Safety Trial of Live Attenuated Influenza (H7N3) Vaccine | NCT01511419

NCT01511419

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

No data available

No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Ministry of Health, Russian Federation	OTHER_GOV
Research Institute of Influenza, Russia	OTHER
Institute of Experimental Medicine, Russia	OTHER

Description Module

Detailed Description

This is a phase I, double-blind, individually-randomized (3:1, vaccine:placebo), controlled trial with two groups, LAIV H7N3 and matched placebo. Healthy male and female adults 18 through 49 years of age will be invited to participate. For feasibility reasons and in order for an independent Safety Monitoring Committee (SMC) to review safety data in a small group of subjects initially, the total cohort of 40 subjects will be enrolled in two sub-cohorts: one cohort of 12 subjects, randomized at 3:1 (9 vaccine and 3 placebo), followed two weeks later by a second cohort of 28 subjects randomized at 3:1 (21 vaccine and 7 placebo). After all 12 volunteers of the first sub-cohort have been observed for the first isolation period (Day 1 to Day 7), an interim safety review will be performed by the SMC. The SMC will review all adverse events (AEs), including clinical laboratory evaluations (pre- and post-vaccination) and shedding data, for all subjects and will advise if the volunteers of the first sub-cohort may receive dose two of study vaccine or placebo and if the additional 28 volunteers of the second sub-cohort may be enrolled into the study. As for the first sub-cohort, the SMC will also review all safety data for the second sub-cohort and for the entire participant population of the trial. For each sub-cohort, the procedures and timelines are here summarized.

On the day of first screening, about 7 days (between 4 and 14 days) prior to administration of dose one of study vaccine or placebo, subjects will be screened for eligibility through medical history review, physical examination, testing for serologic evidence of chronic viral infection [human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV), with proper pre- and post-test counseling], routine biochemical and hematological blood tests and urinalysis by dipstick.

Subject screening for eligibility will continue and be completed on the second screening day (S2). This second screening day will occur the same day as scheduled admission to the isolation unit and administration of study vaccine or placebo (Day 0). Women will undergo pregnancy tests using urine samples. All subjects will undergo an ear, nose and throat (ENT) examination. Fully eligible subjects will be admitted to the isolation unit. At that time, nasal swab, nasal wick, and blood specimens will be collected for virologic and immunological testing prior to administration of study vaccine or placebo. Blood and urine specimens will be again collected for routine biochemical and hematological blood tests and urinalysis by dipstick; these results will serve to define baseline status for subject prior to receipt of study vaccine or placebo but will not be used for screening purposes. Subjects will be unaware of which allocation, LAIV H7N3 or matched placebo, is received; study vaccine and placebo will be masked. Subjects will be carefully monitored for adverse reactions while in the isolation unit.

All subjects will remain in the isolation unit for at least 7 days after receipt of study vaccine or placebo. Nasal swabs will be collected daily while subjects are in isolation to test for presence of influenza virus shed in the nasal passage. Any subject exhibiting conjunctivitis will also have a conjunctival swab collected on the day of appearance of the sign. Any subject exhibiting influenza A virus shedding, as determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) positivity on a nasal swab specimen, in the 2 days prior to each planned discharge day after each dose (Days 6 or 7 or Days 34 or 35) will be kept in the isolation until PCR-diagnosis results confirm that no influenza virus is present in a tested clinical specimen for at least two consecutive days. Any subject still exhibiting evidence of influenza virus shedding in a nasal swab on Days 6 or 7 or Days 34 or 35 post-administration with each dose might be placed on influenza antiviral (oseltamivir) treatment at the standard dose for treatment of 75 milligrams (mg) twice a day for a course of 5 days.

After discharge from the isolation unit, subjects will complete diary cards for AEs and use of concomitant medications. Subjects will return to the isolation unit at four weeks (Day 28) after administration of dose one of study vaccine or placebo. At that time, similar procedures will be used for admittance to the isolation unit, for receipt of dose two of study vaccine or placebo and for isolation and follow-up, with the additional procedure of review of interim histories (and diary cards) since first discharge after dose one.

After second discharge from the isolation unit, subjects will again complete diary cards for AEs and use of concomitant medications. Subjects will then return to the study center at four weeks (Day 56) after administration of dose two of study vaccine or placebo for their final study visit. Interim histories (and diary cards) will again be reviewed and final blood and nasal wick specimens will be collected. Women will also undergo a final pregnancy screen. Subjects will complete the study at this time.

For assessment of safety, subjects will be observed for two hours after each administration of study vaccine or placebo. Twice daily (early morning and late afternoon) examination will be also used to assess reactions for 7 days after each administration of study vaccine or placebo. ENT examination will also occur once per day on Days 7, 28, 35 and 56. Subjects will complete diary cards for unsolicited AEs from the day of each discharge until return to the isolation unit for dose two (at Day 28) or until return to the study center for the final study visit at four weeks post dose two (at Day 56). To assess safety, blood and urine specimens will also be collected on days 7, 28 (prior to administration of dose two of study vaccine or placebo), 35 and 56, for testing by routine biochemical and hematological blood tests and by urinalysis by dipstick.

