Clinical trial NCT03739112: Efficacy of a Plant-derived Quadrivalent Virus-like Particle (VLP) Vaccine in the Elderly
Official title: A Randomized, Observer-blind, Active Comparator-controlled, Multicenter, Phase 3 Study to Assess the Efficacy, Safety, and Immunogenicity of a Plant-derived Quadrivalent VLP Influenza Vaccine in Adults 65 Years of Age and Older
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Virus Diseases
RNA Virus Infections
Respiratory Tract Diseases
Respiratory Tract Infections
Keywords: vaccine
safety
efficacy
plant-made
virus-like particle
hemagglutinin
Lead sponsor: Medicago
Sponsor class: INDUSTRY
First posted: 2018-11-13
Enrollment: 12794
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomized, observer-blind, active comparator-controlled, multicenter, Phase 3 efficacy study.
Primary purpose: PREVENTION

Brief summary: This Phase 3 study was intended to assess the relative efficacy of the Quadrivalent VLP Influenza Vaccine during the 2018-2019 influenza season compared to a licensed vaccine in elderly adults 65 years of age and older. One dose of VLP Influenza Vaccine (30 μg/strain) or of Comparator (15 μg/strain) was to be administered to 12,738 participants.

Detailed description: This randomized, observer-blind, active-controlled multicenter, Phase 3 study was conducted at multiple sites. The composition of the Quadrivalent VLP Influenza Vaccine used in this study included a mix of recombinant H1, H3, and two B hemagglutinin proteins expressed as VLPs for the 2018-2019 influenza virus strains.

A total of 12,794 healthy male and female participants aged 65 years and older were randomized in a 1:1 ratio into one of two parallel treatment groups, such that 6,396 participants were randomized to receive the Quadrivalent VLP Influenza Vaccine at a dose of 30 μg/strain and 6,398 participants were randomized to receive the comparator. Within the two treatment groups, participants were stratified by site and two age groups (65-74 years of age and 75 years of age and older in a 2:1 ratio).

Participants participated in this study for approximately nine months, during which a first visit was scheduled on Day 0 for screening and vaccine administration.

Eligibility criteria: Inclusion Criteria:

1. Participants must have read, understood, and signed the informed consent form (ICF) prior to participating in the study; participants must also complete study-related procedures and communicate with the study staff at visits and by phone during the study;
2. Participants must have a body mass index (BMI) ≤35 kg/m\^2;
3. 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;
4. Male and female participants must be 65 years of age and older at the Screening/Vaccination visit (Visit 1);
5. Participants must be non-institutionalized (e.g. not living in rehabilitation centres or old-age homes; living in an elderly community is acceptable) and have no acute or evolving medical problems prior to study participation and 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 are 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.

Exclusion Criteria:

