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Reducing the Burden of Influenza After Solid-Organ Transplantation (STOP-FLU)

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ClinicalTrials.gov Identifier: NCT03699839
Recruitment Status : Recruiting
First Posted : October 9, 2018
Last Update Posted : November 16, 2018
Sponsor:
Collaborators:
University Hospital, Basel, Switzerland
University of Bern
University Hospital, Geneva
University of Zurich
Cantonal Hospital of St. Gallen
Fondazione Epatocentro Ticino
Information provided by (Responsible Party):
Oriol Manuel, University of Lausanne Hospitals

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.

Condition or disease Intervention/treatment Phase
Influenza Organ Transplantation Biological: High-dose influenza vaccine Biological: MF59-adjuvanted influenza vaccine Biological: Standard intramuscular influenza vaccine Phase 2 Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 780 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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]
Actual Study Start Date : October 26, 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

Arm Intervention/treatment
Experimental: High dose influenza vaccine
Administration of high-dose influenza vaccine
Biological: High-dose influenza vaccine
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.

Experimental: MF59-adjuvanted influenza vaccine
Administration of MF59-adjuvanted vaccine
Biological: MF59-adjuvanted influenza vaccine
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.

Active Comparator: Standard influenza vaccine
Administration of standard intramuscular influenza vaccine
Biological: Standard intramuscular influenza vaccine
The control intervention consists in an intramuscular injection of one dose of VaxigripTetra®, the standard non-adjuvanted intramuscular influenza vaccine (as routinely done).




Primary Outcome Measures :
  1. Vaccine response rate [ Time Frame: day 28 after vaccination ]
    Seroconversion rate for at least one viral antigen


Secondary Outcome Measures :
  1. Influenza infection [ Time Frame: Within 6 month after vaccination ]
    PCR positive for influenza in a nasopharyngeal swab or other clinical specimen

  2. Seroprotection rates [ Time Frame: At day 28 and month 6 after vaccination ]
    Antibody levels >40 after vaccination

  3. Reactogenicity [ Time Frame: within 28 days after vaccination ]
    Self-collected adverse events

  4. Development of anti-HLA antibodies [ Time Frame: Within 6 months post vaccination ]
    De novo anti-HLA antibodies measured by Luminex



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03699839


Contacts
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Contact: Oriol Manuel, MD +41213143020 oriol.manuel@chuv.ch
Contact: Aurélie Mello, MD +41213143293 aurelie.mello@chuv.ch

Locations
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Switzerland
University Hospital Basel Recruiting
Basel, Switzerland, 4031
Contact: Michael Dickenmann, MD    +41 61 265 44 04    michael.dickenmann@usb.ch   
University Hospital Bern Recruiting
Bern, Switzerland, 3010
Contact: Uyen Huynh-Do, MD    +41 31 632 31 44    Uyen.Huynh-Do@insel.ch   
Hopitaux Universitaires de Genève Recruiting
Genève, Switzerland, 1205
Contact: Christian Van Delden, MD       Christian.vanDelden@hcuge.ch   
Principal Investigator: Christian Van Delden, MD         
CHUV Recruiting
Lausanne, Switzerland, 1011
Contact: Oriol Manuel, MD    +41213143020    oriol.manuel@chuv.ch   
Contact: Matteo Mombelli, MD    +41795565615    matteo.mombelli@chuv.ch   
Epatocentro Ticino Recruiting
Lugano, Switzerland, 6900
Contact: Christian Garzoni, MD    +41 91 960 85 03    christian.garzoni@gmail.com   
Canton Hospital St-Gallen Not yet recruiting
Saint Gallen, Switzerland, 9007
Contact: Isabelle Binet, MD    +41 71 494 10 32    Francoise-Isabelle.Binet@kssg.ch   
UniversitätsSpital Zürich Recruiting
Zürich, Switzerland, 8091
Contact: Nicolas Mueller, MD       Nicolas.Mueller@usz.ch   
Principal Investigator: Nicolas Mueller, MD         
Sponsors and Collaborators
Oriol Manuel
University Hospital, Basel, Switzerland
University of Bern
University Hospital, Geneva
University of Zurich
Cantonal Hospital of St. Gallen
Fondazione Epatocentro Ticino

Publications of Results:

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Responsible Party: Oriol Manuel, Principal Investigator, University of Lausanne Hospitals
ClinicalTrials.gov Identifier: NCT03699839     History of Changes
Other Study ID Numbers: 2017-01922
First Posted: October 9, 2018    Key Record Dates
Last Update Posted: November 16, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Oriol Manuel, University of Lausanne Hospitals:
Vaccination
Adjuvanted vaccine
High-dose vaccine

Additional relevant MeSH terms:
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Orthomyxoviridae Infections
RNA Virus Infections
Respiratory Tract Infections
Influenza, Human
Virus Diseases
Respiratory Tract Diseases
Vaccines
MF59 oil emulsion
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic