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A Randomised, Double-blind, Placebo-controlled Phase IIb Trial to Test FLU-v Vaccine

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02962908
Recruitment Status : Completed
First Posted : November 15, 2016
Results First Posted : April 8, 2019
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
Seventh Framework Programme
University of Groningen
University Medical Center Groningen
Robert Koch Institut
Norwegian Institute of Public Health
Information provided by (Responsible Party):
PepTcell Limited

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.


Condition or disease Intervention/treatment Phase
Influenza Biological: FLU-v Biological: adjuvanted FLU-v Biological: Saline Biological: Adjuvanted placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 175 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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 Start Date : August 2016
Actual Primary Completion Date : July 18, 2017
Actual Study Completion Date : July 18, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu

Arm Intervention/treatment
Experimental: Group 1
(n=74): FLU-v on Day 0 and Day 21
Biological: FLU-v
Subcutaneous injection in the upper arm with 500 ug of FLU-v as 0.5ml suspension in 0.01M HCl and 0.01M NaOH

Experimental: Group 2
(n=74): adjuvanted FLU-v on Day 0, saline (0.5mL) on Day 21
Biological: adjuvanted FLU-v
Subcutaneous injection in the upper arm with 500ug of FLU-v emulsified in 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection

Biological: Saline
Subcutaneous injection in the upper arm with 0.5ml of saline
Other Name: NaCl

Placebo Comparator: Group 3
(n=37): saline solution (0.5ml) on Day 0 and Day 21
Biological: Saline
Subcutaneous injection in the upper arm with 0.5ml of saline
Other Name: NaCl

Placebo Comparator: Group 4
(n=37): Adjuvanted placebo on Day 0, saline (0.5mL) on Day 21
Biological: Saline
Subcutaneous injection in the upper arm with 0.5ml of saline
Other Name: NaCl

Biological: Adjuvanted placebo
Subcutaneous injection in the upper arm with an emulsion made with 0.25ml of Montanide ISA-51 adjuvant (Seppic, France) and 0.25ml of water for injection




Primary Outcome Measures :
  1. CD4+ and CD8+ Th1 Cellular Immunogenicity on Day 42 [ Time Frame: day 0 to day 42 ]
    Comparison of the TH1 response in the treatment arms compared to placebo from baseline to day 42 following vaccination, calculated as the median fold change in the number of CD4+ and CD8+ T cells positive for IFN-gamma, TNF-alpha, IL-2 and CD107a. Fold change is calculated as the number of cells on day 42 divided by number of cells on day 0.

  2. CD4+ and CD8+ Th1 Cellular Immunogenicity on Day 180 [ Time Frame: Day 0 to day 180 ]
    Comparison of the TH1 response in the treatment arms compared to placebo from baseline to day 180 following vaccination, calculated as the median fold change in the number of CD4+ and CD8+ T cells positive for IFN-gamma, TNF-alpha, IL-2 and CD107a. Fold change is calculated as the number of cells on day 180 divided by number of cells on day 0.

  3. 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) [ Time Frame: prevaccination, day 42 (21 days after last vaccination) and day 180. ]
    To compare the number of subjects that showed at least a two-fold increase on day 42 and day 180 following vaccination in the number of CD4+and CD8+ T-cells secreting TH1 cytokines in all groups.

  4. Percentage of CD4+ and CD8+ TH1 Cytokine Responders Determined by Mixture Models for Single-cell Assays (MIMOSA) [ Time Frame: day 0 to day 42 and day 180 ]
    To compare the number of subjects identified as responders for cytokine markers as determined by MIMOSA analysis (Responders based on a false discovery rate derived P-value <0.05).

  5. IFN-gamma Responses Measured by ELISA [ Time Frame: day 0 to day 42, day 0 to day 180 ]
    Median fold change in IFN-gamma secretion from PBMCs stimulated in vitro with FLU-v antigens. IFN-gamma secretion was measured by ELISA.Fold change was measured as secretion on day 42 divided by secretion on day 0, and secretion on day 180 divided by secretion on day 0.

