Study of Efficacy and Safety of IV VIS410 Plus Oseltamivir Versus Oseltamivir in Hospitalized Adults With Influenza A

Phase 2

Completed

Conditions: Influenza A

Interventions: Drug: Low dose of VIS410
Drug: High dose of VIS410
Drug: Placebo

Registration Number: NCT03040141

Lead Sponsor: Visterra, Inc.

Brief Summary: This study is to compare the efficacy and safety of VIS410 in combination with oseltamivir vs oseltamivir alone in severely ill subjects with influenza A infection requiring oxygen support.

Detailed Description: This study is to compare the efficacy and safety of VIS410 in combination with oseltamivir vs oseltamivir alone in severely ill subjects with influenza A infection requiring oxygen support. Subjects will be followed for 56 days.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 89

Inclusion Criteria

Male and female subjects aged ≥ 18 years.
Test positive for influenza A by rapid antigen test or with another commercially available test on an adequate nasopharyngeal specimen in accordance with the manufacturer's instructions, or an acceptable local test, including PCR (Polymerase chain reaction), FIA (Fluorescent immunoassay), or ELISA
Onset of influenza symptoms no more than 5 days before VIS410/placebo infusion; symptoms may include cough, dyspnea, sore throat, fever, myalgias, headache, nasal symptoms (rhinorrhea, congestion), fatigue, diarrhea, anorexia, nausea, and vomiting.
Requirement for oxygen support including any positive pressure ventilation
Women of childbearing potential must have a negative pregnancy test within 2 days prior to VIS410/placebo infusion.
Women should fulfill one of the following criteria:
- Post-menopausal; either amenorrhea ≥ 12 months or follicle stimulating hormone > 40 mIU/mL as documented in their medical history
- Surgically sterile; hysterectomy, bilateral oophorectomy, or tubal ligation
- Women of childbearing potential participating in heterosexual sexual relations must be willing to use adequate contraception from screening until 60 days post VIS410/placebo infusion.
Non-vasectomized (or vasectomized less than 6 months prior to dosing) male subjects who have a female partner of childbearing potential must use an effective birth control method from screening until 60 days post VIS410/placebo infusion.
Subject, or a legally acceptable representative (LAR), is able to understand the purpose and risks of the study and willing to give voluntary written informed consent.

Exclusion Criteria

Known or suspected intolerance or hypersensitivity to VIS410, oseltamivir, pretreatment medications (diphenhydramine, or to both ibuprofen and acetylsalicylic acid [ASA]), or closely related compounds (eg, other monoclonal antibodies)
Subjects who have received VIS410 in the past
History of receiving monoclonal antibody products (including VIS410) within 3 months prior to VIS410/placebo dosing or planned administration during the study period
Subjects who have taken more than 6 doses of an approved antiviral therapy for influenza within the prior 96 hours (eg, oral oseltamivir, inhaled zanamivir, IV peramivir, or oral ribavirin) between onset of symptoms and VIS410/placebo dosing
Subjects with known co-infection with influenza B or other viral respiratory infections (e.g., respiratory syncytial virus, parainfluenza viruses, respiratory adenoviruses)
Subjects with lung transplant or history of severe chronic lung disease, including cystic fibrosis or any condition requiring home oxygen therapy
Subjects on extracorporeal membrane oxygenation (ECMO) at time of randomization
Subjects with end stage renal disease who are not undergoing hemodialysis
Subjects with active graft-vs-host disease, hematopoietic stem cell transplant within the previous 90 days, or human immunodeficiency virus infection with a CD4 cell count of less than 200 per cubic millimeter
Hospitalization for > 48 hours prior to randomization
High probability of mortality within 48 hours of randomization as determined by the Investigator
Subjects weighing less than 45 kg
Enrollment in any other investigational drug or device study, any disease or vaccine study within 30 days prior to Day 1 or within 5 half-lives of the investigational compound, whichever is longer
Known or suspected alcohol or drug abuse, that is, abuse of a level that would compromise the safety or cooperation of the subject in the opinion of the Investigator

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
VIS410 low dose	Low dose of VIS410	Single intravenous infusion of fixed low dose of VIS410 in addition to oseltamivir
VIS410 high dose	High dose of VIS410	Single intravenous infusion of fixed high dose of VIS410 in addition to oseltamivir
Placebo	Placebo	Single intravenous infusion of placebo in addition to oseltamivir

Primary Outcome Measures

Name	Time	Method
The Number of Participants With Adverse Events and Serious Adverse Events Following Administration of VIS410	56 days	Safety and tolerability of 2 dose levels of a single intravenous (IV) dose of VIS410 when administered in combination with oseltamivir in hospitalized participants with influenza A infection. Data presents the count of participants who experienced an adverse event (AE) or serious treatment emergent adverse events (TEAE).
Clinical Status of Participants on Day 7	7 days	Evaluate the effect of 2 dose levels of VIS410 + oseltamivir on clinical status using a seven-level ordinal scale. Comparison between treatment groups and between all VIS410 recipients versus placebo were assessed.

Secondary Outcome Measures

Name	Time	Method
Number of Participants in Whom Peak Viral Load Occurred Post Baseline Measured by qRT-PCR	14 days	Number of participants in whom peak viral load is observed post-baseline based on quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Post-baseline was considered the day 3 sample or later.
Peak Viral Load by TCID50	Day 7	Peak viral load based on TCID50 from nasopharyngeal swabs
Time to Cessation of Oxygen Support Compared to Oseltamivir Alone Among Patients Requiring Supplemental Oxygen Therapy With Baseline Room Air <= 92%	Baseline to Day 56	Time to cessation of O2 support in patients with supplemental oxygen with baseline room air \<= 92%. Patients with treatment resulting in a stable SpO2 by pulse oximetry. Stable SpO2 is defined as two consecutive SpO2 values of \>92% on room air that are at least 8 hours apart.
Time to Cessation of Oxygen Support for Any Patient Requiring Supplemental Oxygen Therapy	Baseline to Day 56	Time to cessation of oxygen support in all patients with supplemental oxygen (regardless of oxygen saturation).
Number of Participants in Whom Peak Viral Load Occurred Post Baseline Measured by TCID50	56 days	Number of participants in whom peak viral load occurred post-baseline measured by TCID50. Post-baseline was considered the day 3 sample or later.
Viral Titer in Upper Respiratory Samples by qRT-PCR	Day 14	The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in peak viral load by qRT-PCR from nasopharyngeal swabs through Day 14
Viral Nasopharyngeal AUC	Day 1 Predose, Day 1 End of Infusion, Day 3, Day 5	The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in nasopharyngeal qRT-PCR area under the viral load-time curve (AUC) from baseline to Day 5.
Area Under the Viral Load-Time Curve (VL AUC) Based on qRT-PCR From Nasopharyngeal Swabs Through Day 7	Day 1 Predose, Day 1 End of Infusion, Day 3, Day 5, Day 7	The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in nasopharyngeal qRT-PCR area under the viral load-time curve (AUC) from baseline to Day 7.
Area Under the Viral Load-Time Curve (VL AUC) Based on qRT-PCR From Nasopharyngeal Swabs Through Day 14	Day 1 Predose, Day 1 End of Infusion, Day 3, Day 5, Day 7, Day 14	The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in nasopharyngeal qRT-PCR area under the viral load-time curve (AUC) from baseline to Day 14.
Viral Nasopharyngeal AUC by TCID50	7 days	The area under the viral load-time curve (AUC) for VIS410 + oseltamivir and oseltamivir alone treatment groups from baseline to Day 7 measured by TCID50 from nasopharyngeal swabs.
Comparison of Clinical Status on Seven-level Ordinal Scale Scores	Day 14	Summary of Clinical Outcome on Seven-Level Ordinal Scale through Day 14. Worst post-baseline assessment observed. Seven-Level Ordinal Scale is a hierarchical scale with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order with 7=death, 6=Intensive care unit (ICU) stay with mechanical ventilation , 5=ICU stay without mechanical ventilation, 4=Non-ICU hospitalization with supplemental oxygen, 3=Non-ICU hospitalization without supplemental oxygen, 2=Discharge with partial resumption of normal activities, 1=Discharge with full resumption of normal activities.
All Cause and Attributable Mortality at Day 14	Day 14	Number of patients experiencing all-cause and attributable mortality rates at Day 14. Attributable mortality was derived from the Complication of Influenza eCRF; all-cause mortality was derived from Complication of Influenza, Seven-Level Ordinal Scale, AE and Study Completion eCRFs
