Study of RV521 in the Treatment of Adult Subjects Who Have Undergone HCT With an URTI With RSV

Study Overview
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Brief Summary
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RV521 is to being developed to treat RSV infection and disease in susceptible individuals at high risk for complications. This is an international, multicenter, placebo-controlled study. Eligible subjects are adults with a documented symptomatic RSV infection who have undergone HCT transplantation and are moderately to severely immunocompromised. Qualified subjects will be randomized in a 1:1 ratio to receive RV521 or placebo, twice daily for 10 days.

Detailed Description
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The purpose of this study is to compare the viral load, safety, tolerability, and clinical efficacy of RV521 compared to placebo. This is a Phase 2, international, multicenter, randomized, double-blind, placebo-controlled study. Up to 200 adult subjects with a documented symptomatic RSV URTI who have undergone HCT within 1 year of randomization and who are moderately to severely immunocompromised will be randomized. Qualified subjects will be randomized in a 1:1 ratio to receive RV521 capsules or matching placebo twice daily for 10 days. After the completion of the 10-day double-blind treatment period, subjects will be followed for an additional 28 days. Study drug may be taken on an outpatient or inpatient basis, depending on clinical status and site practices. Randomization will be stratified by type of HCT graft and ALC count. There are 9 clinic visits planned for this study.

Official Title
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Randomized, Double-blind, Placebo-controlled Trial of the Safety, Tolerability, and Efficacy of RV521 in the Treatment of Adult Subjects Who Have Undergone Hematopoietic Cell Transplantation (HCT) With a Documented Upper Respiratory Tract Infection (URTI) With Respiratory Syncytial Virus (RSV)

Conditions
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RSV Infection, Stem Cell Transplant Complications, Lower Resp Tract Infection