  6. Percentage of Responders on Day 42 and Day 180 for IFNgamma Secretion by PBMCs [ Time Frame: prevaccination (day 0) to postvaccination (day 42 and day 180) ]
    Responders were defined as subjects having at least a two-fold increase in the amount of IFNg secreted on day 42 and day 180 compared the amount secreted on day 0. IFNg was measured by ELISA

  7. Solicited AEs [ Time Frame: until 21 days after the last dosing of the study vaccine ]
    To evaluate the solicited AEs in all subjects


Secondary Outcome Measures :
  1. Antibody Responses to FLU-v [ Time Frame: prevaccination, day 42 (21 days after last vaccination) and day 180. ]
    To evaluate the IgG levels as a measure of antibody responses to FLU-v on day 0 (baseline) and on days 42 and 180 following FLU-v vaccination. IgG antibodies were measured by ELISA. The geometric mean for each treatment group was provided.

  2. Th2 Cytokine Responses (IL-4) [ Time Frame: prevaccination, day 42 (21 days after last vaccination) and day 180. ]
    To evaluate the level of TH2 cytokines (IL-4) from baseline in all groups 42 and 180 days following FLU-v vaccination.


Other Outcome Measures:
  1. Unsolicited AEs and SAEs [ Time Frame: From the start of the vacciantion until study completion for each subject, approximately no more than 7 months ]
    To evaluate unsolicited AEs and SAEs in all subjects

  2. Percentage of Participants Who Tested Positive for Influenza Strains [ Time Frame: For up to 4 months during the influenza season ]
    During the influenza season (Dec 2016 to March 2017), fully vaccinated subjects will contact the trial center immediately if they feel unwell for 24h, with a sudden onset of flu-like symptoms. The medical staff will arrange for a nasopharyngeal swab to be performed if the subject has at least one respiratory (cough, sore throat, shortness of breath, runny nose, stuffy nose, sneezing and earache) and one systemic symptom (fever, malaise, headache and myalgia (muscle and joint pain). Swabs should be taken from the reported subjects within 3 days from the trial center being contacted or within 4 days of the onset of symptoms, whatever time is shorter.

  3. Severity of Symptoms in RT-PCR Influenza-confirmed Subjects. [ Time Frame: Symptoms experienced during an influenza infection episode, approximately 7-10 days. ]
    Subjects recorded daily influenza symptoms from December 2016 up to March 2017. Subjects with a sudden onset of at least one respiratory and one systemic symptom were swabbed. If the results were positive for influenza then the symptoms were included in the analysis. The duration of symptoms was recorded as the number of symptomatic days during the influenza episode. Fever (≥38oC), malaise, headache, myalgia (muscle and joint pain), cough, sore throat, shortness of breath, runny nose, stuffy nose, sneezing and earache were scored on a severity scale of 0 to 3 (0: no symptom, 1: mild, 2: moderate, 3: severe). The daily severity score was the sum of the severity score for all symptoms listed above on a single day. The total score was the sum of all daily scores during the influenza episode. The peak score was the highest daily score during the influenza episode. The average score was the total score divided by the number of days the influenza episode lasted.

  4. Duration of Influenza Symptoms in RT-PCR Confirmed Infected Subjects. [ Time Frame: During an influenza episode ]
    Subjects recorded daily influenza symptoms from December 2016 up to March 2017. Subjects with a sudden onset of at least one respiratory and one systemic symptom were swabbed. If the results were positive for influenza then the symptoms were included in the analysis. The duration of symptoms was recorded as the number of symptomatic days during the influenza episode. The following symptoms were recorded: fever (≥38oC), malaise, headache, myalgia (muscle and joint pain), cough, sore throat, shortness of breath, runny nose, stuffy nose, sneezing and earache.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

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): NCT02962908


Locations
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Netherlands
Isala
Zwolle, Netherlands, 8025 AB
Sponsors and Collaborators
PepTcell Limited
Seventh Framework Programme
University of Groningen
University Medical Center Groningen
Robert Koch Institut
Norwegian Institute of Public Health
Investigators
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Principal Investigator: Paul Groeneveld, PhD Isala
  Study Documents (Full-Text)

Documents provided by PepTcell Limited:
Informed Consent Form  [PDF] July 6, 2016
Study Protocol  [PDF] April 28, 2017
Statistical Analysis Plan  [PDF] February 16, 2018

Additional Information:
Publications of Results:
Other Publications:

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Responsible Party: PepTcell Limited
ClinicalTrials.gov Identifier: NCT02962908    
Other Study ID Numbers: FLU-v 003
2015-001932-38 ( EudraCT Number )
First Posted: November 15, 2016    Key Record Dates
Results First Posted: April 8, 2019
Last Update Posted: September 16, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by PepTcell Limited:
broad
universal
vaccine
influenza
peptide
Tcell
UNISEC
Additional relevant MeSH terms:
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Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases