Clinical Trials Register

Summary
EudraCT Number:	2016-004009-15
Sponsor's Protocol Code Number:	VIS410-203
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-07-28
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2016-004009-15

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

VIS410-203

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Visterra, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Visterra, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Visterra, Inc.
B.5.2	Functional name of contact point	David Oldach MD,
B.5.3	Address:
B.5.3.1	Street Address	275 Second Avenue, 4th Floor
B.5.3.2	Town/ city	Waltham, MA
B.5.3.3	Post code	02451
B.5.3.4	Country	United States
B.5.4	Telephone number	1443629 0913
B.5.5	Fax number	1617498 1073

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	VIS410
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	VIS410
D.3.9.2	Current sponsor code	VIS410
D.3.9.3	Other descriptive name	VIS410
D.3.9.4	EV Substance Code	SUB175945
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Influenza A infection in hospitalized patients who need supplemental oxygen

E.1.1.1

Medical condition in easily understood language

Flu infection in hospitalized patients who need mechanical breathing assistance

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10022002
E.1.2	Term	Influenza A virus infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary efficacy objective is the evaluation of 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

E.2.2

Secondary objectives of the trial

• 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 VIS410 + oseltamivir vs oseltamivir alone on the
parameters described on the protocol.
•Pharmacokinetics of VIS410 in serum
• Immunogenicity of VIS410
• Emergence of resistance to VIS410 and oseltamivir

E.2.3

Trial contains a sub-study

E.3

Principal 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 and 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 (LAR), is able to understand the purpose and risks of the study and willing to give voluntary written informed consent.

E.4

Principal 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.

E.5 End points

E.5.1

Primary end point(s)

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.

E.5.1.1

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.

E.5.2

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 qRTPCR
• 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
_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

E.5.2.1

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Belarus

Belgium

Bulgaria

Canada

Estonia

France

Georgia

Latvia

Malaysia

New Zealand

Russian Federation

Serbia

Singapore

South Africa

Spain

Thailand

Turkey

Ukraine

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

120

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-09-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-28

P. End of Trial
P.	End of Trial Status	Completed

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