1. According to the Investigator's opinion, history of an ongoing acute or evolving medical or neuropsychiatric illness. 'Evolving' was 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.
2. Any medical or neuropsychiatric condition or any history of excessive alcohol use or drug abuse that would render the participant unable to provide informed consent or unable to provide valid safety observations and reporting, including methadone (methadone as treatment for opioid dependence may be acceptable if the participant has been otherwise opioid-free for at least three years);
3. Any autoimmune disease other than hypothyroidism on stable replacement therapy (including, but not limited to rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, type 1 diabetes, 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;
4. Any history of status asthmaticus or ongoing serious problems with asthma, hospitalization for asthma control, or recurrent asthma episodes requiring medical attention in the last three years (one or more episodes per year);
5. 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 was evaluated case-by-case by the Investigator;
6. Administration of any adjuvanted or investigational influenza vaccine within one year prior to randomization or planned administration prior to the completion of the study;
7. 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 IM route) within six months prior to randomization and up to completion of the study;
8. 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;
9. Treatment with systemic glucocorticoids at a dose exceeding 10 mg of prednisone (or equivalent) per day for more than seven consecutive days or for ten 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;
10. 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 \[no more than 100 mg/day\]), and without a clinically apparent bleeding tendency are eligible. Participants treated with new generation drugs that do not increase the risk of IM bleeding (e.g. clopidogrel) are also eligible;
11. History of allergy to any of the constituents of the Quadrivalent VLP Influenza Vaccine, any components of the active comparator quadrivalent vaccine, or tobacco;
12. History of anaphylactic allergic reactions to plants or plants components (including fruits and nuts);
13. Use of antihistamines within 48 hours prior to study vaccination;
14. Daily use of large doses of medication for pain control or inflammation (e.g. opioids, nonsteroidal anti-inflammatory drugs \[NSAIDs\]). Use of a singular regular dose either in the morning or at bedtime would not be exclusionary;
15. 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;
16. Planned use of influenza antiviral treatment medication before the collection of nasopharyngeal (NP) swabs (e.g. oseltamivir, zanamivir, rapivab);
17. Have a rash, dermatological condition, tattoos, muscle mass, or any other abnormalities at the injection site that may interfere with injection site reaction rating;
18. Participants who have received a blood transfusion within 90 days prior to study vaccination;
19. Participants with abnormal vital signs (systolic blood pressure \[BP\] ≥ 150 mmHg and/or diastolic BP ≥ 95 mmHg for individuals taking antihypertensive medication and ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg for individuals not taking antihypertensive medication; heart rate \[HR\] ≤ 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 HR ≤ 45 in highly trained athletes);
20. Presence of any febrile illness (including an oral temperature \[OT\] ≥ 38.0 ˚C within 24 hours prior to vaccination;
21. 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;
22. 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) of the Investigator or any employee of Medicago (or their family members);
23. Participants with a history of Guillain-Barré Syndrome.

