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Trial registered on ANZCTR


Registration number
ACTRN12622000454774
Ethics application status
Approved
Date submitted
18/02/2022
Date registered
23/03/2022
Date last updated
31/01/2023
Date data sharing statement initially provided
23/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Influenza vaccination strategies in haematological cancers
Scientific title
A randomised trial of influenza vaccination strategies in patients with haematological malignancy
Secondary ID [1] 306463 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Influenza vaccination 325313 0
Haematological malignancy 325314 0
Condition category
Condition code
Infection 322705 322705 0 0
Other infectious diseases
Cancer 322706 322706 0 0
Myeloma
Cancer 322707 322707 0 0
Leukaemia - Chronic leukaemia
Cancer 322708 322708 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Influenza vaccination (intramuscular injection) comparing new two-dose strategies consisting of quadrivalent adjuvant influenza vaccine (Fluad Quad [AD]) followed by a second (AD) dose one month later (AD-AD, Arm 1) and quadrivalent standard dose (Afluria Quad [SD]) followed by a second SD one month later (SD-SD, Arm 2). Each dose is a 0.5 mL intramuscular injection into the deltoid muscle by the research nurse.

Patients will be randomised to one of two cohorts: (AD-AD, Arm 1) or (SD-SD, Arm 2). Patients will be vaccinated according to randomly allocated cohort to compare responses to two vaccination strategies.

Intervention code [1] 322894 0
Prevention
Comparator / control treatment
The comparator arm in the study is (SD-SD, Arm 2).
Control group
Active

Outcomes
Primary outcome [1] 330516 0
To determine and compare rates of seroconversion afforded by two novel influenza vaccination strategies (Arm 1 vs. Arm 2) among patients with haematological malignancy.

Seroconversion rate is defined by percentage of samples with prevaccination HI titre that is less than 1:10 and a postvaccination HI titre that is greater than or equal to 1:40 or a prevaccination titre that is greater than or equal to 1:10 and a greater than or equal to 4-fold increase in postvaccination titre.

To achieve this outcome, serum samples will be used to measure antibody titres. Serum antibody titre will be measured by haemagglutination inhibition (HI) assay or other serology assays such as microneutralisation assays or enzyme-linked immunosorbent assays (ELISA). The assays will detect antibodies to influenza strains included in the 2022 QIV vaccine.
Timepoint [1] 330516 0
Seroconversion rate at V3 (21-28 days post second dose)(Primary timepoint)
Seroconversion rate at V2 (21-28 days post first dose)
Secondary outcome [1] 406501 0
To determine and compared rates of seroprotection afforded by two novel influenza vaccination strategies (Arm 1 vs. Arm 2) among patients with haematological malignancy

Seroprotection rate is defined by percentage of samples with HI antibody titre of that is greater than or equal to 40. To acheive this outcome, serum samples will be used to measure antibody titres by HI assay or other serology assays.
Timepoint [1] 406501 0
Seroprotection rate at V3 (21-28 days post second dose)
Seroprotection rate at V2 (21-28 days post first dose)
Secondary outcome [2] 406504 0
To compare pre/post vaccination serum antibody titres by vaccination strategy

Geometric mean antibody titre (GMT) will be measured at baseline, 21-28 days after first vaccination, 21-28 days after second vaccination and six-month after first vaccination. To achieve this outcome, serum samples will be used to measure antibody titres by HI assay or other serological assays.
Timepoint [2] 406504 0
Measurement of GMT at baseline (V1)
Measurement of GMT at V2 (21-28 days post first dose)
Measurement of GMT at V3 (21-28 days post second dose)
Measurement of GMT at V4 (6 months after first dose)
Secondary outcome [3] 406505 0
To report rates of influenza-like illness (ILI)

Patients positive for influenza-like illness (ILI) will be reported by patients via SMS or collected via clinical medical records.
Timepoint [3] 406505 0
Clinical monitoring of ILI from the time of administration of the first vaccination to 6 months after the first vaccination.

