Reducing the Burden of Influenza After Solid-Organ Transplantation (STOP-FLU)
Reducing the Burden of Influenza After Solid-Organ Transplantation: the STOP-FLU Trial [Swiss Trial in Solid Organ Transplantation on Prevention of Influenza]
Study Overview
Status
Conditions
Detailed Description
Objectives: The primary objective of this study is to compare the immunogenicity of two novel vaccination strategies, consisting in vaccination with a HD influenza vaccine or an MF59a influenza vaccine, to the standard-dose non-adjuvanted vaccination (standard of care) in a population of SOT recipients.
The main secondary objectives are to evaluate the efficacy of the novel vaccination strategies in reducing the incidence of influenza, to correlate the humoral responses to vaccination with protection from influenza and to assess the influence of immunosuppression on influenza vaccine responses.
Safety objectives include the assessment of the reactogenicity of the different vaccines and to describe the incidence of acute rejection and the development of anti-Human Leucocyte Antigens (HLA) antibodies after vaccination.
Study design: Prospective double-blinded randomized controlled three-arm parallel group superiority multicenter trial.
Inclusion / Exclusion criteria: Study participants will be enrolled among ≥18-year old stable SOT recipients ≥3 months after transplantation, regularly followed at their respective outpatient clinic at the 7 transplant centers and scheduled to receive the annual influenza vaccine. Candidates will be excluded in case of previous severe reaction or allergy to one of the study vaccines or in case of treatment for acute rejection, among others.
Measurements and procedures: At day 0, after giving informed consent, eligible patients will be randomized in a 1:1:1 ratio into 3 arms: standard quadrivalent intramuscular vaccine (control), HD trivalent vaccine and MF59a trivalent vaccine. After vaccination participants will be followed for a period of 6 months. Safety will be assessed immediately after vaccination and 7, 28 and 180 days after vaccination, and blood sampling for immunogenicity analysis will be performed at baseline, 7, 28 and 180 days after vaccination. Additionally to evaluate the vaccine safety, anti-HLA antibodies will be measured at baseline and at days 28 and 180 after vaccination. Hemagglutinin titers will be determined by hemagglutination inhibition assay (HIA) according to standardized methods. During the influenza season, the development of influenza will be systematically assessed by polymerase chain reaction (PCR) by surveillance nasopharyngeal swab.
Study Product / Intervention: The study intervention consists in the intramuscular administration of either a HD vaccine (containing 60 µg of antigen of each of the three viral strains) [Fluzone-HD®] or a MF59a vaccine (containing 15 µg of antigen of each of the three viral strains with a MF59 adjuvant) [Fluad®].
Control Intervention: The control intervention consists in the administration of the standard quadrivalent non-adjuvanted intramuscular influenza vaccine (VaxigripTetra®), containing 15 µg of each of the four viral strains.
Number of Participants with Rationale: The investigators plan to enroll 780 patients (260 patients per study group). Sample size was calculated to find a significant difference between the three groups for the primary endpoint. The lowest seroconversion rate of 46% for standard dose, a mid seroconversion rate of 59% with MF59a vaccine, and the highest seroconversion rate of 70% with HD vaccine has been assumed. A 10% drop out rate is assumed and the number of patients has been rounded up to get balanced groups. In each group 260 patients are required which amounts to 780 patients.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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Andalucia
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Seville, Andalucia, Spain, 41013
- Hospitales Universitarios Virgen del Rocío
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Basel, Switzerland, 4031
- University Hospital Basel
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Bern, Switzerland, 3010
- University Hospital Bern
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Genève, Switzerland, 1205
- Hopitaux Universitaires de Geneve
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Lausanne, Switzerland, 1011
- CHUV
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Lugano, Switzerland, 6900
- Epatocentro Ticino
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Saint Gallen, Switzerland, 9007
- Canton Hospital St-Gallen
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Zürich, Switzerland, 8091
- Universitätsspital Zürich
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Graubunden
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Chur, Graubunden, Switzerland, 7000
- Cantonal Hospital Chur
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Provision of written, informed consent
- Age ≥18 years
- Stable outpatients based on clinical judgement
- ≥ 3 months after solid organ transplantation
Exclusion Criteria:
Known hypersensitivity to any component (antigen, adjuvant, excipient or preservative) of study vaccines; the composition of the study vaccines is as follows:
- VaxigripTetra®: hemagglutinin, egg protein, formaldehyde, octylphenol ethoxylate/octoxynol 9 (Triton® X-100), neomycin
- Fluad®: hemagglutinin, neuraminidase, egg protein, squalene, polysorbate 80, sorbitan trioleate, sodium citrate, citric acid, kanamycin sulphate, neomycin sulphate, barium sulphate, formaldehyde, cetyl trimethylammonium bromide
- Fluzone-HD®: hemagglutinin, egg protein, formaldehyde, octylphenol ethoxylate/octoxynol 9 (Triton® X-100)
- Previous life-threatening reaction to influenza vaccine (i.e. Guillain Barré Syndrome)
- Ongoing therapy for rejection (including steroid pulse or prednisone > 2mg/kg/day over more than 14 days)
- Ongoing therapy with intravenous immunoglobulin (IVIG) and/or eculizumab
- Current or past (within 6 months) therapy with rituximab
- Abo incompatible transplantation
- Unable to comply with study protocol
- Pregnancy or breastfeeding
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: High dose influenza vaccine
Administration of high-dose influenza vaccine
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The experimental intervention consists in an intramuscular injection of a MF59-adjuvanted trivalent inactivated influenza vaccine containing 15 µg of antigen per strain (Fluad®) or an intramuscular injection of trivalent inactivated influenza vaccine containing 60 µg of antigen per strain (Fluzone-HD®) and will be performed at day 0.
