Clinical trial NCT03301051: Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent Virus-Like Particles (VLPs) Influenza Vaccine in Adults
Official title: A Randomized, Observer-blind, Placebo-controlled, Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-Derived Quadrivalent Virus-Like Particles Influenza Vaccine in Adults 18-64 Years of Age
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Virus Diseases
RNA Virus Infections
Respiratory Tract Diseases
Respiratory Tract Infections
Influenza
Keywords: Influenza
Human
RNA Virus Infections
Efficacy
Immunologic
Immunogenic Factors
Physiological Effects of Drug
Virus Diseases
Orthomyxoviridae Infections
Infection
Vaccine
Safety
Plant-made
Virus-like Particle
Hemagglutinin
Quadrivalent Influenza Vaccine
Lead sponsor: Medicago
Sponsor class: INDUSTRY
First posted: 2017-10-04
Enrollment: 10160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This Phase 3 study is intended to assess the efficacy of the Quadrivalent VLP Influenza Vaccine during the 2017-2018 influenza season in healthy adults 18 to 64 years of age. One dose of Quadrivalent VLP Influenza Vaccine (30 μg/strain) or of placebo will be administered to approximately 10,000 participants

Detailed description: This randomized, observer-blind, placebo-controlled multicenter, Phase 3 study will be conducted at multiple sites. The composition of the Quadrivalent VLP Influenza Vaccine to be used in this study includes a mix of recombinant H1, H3, and two B hemagglutinin proteins expressed as VLPs for the 2017-2018 influenza virus strains.

Approximately 10,000 healthy male and female participants aged 18 to 64 years will be randomized in a 1:1 ratio into one of two parallel treatment groups, such that approximately 5,000 participants will receive the Quadrivalent VLP Influenza Vaccine at a dose of 30 μg/strain and approximately 5,000 participants will receive the placebo. Within the two treatment groups, participants will be stratified by site and two age groups (18-49 years of age and 50-64 years of age in a 1:1 ratio).

Participants will participate in this study for approximately eight to ten months, during which a first visit will be scheduled on Day 0 for screening and vaccine administration.

Eligibility criteria: Inclusion Criteria

Participants must meet all of the following inclusion criteria to be eligible for participation in this study; no protocol waivers are allowed:

1. Participants must have a body mass index (BMI) below 40 kg/m\^2;
2. Participants are considered by the Investigator to be reliable and likely to cooperate with the assessment procedures and be available for the duration of the study;
3. Participants must be in good general health prior to study participation, with no clinically relevant abnormalities that could jeopardize participant safety or interfere with study assessments, as assessed by the Principal Investigator or sub-Investigator (thereafter referred as Investigator) and determined by medical history, physical examination, and vital signs; Note: Participants with a pre-existing chronic disease will be allowed to participate if the disease is stable and, according to the Investigator's judgment, the condition is unlikely to confound the results of the study or pose additional risk to the participant by participating in the study. Stable disease is generally defined as no new onset or exacerbation of pre-existing chronic disease three months prior to vaccination. Based on the Investigator's judgment, a participant with more recent stabilization of a disease could also be eligible.
4. Female participants must have a negative urine pregnancy test result at the Screening/Vaccination visit (Visit 1).
5. Female participants of childbearing potential must use an effective method of contraception for one month prior to vaccination and agree to continue employing adequate birth control measures for at least 60 days post-vaccination. Moreover, female participants must have no plan to become pregnant for at least two months post-vaccination. Abstinent participants should be asked what method(s) they would use should their circumstances change, and participants without a well-defined plan should be excluded. The following relationship or methods of contraception are considered to be effective:

   * Hormonal contraceptives (e.g. oral, injectable, topical \[patch\], or estrogenic vaginal ring);
   * Intra-uterine device with or without hormonal release;
   * Male partner using a condom plus spermicide or sterilized partner (at least one year prior to vaccination);
   * Credible self-reported history of heterosexual vaginal intercourse abstinence until at least 60 days post-vaccination;
   * Female partner;
6. Non-childbearing females are defined as:

   * Surgically-sterile (defined as bilateral tubal ligation, hysterectomy or bilateral oophorectomy performed more than one month prior to vaccination); or
   * Post-menopausal (absence of menses for 24 consecutive months and age consistent with natural cessation of ovulation).

Exclusion Criteria:

Participants who meet any of the following criteria will be excluded from participating in this study; no protocol waivers are allowed:

1. Any participant whose medical condition(s) is sufficiently severe that annual influenza vaccination would be routinely recommended in the jurisdiction of recruitment, as per the Investigator's judgement;
2. According to the Investigator's opinion, history of significant acute or chronic, uncontrolled medical or neuropsychiatric illness. 'Uncontrolled' is defined as:

   * Requiring a new medical or surgical treatment during the three months prior to study vaccine administration unless the criteria outlined in inclusion criterion no. 5 can be met (i.e. the Investigator can justify inclusion based upon the innocuous nature of medical/surgical events and/or treatments);
   * Requiring any significant change in a chronic medication (i.e. drug, dose, frequency) during the three months prior to study vaccine administration due to uncontrolled symptoms or drug toxicity unless the innocuous nature of the medication change meets the criteria outlined in inclusion criterion no. 5 and is appropriately justified by the Investigator.
3. Any medical or neuropsychiatric condition or any history of excessive alcohol use or drug abuse which, in the Investigator's opinion, would render the participant unable to provide informed consent or unable to provide valid safety observations and reporting;
4. Any autoimmune disease other than hypothyroidism on stable replacement therapy (including, but not limited to rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and inflammatory bowel disease) or any confirmed or suspected immunosuppressive condition or immunodeficiency including known or suspected human immunodeficiency virus (HIV), Hepatitis B or C infection, the presence of lymphoproliferative disease;
5. History of chronic pulmonary (including asthma, bronchopulmonary dysplasia, and cystic fibrosis) or cardiovascular (except isolated hypertension), renal, hepatic, neurologic, hematologic (including anemia and hemoglobinopathy), or metabolic disorders (including diabetes mellitus);
6. Because this is a placebo-controlled study, any participants in close contact with individuals considered to be at high risk for developing influenza-related complications (individuals considered at high risk for complications include adults and children who have chronic pulmonary or cardiovascular \[except isolated hypertension\], renal, hepatic, neurologic, hematologic, or metabolic disorders \[including diabetes mellitus\]).
7. Administration or planned administration of any non-influenza vaccine within 30 days prior to randomization up to blood sampling on Day 21. Immunization on an emergency basis will be evaluated case-by-case by the Investigator;
8. Administration of any adjuvanted or investigational influenza vaccine within one year prior to randomization or planned administration prior to the completion of the study;
9. Administration of any 'standard', non-adjuvanted influenza vaccine (e.g. live attenuated trivalent/quadrivalent inactivated influenza vaccine or split trivalent/quadrivalent inactivated influenza vaccine administered by intranasal, intradermal, or intramuscular route) within six months prior to randomization and up to completion of the study;
10. Use of any investigational or non-registered product within 30 days or five half-lives, whichever is longer, prior to randomization or planned use during the study period. Participants may not participate in any other investigational or marketed drug study while participating in this study until after the study;
11. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or equivalent) per day for more than seven consecutive days or for 10 or more days in total, within one month of study vaccine administration; any other cytotoxic or immunosuppressant drug, or any immunoglobulin preparation within three months of vaccination and until the completion of the study. Low doses of nasal or inhaled glucocorticoids are allowed. Topical steroids are permitted;
12. Any significant disorder of coagulation including, but not limited to, treatment with warfarin derivatives or heparin. Persons receiving prophylactic anti-platelet medications (e.g. low-dose aspirin \[no more than 325 mg/day\]), and without a clinically apparent bleeding tendency are eligible. Participants treated with new generation drugs that do not increase the risk of intramuscular bleeding (e.g. clopidogrel) are also eligible;
13. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine or tobacco;
14. History of anaphylactic allergic reactions to plants or plants components;
15. Use of antihistamines with systemic absorption for more than 14 days in the four weeks prior to vaccination or use of antihistamines 48 hours prior to study vaccination (the use of topical antihistamines and nasal or inhaled steroids is acceptable);
16. Use of prophylactic medications (e.g. acetaminophen/paracetamol, aspirin, naproxen, or ibuprofen) within 24 hours of randomization to prevent or pre-empt symptoms due to vaccination. Any participant discovered to have taken a prophylactic medication to prevent or pre-empt symptoms due to vaccination within the 24 hours prior to planned randomization must be delayed until at least the 24 hours period is met;
17. Planned use of influenza antiviral treatment medication before the collection of nasopharyngeal swabs (e.g. oseltamivir, zanamivir, rapivab);
18. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at the injection site that may interfere with injection site reaction rating;
19. Participants who have received a blood transfusion within 90 days prior to study vaccination;
20. Any female participant who has a positive or doubtful pregnancy test result prior to vaccination or who is lactating;
21. Participants with abnormal vital signs (systolic blood pressure \[BP\] \> 140 mmHg and/or diastolic BP ≥ 90 mmHg, heart rate ≤ 45 beats/min and ≥ 100 beats/min) evaluated by an Investigator to be clinically significant. A participant with abnormal vital signs results may be included in the study based on Investigator's judgment (e.g. a resting hear rate ≤ 45 in highly trained athletes);
22. Presence of any febrile illness (including an oral temperature ≥ 38.0 ˚C within 24 hours prior to vaccination. Such participants may be re-evaluated for enrolment after resolution of illness;
23. Cancer or treatment for cancer within three years prior to study vaccine administration.

    Persons with a history of cancer who are disease-free without treatment for three years or more are eligible. However, individuals with conditions such as treated and uncomplicated basal cell carcinoma of the skin or non-treated, non-disseminated local prostate cancer may be eligible;
24. Participants identified as an Investigator or employee of the Investigator or clinical site with direct involvement in the proposed study, or identified as an immediate family member (i.e. parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study or any employee of Medicago;
25. Participants with a history of Guillain-Barré Syndrome.

Primary outcomes:
measure: Number of Occurrences of Protocol-Defined Respiratory Illness Caused by Vaccine-Matched Influenza Strains
timeFrame: Day 14 (post-vaccination) up to ~8 months
Secondary outcomes:
measure: Number of Occurrences of Protocol-Defined Respiratory Illness Cases Caused by Any Laboratory Confirmed Influenza Strain
timeFrame: Day 14 (post-vaccination) up to ~8 months
measure: Number of Occurrences of Laboratory-Confirmed Protocol-Defined Influenza-Like Illness (ILI) Caused by Vaccine-Matched Influenza Strains
timeFrame: Day 14 (post-vaccination) up to ~8 months
measure: Number of Occurrences of Laboratory-Confirmed ILI Caused by Any Influenza Strain
timeFrame: Day 14 (post-vaccination) up to ~8 months
measure: Number of Occurrences of Protocol-Defined ILI Cases
timeFrame: Day 14 (post-vaccination) up to ~8 months
measure: Number of Participants With at Least One Immediate Complaint
timeFrame: 15 minutes post vaccination
measure: Number of Participants With at Least One Solicited Local and Systemic Reactions
timeFrame: Day 0 (post-vaccination) up to Day 7
measure: Number of Participants With ≥ Severe Solicited Local and Systemic Reactions
timeFrame: Day 0 (post-vaccination) up to Day 7
measure: Number of Participants With ≥ Severe Related Solicited Reactions
timeFrame: Day 0 (post-vaccination) up to Day 7
measure: Number of Participants With Unsolicited Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 0 (post-vaccination) up to Day 21
measure: Number of Participants With ≥ Severe Unsolicited TEAEs
timeFrame: Day 0 (post-vaccination) up to Day 21
measure: Number of Participants With ≥ Severe Related Unsolicited Reactions
timeFrame: Day 0 (post-vaccination) up to Day 21
measure: Number of Participants With an Occurrence of Death
timeFrame: Day 0 up to ~8 months
measure: Number of Participants With at Least One Serious TEAE
timeFrame: Day 0 up to ~8 months
measure: Number of Participants With at Least One AE Leading to Withdrawal
timeFrame: Day 0 up to ~8 months
measure: Number of Participants With at Least One New Onset Chronic Diseases (NOCDs)
timeFrame: Day 0 up to ~8 months
measure: Geometric Mean Titers (GMTs) of Hemagglutination Inhibition (HI) Antibody Response for Each Homologous and Heterologous Influenza Strain
timeFrame: Day 0 (pre-vaccination), Day 21
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Homologous and Heterologous Strain
timeFrame: Day 0 (pre-vaccination) up to Day 21
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Homologous and Heterologous Strain
timeFrame: Day 0 (pre-vaccination) up to Day 21
measure: Geometric Mean Fold Ratio (GMFR) of HI Antibody Response for Each Homologous and Heterologous Strain
timeFrame: Day 0 (pre-vaccination), Day 21
measure: GMTs of Microneutralization (MN) Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination), Day 21
measure: Percentage of Participants With Seroconversion Measured by MN Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination) up to Day 21
measure: GMFR of MN Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination), Day 21
measure: Geometric Mean Area (GMA) of Single Radial Hemolysis (SRH) Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination), Day 21
measure: Percentage of Participants With Seroconversion Measured by SRH Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination) up to Day 21
measure: Percentage of Participants With Seroprotection Measured by SRH Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination) up to Day 21
measure: GMFR of SRH Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination), Day 21
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Site 222
state: Alabama
city: Anaheim
country: United States
facility: Site 210
state: California
city: Milford
country: United States
facility: Site 223
state: Connecticut
city: Coral Gables
country: United States
facility: Site 217
state: Florida
city: Hollywood
country: United States
facility: Site 220
