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Trial registered on ANZCTR


Registration number
ACTRN12620000548932
Ethics application status
Approved
Date submitted
21/04/2020
Date registered
8/05/2020
Date last updated
8/05/2020
Date data sharing statement initially provided
8/05/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of efficacy and safety of an enhanced influenza vaccination schedule in immunocompromised children undergoing treatment for cancer.
Scientific title
Evaluation of an enhanced influenza vaccination schedule in immunocompromised children undergoing treatment for cancer by assessment of cellular and humoral response

Secondary ID [1] 301087 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza infection 317157 0
Cancer 317158 0
Response to influenza vaccine 317159 0
Condition category
Condition code
Cancer 315309 315309 0 0
Children's - Brain
Cancer 315310 315310 0 0
Children's - Leukaemia & Lymphoma
Cancer 315311 315311 0 0
Children's - Other
Infection 315312 315312 0 0
Other infectious diseases
Infection 315313 315313 0 0
Studies of infection and infectious agents
Respiratory 315314 315314 0 0
Other respiratory disorders / diseases
Public Health 315315 315315 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study interventions

Participants in the 6 months to <9 years group will be asked to present for 4 visits in total, spaced by 4-6 weeks. The first 3 visits will comprise of the influenza vaccine injection and obtaining study blood samples. The 4th and last visit is an exit visit that will comprise of obtaining study samples only.

Participants in the 9 years to 18 years group will be asked to present for 3 visits in total, spaced by 4-6 weeks. The first 2 visits will comprise of the influenza vaccine injection and obtaining study blood samples. The 3rd and last visit is an exit visit that will comprise of obtaining study samples only.

Each visit (with the exception of the exit visit) will comprise of two main components:

1. A blood sample will be taken to perform the following tests:
a. A full blood count (FBC) including the differential will be requested prior each vaccination. Vaccination will only proceed if absolute neutrophil count (ANC) is geater than or equal to 0.5 x 109/L, as per the Australian Immunisation Handbook 10th Edition recommendations.
b. Lymphocyte subsets (Visit 1 only). This is to measure the number of B-cells, CD4 and CD8 positive T-cells, NK cells and memory T and B-cells.
c. IgG, IgA and IgM levels (Visit 1 only).
d. Cellular response to the influenza vaccine.
e. HI antibody titer measurement.

2. Influenza vaccine injection will be given (with the exception of the exit visit) to the participant after a baseline medical check. Participants found to be physically unfit, after an examination performed by the oncology team doctor, will have their vaccination postponed. The influenza vaccine injection will be administered by an oncology nurse either in the outpatient or inpatient setting. A minimum 30 minute observation period will be provided to monitor for development of an acute adverse event following vaccination (AEFI).

Study visits will be spaced by a minimum of 4 weeks and maximum of 6 weeks as per the Australian Immunisation Handbook 10th Edition recommendations regarding timing of influenza vaccination and to allow for flexibility in arranging suitable appointments for study participants.

The influenza vaccine used in the study will be:

FluQuadri
For all study participants irrespective of the age
Administration route: intramuscular injection
Sponsor: Sanofi-Aventis Australia
Quadrivalent inactivated influenza vaccine
Each 0.5 mL pre-filled syringe contains:
15 µg hemagglutinin for each of the 4 recommended influenza virus strains
=100 µg formaldehyde
=250 µg octoxinol 9
=1 µg ovalbumin

Any AEFIs will be documented at each visit. Each participant’s parent/guardian will also be contacted by telephone one week after the influenza vaccination to document any delayed AEFIs related to the influenza vaccine.

Participants who develop an influenza-like illness (ILI) during the study period will be asked to contact the study team, except in the case of a fever defined as an isolated temperature of more or equal to 38.5°C, or two temperatures of more or equal to 38.0°C in 12 hours; when they would present to the Emergency Department as per the standard Oncology Department guidelines.

ILI is defined by the following criteria, occurring greater than 72 hours after influenza vaccine administration:
• Elevated temperature (>37.5°C) or a clear history of fever (chills, rigors)
AND
• Presence of at least one respiratory symptom such as:
o Cough
o Sore throat
o Rhinorrhoea

Participants reporting symptoms of an ILI will be asked to present for a review. A nasopharyngeal test will be collected for virological testing at the time of the visit should their symptoms be objectively confirmed by the study team. Patients who present to the Emergency Department with a fever will be admitted to the Oncology ward as per the standard pathway and a nasopharyngeal test will be collected for virological testing.
Intervention code [1] 317399 0
Prevention
Intervention code [2] 317400 0
Treatment: Drugs
Comparator / control treatment
There is no control group in this trial.
Each participant serves as a self control with base-line parameters obtained at Visit 1.