For the evaluation of mucosal immunoglobulin A (IgA) antibody, nasal wick specimens will be collected on Day 0 (prior to administration of dose one of study vaccine or placebo), on Day 28 (prior to administration of dose two of study vaccine or placebo) and on Day 56. For the evaluation of serum antibodies (by hemagglutination inhibition [HAI], microneutralization and IgA and immunoglobulin G [IgG] EIA), serum specimens will be collected on Day 0 (prior to administration of dose one of study vaccine or placebo), on Day 28 (prior to administration of dose two of study vaccine or placebo) and on Day 56. To study virus infectivity (by isolation in chicken embryos) and stability (by molecular sequencing of any isolated virus), nasal swab specimens will be taken on Days 1, 2, 3, 5, 7, 29, and 31. To assess priming and stimulation of cytotoxic T lymphocytes and other cytokine indicators, whole blood for isolation of peripheral blood mononuclear cells (PBMCs) will be collected on Days 0 (prior to administration of dose one of study vaccine or placebo), on Day 28 (prior to administration of dose two of study vaccine or placebo) and on Day 56.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
LAIV H7N3	Experimental	Test drug/agent: Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine (LAIV H7N3) grown in embryonated chicken eggs. Name of active ingredient(s): Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine. Dose: ≥7.5 log egg infectious dose (EID) 50/0.5 ml dose; 0.25 ml/nare. Route of administration: Intranasal aerosol. Duration of treatment: Two doses were delivered, one on Day 0 and one on Day 28.	Biological: LAIV H7N3
Placebo	Placebo Comparator	Reference drug: Placebo; saline inoculated in embryonated chicken eggs and subsequently prepared in the same way as test vaccine. Dose: 0.5 ml; 0.25 ml/nare Route of administration: Intranasal aerosol Duration of treatment: Two doses were delivered, one on Day 0 and one on Day 28	Biological: placebo

Name	Type	Description	Arm Group Labels	Other Names
LAIV H7N3	Biological	2 doses of vaccine	LAIV H7N3	A/17/mallard/Netherlands/00/95 (H7N3)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Immediate Reactions	From administration of any dose, immediate reaction measured as observed by study staff or reported by the subject to study staff in case of an anaphylactic reaction.	2 hours post-administration on Days 0 and 28
Adverse Events Associated With Intranasal Vaccination	From solicited local and systemic reactions	Greater than 2 hours through 7 days following any dose
All Other Adverse Events	Including unsolicited events and abnormal laboratory findings	7 days following any dose
Participants With Serious Adverse Events (SAEs)	Including abnormal laboratory findings	Within 4 weeks of receipt of any dose

Secondary Outcomes

Measure	Description	Time Frame
Number/Percentage of Subjects With Seroconversion for Serum Hemagglutination Inhibition (HAI)	Seroconversion was defined as at least a four-fold rise after each dose from baseline or as the mean titer after each dose	28 days (Dose 1) and 56 days (Dose 2)
Number/Percentage of Subjects With Serum Neutralizing Antibodies

Other Outcomes

Measure	Description	Time Frame
Number/Percentage of Subjects Exhibiting CD4+ IFNγ+ Responses	H7N3-specific T cell responses were examined in peripheral blood mononuclear cells (PBMCs) obtained from all the study subjects before vaccination (Day 0), 28 days after the first vaccination (Day 28) and 28 days after revaccination (Day 56). To calculate the frequency of virus-specific T cells we quantified all cells positive for IFNγ after in vitro stimulation with whole H7N3 virion. Increases in the antigen-specific CD4+T-cell levels exceeding 3 standard deviations from the levels in the mean of the placebo were considered positive responses.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Legal male or female adult 18 through 49 years of age at the enrollment visit.
Literate and willing to provide written informed consent.
Free of obvious health problems, as established by the medical history and screening evaluations, including physical examination.
Capable and willing to complete diary cards and willing to return for all follow-up visits
Willing to comply with the rules of the isolation unit (including willing and able to take oseltamivir influenza antiviral medication, should that be recommended by a study physician).
For females, willing to take reliable birth control measures throughout the entire period of participation in the study.

Exclusion Criteria:

Participation in another clinical trial involving any therapy within the previous three months or planned enrollment in such a trial during the period of this study.
Receipt of any non-study vaccine within four weeks prior to enrollment or refusal to postpone receipt of such vaccines until four weeks after study completion.
Practice of nasal irrigation on a regular basis within the past six months or has engaged in nasal irrigation within two weeks prior to enrollment.
Recent history of frequent nose bleeds (>5 within the past year).
Clinically relevant abnormal paranasal anatomy.
Recent history (within the past month) of rhino or sinus surgery, or surgery for any traumatic injury of the nose.
Current or recent (within two weeks of enrollment) acute respiratory illness with or without fever.
Other acute illness at the time of study enrollment.
Receipt of immune globulin or other blood products within three months prior to study enrollment or planned receipt of such products during the period of subject participation in the study.
Chronic administration (defined as more than 14 consecutively-prescribed days) of immunosuppressants or other immune-modulating therapy within six months prior to study enrollment. (For corticosteroids, this means prednisone or equivalent, >=0.5 mg per kg per day; topical steroids are allowed, exclusive of nasal.)
Participation in any previous trial of any H5 or H7 containing influenza vaccine.
History of asthma.
Hypersensitivity after previous administration of any influenza vaccine.
History of wheezing after past receipt of any live influenza vaccine.
Other AE following immunization, at least possibly related to previous receipt of any influenza vaccine.
Suspected or known hypersensitivity to any of the study vaccine components, including chicken or egg protein.
Seasonal (autumnal) hypersensitivity to the natural environment.
Acute or chronic clinically significant pulmonary, cardiovascular, hepatic, metabolic, neurologic, psychiatric or renal functional abnormality, as determined by medical history, physical examination or clinical laboratory screening tests, which in the opinion of the investigator, might interfere with the study objectives. Subjects with physical examination findings or clinical laboratory screening results which would be graded 2 or higher on the AE severity grading scale will be excluded from entry into the study and will be excluded from receipt of dose two of study vaccine or placebo.
History of leukemia or any other blood or solid organ cancer.
History of thrombocytopenic purpura or known bleeding disorder.
History of seizures.
Known or suspected immunosuppressive or immunodeficient condition of any kind, including HIV infection.
Known chronic HBV or HCV infection.
Known tuberculosis infection or evidence of previous tuberculosis exposure.
History of chronic alcohol abuse and/or illegal drug use.
Claustrophobia or sociophobia.
Pregnancy or lactation. (A negative pregnancy test will be required before administration of study vaccine or placebo for all women of childbearing potential.)
Any condition that, in the opinion of the investigator, would increase the health risk to the subject if he/she participates in the study or would interfere with the evaluation of the study objectives.

Name	Affiliation	Role
Oleg I Kiselev, MD, PhD, DSc	Research Institute of Influenza	Principal Investigator
Larisa G Rudenko, MD, PhD, DSc	Institute of Experimental Medicine	Study Director
Kathleen M Neuzil, MD, MPH	PATH Vaccine Solutions	Study Director
Igor Victorevich	Microgen	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Research Institute of Influenza		Saint Petersburg		197376	Russia

PubMed Identifier	Type	Citation	Retractions
26432909	Derived	Kiseleva I, Dubrovina I, Fedorova E, Larionova N, Isakova-Sivak I, Bazhenova E, Pisareva M, Kuznetsova V, Flores J, Rudenko L. Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses. Vaccine. 2015 Dec 8;33(49):7008-14. doi: 10.1016/j.vaccine.2015.09.050. Epub 2015 Oct 2.
24533064	Derived

Arm/Group Information

ID	Title	Description
FG000	LAIV H7N3	Test drug/agent: Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine (LAIV H7N3) grown in embryonated chicken eggs. Name of active ingredient(s): Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine. Dose: ≥7.5 log egg infectious dose (EID) 50/0.5 ml dose; 0.25 ml/nare. Route of administration: Intranasal aerosol. Duration of treatment: Two doses were delivered, one on Day 0 and one on Day 28.
FG001	Placebo	Reference drug: Placebo; saline inoculated in embryonated chicken eggs and subsequently prepared in the same way as test vaccine. Dose: 0.5 ml; 0.25 ml/nare Route of administration: Intranasal aerosol Duration of treatment: Two doses were delivered, one on Day 0 and one on Day 28 placebo: 2 doses of placebo

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	LAIV H7N3	Test drug/agent: Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine (LAIV H7N3) grown in embryonated chicken eggs. Name of active ingredient(s): Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine. Dose: ≥7.5 log EID50/0.5 ml dose; 0.25 ml/nare. Route of administration: Intranasal aerosol. Duration of treatment: Two doses were delivered, one on Day 0 and one on Day 28. LAIV H7N3: 2 doses of vaccine

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Immediate Reactions

From administration of any dose, immediate reaction measured as observed by study staff or reported by the subject to study staff in case of an anaphylactic reaction.

Intent-to-treat (ITT) population

Posted

Count of Participants

Participants

2 hours post-administration on Days 0 and 28

ID	Title	Description
OG000	LAIV H7N3: Dose 1 (Day 0)	Test drug/agent: Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine (LAIV H7N3) grown in embryonated chicken eggs. Name of active ingredient(s): Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine. Dose: ≥7.5 log EID50/0.5 ml dose; 0.25 ml/nare. Route of administration: Intranasal aerosol.
OG001	Placebo: Dose 1 (Day 0)

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	LAIV H7N3: Dose 1	Test drug/agent: Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine (LAIV H7N3) grown in embryonated chicken eggs. Name of active ingredient(s): Live-attenuated A/17/mallard/Netherlands/00/95 influenza vaccine. Dose: ≥7.5 log EID50/0.5 ml dose; 0.25 ml/nare. Route of administration: Intranasal aerosol.

ID	Term
D007251	Influenza, Human
D005585	Influenza in Birds

ID	Term
D012141	Respiratory Tract Infections
D007239	Infections
D009976	Orthomyxoviridae Infections
D012327	RNA Virus Infections