Primary outcomes:
measure: Number of Occurrences of Protocol-Defined Influenza-Like Illness (ILI) Due to Any Laboratory-Confirmed Influenza Strains
timeFrame: Day 14 (post-vaccination) up to ~9 months
Secondary outcomes:
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 ~9 months
measure: Number of Occurrences of Protocol-Defined Respiratory Illness Due to Any Laboratory-Confirmed Influenza Strains
timeFrame: Day 14 (post-vaccination) up to ~9 months
measure: Number of Occurrences of Protocol-Defined Respiratory Illness Vaccine Caused by Vaccine-Matched Influenza Strains
timeFrame: Day 14 (post-vaccination) up to ~9 months
measure: Number of Occurrences of Protocol-Defined ILI
timeFrame: Day 14 (post-vaccination) up to ~9 months
measure: Number of Participants With at Least One Immediate Complaints
timeFrame: 15 minutes post vaccination
measure: Number of Participants With at Least One Solicited Local and Systemic Reactions
timeFrame: Day 0 (post-vaccination) to Day 7
measure: Number of Participants With ≥ Severe Solicited Local and Systemic Reaction
timeFrame: Day 0 (post-vaccination) to Day 7
measure: Number of Participants With ≥ Severe Related Solicited Reactions
timeFrame: Day 0 (post-vaccination) to Day 7
measure: Number of Participants With Unsolicited Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 0 (post-vaccination) to Day 21
measure: Number of Participants With ≥ Severe Unsolicited TEAEs
timeFrame: Day 0 (post-vaccination) to Day 21
measure: Number of Participants With ≥ Severe Related Unsolicited Reactions
timeFrame: Day 0 (post-vaccination) to Day 21
measure: Number of Participants With at Least One Serious Adverse Event (SAE)
timeFrame: Day 0 to ~9 months
measure: Number of Occurrences of Death
timeFrame: Day 0 up to ~9 months
measure: Number of Participants Who Withdrew Due to an AE
timeFrame: Day 0 up to ~9 months
measure: Number of Participants With at Least One New Onset Chronic Diseases (NOCDs)
timeFrame: Day 0 up to ~9 months
measure: Geometric Mean Titers (GMTs) of Hemagglutination Inhibition (HI) Antibody Response for Each Homologous and Heterologous Influenza Strain
timeFrame: Baseline (Day 0), Day 21
measure: Percentage of Participants With Seroconversion Measured by HI Antibody Response for Each Homologous and Heterologous Strain
timeFrame: Day 0 (pre-vaccination) to Day 21
measure: Percentage of Participants With Seroprotection Measured by HI Antibody Response for Each Homologous and Heterologous Strain
timeFrame: Baseline (Day 0), Day 21
measure: Geometric Mean Fold Rise (GMFR) of HI Antibody Response for Each Homologous and Heterologous Strain
timeFrame: Baseline (Day 0), Day 21
measure: GMTs of Microneutralization (MN) Antibody Response for Each Homologous Strain
timeFrame: Baseline (Day 0), Day 21
measure: Percentage of Participants With Seroconversion Measured by MN Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination) to Day 21
measure: GMFR of MN Antibody Response for Each Homologous Strain
timeFrame: Baseline (Day 0), Day 21
measure: Geometric Mean Areas (GMA) of Single Radial Hemolysis (SRH) Antibody Response for Each Homologous Strain
timeFrame: Baseline (Day 0), Day 21
measure: Percentage of Participants With Seroconversion Measured by SRH Antibody Response for Each Homologous Strain
timeFrame: Day 0 (pre-vaccination) to Day 21
measure: Percentage of Participants With Seroprotection Measured by SRH Antibody Response for Each Homologous Strain
timeFrame: Baseline (Day 0), Day 21
measure: GMFR of SRH Antibody Response for Each Homologous Strain
timeFrame: Baseline (Day 0), Day 21
Other outcomes:
Locations:
city: Mobile
country: United States
facility: (Site 225) Coastal Clinical Research
state: Alabama
city: Tempe
country: United States
facility: (Site 201) Clinical Research Consortium
state: Arizona
city: Banning
country: United States
facility: (Site 213) Advanced Clinical Research
state: California
city: Redding
country: United States
facility: (Site 246) Paradigm Clinical Research / Pharmaseek
state: California
city: Sacramento
country: United States
facility: (Site 212) Benckmark Research
state: California
city: San Diego
country: United States
facility: (Site 244) Paradigm Clinical Research Center Inc
state: California
city: Wheat Ridge
country: United States
facility: (Site 242) Paradigm Clinical Research Centers Inc
state: Colorado
city: Coral Gables
country: United States
facility: (Site 239) Alliance for Multispeciality Research
state: Florida
city: Hollywood
country: United States
