Clinical trial NCT03699839: Reducing the Burden of Influenza After Solid-Organ Transplantation
Official title: Reducing the Burden of Influenza After Solid-Organ Transplantation: the STOP-FLU Trial [Swiss Trial in Solid Organ Transplantation on Prevention of Influenza]
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Influenza
Organ Transplantation
Keywords: Vaccination
Adjuvanted vaccine
High-dose vaccine
Lead sponsor: University of Lausanne Hospitals
Sponsor class: OTHER
Collaborators: name: University Hospital, Basel, Switzerland
name: University of Bern
name: University Hospital, Geneva
name: University of Zurich
name: Cantonal Hospital of St. Gallen
name: Fondazione Epatocentro Ticino
name: Cantonal Hospital Chur
name: Hospitales Universitarios Virgen del Rocío
First posted: 2018-10-09
Enrollment: 619
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Influenza is associated with significant morbidity and mortality in solid-organ transplant (SOT) recipients and it is mainly prevented by seasonal influenza vaccination. Unfortunately, the immunogenicity of standard influenza vaccine is suboptimal in this population. Vaccination with a high-dose (HD) influenza vaccine or an MF59-adjuvanted (MF59a) vaccine have significantly reduced the incidence of influenza and increased the immunogenicity of influenza vaccine in the elderly. The investigators will compare the immunogenicity and efficacy of two new 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Vaccine response rate
timeFrame: day 28 after vaccination
Secondary outcomes:
measure: Influenza infection
timeFrame: Within 6 month after vaccination
measure: Seroprotection rates
timeFrame: At day 28 and month 6 after vaccination
measure: Reactogenicity
timeFrame: within 28 days after vaccination
measure: Development of anti-HLA antibodies
timeFrame: Within 6 months post vaccination
Other outcomes:
Locations:
city: Seville
country: Spain
facility: Hospitales Universitarios Virgen del Rocio
state: Andalucia
city: Chur
country: Switzerland
facility: Cantonal Hospital Chur
state: Graubunden
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: University Hospital Bern
city: Genève
country: Switzerland
facility: Hopitaux Universitaires de Genève
city: Lausanne
country: Switzerland
facility: CHUV
city: Lugano
country: Switzerland
facility: Epatocentro Ticino
city: Saint Gallen
country: Switzerland
facility: Canton Hospital St-Gallen
city: Zürich
country: Switzerland
facility: UniversitätsSpital Zürich
Study officials:
References:
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citation: 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.
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citation: 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.
citation: 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.