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

Influenza A Clinical Trial

Official title:

Phase 2b, Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of IV VIS410 in Addition to Oseltamivir Compared With Oseltamivir Alone in Hospitalized Adults With Influenza A Infection Requiring Oxygen Support

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03040141
• Other study ID #: VIS410-203
• Status: Completed
• Phase: Phase 2
• Start date: January 3, 2018
• Est. completion date: November 22, 2018

Study information

• Verified date: December 2022
• Source: Visterra, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 89
• Est. completion date: November 22, 2018
• Est. primary completion date: November 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Influenza A
• Influenza, Human

Intervention

Drug:
• Low dose of VIS410
Single intravenous infusion of fixed low dose of VIS410 in addition to oseltamivir
• High dose of VIS410
Single intravenous infusion of fixed high dose of VIS410 in addition to oseltamivir
• Placebo
Single intravenous infusion of placebo in addition to oseltamivir

Locations

Country	Name	City	State
Australia	Visterra	Adelaide	South Australia
Australia	Visterra	Melbourne
Australia	Visterra	Parkville
Australia	Visterra	South Brisbane
Australia	Visterra	Westmead
Australia	Visterra	Woolloongabba
Belarus	Visterra	Brest
Belarus	Visterra	Gomel
Belarus	Visterra	Gomel
Belarus	Visterra	Grodno
Belarus	Visterra	Grodno
Belarus	Visterra	Lesnoy
Belarus	Visterra	Minsk
Belarus	Visterra	Vitebsk
Belgium	Visterra	Brussels
Belgium	Visterra	Edegem
Bulgaria	Visterra	Kozloduy
Bulgaria	Visterra	Montana
Bulgaria	Visterra	Plovdiv
Bulgaria	Visterra	Sofia
Bulgaria	Visterra	Sofia
Bulgaria	Visterra	Sofia
Bulgaria	Visterra	Veliko Tarnovo
Canada	Visterra	Moncton	New Brunswick
Estonia	Visterra	Pärnu
Estonia	Visterra	Tallinn
Estonia	Visterra	Tallinn
Estonia	Visterra	Tallinn
Estonia	Visterra	Tartu
France	Visterra	La Roche-sur-Yon
France	Visterra	La Tronche
France	Visterra	Limoges
France	Visterra	Metz-Tessy
France	Visterra	Nantes
France	Visterra	Paris
France	Visterra	Paris
France	Visterra	Quimper
Georgia	Visterra	Tbilisi
Georgia	Visterra	Tbilisi
Georgia	Visterra	Tbilisi
Latvia	Visterra	Daugavpils
Latvia	Visterra	Liepaja
Latvia	Visterra	Rezekne
Latvia	Visterra	Riga
Latvia	Visterra	Valmiera
Latvia	Visterra	Ventspils
Malaysia	Visterra	Alor Setar	Kedah
Malaysia	Visterra	Kuala Lumpur	Wilayah Persekutuan
Malaysia	Visterra	Taiping	Perak
New Zealand	Visterra	Auckland
New Zealand	Visterra	Auckland
New Zealand	Visterra	Wellington
Russian Federation	Visterra	Arkhangel'sk
Russian Federation	Visterra	Kazan
Russian Federation	Visterra	Novosibirsk
Russian Federation	Visterra	Smolensk
Russian Federation	Visterra	Tomsk
Russian Federation	Visterra	Vladimir
Serbia	Visterra	Kragujevac
Serbia	Visterra	Niš
Serbia	Visterra	Novi Sad
Singapore	Visterra	Singapore
Singapore	Visterra	Singapore
South Africa	Visterra	Auckland Park	Gauteng
South Africa	Visterra	Benoni
South Africa	Visterra	Cape Town
South Africa	Visterra	Durban
South Africa	Visterra	Lyttelton	Centurion
South Africa	Visterra	Pretoria	Gauteng
South Africa	Visterra	Thabazimbi	Limpopo
South Africa	Visterra	Worcester
Spain	Visterra	Alicante
Spain	Visterra	Badalona
Spain	Visterra	Barakaldo
Spain	Visterra	Barcelona
Spain	Visterra	Córdoba
Spain	Visterra	Granada
Spain	Visterra	Madrid
Spain	Visterra	Madrid
Spain	Visterra	Terrassa
Thailand	Visterra	Bangkok
Thailand	Visterra	Khon Kaen
Thailand	Visterra	Mueang Nonthaburi
Turkey	Visterra	Ankara
Turkey	Visterra	Istanbul
Turkey	Visterra	Trabzon
Ukraine	Visterra	Ivano-Frankivs'k
Ukraine	Visterra	Kyiv
Ukraine	Visterra	Kyiv
Ukraine	Visterra	Odesa
Ukraine	Visterra	Poltava
Ukraine	Visterra	Sumy
Ukraine	Visterra	Zhytomyr
United States	Visterra	Albany	New York
United States	Visterra	Allentown	Pennsylvania