Median Time to Resolution of Viral Load by Treatment Arm by qRT-PCR - From End of Infusion	14 days	Number of days from the end of infusion until virus is no longer detectable (at or below the limit of detection) with no samples following that are greater than the BLQ through the Day 14 (quantitative reverse-transcription polymerase chain reaction - qRT-PCR)
Negative Viral Cultures by Study Day	Nominal days 3, 5, 7	Number of participants negative for viral titer by study day determined by TCID50 on nominal days 3, 5, 7
Time to Complete Clinical Response (Resolution of All Vital Signs)	Day 56	Median time to clinical response defined by resolution of at all 5 vital signs: * Afebrile with core temperature ≤ 37.8°C, without use of antipyretics (oral ≤ 37.2°C) * Oxygen saturation ≥ 95% on room air without support or a return to pre-infection status, if pre-infection status was \< 95% * Pulse rate ≤ 100/min * Systolic blood pressure ≥ 90 mm/Hg, without vasopressor use * Respiratory rate ≤ 24 beats per minute
Total Number of Days on Ventilation	56 days	Total number of days on ventilation for participants who used ventilation, including participants on ventilation at baseline
Comparison of Ordinal Scale Parameters - Days in ICU	56 days	Total number of days in intensive care for participants who admitted to ICU, including participants in ICU at baseline. Better and worse outcome groups defined based on the Seven-Level Ordinal Scale scores, "\<= 4 Seven-Level Ordinal Scale Score" is better; "\> 4 Seven-Level Ordinal Scale Score" is worse group. Seven-Level Ordinal Scale is a hierarchical scale with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order with 7=death, 6=Intensive care unit (ICU) stay with mechanical ventilation , 5=ICU stay without mechanical ventilation, 4=Non-ICU hospitalization with supplemental oxygen, 3=Non-ICU hospitalization without supplemental oxygen, 2=Discharge with partial resumption of normal activities, 1=Discharge with full resumption of normal activities.
Median Time to Resolution of Viral Load by Treatment Arm by TCID50 - From End of Infusion	7 Days	Number of days from the end of infusion until virus is no longer detectable (at or below the limit of detection) with no samples following that are greater than the BLQ through the Day 7 (TCID50)
Time to Clinical Response (4 Out of 5 Vital Signs)	Day 56	Median time to clinical response defined by resolution of at least 4 of 5 vital signs: * Afebrile with core temperature ≤ 37.8°C, without use of antipyretics (oral ≤ 37.2°C) * Oxygen saturation ≥ 95% on room air without support or a return to preinfection status, if pre-infection status was \< 95% * Pulse rate ≤ 100/min * Systolic blood pressure ≥ 90 mm/Hg, without vasopressor use * Respiratory rate ≤ 24 beats per minute
Comparison of Ordinal Scale Parameters - Days on Ventilation	56 days	Total number of days on ventilation for participations who used ventilation, including participants on ventilation at baseline. Better and worse outcome groups defined based on the Seven-Level Ordinal Scale scores, "\<= 4 Seven-Level Ordinal Scale Score" is better; "\> 4 Seven-Level Ordinal Scale Score" is worse group. Seven-Level Ordinal Scale is a hierarchical scale with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order with 7=death, 6=Intensive care unit (ICU) stay with mechanical ventilation , 5=ICU stay without mechanical ventilation, 4=Non-ICU hospitalization with supplemental oxygen, 3=Non-ICU hospitalization without supplemental oxygen, 2=Discharge with partial resumption of normal activities, 1=Discharge with full resumption of normal activities.
Number of Participants With Influenza-related Complications	Day 56	Summary of influenza symptom complications, including baseline and incident complications
The Maximum Concentration (Cmax) of VIS410 in Participant's Serum	Baseline, end of infusion, Day 5, Day 14, Day 28, Day 56	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by maximum concentration (Cmax) of VIS410 in participant's serum.
The Clearance Rate (Cl) of VIS410 in Participant's Serum	PK samples were collected on days 1, 5, 14, 28 and 56.	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by the clearance rate (Cl) of VIS410 in participant's serum.
Anti-VIS410 Antibody Testing	From anti-VIS410 antibody samples collected on days 28 and 56.	Summary of the maximum fold increase for anti-VIS410 antibody testing for VIS410 groups and placebo.
Median Time to Resolution of Viral Load by Treatment Arm by TCID50 - From Onset of Symptoms	7 Days	Number of days from the onset of symptoms until virus is no longer detectable (at or below the limit of detection) with no samples following that are greater than the BLQ through the Day 7 (TCID50)
