Respiratory Syncytial Virus Infection
Conditions
Keywords
Respiratory Syncytial Virus (RSV), Antiviral, Hematopoietic Cell Transplant (HCT), Lower respiratory tract infection
Brief summary
The primary objective of this study is to evaluate the effect of presatovir on respiratory syncytial virus (RSV) viral load in autologous or allogeneic hematopoietic cell transplant (HCT) recipients with an acute RSV lower respiratory tract infection (LRTI).
Interventions
DRUGPresatovir
Presatovir 200 mg (4 × 50 mg tablets) administered orally or via nasogastric (NG) tube
DRUGPlacebo
Placebo to match presatovir administered orally or via nasogastric tube
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Received an autologous or allogeneic HCT using any conditioning regimen * Evidence of new abnormalities on chest X-ray obtained \< 48 hours prior to screening, determined to be consistent with LRTI by the local radiologist, relative to the most recent previous chest X-ray. If chest X-ray is not available, a chest X-ray must be obtained for screening. * Documented RSV in both the upper (eg, nasal swab, nasopharyngeal swab, nasal wash) and lower (eg, induced sputum, bronchoalveolar lavage, lung biopsy, but not spontaneous sputum) respiratory tract as determined by local testing (eg, polymerase chain reaction, direct fluorescence antibody, respiratory viral panel assay, or culture). All samples must have been collected ≤ 6 days prior to Day 1, or as determined at screening as per protocol. * An informed consent document signed and dated by the participant or a legal guardian of the participant and investigator or his/her designee. * A negative urine or serum pregnancy test is required for female participants (unless surgically sterile or greater than two years post-menopausal) * Male and female participants of childbearing potential must agree to contraceptive requirements as described in the study protocol * Willingness to complete necessary study procedures and have available a working telephone or email Key
Exclusion criteria
Related to concomitant or previous medication use: * Use of non-marketed (according to region) investigational agents within 30 days, OR use of any monoclonal anti-RSV antibodies within 4 months or 5 half-lives of screening, whichever is longer, OR use of any investigational RSV vaccines after HCT * Use of a moderate or strong cytochrome P450 enzyme 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 study drug Related to medical history: * Pregnant, breastfeeding, or lactating females * Unable to tolerate nasal sampling required for this study, as determined by the investigator * Known history of HIV/AIDS with a CD4 count \<200 cells/μL within the last month * History of drug and/or alcohol abuse that, in the opinion of the investigator, may prevent adherence to study activities Related to medical conditions: * Requiring invasive mechanical ventilation at the time of randomization * Documented to be positive for other respiratory viruses (limited to influenza, parainfluenza, human rhinovirus, adenovirus, human metapneumovirus, or coronavirus), from the lower respiratory tract sample as determined by local testing * Clinically significant bacteremia or fungemia within 7 days prior to screening that has not been adequately treated, as determined by the investigator * Clinically significant bacterial, fungal, or viral pneumonia within 2 weeks prior to screening that has not been adequately treated, as determined by the investigator * Excessive nausea/vomiting at screening, as determined by the investigator, or an inability to swallow pills that precludes oral administration of the investigational medical product (for individuals without an NG tube in place) * Any condition which, in the opinion of the investigator, would prevent full participation in this trial or would interfere with the evaluation of the trial endpoints Related to laboratory results: * Creatinine clearance \< 30 mL/min (calculated using the Cockcroft-Gault method) * Clinically significant aspartate aminotransferase/alanine aminotransferase, as determined by the investigator * Clinically significant total bilirubin, as determined by the investigator Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9 | Baseline to Day 9 | 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 factors. |
Secondary
| Measure | Time frame |
|---|---|
| Number of Supplemental O2-Free Days Through Day 28 | Up to Day 28 |
| Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28 | Up to Day 28 |
| Percentage of All-Cause Mortality Among Participants Through Day 28 | Up to Day 28 |
Countries
France, South Korea, Sweden, Switzerland, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in Asia Pacific, Europe, and the United States. The first participant was screened on 31 January 2015. The last study visit occurred on 17 April 2017.