facility: (Site 222) Research Centers of America
state: Florida
city: Ponte Vedra
country: United States
facility: (Site 221) St-Johns Center for Clinical Research
state: Florida
city: South Miami
country: United States
facility: (Site 231) QPS-MRA LLC
state: Florida
city: Richmond Hill
country: United States
facility: (Site 251) Meridian Clinical Research
state: Georgia
city: Savannah
country: United States
facility: (Site 240) Meridian Clinical Research LLC
state: Georgia
city: Stockbridge
country: United States
facility: (Site 223) Clinical Research Atlanta
state: Georgia
city: Meridian
country: United States
facility: (Site 249) Advanced Clinical Research
state: Idaho
city: Augusta
country: United States
facility: (Site 219) Heartland Research Associates LLC
state: Kansas
city: Newton
country: United States
facility: (Site 234) Heartland Research Associates LLC
state: Kansas
city: Wichita
country: United States
facility: (Site 215) Heartland Research Associates LLC
state: Kansas
city: Wichita
country: United States
facility: (Site 235) Heartland Research Associates LLC
state: Kansas
city: Lexington
country: United States
facility: (Site 241) Central Kentucky Reserach Associates
state: Kentucky
city: Metairie
country: United States
facility: (Site 203) Benchmark Research
state: Louisiana
city: Saint Louis
country: United States
facility: (Site 227) Sundande Clinical Research
state: Missouri
city: Norfolk
country: United States
facility: (Site 226) Meridian Clinical Research LLC
state: Nebraska
city: Omaha
country: United States
facility: (Site 211) Meridian Clinical Research
state: Nebraska
city: Binghamton
country: United States
facility: (Site 209) United Medical Associates
state: New York
city: Endwell
country: United States
facility: (Site 217) Regional Clinical Research inc
state: New York
city: Cary
country: United States
facility: (Site 237) PMG Research of Cary LLC
state: North Carolina
city: Charlotte
country: United States
facility: (Site 230) PMG Research of Charlotte LLC
state: North Carolina
city: Rocky Mount
country: United States
facility: (Site 205) PMG Research of Rocky Mount LLC
state: North Carolina
city: Statesville
country: United States
facility: (Site 236) PMG Research
state: North Carolina
city: Winston-Salem
country: United States
facility: (Site 228) Research of Winston-Salem
state: North Carolina
city: Cincinnati
country: United States
facility: (Site 233) Sterling Research Group
state: Ohio
city: Cincinnati
country: United States
facility: (Site 208) Sterling Research Group
state: Ohio
city: Cleveland
country: United States
facility: (Site 245) Rapid Medical Research
state: Ohio
city: Columbus
country: United States
facility: (Site 202) Aventiv Research Inc
state: Ohio
city: Norman
country: United States
facility: (Site 207) Lynn Institute of Norman
state: Oklahoma
city: Oklahoma City
country: United States
facility: (Site 238) Tekton Research
state: Oklahoma
city: Mount Pleasant
country: United States
facility: (Site 216) PMG Research of Charleston LLC
state: South Carolina
city: Mount Pleasant
country: United States
facility: (Site 248) Coastal Carolina Research Center
state: South Carolina
city: Dakota Dunes
country: United States
facility: (Site 201) Meridian Clinical Research
state: South Dakota
city: Knoxville
country: United States
facility: (Site 247) New orleans Center for Clinical Research
state: Tennessee
city: Austin
country: United States
facility: (Site 206) Benchmark Research
state: Texas
city: Austin
country: United States
facility: (Site 218) Tekton Research Inc
state: Texas
city: Fort Worth
country: United States
facility: (Site 214) Ventavia Research Group LLC
state: Texas
city: Fort Worth
country: United States
facility: (Site 224) Benchmark Research
state: Texas
city: San Angelo
country: United States
facility: (Site 232) Benchmark Research
state: Texas
city: San Antonio
country: United States
facility: (Site 250) Clinical Trials of Texas Inc
state: Texas
city: Salt Lake City
country: United States
facility: (Site 204) Jean Brown Research
state: Utah
city: West Jordan
country: United States
facility: (Site 220) Advanced Clinical Research
state: Utah
city: Norfolk
country: United States
facility: (Site 229) Clinical Research Associates of Tidewater
state: Virginia
city: Truro
country: Canada
facility: (Site 106) Colchester Research Group
state: Nova Scotia
city: Guelph
country: Canada
facility: (Site 113) Dawson Road Family Medical Clinic
state: Ontario
city: Toronto
country: Canada
facility: (Site 110) Manna Research Inc.