Clinical Status Ordinal Scale Mean Area Under the Curve Through Day 7	Baseline to Day 7	Summary of area under the curve (AUC) over time for seven-level ordinal scale. Area under the curve (AUC) is calculated using the linear trapezoidal rule. Seven-Level Ordinal Scale is a hierarchical scale with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order with 7=death, 6=Intensive care unit (ICU) stay with mechanical ventilation , 5=ICU stay without mechanical ventilation, 4=Non-ICU hospitalization with supplemental oxygen, 3=Non-ICU hospitalization without supplemental oxygen, 2=Discharge with partial resumption of normal activities, 1=Discharge with full resumption of normal activities. Time frame is from baseline to day 7. Therefore, maximum and minimum values possible for the AUC Clinical Status Ordinal Scale scores range from 7 to 49.
Total Number of Days in ICU	56 days	Total number of days in intensive care (ICU) for participants who admitted to the ICU, including participants in ICU at baseline
Number of Days to Resumption of Usual Activities	Day 56	Number of days until resumption of usual activities by treatment group
Healthcare Resource Utilization. Days in Hospital and/or ICU	Day 56	Total number of days in hospital and/or ICU from admission to discharge
Number of Participants With Rehospitalization Due to Relapse	Day 56	Number of participants with rehospitalization due to influenza A relapse
The Half-life of VIS410 in Participant's Serum	PK samples were collected on days 1, 5, 14, 28 and 56.	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by the half-life (t1/2) of VIS410 in participant's serum.
Clinical Status Ordinal Scale Mean Area Under the Curve Through Day 14.	Baseline to Days 14	Summary of area under the curve (AUC) over time for seven-level ordinal scale. Area under the curve (AUC) is calculated using the linear trapezoidal rule. Seven-Level Ordinal Scale is a hierarchical scale with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order with 7=death, 6=Intensive care unit (ICU) stay with mechanical ventilation , 5=ICU stay without mechanical ventilation, 4=Non-ICU hospitalization with supplemental oxygen, 3=Non-ICU hospitalization without supplemental oxygen, 2=Discharge with partial resumption of normal activities, 1=Discharge with full resumption of normal activities. Time frame is from baseline to day 14. Therefore, maximum and minimum values possible for the AUC Clinical Status Ordinal Scale scores range from 14 to 98.
All Cause and Attributable Mortality by Day 28	Day 28	Number of patients experiencing all-cause and attributable mortality by Day 28. Attributable mortality was derived from the Complication of Influenza eCRF; all-cause mortality was derived from Complication of Influenza, Seven-Level Ordinal Scale, AE and Study Completion eCRFs
All Cause and Attributable Mortality Day 56	Day 56	Number of patients experiencing all-cause and attributable mortality by Day 56. Attributable mortality was derived from the Complication of Influenza eCRF; all-cause mortality was derived from Complication of Influenza, Seven-Level Ordinal Scale, AE and Study Completion eCRFs
Comparison of Ordinal Scale Parameters - Days in Hospital/ICU	56 days	Total number of days in hospital or intensive care for participations who were admitted to Hospital/ICU, including participants in Hospital/ICU at baseline. Better and worse outcome groups defined based on the Seven-Level Ordinal Scale scores, "\<= 4 Seven-Level Ordinal Scale Score" is better; "\> 4 Seven-Level Ordinal Scale Score" is worse group. Seven-Level Ordinal Scale is a hierarchical scale with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order with 7=death, 6=Intensive care unit (ICU) stay with mechanical ventilation , 5=ICU stay without mechanical ventilation, 4=Non-ICU hospitalization with supplemental oxygen, 3=Non-ICU hospitalization without supplemental oxygen, 2=Discharge with partial resumption of normal activities, 1=Discharge with full resumption of normal activities.
The Area Under the Concentration/Time Curve of VIS410 in Participant's Serum	Baseline, end of infusion, Day 5, Day 14, Day 28, Day 56	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by the area under the concentration/time curve from 0 to infinity (AUC0-inf) of VIS410 in participant's serum.