Control group
Uncontrolled

Outcomes
Primary outcome [1] 323567 0
Immune response to inactivated influenza vaccine in children undergoing treatment for cancer by assessing influenza-specific hemagglutinin inhibition (HI) antibody titers from blood samples
Timepoint [1] 323567 0
4-6 weeks post each influenza vaccine administration with the primary outcome timepoint being 4-6 weeks after the 3rd visit (visit 4) in those less than 9 years old and after the 2nd visit (visit 3) in those 9-18 years old.
Primary outcome [2] 323568 0
Immune response to inactivated influenza vaccine in children undergoing treatment for cancer by assessing levels of IFN-gamma produced by T lymphocytes measured using sandwich immune-enzyme technology (ELISpot)
Timepoint [2] 323568 0
4-6 weeks post each influenza vaccine administration with the primary outcome timepoint being 4-6 weeks after the 3rd visit (visit 4) in those less than 9 years old and after the 2nd visit (visit 3) in those 9-18 years old.
Primary outcome [3] 323569 0
Detection of adverse effects following immunisation (AEFIs)

Immediate AEFIs, ie anaphylaxis will be detected against base-line blood pressure and heart rate obtained for each study participant prior to influenza vaccine administration.

Delayed AEFIs are divided into two main groups - local symptoms, ie erythema, swelling, induration, tenderness, pain; and systemic symptoms, ie fever, irritability, drowsiness, decreased appetite, vomiting, diarrhoea, myalgia, headache. Participants primary care givers will be provided with a 7-day Side Effect Diary at the time of the influenza vaccine administration. This consists of the front page (table for documentation of AEFIs) and the back page (list of most common local and systemic symptoms with attached grading).
Timepoint [3] 323569 0
Each participant will be observed for a minimum of 30min post influenza vaccine administration to check for any signs or symptoms of anaphylaxis such as drop in blood pressure and increased heart rate.

Each participants' primary care giver will be asked to complete a 7-day Side Effect Diary to capture any mild or moderated local or systemic AEFIs. They will be advised to immediately contact study investigators should their child develop a severe AEFI.

Study investigators will contact each participant 7 days post administration of the influenza vaccine to check on any AEFIs.

Each participant will be asked about any delayed AEFIs occurring beyond 7 days post the influenza vaccination at their following visit.
Secondary outcome [1] 382241 0
Development of influenza like infection (ILI) assessed by nasopharyngeal swab
Timepoint [1] 382241 0
Participants reporting symptoms of ILI will be asked to present for a review at any timepoint during the study, or a maximum of 24 weeks from the 1st influenza vaccine injection in the last recruited participant.
Secondary outcome [2] 382242 0
Explore the kinetics of influenza vaccine immune response assessed by the measurement of HI antibody titers (humoral response) and Interferon-gamma levels (cellular response).
Timepoint [2] 382242 0
Additional blood samples will be obtained between visits, from base-line to maximum of 6 weeks post last vaccine administration. No set time points will be established as these samples will only be obtained if participants are having blood taken or their central line accessed for other purposes.
Secondary outcome [3] 382553 0
This is a composite secondary outcome of measuring immune parameters: total lymphocyte count, B-cell count, CD4 and CD8 T-cell count, NK cell count, memory B cell and T cell count, and immunoglobulin levels; in the whole blood and serum.
Timepoint [3] 382553 0
This will be measured at base-line, immediately prior the first influenza vaccine injection.

Eligibility
Key inclusion criteria
Male or female children of grater than or equal to 6 months and lest than or equal to 18 years of age undergoing therapy for cancer or within 6 months of completion of treatment.

Children immunosuppressed as a result of cancer therapy. This includes chemotherapy and radiotherapy but excludes biological agents such as Rituximab.

Patients receiving the influenza vaccine outside the hospital will be included provided that the dose and type of vaccine corresponds to the one recommended by the Health Department.

Minimum age
6 Months
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Known contraindication to influenza vaccine as defined by the Australian Immunisation Handbook 10th Edition.

Patients who have received immunoglobulins within the last three months preceding the influenza vaccination.

Patients with a history of Guillain-Barre syndrome post influenza vaccine.

Patients post autologous or allogeneic haematopoietic stem cell transplantation.

Patients with non-malignant haematological disease.

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical design

This is a non-randomised open label study of influenza vaccine response to an enhanced immunisation schedule in a population of paediatric patients treated for cancer.

The primary aim will be to assess the within-patient differences in immune response after repeat doses of the inactivated influenza vaccine in children and adolescents who are being treated for cancer: for those greater than or equal to 9 years of age comparing two doses to one dose, and for those <9 years of age comparing three doses to two doses.

Two separate methods of immune response evaluation will be assessed:
1. The humoral response will be assessed by measuring HI antibodies in participants’ sera produced by stimulated B-lymphocytes in response to the influenza vaccine.
2. The cellular response will be assessed by measuring INF-gamma produced by stimulated T-lymphocytes in vitro in response to an influenza vaccine concentrate.

Sample size estimation

Sample size calculations have been based on differences in the paired proportions of vaccinated children demonstrating immunogenicity (seroprotection and seroconversion) after the standard number of doses and the extra dose, respectively. If the immunogenicity status of 15% of participants changes over the two time-points, 60 participants would have 80% power to detect an increase of 13.7% in the seroprotection and seroconversion rates and 80 participants would have 80% power to detect an increase of 12.0% (McNemar test, a=0.05). If discordancy in the immunogenicity status is observed in 20% of participants, the study would have 90% power to detect differences in rates of 18.1% and 15.8% for 60 and 80 participants, respectively. These rate increases would seem reasonable given increases achieved in healthy children after fewer doses.

Statistical analysis

The primary immunogenicity endpoints will be the percentage of participants achieving seroprotection and seroconversion. To assess if the extra vaccination dose improves immunogenicity, a McNemar test will be used to assess the difference in these percentages as calculated from the immunogenicity status obtained after the last two doses of each individual. We will also evaluate geometric mean titers of HI antibodies at baseline and after vaccination. The geometric mean fold increase (GMFI), with 95% confidence intervals, will be calculated for each strain, using a log-normal approximation for the distribution of HI antibody levels pre and post vaccination.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 16523 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 30079 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 305523 0
Government body
Name [1] 305523 0
WA Cancer and Palliative Care Network Unit, Department of Health
Address [1] 305523 0
189 Royal Street
East Perth
WA 6004
Country [1] 305523 0
Australia
Funding source category [2] 305530 0
Government body
Name [2] 305530 0
PathWest
Address [2] 305530 0
QEII Medical Centre J Block
Hospital Avenue
Nedlands
WA 6009
Country [2] 305530 0
Australia
Funding source category [3] 305531 0
Government body
Name [3] 305531 0
Perth Children's Hospital, Child and Adolescent Health Service
Address [3] 305531 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country [3] 305531 0
Australia
Funding source category [4] 305532 0
Charities/Societies/Foundations
Name [4] 305532 0
Telethon Kids Institute
Address [4] 305532 0
Telethon Kids Institute
15 Hospital Avenue
Nedlands
WA 6009
Country [4] 305532 0
Australia
Primary sponsor type
Government body
Name
CAHS
Address
Child and Adolescent Health Service
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country
Australia
Secondary sponsor category [1] 305935 0
Individual
Name [1] 305935 0
Jennifer McConnell
Address [1] 305935 0
Perth Children's Hospital
15 Hospital Avenue
Nedlands
WA, 6009
Country [1] 305935 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305835 0
Child and Adolescent Health Service Human Research Ethics Committe
Ethics committee address [1] 305835 0
15 Hospital Avenue
Nedlands
WA, 6009
Ethics committee country [1] 305835 0
Australia
Date submitted for ethics approval [1] 305835 0
19/12/2019
Approval date [1] 305835 0
03/01/2020
Ethics approval number [1] 305835 0
RGS0000003544

Summary
Brief summary
This study aims to evaluate the efficacy and safety of an enhanced influenza vaccination schedule in immunocompromised children undergoing treatment for cancer.

Who is it for?
You may be eligible to join the study if you are aged between 6 months and 18 years, and undergoing therapy for cancer or within 6 months of completion of treatment.

Study details
All participants in this study will receive an influenza vaccine: 3 doses given at least 4 weeks apart for children younger than 9 years and 2 doses given at least 4 weeks apart for children aged 9 years or older.

Blood samples will be collected throughout the study to determine immune response to the vaccine. Safety of the enhanced vaccine schedule will be closely monitored in each participant throughout the study.

Overall, we aim to establish an optimised and safe influenza immunisation schedule for children and adolescents undergoing treatment for cancer.


Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101762 0
Dr Eliska Furlong
Address 101762 0
Perth Children Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 101762 0
Australia
Phone 101762 0
+61 8 6456 0241
Fax 101762 0
Email 101762 0
eliska.furlong@health.wa.gov.au
Contact person for public queries
Name 101763 0
Dr Eliska Furlong
Address 101763 0
Perth Children Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 101763 0
Australia
Phone 101763 0
+61 8 6456 0241
Fax 101763 0
Email 101763 0
eliska.furlong@health.wa.gov.au
Contact person for scientific queries
Name 101764 0
Dr Eliska Furlong
Address 101764 0
Perth Children Hospital
15 Hospital Avenue
Nedlands
WA 6009
Country 101764 0
Australia
Phone 101764 0
+61 8 6456 0241
Fax 101764 0
Email 101764 0
eliska.furlong@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 7701 0
Study protocol
Citation [1] 7701 0
Link [1] 7701 0
Email [1] 7701 0
Other [1] 7701 0
Type [2] 7702 0
Informed consent form
Citation [2] 7702 0
Link [2] 7702 0
Email [2] 7702 0
Other [2] 7702 0
Type [3] 7703 0
Ethical approval
Citation [3] 7703 0
Link [3] 7703 0
Email [3] 7703 0
Other [3] 7703 0
Summary results
No Results