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

• ClinicalTrials.gov Identifier: NCT03699839
• Recruitment Status: Completed
• First Posted: October 9, 2018
• Last Update Posted: December 17, 2020
• Sponsor: Oriol Manuel
• Collaborators: University Hospital, Basel, Switzerland; University of Bern; University Hospital, Geneva; University of Zurich; Cantonal Hospital of St. Gallen; Fondazione Epatocentro Ticino; Cantonal Hospital Chur; Hospitales Universitarios Virgen del Rocío
• Information provided by (Responsible Party): Oriol Manuel, University of Lausanne Hospitals

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 619 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
• Actual Primary Completion Date: August 15, 2020
• Actual Study Completion Date: August 15, 2020

Arms and Interventions

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).

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Locations

Spain

Hospitales Universitarios Virgen del Rocio

Seville, Andalucia, Spain, 41013

Switzerland

Cantonal Hospital Chur

Chur, Graubunden, Switzerland, 7000

University Hospital Basel

Basel, Switzerland, 4031

University Hospital Bern

Bern, Switzerland, 3010

Hopitaux Universitaires de Genève

Genève, Switzerland, 1205

CHUV

Lausanne, Switzerland, 1011

Epatocentro Ticino

Lugano, Switzerland, 6900

Canton Hospital St-Gallen

Saint Gallen, Switzerland, 9007

UniversitätsSpital Zürich

Zürich, Switzerland, 8091

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

Cantonal Hospital Chur

Hospitales Universitarios Virgen del Rocío

More Information

Publications of Results:

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 4:212-9. doi: 10.1111/ajt.12113.

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, Müller 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.

• Responsible Party: Oriol Manuel, Principal Investigator, University of Lausanne Hospitals
• ClinicalTrials.gov Identifier: NCT03699839
• Other Study ID Numbers: 2017-01922
• First Posted: October 9, 2018
• Last Update Posted: December 17, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

Influenza, Human; Orthomyxoviridae Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Vaccines; Immunologic Factors; Physiological Effects of Drugs