Clinical trial to compare the benefit and safety of a single infusion of VIS410, the study medicine added to standard Tamiflu® treatment to that of treatment with Tamiflu® alone in hospitalized adults with flu infection requiring oxygen support

• Register: EUCTR
• Last refreshed on: 7 January 2019
• Main ID: EUCTR2016-004009-15-EE
• Date of registration: 02/08/2017
• Prospective Registration: Yes
• Primary sponsor: Visterra, Inc.
• Public title: Clinical trial to compare the benefit and safety of a single infusion of VIS410, the study medicine added to standard Tamiflu® treatment to that of treatment with Tamiflu® alone in hospitalized adults with flu infection requiring oxygen support
• Scientific title: Phase 2b, Multicenter, Randomized, Double-blind, Controlled Study to Evaluate the Efficacy and Safety of Intravenous VIS410 in Addition to Oseltamivir (Tamiflu®) Compared With Oseltamivir Alone in Hospitalized Adults With Influenza A Infection Requiring Oxygen Support
• Date of first enrolment: 26/09/2017
• Target sample size: 120
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004009-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

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

Contacts

• Name: Jose Miguel Trevejo MD, PhD
• Affiliation: Visterra, Inc.

• Name: Jose Miguel Trevejo MD, PhD
• Affiliation: Visterra, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Subjects meeting all of the following criteria are eligible to participate in this study:
1. Male and female subjects aged = 18 years. For a country where the legal age of consent is >18 years old, the country requirements should be followed.
2. 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, FIA, or ELISA
3. 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.
4. Requirement for oxygen support including any positive pressure ventilation (PPV).
5. Women of childbearing potential must have a negative pregnancy test within 2 days prior to VIS410/placebo infusion.
6. Women should fulfill one of the following criteria:
a. Post-menopausal; either amenorrhea = 12 months or follicle stimulating hormone > 40 mIU/mL as documented in their medical history
b. Surgically sterile; hysterectomy, bilateral oophorectomy, or tubal ligation
c. Women of childbearing potential participating in heterosexual relations must be willing to use adequate contraception from screening until 60 days post VIS410/placebo infusion (see Section 6.2).
7. 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 (see Section 6.2) when having heterosexual intercourse, from screening until 60 days post VIS410/placebo infusion.
8. Subject is able and willing to comply with study procedures, as per protocol.
9. Subject, or a legally acceptable representative is able to understand the purpose and risks of the study and willing to give voluntary written informed consent.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 60
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 60

Exclusion criteria:
Subjects meeting any of the following criteria are excluded from participation in this study:
1. 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).
2. Subjects who have received VIS410 in the past.
3. Subjects who have a history of receiving monoclonal antibody products within 3 months prior to VIS410/placebo dosing or planned administration of another monoclonal antibody during the study period.
4. 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.
5. Subjects with known co-infection with influenza B or other viral respiratory infections (eg, respiratory syncytial virus [RSV], parainfluenza viruses, respiratory adenoviruses).
6. Subjects with lung transplant or history of severe chronic lung disease, including cystic fibrosis or any condition requiring home oxygen therapy.
7. Subjects on extracorporeal membrane oxygenation at time of randomization.
8. Subjects with end-stage renal disease (ESRD) who are not undergoing hemodialysis.
9. 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.
10. High probability of mortality within 48 hours of randomization as determined by the Investigator.
11. Women who are pregnant, breast-feeding, or considering to become pregnant.
12. Subjects in whom nasopharyngeal swabbing is not possible.
13. Subjects weighing less than 45 kg.
14. 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.
15. Presence of any preexisting illness that, in the opinion of the Investigator, would place the subject at an unreasonably increased risk through participation in this study.
16. Subjects unable to comply with study protocol procedures and study visit schedules for whatever reason.
17. 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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Virus Diseases [C02]

Influenza A infection in hospitalized patients who need supplemental oxygen
MedDRA version: 20.1 Level: LLT Classification code 10022002 Term: Influenza A virus infection System Organ Class: 100000004862

Intervention(s)

