Respiratory Syncytial Virus
Conditions
Keywords
Respiratory Syncytial Virus (RSV), Antiviral, Hematopoietic Cell Transplant (HCT), Upper 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 upper respiratory tract infection (URTI), the effect of presatovir on development of lower respiratory tract complication, being free of any supplemental oxygen progression to respiratory failure, and pharmacokinetics (PK), safety, and tolerability of presatovir.
Interventions
DRUGPresatovir
Presatovir 200 mg (4 × 50 mg tablets) administered orally or via nasogastric (NG) tube
DRUGPlacebo
Tablets 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
* Received an autologous or allogeneic HCT using any conditioning regimen * Documented to be RSV-positive as determined by local testing (eg, polymerase chain reaction, direct fluorescence antibody, respiratory viral panel assay, or culture) using an upper respiratory tract sample collected ≤ 6 days prior to Day 1 * New onset of at least 1 of the following respiratory symptoms for ≤ 7 days prior to Day 1: nasal congestion, runny nose, cough, or sore throat, or worsening of one of these chronic (associated with a previously existing diagnosis, eg, chronic rhinorrhea, seasonal allergies, chronic lung disease) respiratory symptoms ≤ 7 days prior to Day 1 * No evidence of new abnormalities consistent with lower respiratory tract infection (LRTI) on a chest X-ray relative to the most recent chest X-ray, as determined by the local radiologist. If a chest X-ray is not available or was not obtained during standard care \< 48 hours prior to screening, a chest X-ray must be obtained for screening * O2 saturation ≥ 92% on room air * An informed consent document signed and dated by the participant or a legal guardian of the participant and the 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
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 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 condition at screening: * Documented to be positive for other respiratory viruses (limited to influenza, parainfluenza, human rhinovirus, adenovirus, or human metapneumovirus, or coronavirus) within 7 days prior to the screening visit, as determined by local testing (additional testing is not required) * 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 participants without an nasogastric 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time-Weighted Average Change in Nasal Respiratory Syncytial Virus (RSV ) Viral Load From Baseline (Day 1) to Day 9 | Baseline; 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 factor. |
| Percentage of Participants Who Developed a Lower Respiratory Tract Complication | Up to Day 28 | A Lower Respiratory Tract Complication (LRTC) was defined as one of the below as determined by the adjudication committee: * Primary RSV lower respiratory tract infection (LRTI) * Secondary bacterial LRTI * LRTI due to unusual pathogens * Lower respiratory tract complication of unknown etiology |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Developed Respiratory Failure (of Any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) or All-cause Mortality | Up to Day 28 | Participants were considered to have an event if either condition is met: * Participant develops a respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) or; * Participant dies prior to or on Day 28 |
Countries
Australia, Brazil, Canada, France, Germany, Israel, Netherlands, Singapore, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study centers in North America, Europe, Australia and Asia. The first participant was screened on 23 January 2015 and the last study visit occurred on 14 July 2017.
Pre-assignment details
213 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Presatovir Presatovir 200 mg (4 x 50 mg tablets) administered as a single dose, orally or via NG tube on Days 1, 5, 9, 13, and 17 | 95 |
| Placebo Placebo administered orally or via NG tube on Days 1, 5, 9, 13, and 17 | 90 |
| Total | 185 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 2 | 3 |
| Overall Study | Investigator's Discretion | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Randomized But Not Treated | 1 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Presatovir | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 52.1 years STANDARD_DEVIATION 12.21 | 51.4 years STANDARD_DEVIATION 14.58 | 51.8 years STANDARD_DEVIATION 13.39 |
| Nasal Viral Load | 6.31 log10 copies/mL STANDARD_DEVIATION 1.899 | 6.51 log10 copies/mL STANDARD_DEVIATION 1.437 | 6.41 log10 copies/mL STANDARD_DEVIATION 1.691 |
| Race/Ethnicity, Customized Asian | 13 Participants | 9 Participants | 22 Participants |
| Race/Ethnicity, Customized Black or African American | 6 Participants | 3 Participants | 9 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 Participants | 6 Participants | 14 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 81 Participants | 75 Participants | 156 Participants |
| Race/Ethnicity, Customized Not Permitted | 6 Participants | 8 Participants | 15 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 66 Participants | 70 Participants | 136 Participants |
| Region of Enrollment Australia | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Canada | 3 participants | 5 participants | 8 participants |
| Region of Enrollment France | 7 participants | 10 participants | 18 participants |
| Region of Enrollment Israel | 10 participants | 11 participants | 21 participants |
| Region of Enrollment Singapore | 3 participants | 2 participants | 5 participants |
| Region of Enrollment South Korea | 5 participants | 1 participants | 6 participants |
| Region of Enrollment Switzerland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 3 participants | 2 participants | 5 participants |
| Region of Enrollment United States | 58 participants | 55 participants | 116 participants |
| Sex: Female, Male Female | 40 Participants | 35 Participants | 75 Participants |
| Sex: Female, Male Male | 55 Participants | 55 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 95 | 4 / 90 |
| other Total, other adverse events | 49 / 95 | 47 / 90 |
| serious Total, serious adverse events | 18 / 95 | 23 / 90 |
Outcome results
Primary
Percentage of Participants Who Developed a Lower Respiratory Tract Complication
A Lower Respiratory Tract Complication (LRTC) was defined as one of the below as determined by the adjudication committee: * Primary RSV lower respiratory tract infection (LRTI) * Secondary bacterial LRTI * LRTI due to unusual pathogens * Lower respiratory tract complication of unknown etiology
Time frame: Up to Day 28
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Presatovir | Percentage of Participants Who Developed a Lower Respiratory Tract Complication | 11.2 percentage of participants |
| Placebo | Percentage of Participants Who Developed a Lower Respiratory Tract Complication | 19.5 percentage of participants |
p-value: 0.1195% CI: [0.22, 1.18]Cochran-Mantel-Haenszel
p-value: 0.15Fisher Exact
Primary
Time-Weighted Average Change in Nasal Respiratory Syncytial Virus (RSV ) Viral Load From Baseline (Day 1) 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 factor.
Time frame: Baseline; Day 9
Population: Full Analysis Set: 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 quantitative real-time polymerase chain reaction (RT-qPCR) assay in the Day 1 nasal sample, as determined by RT-qPCR.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Presatovir | Time-Weighted Average Change in Nasal Respiratory Syncytial Virus (RSV ) Viral Load From Baseline (Day 1) to Day 9 | -1.26 log10 copies/mL | Standard Deviation 0.964 |
| Placebo | Time-Weighted Average Change in Nasal Respiratory Syncytial Virus (RSV ) Viral Load From Baseline (Day 1) to Day 9 | -0.91 log10 copies/mL | Standard Deviation 1.145 |
p-value: 0.0495% CI: [-0.64, -0.02]ANCOVA
Secondary
Percentage of Participants Who Developed Respiratory Failure (of Any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) or All-cause Mortality
Participants were considered to have an event if either condition is met: * Participant develops a respiratory failure (of any cause) requiring mechanical ventilation (invasive or noninvasive) or; * Participant dies prior to or on Day 28
Time frame: Up to Day 28
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Presatovir | Percentage of Participants Who Developed Respiratory Failure (of Any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) or All-cause Mortality | 5.6 percentage of participants |
| Placebo | Percentage of Participants Who Developed Respiratory Failure (of Any Cause) Requiring Mechanical Ventilation (Invasive or Noninvasive) or All-cause Mortality | 5.7 percentage of participants |
p-value: 0.9895% CI: [0.28, 3.63]Cochran-Mantel-Haenszel
p-value: 1Fisher Exact