Intervention / Treatment
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* Drug: RV521 oral tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has undergone autologous or allogeneic HCT using any conditioning regimen within 1 year of randomization. Subjects who have undergone HCT more than 1 year before Randomization are eligible if all other inclusion/exclusion criteria are satisfied and under at least one of the following conditions: Diagnosed with Chronic Graft-vs-Host Disease (GVHD), or Has used systemic corticosteroids in the 30 days prior to RSV infection Has moderate to severe immunocompromise, defined as a score ≥ 5 on the ISI-RSV and/or an ALC of ≤ 500 cells/ mm3 Documentation of positive RSV infection in the upper airway Exclusion Criteria: Use of non-marketed investigational agents within 30 days, OR use of an investigational 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. Receiving a prescription, OTC, or herbal medication that is a potent inducer or inhibitor of CYP3A4, within 2 weeks of Randomization. Receiving a prescription, OTC, or herbal medication that is a substrate of CYP3A4 with a narrow therapeutic index where monitoring blood levels is not possible. Known chronic infection with hepatitis B, C, or HIV. Is in the pre-engraftment period during RSV infection. Admitted to the hospital primarily for lower respiratory tract disease of any cause as determined by the Investigator. Any condition requiring mechanical ventilation or vasopressor support at the time of randomization. Clinically significant bacteremia or fungemia within 5 days prior to Screening that has not been adequately treated. Clinically significant bacterial, fungal, or viral pneumonia within 2 weeks prior to Screening that has not been adequately treated. Excessive nausea/vomiting at Screening or an inability to swallow capsules. Elevation of hepatic enzymes or renal compromise.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A Phase 2, international, multicenter, randomized, double-blind, placebo-controlled study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RV521 Capsules<br>RV521 is formulated as a dry powder blend of RV521 drug substance with mannitol as excipient. They are a white, opaque capsule and administered orally. | Drug: RV521 oral tablet<br>* Each RV521 dose is four 50 mg dry powder blend capsules, taken orally twice daily for 10 days (20 doses total; 80 capsules total)<br>* Other names: sisunatovir;|
| Placebo Comparator: RV521 Placebo Capsules<br>RV521 placebo capsules will contain mannitol and microcrystalline cellulose only. They are a white, opaque capsule and administered orally. | Drug: Placebo oral tablet<br>* Each placebo dose is four capsules, taken orally twice daily for 10 days (20 doses total; 80 capsules total)<br>* Other names: vehicle;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with a progression to Lower Respiratory Tract Complication (LRTC) during the study | Progression to LRTC during the study defined as one of the following: Primary LRTI caused by RSV Secondary bacterial LRTI LRTI caused by another pathogen LRTC of unknown etiology | Pre-dose baseline (Day 1) through Visit 8 (Day 28) | 
| Change in RSV nasal viral load (via RT-qPCR) | RSV change measured by the time-weighted average (DAVG) viral load using RT qPCR | Pre-dose baseline (Day 1) through study completion; up to Visit 8 (Day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of participants who experience AEs, TEAEs, SAEs and withdrawals due to TEAEs | Safety analyses will include a summary of AEs, including but not limited to n (%) of subjects in each treatment group and overall. | First dose of study drug through Visit 8 (Day 28) | 
| Evaluate safety and tolerability of RV521 by assessing changes from baseline in systolic and diastolic BP (vital sign parameters) | BP will be collected in mm Hg. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | Baseline through Visit 8 (Day 28) | 
| Evaluate safety and tolerability of RV521 by assessing changes from baseline in body temperature (vital sign parameters) | Body Temperature will be collected in degrees Fahrenheit (°F) or degrees Celsius (°C). Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | Baseline through Visit 8 (Day 28) | 
| Evaluate safety and tolerability of RV521 by assessing changes from baseline in respiration rate (vital sign parameters) | Respiration rate will be measured in breaths per minute. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | Baseline through Visit 8 (Day 28) | 
| Evaluate safety and tolerability of RV521 by assessing changes from baseline in pulse/heart rate (vital sign parameters) | Heart rate will be measured in beats per minute. Quantitative variables will be summarized used the statistics n, mean, standard deviation, median, minimum and maximum. | Baseline through Visit 8 (Day 28) | 
| Evaluate safety and tolerability of RV521 by assessing changes from baseline weight/BMI | Weight and height will be collected and combined to report BMI | Baseline through Visit 8 (Day 28) | 
| Evaluate the proportion of subjects with changes and shifts in hematology/clinical chemistry/urinalysis laboratory values (laboratory tests read by a central lab) from baseline. | Results at each visit will be summarized using the statistics n, mean, standard deviation, median, minimum and maximum. Also, change from baseline will also be summarized by post baseline visits. | Collected at Visit 2/Day 1 (pre-dose), Visit 4/Day 3, Visit 6/Day 14 and Visit 8/Day 28 | 
| Evaluate the proportion of subjects with changes in ECG measurements and changes in clinical impression from baseline | ECGs will be taken with a centrally supplied ECG machine and electronically transmitted to a central ECG repository. ECG will only be evaluated by the Investigator for normal, abnormal NCS and abnormal CS. Parameters collected will be: Ventricular Heart Rate (bpm) PR Interval (msec) QRS Interval (msec) QT Interval (msec) QTcB Interval (msec) Results at each visit will be summarized using the statistics: n (number of observations), mean, SD, median, minimum and maximum. | Measurements will be taken at Day 1/Visit 2 (pre-dose and at 5-hours post-dose), on Day 3/Visit 4 (at 5 hours post-dose), and at Visit 6 (Day 14) | 
| Relationship between plasma exposures of RV521 and RSV viral loads measured in nasal swabs by RT-qPCR | Nasal swabs will be collected for analysis of viral load and RSV F protein gene sequencing at a central laboratory. Viral load will be assessed at intervals from nasal swabs by RT-qPCR. | Pre-dose baseline (Day 1) and every visit through Visit 8 (Day 28) | 
| Relationship between plasma exposures of RV521 and RSV viral loads measured in nasal swabs by CBIA | Nasal swabs will be collected for analysis of viral load and RSV F protein gene sequencing at a central laboratory. Viral load will be assessed at intervals from nasal swabs by CBIA. | Pre-dose baseline (Day 1) and every visit through Visit 8 (Day 28) | 
| Mean change in RSV viral load assessed via CBIA | change measured by the time weighted average (DAVG) viral load using CBIA | Pre-dose baseline (Day 1) through study completion; up to Visit 8 (Day 28) | 
| Mean change from baseline in viral RNA shedding | RSV assessed via nasal swabs collected at each visit and analyzed at a central laboratory. | Pre-dose baseline (Day 1) through study completion; up to Visit 8 (Day 28) | 
| Proportion of subjects who no longer shed RSV assessed by both RT-qPCR and CBIA at each timepoint | RSV assessed via nasal swabs collected at each visit and analyzed at a central laboratory. | Pre-dose baseline (Day 1) through study completion; up to Visit 8 (Day 28) | 
| Time to improvement in RSV-related symptoms | Defined as all symptoms present at initiation of therapy are mild or no longer present. (absent/resolved) | Daily from baseline (Day 1) through Visit 8 (Day 28) | 
| Time to total resolution of all RSV-related symptoms | Defined as all symptoms are no longer present. | Daily from baseline (Day 1) through Visit 8 (Day 28) | 
| Proportion of days with lowest daily SpO2 ≥ 90% on room air | SpO2 measured at every visit. For subjects on oxygen or who are mechanically ventilated may have this waived. | Daily from baseline (Day 1) through Visit 8 (Day 28) | 
| Number of days where supplementary oxygen was required | Use of daily supplementary oxygen will be collected throughout the study. | Baseline (Day 1) through Visit 8 (Day 28) | 
| Proportion of subjects who require hospitalization during the study | Daily hospitalization utilization will be collected | Baseline (Day 1) through Visit 8 (Day 28) | 
| Mean number of days of hospitalization during the study | Daily hospitalization utilization will be collected | Baseline (Day 1) through Visit 8 (Day 28) | 
| Proportion of subjects requiring ICU | Daily ICU utilization will be collected | Baseline (Day 1) through Visit 8 (Day 28) | 
| Mean number of days in ICU | Daily ICU utilization will be collected | Baseline (Day 1) through Visit 8 (Day 28) | 
| Proportion of subjects requiring mechanical ventilation | Daily mechanical ventilation requirements will be collected | Baseline (Day 1) through Visit 8 (Day 28) | 
| Number of subjects who experience death (all-cause mortality) | Patient outcome will be followed and collected | First dose of study drug through Visit 8 (Day 28) | 
| Number of subjects who experience death attributable to LRTC | Patient outcome will be followed and collected | First dose of study drug through Visit 8 (Day 28) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RV521, lower respiratory tract complication, HCT, hematopoietic cell transplantation, LRTI, Respiratory tract infection, immunocompromise