Respiratory Syncytial Virus (RSV)
Conditions
Keywords
Respiratory Syncytial Virus (RSV), Antiviral, Lung Transplant
Brief summary
The primary objective of this study is to evaluate the effect of presatovir on nasal respiratory syncytial virus (RSV) viral load in RSV-positive lung transplant (LT) recipients with acute respiratory symptoms.
Interventions
DRUGPresatovir
Tablets administered orally or via nasogastric (NG) tube once daily
DRUGPlacebo
Tablets administered orally or via NG tube once daily
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: * Males and females ≥18 years of age who have received a LT (single or double) or heart/lung transplant \> 90 days prior to Screening * Confirmed to be RSV-positive by local polymerase chain reaction (PCR) testing (starting from when the upper or lower respiratory tract sample is obtained) ≤ 7 days prior to investigational medicinal product (IMP) administration on Day 1/Baseline * New onset or acute worsening, if the symptom is chronic, of at least 1 of the following respiratory symptoms ≤ 7 days prior to IMP administration on Day 1/Baseline: nasal congestion, earache, runny nose, cough, sore throat, shortness of breath, or wheezing * A negative local urine or serum pregnancy test for female subjects of childbearing potential at Screening, within 1 day prior to IMP administration. When available, existing local pregnancy test results obtained prior to Screening may be used, provided the testing was completed within 1 day prior to IMP administration * Agreement from male and female subjects of childbearing potential who engage in heterosexual intercourse to use protocol specified method(s) of contraception Key
Exclusion criteria
Related to concomitant or previous medication use: * Use of any non-marketed (according to region) investigational agents within 30 days, OR use of any investigational monoclonal anti-RSV antibodies within 4 months or 5 half-lives of Screening, whichever is longer, OR use of any prior investigational RSV vaccines * Use of a strong or moderate cytochrome P450 enzyme (CYP) inducer including but not limited to rifampin, St. John's Wort, carbamazepine, phenytoin, efavirenz, bosentan, etravirine, modafinil, and nafcillin, within 2 weeks prior to the first dose of IMP Related to transplant history: • Recipient of any other organ transplant prior to Screening, with the exception of a LT (single or double) or heart/lung transplant Related to medical condition at Screening: * Known viral coinfection (including but not limited to influenza, metapneumovirus, human rhinovirus, parainfluenza, cytomegalovirus, or coronavirus) in the upper or lower respiratory tract ≤ 14 days prior to Screening unless discussed with the medical monitor and deemed acceptable * Active systemic infection or infectious pneumonia of any etiology (ie, bacterial, viral \[other than RSV\] or fungal), including aspiration pneumonia, that is considered clinically significant by the investigator unless discussed with the medical monitor and deemed acceptable Related to laboratory values: * Clinically significant kidney dysfunction as defined by: An estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease (MDRD) study 4 parameter equation obtained from screening laboratory measurements or via local laboratory measurements obtained ≤ 7 days prior to Screening. The eGFR may be manually calculated or the reported eGFR value may be used, but any automatically calculated eGFR must be calculated using the MDRD equation. * Clinically significant liver function test abnormalities as defined by an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 5 times the upper limit of normal (ULN) obtained in screening laboratory measurements or via local laboratory measurements obtained ≤ 7 days prior to Screening * Clinically significant elevations in total bilirubin (TB), as determined by the investigator Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in Participants in the Full Analysis Set | Up to 7 days |
| Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in a Subset of Participants in the Full Analysis Set Whose Duration of RSV Symptoms Prior to the First Dose of Study Drug is ≤ Median | Up to 7 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change in FLU-PRO Score From Day 1/Baseline Through Day 7 | Up to 7 days | 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) for the 5-point severity scale and 0 (never) to 4 or more times (always) for the 5-point frequency scale. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor. |
| Percent Change From Study Baseline in FEV1% Predicted Value | Baseline; Day 28 | FEV1 is defined as forced expiratory volume in the first second. |
Countries
Australia, Belgium, Canada, France, Germany, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at sites in Europe, North America, and Australia.The first participant was screened on 31 December 2015 and the last study visit occurred on 27 September 2017.
Pre-assignment details
111 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Presatovir 200 mg (4 x 50 mg) on Day1/Baseline followed by 100 mg (2 x 50 mg) on Days 2 through 14 administered orally or via NG tube once daily | 40 |
| Placebo Tablets administered orally or via NG tube once daily for 14 days | 20 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Randomized But Not Treated | 1 | 0 |
| Overall Study | Withdrew Consent | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Presatovir |
|---|---|---|---|
| Age, Continuous | 55.1 years STANDARD_DEVIATION 14.23 | 56.0 years STANDARD_DEVIATION 13.02 | 56.4 years STANDARD_DEVIATION 12.54 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 55 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| inFLUenza Patient-Reported Outcome (FLU-PRO) Score | 2.11 units on a scale STANDARD_DEVIATION 0.684 | 2.07 units on a scale STANDARD_DEVIATION 0.628 | 2.05 units on a scale STANDARD_DEVIATION 0.607 |
| Nasal Viral Load | 6.59 log10 copies/mL STANDARD_DEVIATION 2.092 | 6.13 log10 copies/mL STANDARD_DEVIATION 2.098 | 5.88 log10 copies/mL STANDARD_DEVIATION 2.088 |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Permitted | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 16 Participants | 52 Participants | 36 Participants |
| Region of Enrollment Australia | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Belgium | 2 Participants | 4 Participants | 2 Participants |
| Region of Enrollment Canada | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment France | 0 Participants | 2 Participants | 2 Participants |
| Region of Enrollment Germany | 4 Participants | 11 Participants | 7 Participants |
| Region of Enrollment Netherlands | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 12 Participants | 37 Participants | 25 Participants |
| Sex: Female, Male Female | 10 Participants | 29 Participants | 19 Participants |
| Sex: Female, Male Male | 10 Participants | 31 Participants | 21 Participants |
| The Forced Expiratory Volume in One Second (FEV1) % Predicted | 61.95 percent FEV1 STANDARD_DEVIATION 18.625 | 63.10 percent FEV1 STANDARD_DEVIATION 22.834 | 63.64 percent FEV1 STANDARD_DEVIATION 24.787 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 20 |
| other Total, other adverse events | 24 / 40 | 17 / 20 |
| serious Total, serious adverse events | 2 / 40 | 4 / 20 |
Outcome results
Primary
Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in a Subset of Participants in the Full Analysis Set Whose Duration of RSV Symptoms Prior to the First Dose of Study Drug is ≤ Median
Time frame: Up to 7 days
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in a Subset of Participants in the Full Analysis Set Whose Duration of RSV Symptoms Prior to the First Dose of Study Drug is ≤ Median | -0.83 log10 copies/mL | Standard Deviation 1.013 |
| Placebo | Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in a Subset of Participants in the Full Analysis Set Whose Duration of RSV Symptoms Prior to the First Dose of Study Drug is ≤ Median | -0.83 log10 copies/mL | Standard Deviation 0.757 |
p-value: 0.7695% CI: [-0.94, 0.69]ANCOVA
Primary
Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in Participants in the Full Analysis Set
Time frame: Up to 7 days
Population: Participants in the Full Analysis Set (participants who received at least 1 full dose of study drug and had an RSV viral load ≥ lower limit of quantification (LLOQ) of the real-time quantitative polymerase chain reaction (RT-qPCR) assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab) with available data were analyzed .
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in Participants in the Full Analysis Set | -0.73 log10 copies/mL | Standard Deviation 0.938 |
| Placebo | Time-Weighted Average Change in Viral Load From Day 1/Baseline Through Day 7 in Participants in the Full Analysis Set | -0.90 log10 copies/mL | Standard Deviation 0.815 |
p-value: 0.7295% CI: [-0.43, 0.63]ANCOVA
Secondary
Percent Change From Study Baseline in FEV1% Predicted Value
FEV1 is defined as forced expiratory volume in the first second.
Time frame: Baseline; Day 28
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Percent Change From Study Baseline in FEV1% Predicted Value | 22.69 percent change | Standard Deviation 27.437 |
| Placebo | Percent Change From Study Baseline in FEV1% Predicted Value | 26.36 percent change | Standard Deviation 23.312 |
p-value: 0.695% CI: [-15.58, 9.08]ANCOVA
Secondary
Time-Weighted Average Change in FLU-PRO Score From Day 1/Baseline Through Day 7
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) for the 5-point severity scale and 0 (never) to 4 or more times (always) for the 5-point frequency scale. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factor.
Time frame: Up to 7 days
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-Weighted Average Change in FLU-PRO Score From Day 1/Baseline Through Day 7 | -0.27 units on a scale | Standard Deviation 0.313 |
| Placebo | Time-Weighted Average Change in FLU-PRO Score From Day 1/Baseline Through Day 7 | -0.31 units on a scale | Standard Deviation 0.298 |
p-value: 0.8695% CI: [-0.12, 0.15]ANCOVA