Pre-assignment details
71 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Presatovir Presatovir 200 mg (4 x 50 mg tablets) on Days 1, 5, 9, 13, and 17 administered orally or via nasogastric tube | 30 |
| Placebo Placebo tablets on Days 1, 5, 9, 13, and 17 administered orally or via nasogastric tube | 29 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Randomized but Not Treated | 1 | 0 |
| Overall Study | Withdrew Consent | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo | Presatovir | Total |
|---|---|---|---|
| Age, Continuous | 54.4 years STANDARD_DEVIATION 12.59 | 50.5 years STANDARD_DEVIATION 16.27 | 52.4 years STANDARD_DEVIATION 14.58 |
| Nasal Viral Load | 6.02 log10 copies/mL STANDARD_DEVIATION 1.574 | 6.22 log10 copies/mL STANDARD_DEVIATION 1.365 | 6.12 log10 copies/mL STANDARD_DEVIATION 1.462 |
| Oxygen Saturation | 93 percent saturation STANDARD_DEVIATION 5.1 | 94 percent saturation STANDARD_DEVIATION 3.8 | 93 percent saturation STANDARD_DEVIATION 4.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 18 Participants | 23 Participants | 41 Participants |
| Race/Ethnicity, Customized Not Permitted | 5 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 18 Participants | 23 Participants | 41 Participants |
| Region of Enrollment France | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment South Korea | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Sweden | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Switzerland | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United States | 20 Participants | 27 Participants | 47 Participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 15 Participants |
| Sex: Female, Male Male | 23 Participants | 21 Participants | 44 Participants |
| Stratification Factor: Supplemental O2 Requirement at Time of Randomization Supplemental O2 Requirement ≤ 2 L/min | 19 Participants | 19 Participants | 38 Participants |
| Stratification Factor: Supplemental O2 Requirement at Time of Randomization Supplemental O2 Requirement > 2 L/min | 10 Participants | 11 Participants | 21 Participants |
| Stratification Factor: Treatment of Current RSV Infection with Ribavirin No | 18 Participants | 18 Participants | 36 Participants |
| Stratification Factor: Treatment of Current RSV Infection with Ribavirin Yes | 11 Participants | 12 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 4 / 29 |
| other Total, other adverse events | 19 / 30 | 17 / 29 |
| serious Total, serious adverse events | 7 / 30 | 7 / 29 |
Outcome results
Primary
Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9
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 factors.
Time frame: Baseline to Day 9
Population: Full Analysis Set: all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9 | -1.00 log10 copies/mL | Standard Error 0.215 |
| Placebo | Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9 | -0.97 log10 copies/mL | Standard Error 0.218 |
p-value: 0.9495% CI: [-0.62, 0.57]ANCOVA
Secondary
Number of Supplemental O2-Free Days Through Day 28
Time frame: Up to Day 28
Population: Full Analysis Set: all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Presatovir | Number of Supplemental O2-Free Days Through Day 28 | 26 days |
| Placebo | Number of Supplemental O2-Free Days Through Day 28 | 28 days |
p-value: 0.84Negative binomial
Secondary
Percentage of All-Cause Mortality Among Participants Through Day 28
Time frame: Up to Day 28
Population: Full Analysis Set: all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Presatovir | Percentage of All-Cause Mortality Among Participants Through Day 28 | 0.0 percentage of participants |
| Placebo | Percentage of All-Cause Mortality Among Participants Through Day 28 | 7.1 percentage of participants |
p-value: 0.19Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28
Time frame: Up to Day 28
Population: Full Analysis Set: all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Presatovir | Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28 | 10.3 percentage of participants |
| Placebo | Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28 | 10.7 percentage of participants |
p-value: 0.98Cochran-Mantel-Haenszel