On a weekly basis, patients will receive an SMS asking whether they have experienced ILI symptoms. Participants will also be asked at study visits if they have experienced an ILI and/or have their medical records reviewed. The number of ILI events will be recorded by the study coordinator throughout the study.

Secondary outcome [4] 406506 0
To describe the proportion of patients testing positive for influenza post-vaccination by vaccination strategy group
Timepoint [4] 406506 0
No fixed timepoint. Clinical monitoring for possible influenza virus infection from the time of administration of the first vaccination to 6 months after the first vaccination.

Participants that report an ILI will be asked to provide a nasal swab and present for a medical review by their regular treating team at their study site and if not feasible, with their general practitioner. Nasal swabs will be sent to the respective hospital microbiology laboratory for routine processing and virus identification as per standard clinical management. A respiratory multiplex PCR will be used to identify a range of respiratory viruses including influenza and SARS-CoV-2.

In conjunction with the treating team/general practitioner, clinical management (e.g treatment, admission) will follow standard of care for all patients with ILI including the use of antiviral therapy with oseltamivir if appropriate or if influenza subsequently confirmed. The results of any PCR testing undertaken by the participant will be determined from medical records.
Secondary outcome [5] 407088 0
To identify factors associated with achievement of seroconversion including vaccination history, type of disease, therapy.

Seroconversion at V3 will be determined by evaluating of serum samples and will utilise the following definition: Seroconversion rate is defined by percentage of samples with prevaccination HI titre that is less than 1:10 and a postvaccination HI titre that is greater than or equal to 1:40 or a prevaccination titre that is greater than or equal to 1:10 and a greater than or equal to 4-fold increase in postvaccination titre.

Clinical patient factors will be collected from electronic medical records utilising standardised case report forms developed for this study and stored on a password secured electronic database (Redcap).
Timepoint [5] 407088 0
The endpoint is the proportion of patients achieving seroconversion at V3 (21-28 days post second dose)

Eligibility
Key inclusion criteria
1. Male and female subjects aged greater than or equal to 18 years and currently receiving or have received within last 12 months treatment for MM, CLL and NHL. Women of child-bearing potential will need to be on adequate contraception.
2. Willing and able to provide a blood sample just prior to vaccination, 21-28 days post each dose and roughly 6 months post-vaccination.
3. Has not received influenza vaccine for the 2022 season
4. No known contraindications for influenza vaccination.
5. Willing to provide current mobile phone number for SMS reminders
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known contraindication(s) for QIV (e.g. hypersensitivity to vaccine component (including eggs)).
2. Recent stem cell transplant (less than 12 months)
3. Hypogammaglobulinaemia on immunoglobulin replacement
4. Recently (within last 7 days) unwell with a fever above 38°C.
5. Prior participation in the study (i.e. during the 2022 enrolment year)

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A computer generated randomisation list, generated by the study statistician will be uploaded to the online study database (REDCap). Randomisation will then occur within the study database upon enrolment of the participant and will perform by the study coordinators. The randomisation list will be concealed and password protected. Study investigators will not have access to the randomisation list.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomised 1:1 to AD-AD or SD-SD arms with stratification by underlying disease group (myeloma, CLL, NHL) to ensure balanced study population. The trial statistician will generate a randomisation sequence list for each disease group which will be uploaded into REDCap. This interactive web-based program will then be utilised to randomly allocate the treatment arm. Patients will be vaccinated according to randomly allocated cohort.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Single blind - study investigators performing data and laboratory analyses will be blinded to patient allocation.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Baseline comparisons
The data collected will be reviewed and cleaned prior to any statistical analyses. Cross-tabs will first be run for categorical variables to identify any unusual associations. The paper or electronic record will be checked to identify the data entry error. For continuous variables, histograms and boxplots will be plotted to identify outliers. All outliers will be checked against the paper/electronic records. Descriptive statistics will be calculated to summarise the data collected at baseline. Descriptive statistics to be reported will be frequency data for categorical variables, and mean, median, standard deviation and range for continuous variables.

Primary study objective:
To compare the rates of seroconversion afforded by two different influenza vaccination strategies (Arm 1 vs. Arm 2) among patients with haematological malignancy.

Analysis: The seroconversion rate at V3 will be calculated and compared among treatment arms using chi-square or fisher’s exact test (as appropriate), with seroconversion coded as 1 if the prevaccination HI titre <1:10 and a postvaccination HI titre =1:40 or a prevaccination titre =1:10 and a =4-fold increase in postvaccination titre and 0 if the fold-rise in titre is <4 or <1:40 post-vaccination.


Secondary study objectives:
1) To compare the rate of seroprotection by vaccination strategy (Arm 1 vs. Arm 2)

Analysis: The seroprotection rate at V3 of the two treatment arms will be calculated and compared using chi-square or fisher’s exact test (as appropriate), with seroprotection coded as 1 if the titre =40, and 0 if the titre is <40.


2) To compare the rate of seroconversion and seroprotection by vaccination strategy and disease groups (Arm 1 vs. Arm 2)

Analysis: The seroprotection and seroconversion rate at V3 by disease group in each treatment arm will be calculated and compared using chi-square or fisher’s exact test (as appropriate), with seroprotection/seroconversion coded as 1 if the titre =40/4-fold rise, and 0 if the titre is <40/<4-fold rise.

The seroprotection and seroconversion rate at V3 by cancer treatment (anti CD-20 treatment vs. no anti CD-20 treatment within 6 months) in each treatment arms will be calculated and compared using chi-square or fisher’s exact test (as appropriate), with seroprotection/seroconversion coded as 1 if the titre =40/4-fold rise, and 0 if the titre is <40/<4-fold rise.

3) To compare the rate of seroconversion and seroprotection by each dose
Analysis: The seroprotection and seroconversion rate at V2 and V3 in each treatment arm will be calculated and compared (by treatment arm, V2 vs. V3) using chi-square or fisher’s exact test (as appropriate), with seroprotection/seroconversion coded as 1 if the titre =40/4-fold rise, and 0 if the titre is <40/<4-fold rise.


4) To compare pre/post vaccination serum antibody titres
Analysis: The change in geometric mean antibody titres (GMT) will be compared between treatment arms (Arm 1 vs. Arm 2) and between times (V1 vs. V2, V1 vs. V3, and V1 vs. V4) in a difference of differences analysis; i.e.:
- Change in GMT V1 to V2 in Arm 1 versus change in GMT from V1 to V2 in Arm 2
- Change in GMT V1 to V3 in Arm 1 versus change in GMT from V1 to V3 in Arm 2
- Change in GMT V1 to V4 in Arm 1 versus change in GMT from V1 to V4 in Arm 2
Mixed effects linear regression will be used to estimate the GMT for each treatment arm at each of the specified times. The absolute differences in GMT between times and treatment arms will be calculated.


5) To compare the post-vaccination influenza-like illness attack rate by vaccination strategy group
Analysis: To compare the proportion of patients experiencing ILI by treatment arms, the ILI attack rate will be calculated in each group as the number of cases experiencing ILI in a particular vaccination group among all people in that vaccination group. This will be performed using chi-square test.


6) To describe the proportion of patients testing positive for influenza post-vaccination by vaccination strategy group
Analysis: To describe the proportion of laboratory-confirmed influenza infections by treatment arms, the influenza attack rate will be calculated in each group as the number of influenza-positive cases in a particular vaccination group among all people in that vaccination group.

7) To evaluate the factors associated with achievement of seroconversion, including underlying disease and treatment.
Analysis: To evaluate factors associated with seroconversion at V3, logistic regression will be used with seroconversion coded as 1 and non-cases coded as 0. The model will include at a minimum, the treatment arm and, if possible, disease and treatment factors. Models that include more than just the treatment arm will be assessed for potential overparameterization and multicollinearity before deciding to proceed.

8) To describe the proportion of patients achieving seroprotection and seroconversion by treatment arms for each influenza season, the rate will be calculated as the number of patients achieving seroconversion and seroprotection at V3 in a particular vaccination group among all people in that vaccination group for the each respective vaccination year (2022, 2023).


All statistical analyses will be conducted using R version 3.4.3.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/04/2022
Actual
11/05/2022
Date of last participant enrolment
Anticipated
31/10/2023
Actual
Date of last data collection
Anticipated
1/05/2024
Actual
Sample size
Target
120
Accrual to date
64
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21777 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 21778 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 36834 0
3000 - Melbourne
Recruitment postcode(s) [2] 36835 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 310812 0
Commercial sector/Industry
Name [1] 310812 0
Seqirus
Country [1] 310812 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan Street, VIC 3000, Melbourne
Country
Australia
Secondary sponsor category [1] 312073 0
None
Name [1] 312073 0
Address [1] 312073 0
Country [1] 312073 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310380 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 310380 0
305 Grattan Street, VIC 3000, Melbourne
Ethics committee country [1] 310380 0
Australia
Date submitted for ethics approval [1] 310380 0
09/02/2022
Approval date [1] 310380 0
16/03/2022
Ethics approval number [1] 310380 0
HREC/82359/PMCC

Summary
Brief summary
What is this study about?
We are looking at the immune response to influenza vaccine and how this can be improved in patients during or after treatment for certain types of blood cancers. When you are vaccinated, your body makes antibodies against influenza virus, which protect you from influenza infection. We know that the body’s immune response to influenza vaccine is not as strong after treatment for blood cancer. Currently, having one dose is recommended to try to protect you against influenza.

We would like to study if two adjuvant dose influenza vaccines or two standard vaccines will improve the immune response. An adjuvant vaccine is a vaccine that contains an ingredient which can stimulate a stronger immune response and is generally used in people 65 years and above.

Who is it for?
You may be eligible to participate in this study if you are aged 18 years or older, have been receiving treatment for blood cancer (myeloma, chronic lymphocytic leukaemia or non-Hodgkins lymphoma) or have received treatment for the listed blood cancers within the last 12 months, and have not yet received a flu vaccine for the current season of recruitment (i.e. 2022 influenza vaccine for 2022 recruitment, 2023 influenza vaccine for 2023 recruitment).

Study details
There will be two groups of participants and both groups will two doses of influenza vaccine, one month apart. One group (Group 1) will receive two doses of the adjuvant influenza vaccine 1 month apart and a second group (Group 2) standard dose influenza vaccine followed by the standard dose vaccine 1 month later.

Blood samples will be collected at four time points: before the first vaccine, before the second vaccine, 21-28 days after the second vaccine, and 6 months after the first vaccine. Participants will also be asked to provide information on vaccination history, side effects and if an influenza-like illness (ILI) occurs. Participants will be contacted weekly to see if they have developed any influenza-like illness from first vaccination until 6 months later. If respiratory symptoms occur, the participant will be asked to give a nasal swab and get checked out by their regular treating or general practitioner.

This study will help us understand if two doses of the adjuvant or standard dose vaccine should be used in patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117450 0
A/Prof Benjamin Teh
Address 117450 0
305 Grattan Street, VIC 3000, Melbourne
Peter MacCallum Cancer Centre
Country 117450 0
Australia
Phone 117450 0
+61 3 8559 7994
Fax 117450 0
Email 117450 0
Ben.Teh@petermac.org
Contact person for public queries
Name 117451 0
A/Prof Benjamin Teh
Address 117451 0
305 Grattan Street, VIC 3000, Melbourne
Peter MacCallum Cancer Centre
Country 117451 0
Australia
Phone 117451 0
+61 3 8559 7994
Fax 117451 0
Email 117451 0
Ben.Teh@petermac.org
Contact person for scientific queries
Name 117452 0
A/Prof Benjamin Teh
Address 117452 0
305 Grattan Street, VIC 3000, Melbourne
Peter MacCallum Cancer Centre
Country 117452 0
Australia
Phone 117452 0
+61 3 8559 7994
Fax 117452 0
Email 117452 0
Ben.Teh@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Access to the data for people beyond those directly involved in the randomised trial of influenza
vaccination strategies for patients with haematological malignancy will not be granted as strictly
stated in the protocol: No information concerning the study or the data will be released to any
unauthorized third party, without prior written approval of the sponsoring institution (PMCC).


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.