline characteristics
| Characteristic | Presatovir | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 69.4 years STANDARD_DEVIATION 14.24 | 65.9 years STANDARD_DEVIATION 13.87 | 67.6 years STANDARD_DEVIATION 14.13 |
| Duration of Hospitalization Prior to First Dose | 2.9 days STANDARD_DEVIATION 3.14 | 3.2 days STANDARD_DEVIATION 7.13 | 3.0 days STANDARD_DEVIATION 5.52 |
| Flu-PRO score | 1.11 units on a scale STANDARD_DEVIATION 0.553 | 1.04 units on a scale STANDARD_DEVIATION 0.566 | 1.07 units on a scale STANDARD_DEVIATION 0.559 |
| Nasal Viral Load | 5.58 log10 copies/mL STANDARD_DEVIATION 2.104 | 5.07 log10 copies/mL STANDARD_DEVIATION 2.528 | 5.32 log10 copies/mL STANDARD_DEVIATION 2.337 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 11 Participants | 17 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 85 Participants | 91 Participants | 176 Participants |
| Race/Ethnicity, Customized Not Permitted | 7 Participants | 2 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 72 Participants | 69 Participants | 141 Participants |
| Region of Enrollment Australia | 10 Participants | 5 Participants | 15 Participants |
| Region of Enrollment Belgium | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment France | 18 Participants | 17 Participants | 35 Participants |
| Region of Enrollment Israel | 32 Participants | 26 Participants | 58 Participants |
| Region of Enrollment Italy | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Netherlands | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment New Zealand | 9 Participants | 9 Participants | 18 Participants |
| Region of Enrollment Poland | 1 Participants | 5 Participants | 6 Participants |
| Region of Enrollment South Korea | 5 Participants | 11 Participants | 16 Participants |
| Region of Enrollment United Kingdom | 1 Participants | 4 Participants | 5 Participants |
| Region of Enrollment United States | 15 Participants | 14 Participants | 29 Participants |
| Sex: Female, Male Female | 50 Participants | 52 Participants | 102 Participants |
| Sex: Female, Male Male | 42 Participants | 42 Participants | 84 Participants |
| Stratification Factor: Disease Status Asthma | 22 Participants | 22 Participants | 44 Participants |
| Stratification Factor: Disease Status Chronic Obstructive Pulmonary Disease | 27 Participants | 30 Participants | 57 Participants |
| Stratification Factor: Disease Status No Chronic Airways or Lung Disease | 31 Participants | 31 Participants | 62 Participants |
| Stratification Factor: Disease Status Other Chronic Airways or Lung Disease | 12 Participants | 11 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 92 | 0 / 94 |
| other Total, other adverse events | 34 / 92 | 31 / 94 |
| serious Total, serious adverse events | 8 / 92 | 13 / 94 |
Outcome results
Primary
Time-Weighted Average Change in Respiratory Syncytial Viral (RSV) Load From Baseline to Day 5
The time-weighted average change, often referred to as the DAVG, provides the average viral burden change from baseline. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor.
Time frame: Baseline to Day 5
Population: Evaluable Analysis Set: all randomized participants who received at least 1 dose of study medication, had an RSV viral load greater than lower limit of quantification (LLOQ) of the RT-qPCR assay in the Day 1 nasal-swab sample, and had a minimum of 3 quantifiable samples (including baseline) within a 5 day period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-Weighted Average Change in Respiratory Syncytial Viral (RSV) Load From Baseline to Day 5 | -0.77 log10 copies/mL | Standard Error 0.113 |
| Placebo | Time-Weighted Average Change in Respiratory Syncytial Viral (RSV) Load From Baseline to Day 5 | -0.89 log10 copies/mL | Standard Error 0.118 |
p-value: 0.4695% CI: [-0.2, 0.43]ANCOVA
Secondary
Number of Hospitalization-Free Days Following Presatovir Administration
Time frame: Up to Day 28
Population: Evaluable Analysis Set: all randomized participants who received at least 1 dose of study medication, had an RSV viral load greater than lower limit of quantification (LLOQ) of the RT-qPCR assay in the Day 1 nasal-swab sample, and had a minimum of 3 quantifiable samples (including baseline) within a 5 day period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Presatovir | Number of Hospitalization-Free Days Following Presatovir Administration | 25 days |
| Placebo | Number of Hospitalization-Free Days Following Presatovir Administration | 25 days |
p-value: 0.39Negative Binomial Model
Secondary
Rate of Unplanned Medical Encounters
The adjusted rate of unplanned medical encounters (clinic visits, emergency room visits, urgent care visits, and rehospitalizations) related to a respiratory illness after initial hospital discharge through Day 28 will be assessed. Event rate was calculated as the total number of unplanned medical encounters divided by the total number of participants. The mean values presented were adjusted for stratification factor.
Time frame: Up to Day 28
Population: Evaluable Analysis Set: all randomized participants who received at least 1 dose of study medication, had an RSV viral load greater than lower limit of quantification (LLOQ) of the RT-qPCR assay in the Day 1 nasal-swab sample, and had a minimum of 3 quantifiable samples (including baseline) within a 5 day period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Presatovir | Rate of Unplanned Medical Encounters | 0.226 encounters per participant |
| Placebo | Rate of Unplanned Medical Encounters | 0.066 encounters per participant |
p-value: 0.004Negative Binomial Model
Secondary
Time-weighted Average Change in the Flu-PRO Score From Baseline to Day 5
The Flu-PRO is a patient-reported outcome questionnaire utilized as a standardized method for evaluating symptoms of influenza. Flu-PRO Score was calculated as the mean of 38 individual scores. Individual scores ranged from 0 (no symptoms) to 4 (worst symptoms). The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor.
Time frame: Baseline to Day 5
Population: Participants in the Evaluable Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-weighted Average Change in the Flu-PRO Score From Baseline to Day 5 | -0.27 units on a scale | Standard Error 0.029 |
| Placebo | Time-weighted Average Change in the Flu-PRO Score From Baseline to Day 5 | -0.35 units on a scale | Standard Error 0.03 |
p-value: 0.04695% CI: [0, 0.16]ANCOVA