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Experimental: MF59-adjuvanted influenza vaccine
Administration of MF59-adjuvanted vaccine
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The experimental intervention consists in an intramuscular injection of a MF59-adjuvanted trivalent inactivated influenza vaccine containing 15 µg of antigen per strain (Fluad®) or an intramuscular injection of trivalent inactivated influenza vaccine containing 60 µg of antigen per strain (Fluzone-HD®) and will be performed at day 0.
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Active Comparator: Standard influenza vaccine
Administration of standard intramuscular influenza vaccine
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The control intervention consists in an intramuscular injection of one dose of VaxigripTetra®, the standard non-adjuvanted intramuscular influenza vaccine (as routinely done).
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Vaccine response rate
Time Frame: day 28 after vaccination
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Seroconversion rate for at least one viral antigen
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day 28 after vaccination
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Influenza infection
Time Frame: Within 6 month after vaccination
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PCR positive for influenza in a nasopharyngeal swab or other clinical specimen
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Within 6 month after vaccination
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Seroprotection rates
Time Frame: At day 28 and month 6 after vaccination
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Antibody levels >40 after vaccination
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At day 28 and month 6 after vaccination
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Reactogenicity
Time Frame: within 28 days after vaccination
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Self-collected adverse events
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within 28 days after vaccination
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Development of anti-HLA antibodies
Time Frame: Within 6 months post vaccination
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De novo anti-HLA antibodies measured by Luminex
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Within 6 months post vaccination
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Collaborators and Investigators
Publications and helpful links
General Publications
- Kumar D, Michaels MG, Morris MI, Green M, Avery RK, Liu C, Danziger-Isakov L, Stosor V, Estabrook M, Gantt S, Marr KA, Martin S, Silveira FP, Razonable RR, Allen UD, Levi ME, Lyon GM, Bell LE, Huprikar S, Patel G, Gregg KS, Pursell K, Helmersen D, Julian KG, Shiley K, Bono B, Dharnidharka VR, Alavi G, Kalpoe JS, Shoham S, Reid GE, Humar A; American Society of Transplantation H1N1 Collaborative Study Group. Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect Dis. 2010 Aug;10(8):521-6. doi: 10.1016/S1473-3099(10)70133-X. Epub 2010 Jul 9.
- Manuel O, Estabrook M; AST Infectious Diseases Community of Practice. RNA respiratory viruses in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl 4(Suppl 4):212-9. doi: 10.1111/ajt.12113. No abstract available.
- Mombelli M, Rettby N, Perreau M, Pascual M, Pantaleo G, Manuel O. Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial. Vaccine. 2018 Oct 1;36(41):6163-6169. doi: 10.1016/j.vaccine.2018.08.057. Epub 2018 Sep 1.
- Kumar D, Campbell P, Hoschler K, Hidalgo L, Al-Dabbagh M, Wilson L, Humar A. Randomized Controlled Trial of Adjuvanted Versus Nonadjuvanted Influenza Vaccine in Kidney Transplant Recipients. Transplantation. 2016 Mar;100(3):662-9. doi: 10.1097/TP.0000000000000861.
- Koller MT, van Delden C, Muller NJ, Baumann P, Lovis C, Marti HP, Fehr T, Binet I, De Geest S, Bucher HC, Meylan P, Pascual M, Steiger J. Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term follow-up cohort. Eur J Epidemiol. 2013 Apr;28(4):347-55. doi: 10.1007/s10654-012-9754-y. Epub 2013 Apr 2.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2017-01922
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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