state: Ontario
city: Chicoutimi
country: Canada
facility: (Site 103) Q & T Recherche Chicoutimi
state: Quebec
city: Gatineau
country: Canada
facility: (Site 105) Q & T Outaouais
state: Quebec
city: Levis
country: Canada
facility: (Site 107) Manna Research Inc.
state: Quebec
city: Mirabel
country: Canada
facility: (Site 109) Manna Research Inc. (Mirabel)
state: Quebec
city: Pointe-Claire
country: Canada
facility: (Site 108) Manna Research
state: Quebec
city: Québec City
country: Canada
facility: (Site 102) CHU de Québec - Université Laval
state: Quebec
city: Québec City
country: Canada
facility: (site 101) Centre de Recherche St-Louis
state: Quebec
city: Québec City
country: Canada
facility: (Site 110) Alpha Recherche Clinique
state: Quebec
city: Sherbrooke
country: Canada
facility: (Site 104) Q & T Recherche Sherbrooke
state: Quebec
city: Victoriaville
country: Canada
facility: (Site 112) Medexa Recherche
state: Quebec
city: Espoo
country: Finland
facility: (Site 309) Espoo Vaccine Research Clinic
city: Helsinki
country: Finland
facility: (Site 303) Helsinki South Vaccine Research Clinic
city: Helsinki
country: Finland
facility: (Site 308) Helsinki East Vaccine Research Center
city: Järvenpää
country: Finland
facility: (Site 301) Jarvenpaa Vaccine Research Clinic
city: Kokkola
country: Finland
facility: (Site 306) Kokkola Vaccine Research Clinic
city: Oulu
country: Finland
facility: (Site 304) Oulu Vaccine Research Clinic
city: Pori
country: Finland
facility: (Site 302) Tampere University Vaccine Research Center
city: Seinäjoki
country: Finland
facility: (Site 305) Seinaejoki Vaccine Research Clinic
city: Tampere
country: Finland
facility: (Site 310) Tampere Vaccine Research Clinic
city: Turku
country: Finland
facility: (Site 307) Turku Vaccine Research Center
city: Berlin
country: Germany
facility: (Site 410) Emovis GmbH
city: Berlin
country: Germany
facility: (Site 418) Klinische Forschung Berlin GbR
city: Berlin
country: Germany
facility: (Site 422) Synexus Clinical Research GmbH
city: Bochum
country: Germany
facility: (Site 402) Synexus Clinical research GmbH
city: Cologne
country: Germany
facility: (Site 409) Gemeinschaftspraxis Dr. med Kleinecke-Pohl
city: Dresden
country: Germany
facility: (Site 401) Cardiologicum Dresden & Pirna
city: Dresden
country: Germany
facility: (Site 406) Diabetologische Germeinschafts praxis Faulman
city: Essen
country: Germany
facility: (Site 405) Doktor Markus Faghih
city: Essen
country: Germany
facility: (Site 407) Klinisches Forschungszentrum Dr. Hagemann am Hausarztzer
city: Essen
country: Germany
facility: (Site 417) Medizentrum Essen-Borbeck
city: Essen
country: Germany
facility: (Site 414) Unterfrintroper Hausarztzentrum Klinische Forschung
city: Frankfurt
country: Germany
facility: (SIte 404) Synexus Clinical Reserach GmbH
city: Goch
country: Germany
facility: (Site 411) MedicoKIT GmbH
city: Hamburg
country: Germany
facility: (Site 425) Clinical Research Hamburg
city: Hamburg
country: Germany
facility: (Site 403) Praxis Dr. Med Cornelia Brauer
city: Künzing
country: Germany
facility: (Site 408) Germeinsschaftspraxis Dr. med Christiane Klein/Minnich
city: Leipzig
country: Germany
facility: (Site 421) SIBAmed Studienzentrum GmbH
city: Leipzig
country: Germany
facility: (Site 420) Synexus Clinical Research GmbH
city: Munich
country: Germany
facility: (Site 423) centrum fuer Diagnostik und Gesundheit
city: Rodgau
country: Germany
facility: (Site 413) Dr. Ingomar F.K. Naudts MD Office
city: Stuhr
country: Germany
facility: (Site 415) Praxisgemeinschaft Stuhr-Brinkum
city: Wangen
country: Germany
facility: (Site 416) Praxis Dr. med Joachim Sauter
city: Wardenburg
country: Germany
facility: (Site 412) MALU-Medizinische Studien GmbH
city: Weinheim
country: Germany
facility: (Site 424) Medislim GmbH
city: Bangkok
country: Thailand
facility: (Site 603) Ramathibodi Hospital, Mahid - Division of Infectious Disease
city: Bangkok
country: Thailand
facility: (Site 606) Faculty of Tropical Medicine, Mahidol University
city: Bangkok
country: Thailand
facility: (Site 608) Phramongkutklao Hospital
city: Bangkok
country: Thailand
facility: (Site 609) Division of Tropical Pediatrics
city: Chiang Mai
country: Thailand
facility: (Site 601) Faculty of Medicine, Chiang Mai University
city: Khon Kaen
country: Thailand
facility: (Site 607) Srinagarind Hospital Khon Kaen University
city: Nakhon Pathom
country: Thailand
facility: (Site 605) Golden Jubilee Medical Center
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.