state: Florida
city: South Miami
country: United States
facility: Site 212
state: Florida
city: Savannah
country: United States
facility: Site 203
state: Georgia
city: Stockbridge
country: United States
facility: Site 218
state: Georgia
city: Wichita
country: United States
facility: Site 206
state: Kansas
city: Metairie
country: United States
facility: Site 202
state: Louisiana
city: Saint Louis
country: United States
facility: Site 225
state: Missouri
city: Norfolk
country: United States
facility: Site 224
state: Nebraska
city: Omaha
country: United States
facility: Site 208
state: Nebraska
city: Las Vegas
country: United States
facility: Site 213
state: Nevada
city: Binghamton
country: United States
facility: Site 205
state: New York
city: Endwell
country: United States
facility: Site 228
state: New York
city: Charlotte
country: United States
facility: Site 216
state: North Carolina
city: Charlotte
country: United States
facility: Site 221
state: North Carolina
city: Winston-Salem
country: United States
facility: Site 227
state: North Carolina
city: Columbus
country: United States
facility: Site 201
state: Ohio
city: Dakota Dunes
country: United States
facility: Site 207
state: South Dakota
city: Bristol
country: United States
facility: Site 209
state: Tennessee
city: Austin
country: United States
facility: Site 204
state: Texas
city: Austin
country: United States
facility: Site 229
state: Texas
city: Fort Worth
country: United States
facility: Site 226
state: Texas
city: Fort Worth
country: United States
facility: Site 219
state: Texas
city: Salt Lake City
country: United States
facility: Site 214
state: Utah
city: West Jordan
country: United States
facility: Site 211
state: Utah
city: Norfolk
country: United States
facility: Site 230
state: Virginia
city: Halifax
country: Canada
facility: Site 105
state: Nova Scotia
city: Truro
country: Canada
facility: Site 106
state: Nova Scotia
city: Brampton
country: Canada
facility: Site 107
state: Ontario
city: Sudbury
country: Canada
facility: Site 110
state: Ontario
city: Toronto
country: Canada
facility: Site 108
state: Ontario
city: Mirabel
country: Canada
facility: Site 109
state: Quebec
city: Pierrefonds
country: Canada
facility: Site 103
state: Quebec
city: Quebec City
country: Canada
facility: Site 101
state: Quebec
city: Quebec City
country: Canada
facility: Site 102
state: Quebec
city: Sherbrooke
country: Canada
facility: Site 104
state: Quebec
city: Espoo
country: Finland
facility: Site 306
city: Helsinki
country: Finland
facility: Site 305
city: Helsinki
country: Finland
facility: Site 310
city: Jarvenpaa
country: Finland
facility: Site 304
city: Kokkola
country: Finland
facility: Site 309
city: Oulu
country: Finland
facility: Site 307
city: Pori
country: Finland
facility: Site 303
city: Seinäjoki
country: Finland
facility: Site 308
city: Tampere
country: Finland
facility: Site 301
city: Turku
country: Finland
facility: Site 302
city: Berlin
country: Germany
facility: Site 402
city: Berlin
country: Germany
facility: Site 403
city: Berlin
country: Germany
facility: Site 406
city: Essen
country: Germany
facility: Site 401
city: Essen
country: Germany
facility: Site 404
city: Hamburg
country: Germany
facility: Site 405
city: Manila
country: Philippines
facility: Site 701
city: Manila
country: Philippines
facility: Site 703
city: Muntinlupa
country: Philippines
facility: Site 702
city: Muntinlupa
country: Philippines
facility: Site 704
city: Muntinlupa
country: Philippines
facility: Site 705
city: Pasay
country: Philippines
facility: Site 706
city: Bangkok Noi
country: Thailand
facility: Site 605
city: Bangkok
country: Thailand
facility: Site 601
city: Bangkok
country: Thailand
facility: Site 603
city: Bangkok
country: Thailand
facility: Site 604
city: Bangkok
country: Thailand
facility: Site 606
city: Bangkok
country: Thailand
facility: Site 607
city: Chiang Mai
country: Thailand
facility: Site 602
city: Corby
country: United Kingdom
facility: Site 510
city: Gillingham
country: United Kingdom
facility: Site 507
city: Northwood
country: United Kingdom
facility: Site 506
city: Romford
country: United Kingdom
facility: Site 508
city: Shipley
country: United Kingdom
facility: Site 509
Study officials:
affiliation: Medicago
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Ward BJ, Makarkov A, Seguin A, Pillet S, Trepanier S, Dhaliwall J, Libman MD, Vesikari T, Landry N. Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (>/=65 years): two multicentre, randomised phase 3 trials. Lancet. 2020 Nov 7;396(10261):1491-1503. doi: 10.1016/S0140-6736(20)32014-6. Epub 2020 Oct 13.