United States	Visterra	Atlanta	Georgia
United States	Visterra	Blackfoot	Idaho
United States	Visterra	Butte	Montana
United States	Visterra	Chicago	Illinois
United States	Visterra	Cleveland	Ohio
United States	Visterra	Columbus	Ohio
United States	Visterra	Decatur	Georgia
United States	Visterra	Detroit	Michigan
United States	Visterra	Durham	North Carolina
United States	Visterra	Greensboro	North Carolina
United States	Visterra	Philadelphia	Pennsylvania
United States	Visterra	Richland	Washington
United States	Visterra	Roanoke	Virginia
United States	Visterra	Saint Petersburg	Florida
United States	Visterra	Stanford	California
United States	Visterra	Syracuse	New York
United States	Visterra	Tacoma	Washington
United States	Visterra	Tucson	Arizona
United States	Visterra	York	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Visterra, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belarus,  Belgium,  Bulgaria,  Canada,  Estonia,  France,  Georgia,  Latvia,  Malaysia,  New Zealand,  Russian Federation,  Serbia,  Singapore,  South Africa,  Spain,  Thailand,  Turkey,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Status of Participants on Day 7	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.	7 days
Primary	The Number of Participants With Adverse Events and Serious Adverse Events Following Administration of VIS410	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).	56 days
Secondary	Time to Cessation of Oxygen Support Compared to Oseltamivir Alone Among Patients Requiring Supplemental Oxygen Therapy With Baseline Room Air <= 92%	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.	Baseline to Day 56
Secondary	Time to Cessation of Oxygen Support for Any Patient Requiring Supplemental Oxygen Therapy	Time to cessation of oxygen support in all patients with supplemental oxygen (regardless of oxygen saturation).	Baseline to Day 56
Secondary	Viral Titer in Upper Respiratory Samples by qRT-PCR	The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in peak viral load by qRT-PCR from nasopharyngeal swabs through Day 14	Day 14
Secondary	Viral Nasopharyngeal AUC	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.	Day 1 Predose, Day 1 End of Infusion, Day 3, Day 5
Secondary	Area Under the Viral Load-Time Curve (VL AUC) Based on qRT-PCR From Nasopharyngeal Swabs Through 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.	Day 1 Predose, Day 1 End of Infusion, Day 3, Day 5, Day 7
Secondary	Area Under the Viral Load-Time Curve (VL AUC) Based on qRT-PCR From Nasopharyngeal Swabs Through 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.	Day 1 Predose, Day 1 End of Infusion, Day 3, Day 5, Day 7, Day 14
Secondary	Median Time to Resolution of Viral Load by Treatment Arm by qRT-PCR - From End of Infusion	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)	14 days
Secondary	Number of Participants in Whom Peak Viral Load Occurred Post Baseline Measured by qRT-PCR	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.	14 days
Secondary	Peak Viral Load by TCID50	Peak viral load based on TCID50 from nasopharyngeal swabs	Day 7
Secondary	Number of Participants in Whom Peak Viral Load Occurred Post Baseline Measured by TCID50	Number of participants in whom peak viral load occurred post-baseline measured by TCID50. Post-baseline was considered the day 3 sample or later.	56 days
Secondary	Viral Nasopharyngeal AUC by TCID50	The area under the viral load-time curve (AUC) for VIS410 + oseltamivir and oseltamivir alone treatment groups from baseline to Day 5 measured by TCID50 from nasopharyngeal swabs.	5 days
Secondary	Viral Nasopharyngeal AUC by TCID50	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.	7 days
Secondary	Negative Viral Cultures by Study Day	Number of participants negative for viral titer by study day determined by TCID50 on nominal days 3, 5, 7	Nominal days 3, 5, 7
Secondary	Median Time to Resolution of Viral Load by Treatment Arm by TCID50 - From End of Infusion	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)	7 Days
Secondary	Median Time to Resolution of Viral Load by Treatment Arm by TCID50 - From Onset of Symptoms	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)	7 Days
Secondary	Time to Clinical Response (4 Out of 5 Vital Signs)	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	Day 56
Secondary	Time to Complete Clinical Response (Resolution of All Vital Signs)	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	Day 56
Secondary	Clinical Status Ordinal Scale Mean Area Under the Curve Through 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.	Baseline to Day 7
Secondary	Clinical Status Ordinal Scale Mean Area Under the Curve Through Day 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.	Baseline to Days 14
Secondary	Comparison of Clinical Status on Seven-level Ordinal Scale Scores	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.	Day 14
Secondary	Total Number of Days on Ventilation	Total number of days on ventilation for participants who used ventilation, including participants on ventilation at baseline	56 days
Secondary	Comparison of Ordinal Scale Parameters - Days on Ventilation	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.	56 days
Secondary	Total Number of Days in ICU	Total number of days in intensive care (ICU) for participants who admitted to the ICU, including participants in ICU at baseline	56 days
Secondary	Comparison of Ordinal Scale Parameters - Days in ICU	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.	56 days
Secondary	Number of Days to Resumption of Usual Activities	Number of days until resumption of usual activities by treatment group	Day 56
Secondary	All Cause and Attributable Mortality at 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	Day 14
Secondary	All Cause and Attributable Mortality by 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	Day 28
Secondary	All Cause and Attributable Mortality 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	Day 56
Secondary	Healthcare Resource Utilization. Days in Hospital and/or ICU	Total number of days in hospital and/or ICU from admission to discharge	Day 56
Secondary	Comparison of Ordinal Scale Parameters - Days in Hospital/ICU	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.	56 days
Secondary	Number of Participants With Rehospitalization Due to Relapse	Number of participants with rehospitalization due to influenza A relapse	Day 56
Secondary	Number of Participants With Influenza-related Complications	Summary of influenza symptom complications, including baseline and incident complications	Day 56
Secondary	The Maximum Concentration (Cmax) of VIS410 in Participant's Serum	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by maximum concentration (Cmax) of VIS410 in participant's serum.	Baseline, end of infusion, Day 5, Day 14, Day 28, Day 56
Secondary	The Area Under the Concentration/Time Curve of VIS410 in Participant's Serum	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.	Baseline, end of infusion, Day 5, Day 14, Day 28, Day 56
Secondary	The Clearance Rate (Cl) of VIS410 in Participant's Serum	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by the clearance rate (Cl) of VIS410 in participant's serum.	PK samples were collected on days 1, 5, 14, 28 and 56.
Secondary	The Half-life of VIS410 in Participant's Serum	Summary of Serum VIS410 Pharmacokinetic Parameters in PK Population by the half-life (t1/2) of VIS410 in participant's serum.	PK samples were collected on days 1, 5, 14, 28 and 56.
Secondary	Anti-VIS410 Antibody Testing	Summary of the maximum fold increase for anti-VIS410 antibody testing for VIS410 groups and placebo.	From anti-VIS410 antibody samples collected on days 28 and 56.