Product Code: VIS410
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: VIS410
Current Sponsor code: VIS410
Other descriptive name: VIS410
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: The primary efficacy objective is to evaluate the effect of 2 dose levels of VIS410 + oseltamivir on clinical outcome as assessed by comparison of clinical status ordinal scale Day 7 scores between treatment groups, and between all VIS410 recipients versus placebo.
The primary safety objective is to evaluate safety and tolerability of 2 dose levels of a single intravenous (IV) dose of VIS410 when administered in combination with oseltamivir in hospitalized subjects with influenza A infection

Primary end point(s): The primary efficacy endpoint:
• The primary efficacy outcome analysis compares Day 7 clinical status ordinal scale scores between treatment groups, and between all VIS410 recipients versus placebo. Clinical status is measured daily for 14 days using the below seven-level ordinal scale, with the classifications presented from the worst clinical outcome to the best clinical outcome in descending order; for each day, subject status will be classified by the worst clinical outcome for which they qualify.
? Death
? ICU stay with mechanical ventilation
? ICU stay without mechanical ventilation
? Non-ICU hospitalization with supplemental oxygen
? Non-ICU hospitalization without supplemental oxygen
? Discharge with partial resumption of normal activities
? Discharge with full resumption of normal activities
The primary safety endpoint is the proportion of subjects with AEs and SAEs following administration of VIS410.

Secondary Objective: • Among patients requiring supplemental oxygen therapy at the time of enrollment with baseline room air oxygen saturation of = 92%, time to cessation of oxygen (O2) support resulting in stable oxygen saturation (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.
• For any patient requiring supplemental oxygen therapy at the time of enrollment (regardless of oxygen saturation), time to cessation of oxygen support.
• Evaluate the effect of 2 dose levels of VIS410 + oseltamivir vs oseltamivir alone on the parameters described in the protocol.
• Pharmacokinetics of VIS410 in serum
• Immunogenicity of VIS410
• Emergence of resistance to VIS410 and oseltamivir

Timepoint(s) of evaluation of this end point: The endpoints can be evaluated by hospital staff at any time while the patient is hospitalized or during patient visit in case of a discharged patient.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: The endpoints can be evaluated by hospital staff at any time while the patient is hospitalized or during patient visit in case of a discharged patient.

Secondary end point(s): The difference between VIS410 + oseltamivir and oseltamivir alone treatment groups in the following endpoints:
• Among patients requiring supplemental oxygen therapy at the time of enrollment with baseline room air oxygen saturation of = 92%, time to cessation of oxygen (O2) support resulting in stable oxygen saturation (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.
• For any patient requiring supplemental oxygen therapy at the time of enrollment (regardless of oxygen saturation), time to cessation of oxygen support
• Peak viral load, viral AUC, duration of viral shedding, and time to resolution of viral load from nasopharyngeal swabs by TCID50 and qRT-PCR
• Time to clinical response defined as 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 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
• Clinical status ordinal scale mean area under the curve for Days 1-7 and Days 1-14 using linear numeric scores for the ordinal categories.
• Comparison of clinical status ordinal scale scores for selected individual days (i.e., Days 3, 4, 5, and 6)
• Comparison of clinical status ordinal scale scores using modified ordinal scale criteria (i.e. pooling of selected severity criteria scores)
• Comparison of discrete ordinal scale parameters, including days of ventilator support, days in intensive care, and duration of hospitalization
• Number of days to resumption of usual activities
• All-cause and attributable mortality rates at Day 14, 28 and 56
• Total number of days in hospital and/or intensive care unit (ICU) from admission to discharge and rate of rehospitalization due to influenza A relapse/complication
• The incidence, severity, and duration of signs and symptoms of influenza-like illness as assessed by the FluPRO Questionnaire (see Appendix 14.1)
• Analysis of time to alleviation of signs and symptoms of influenza in the subset of subjects able to complete the Influenza Patient Reported Outcomes (FluPRO) Questionnaire at baseline and post-dose by Kaplan Meier analysis• The percentage of subjects with new bacterial pneumonia/superinfection
• The percentage of subjects with influenza-related complications
• VIS410 population pharmacokinetic (PK) parameters in serum
• Titer of anti-VIS410 antibody positive samples
• Genotypic and/or phenotypic assessment to determine the emergence of VIS410 and oseltamivir-resistant viruses

Secondary ID(s)

2016-004009-15-ES

VIS410-203

Source(s) of Monetary Support

Visterra, Inc.