Clinical trial NCT02962908: A Randomised, Double-blind, Placebo-controlled Phase IIb Trial to Test FLU-v Vaccine
Official title: A Randomised, Double-blind, Placebo-controlled, Single-centre Phase IIb Trial as Part of the EU-funded UNISEC Project to Assess the Immunogenicity and Safety of Different Formulations and Dosing Regimens of FLU-v Vaccine in Healthy Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Influenza
Keywords: broad
universal
vaccine
influenza
peptide
Tcell
UNISEC
Lead sponsor: PepTcell Limited
Sponsor class: INDUSTRY
Collaborators: name: Seventh Framework Programme
name: University of Groningen
name: University Medical Center Groningen
name: Robert Koch Institut
name: Norwegian Institute of Public Health
First posted: 2016-11-15
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: FLU-v is a vaccine that aims to protect against a wide range of flu viruses. The purpose of this study is to measure the immune responses induced by FLU-v vaccine. This study will look at how safe FLU-v is when administered and how successful it is in preventing flu or reducing the severity of the flu symptoms.

The study requires 222 healthy volunteers 18-60 years old. Participation in the study will take a maximum of 7 months and consists of 5 visits. During visit 1, subjects will be examined by a doctor to make sure they are eligible to enter the study. A 15ml blood sample (a tablespoon) will be taken to check general health followed by a general physical exam. Medical history and some personal information will be collected. Subjects that have received the traditional flu vaccine in the past 6 months, and those females who are pregnant or breastfeeding will not be allowed in the study. Subjects of childbearing age must agree to use effective contraceptive methods.

At visit 2, subjects will be randomly allocated to one of the four treatment groups summarised below:

* Treatment 1: FLU-v (test vaccine) at the start of the study (Day 0) and then again 21 days later
* Treatment 2: FLU-v (test vaccine) with an additional substance added \[known as Montanide ISA 51\] which improves the effect of the test vaccine. Injection will be given on Day 0 and then Placebo (no test vaccine) alone 21 days later
* Treatment 3: Placebo (no test vaccine) injection on Day 0 and then 21 days later
* Treatment 4: Placebo (no test vaccine) with an additional substance added \[known as Montanide ISA 51\] on Day 0 and then Placebo (no test vaccine) alone 21 days later Treatment will be injected under the skin in the upper arm on day 0 (visit 2) and 21 days later (visit 3). Blood samples will be taken before treatment (day 0), and on days 42 (visit 4) and 180 (visit 5) to the immune responses induced by the vaccine.

Subjects will be asked to complete a diary card to write down any side effects that they may experience after vaccination. Subjects will also be asked to complete another diary card to document any flu-like symptoms experienced between December 2016 and March 2017, this time is officially considered as the flu season. During this period, if the subject experiences flu-like symptoms, a collection of a nose and tonsil swab will be arranged by the study site to confirm whether they have the flu or not.

Detailed description: Rationale: Current seasonal influenza vaccines mainly induce immune responses against viral membrane glycoproteins. These proteins, however, undergo continuous mutations by a process called antigenic drift. To prevent immune escape, annual vaccination with the latest predicted viral strains is adopted. Such vaccination strategy not only poses inconvenience and cost-inefficiency, but also results in poor protective effectiveness when the vaccinated strains are mismatched with the actual circulating strains. The latter point is especially of concern during a pandemic outbreak, when a large geographical area is affected and the general population is naïve to the newly re-assorted viral strain due to antigenic shift.

Objective: To evaluate the safety and immunogenicity of the influenza vaccine (FLU-v, as a suspension or adjuvanted as emulsion) targeting conserved immunogenic regions of influenza A and B viruses in healthy adults, in particular to show that the TH1 cytokine response at 42 and 180 days after the first injection is greater in the adjuvanted FLU-v and unadjuvanted FLU-v than in the placebo.

Study design: A total of 222 study participants will be recruited. The study follows a factorial design where the two factors are treatment (FLU-v / placebo) and formulation (unadjuvanted / suspension, adjuvanted / emulsion). Subjects will be randomised in two strata (age 18 to 40, age 41 to 60) to one of the following treatment regimens:

* Group 1 (n=74): FLU-v (unadjuvanted) as a suspension in pH neutral HCl/NaOH (0.5mL) on Day 0 and Day 21
* Group 2 (n=74): (0.5mL) ISA-51-adjuvanted FLU-v emulsified in water for injection (WFI) on Day 0, saline (0.5mL) on Day 21
* Group 3 (n=37): saline solution (0.5mL ) on Day 0 and Day 21
* Group 4 (n=37): WFI and ISA-51 emulsion (0.5mL) on Day 0, saline (0.5mL) on Day 21

Each administration will be given subcutaneously. Solicited and unsolicited adverse events (AEs) will be collected by AE questionnaire/diary card until day 42. Adverse events (AEs) and serious adverse events (SAEs) will be collected for the entire study period. The treatments will be administered starting in third quarter of 2016 in order to provide protection for the subsequent influenza season starting in December 2016. Blood samples will be taken from all subjects on day 0 (before FLU-v vaccination), 42 (21 days after the second dosing) and 180 (159 days after the second dosing) for the evaluation of FLU-v-specific cellular and humoral immune responses. Clinical symptom scores to ascertain severity and the incidence of RT-PCR-confirmed influenza A and/or B infection will be recorded during the subsequent influenza season (December 2016 to March 2017) to decide clinical efficacy of the tested vaccines.

Study population: Healthy volunteers aged 18-60 years. Intervention: FLU-v investigational influenza vaccine lyophilised product containing 500 micrograms of total peptides reconstituted in either 0.01M HCl (0.25ml) and 0.01M NaOH (0.25ml) to achieve a volume of 0.5ml, or emulsified in WFI (water for injection, 0.25ml) and ISA-51 (0.25ml) to achieve a volume of 0.5ml.

Primary study parameters/endpoints: For immunogenicity: To compare the change from baseline (Day 0) between treatments in cellular immune responses, specifically TH1 cytokines, in all groups 42 and 180 days following FLU-v vaccination. For safety: (1) To evaluate the solicited AEs in all subjects until 21 days after the last dosing of the study vaccine (FLU-v); (2) To evaluate the unsolicited AEs and SAEs in all subjects for the entire study period after the first dosing of FLU-v.

Secondary study parameters/endpoints: To evaluate the humoral immune responses specific to FLU-v and TH2 cytokines from baseline in all groups 42 and 180 days following FLU-v vaccination.

Exploratory study parameters/endpoints: For immunogenicity: To evaluate the change from baseline in cellular immune responses based on additional CMI assays such as ELISPOT (Enzyme-Linked ImmunoSpot) in all groups at 42 and 180 days following FLU-v vaccination, in a subset of subjects chosen at random.

Clinical efficacy: (1) To evaluate the efficacy of FLU-v vaccine in reducing the incidence of RT-PCR confirmed influenza A and/or B infections in all subjects during the influenza season 2016-2017. (2) To evaluate the efficacy of FLU-v vaccine in the reduction of symptom score among RT-PCR confirmed influenza A and/or B infection cases during the influenza season 2016-2017. The relationship between efficacy and cellular and humoral response will be explored if possible.

The effect of previous influenza vaccination on the immunogenicity of FLU-v will be assessed in a post-hoc exploratory analysis after stratification of the data based on exposure to the influenza vaccine in the previous 24 months or over.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

The intended application of the IMP is as a prophylactic vaccine to prevent influenza virus infection by inducing an enhanced influenza-specific immune response. The FLU-v vaccine is designed to be delivered either as a naturally particulate suspension (i.e. no adjuvant) or emulsified in adjuvant. Particulate and emulsified protein preparations are preferentially taken up by phagocytic cells (e.g. dendritic cells) responsible for inducing primary immune responses.

Treatment with FLU-v of up to four doses of 263 μg/occasion or up to two doses of 553 μg/occasion, with or without adjuvant, was well tolerated in animals with no signs of systemic toxicity. In pre-clinical studies, subcutaneous administration of ISA 51 resulted in no systemic toxicity. At the injection sites and occasionally in adjacent tissue the injected material remained surrounded by a mild chronic inflammatory response. As the IMP is provided in one presentation (500 μg of the combined peptide) in lyophilized form for suspension in a sealed single-use vial, overdose is highly unlikely.

In a single centre, randomised, double blind phase I study of the safety, tolerability and immunogenicity of FLU-v no safety or tolerability concerns were identified at the doses administered (250 μg and 500 μg FLU-v) to the subjects in this clinical study and no safety or tolerability concerns were identified following administration of the adjuvant to the subjects (1). FLU-v vaccine candidate was demonstrated to be immunogenic in humans, as measured by ex vivo γ-interferon production (1).

Clinical experience with Montanide ISA 51 dates back to the 1990s and most trials were related to cancer and Acquired Immune Deficiency Syndrome (AIDS). Currently, cancer trials in melanoma, colorectal, prostate, cervical, brain cancer and leukemia are ongoing. Frequency of vaccination is often between 2 and 4 weeks, and the number of injections can reach up to 40. Route of immunization is most often subcutaneous and volume of injection can reach up to 3mL. Most common local reactions are local pain, tenderness, erythema and granuloma at the injection site. Less frequently, mild to moderate transient indurations and swelling are described. General reactions are mainly 'flu-like symptoms such as chills, fever and headaches. Lethargy and nausea are also observed. The intensity is usually mild or moderate. No biological changes are generally observed. As the Placebo vaccine is provided in a sealed single-use vial, overdose is highly unlikely (Influenza virus (FLU-v) vaccine Investigator's Brochure, Edition 2.0, 07 September 2015).

Eligibility criteria: Inclusion Criteria:

* Healthy males or healthy non-pregnant females (as indicated by a negative blood pregnancy test done during the screening visit) between the ages of 18 and 60 years, inclusive;
* Women of childbearing potential (not surgically sterile or postmenopausal for greater than or equal to one year) and men must agree to practice appropriate contraception (a combination of barrier and hormonal methods for women and a condom for men) from screening and until at least 30 days (up to Study Day 51 for females) and 90 days (up to Study Day 111 for males), after the last vaccination.
* A subject is in good health, as determined by a comprehensive clinical assessment {vital signs (heart rate, blood pressure, oral temperature)}, blood chemistry test (electrolytes, renal/kidney function, liver function, C-reactive protein, complete blood count), medical history, general physical examination, self-reported illness} and the clinical judgment of the investigator;
* Able to understand and comply with planned study procedures;
* Provides signed informed consent form

Exclusion Criteria:

* Has a known allergy to any of the components of the vaccine.
* Has a history of severe reaction following immunization.
* Persons with immune deficiency/disorder, whether due to genetic defect, immunodeficiency disease, or immunosuppressive therapy.
* Women who have a positive pregnancy test during the screening visit or who are breastfeeding.
* Has a history of any of the following (reported by subjects):

  * Acute disseminated encephalomyelitis (ADEM);
  * Neoplastic disease - current or previous;
  * Asthma or severe allergic disease;
  * Bleeding disorders
  * Chronic Hepatitis B and/or C infection;
  * Chronic liver disease;
  * Diabetes mellitus;
  * Guillain-Barré syndrome;
  * HIV;
  * Rheumatoid arthritis or other autoimmune diseases;
  * Severe renal disease;
  * Transplant recipients;
  * Unstable or progressive neurological disorders.
* Receipt of medicines/treatments that may affect evaluation of immunogenicity such as:

  * Oral or parenteral steroids, high-dose inhaled steroids (greater than 800 micrograms/day of beclomethasone dipropionate or equivalent) or other immunosuppressive or cytotoxic drugs (azathioprine (Imuran), cyclosporine (Neoral, Sandimmune, SangCya); monoclonal antibodies such as basiliximab (Simulect), daclizumab (Zinbryta), infliximab (Remicade), rituximab (MabThera), alemtuzumab (Campath and Lemtrada), omalizumab (Xolair), abatacept (Orencia), adalimumab (Humira and Exemptia) and etanercept (Enbrel)basiliximab (Simulect), daclizumab (Zenapax), and muromonab (Orthoclone OKT3); corticosteroids such as prednisone (Deltasone, Orasone); tacrolimus (Prograf, Advagraf, Protopic); Glatiramer acetate (Copaxone); Mycopehnolate (Cellcept); Sirolimus (Rapamune); (within 6 months of vaccination in this study)
  * Immunoglobulin or other blood products (plasma, blood cells, coagulation factors, haemoglobin)(within 3 months of vaccination in this study);
  * An experimental agent (vaccine, drug, biologic, device, blood product, or medication) within 1 month of vaccination in this study, or expects to receive an experimental agent (during the study period).
  * Influenza antiviral medication (Amantadine (Symmetrel); Rimantadine (Flumadine); Zanamivir (Relenza), Oseltamivir (Tamiflu) (within 4 weeks of vaccination in this study).
* Has received any influenza vaccine within 6 months of vaccination in this study.
* Has influenza-like illness (a sudden onset of symptoms and at least one of the four systemic symptoms-fever or feverishness, malaise, headache, myalgia and at least one of the three respiratory symptoms-cough, sore throat, shortness of breath) or acute respiratory infection (a sudden onset of symptoms and at least one of the four respiratory symptoms-cough, sore throat, shortness of breath, coryza (Rhinitis) and a clinician's judgement that the illness is due to an infection) within 6 months prior to vaccination in this study. These symptoms must have stopped the subject from carrying out their normal daily activities such as attending work or school for a period of at least 3 days.
* Has an acute illness, including an oral temperature greater than 38 degrees Celsius, within 1 week of vaccination.
* Has a history of alcohol or drug abuse within the last 2 years deemed unsuitable for inclusion by the investigator.
* Any abnormal haematology values and/or serum chemistries judged by the Investigator as clinically significant.

Primary outcomes:
measure: CD4+ and CD8+ Th1 Cellular Immunogenicity on Day 42
timeFrame: day 0 to day 42
measure: CD4+ and CD8+ Th1 Cellular Immunogenicity on Day 180
timeFrame: Day 0 to day 180
measure: Percentage of TH1 Cytokine Responders (Responders Defined as Those With >2 Fold Median Increase From Baseline in CD4+ and CD8+ T-cells Positive for Particular Cytokine)
timeFrame: prevaccination, day 42 (21 days after last vaccination) and day 180.
measure: Percentage of CD4+ and CD8+ TH1 Cytokine Responders Determined by Mixture Models for Single-cell Assays (MIMOSA)
timeFrame: day 0 to day 42 and day 180
measure: IFN-gamma Responses Measured by ELISA
timeFrame: day 0 to day 42, day 0 to day 180
measure: Percentage of Responders on Day 42 and Day 180 for IFNgamma Secretion by PBMCs
timeFrame: prevaccination (day 0) to postvaccination (day 42 and day 180)
measure: Solicited AEs
timeFrame: until 21 days after the last dosing of the study vaccine
Secondary outcomes:
measure: Antibody Responses to FLU-v
timeFrame: prevaccination, day 42 (21 days after last vaccination) and day 180.
measure: Th2 Cytokine Responses (IL-4)
timeFrame: prevaccination, day 42 (21 days after last vaccination) and day 180.
Other outcomes:
measure: Unsolicited AEs and SAEs
timeFrame: From the start of the vacciantion until study completion for each subject, approximately no more than 7 months
measure: Percentage of Participants Who Tested Positive for Influenza Strains
timeFrame: For up to 4 months during the influenza season
measure: Severity of Symptoms in RT-PCR Influenza-confirmed Subjects.
timeFrame: Symptoms experienced during an influenza infection episode, approximately 7-10 days.
measure: Duration of Influenza Symptoms in RT-PCR Confirmed Infected Subjects.
timeFrame: During an influenza episode
Locations:
city: Zwolle
country: Netherlands
facility: Isala
Study officials:
affiliation: Isala
name: Paul Groeneveld, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Pleguezuelos O, Dille J, de Groen S, Oftung F, Niesters HGM, Islam MA, Naess LM, Hungnes O, Aldarij N, Idema DL, Perez AF, James E, Frijlink HW, Stoloff G, Groeneveld P, Hak E. Immunogenicity, Safety, and Efficacy of a Standalone Universal Influenza Vaccine, FLU-v, in Healthy Adults: A Randomized Clinical Trial. Ann Intern Med. 2020 Apr 7;172(7):453-462. doi: 10.7326/M19-0735. Epub 2020 Mar 10.