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Trial registered on ANZCTR


Registration number
ACTRN12619000617167
Ethics application status
Approved
Date submitted
11/04/2019
Date registered
26/04/2019
Date last updated
12/08/2019
Date data sharing statement initially provided
26/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Stem cell transplant influenza vaccination strategies
Scientific title
A randomised trial to compare level of protection afforded by two different influenza vaccination strategies in patients following autologous haematopoietic stem cell transplantation
Secondary ID [1] 297946 0
Protocol 19/10
Universal Trial Number (UTN)
U1111-1231-5881
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
autologous haematopoietic stem cell transplantation (autoHSCT) 312361 0
influenza 312428 0
myeloma 312429 0
lymphoma 312430 0
Condition category
Condition code
Cancer 310916 310916 0 0
Myeloma
Infection 310917 310917 0 0
Other infectious diseases
Cancer 310918 310918 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Influenza vaccination (intramuscular injections) comparing a new two dose strategy using the trivalent high dose influenza vaccine (HD) followed by a second dose of quadrivalent standard dose (SD) influenza vaccine one month later (HD-SD, Arm 1) and the current standard two dose strategy of quadrivalent influenza vaccine one month apart (SD-SD, Arm 2). Each dose is a 0.5 mL intramuscular injection into the deltoid muscle. Annual seasonal influenza vaccination is currently recommended for patients following autoHSCT within 12 months of tranpslant. At Peter MacCallum Cancer Centre (PMCC), patients commence a program of re-vaccination at 6 months post-autoHSCT. This includes two doses of seasonal influenza vaccine (separated by 4 weeks) if they have not received this by 6 months post-transplant. Quadrivalent standard dose vaccine (FluQuadri) contains 60 micrograms (µg) haemagglutinin (HA) per 0.5 mL dose in the recommended ratio of 15 µg HA of each of the four influenza strains. Trivalent high dose vaccine (Fluzone-HD) contains 180 micrograms (µg) haemagglutinin (HA) per 0.5mL dose in the recommended ration of 60(µg) HA of each of the three influenza strains.
Throughout the study, patients will be sent a weekly short message service (SMS) asking whether they have experienced an ILI (fever with at least one acute respiratory symptom or sign) in the previous 7 days. Patients will also receive SMS reminders about any follow-up appointments. The use of SMS reminders has been shown to improve retention in research studies. The SMS reminder will include their appointment time and the location. Patients failing to attend their appointment will be contacted by phone to reschedule the appointment.
Intervention code [1] 314182 0
Prevention
Comparator / control treatment
The current standard two dose (each dose is 0.5mL intramuscular injection) strategy of quadrivalent influenza vaccine one month apart (SD-SD, Arm 2).
At Peter MacCallum Cancer Centre (PMCC), patients commence a program of re-vaccination at 6 months post-autoHSCT. This includes two doses of seasonal influenza vaccine (separated by 4 weeks) if they have not received this by 6 months post-transplant.
Control group
Active

Outcomes
Primary outcome [1] 319740 0
To compare the level of protection afforded by a novel influenza vaccination strategy (High dose-standard dose) with standard strategy (standard dose-standard dose) among patients post autologous haematopoietic stem cell transplantation (autoHSCT). By measuring seropositivity rate 21-28 days post-V2 (second vaccination) and 6 months post-V1 (first vaccination) and seroconversion rate 21-28 days post-V2 (second vaccination) and 6 months post-V1 (first vaccination); i.e. percentage of samples with 4-fold increases in HI titre
Timepoint [1] 319740 0
Seropositivity rate 21-28 days post-V2 and 6 months post-V1
Seroconversion rate 21-28 days post-V2 and 6 months post-V1
Blood samples will be collected from participants at four time points: 1) before first influenza vaccination, 2) before second influenza vaccination; 3) 21-28 days post-second-vaccination; and 4) approximately 6 months post-vaccination.
(V1 first vaccination, V2 second vaccination)
Secondary outcome [1] 369356 0
To compare pre/post vaccination serum antibody titres
Timepoint [1] 369356 0
Endpoints: geometric mean antibody titre (GMT) at V1, V2, 21-28 days post-V2, 6 months post-V1
Blood samples will be collected from participants at four time points: 1) before first influenza vaccination, 2) before second influenza vaccination; 3) 21-28 days post-second-vaccination; and 4) approximately 6 months post-vaccination.
Secondary outcome [2] 369357 0
To determine the number and proportion of patients with clinical influenza-like illness episodes post vaccination. The risk of ILI will be evaluated using logistic regression. GMTs and demographic factors that may be associated with risk of infection will also be included in the model. A similar model will be constructed to examine the risk of confirmed.

Throughout the study, patients will be sent a weekly short message service (SMS) asking whether they have experienced an ILI (fever with at least one acute respiratory symptom or sign) in the previous 7 days. Responses will be recorded in the study database and used to calculate ILI risk in the cohort at the end of the study.
Timepoint [2] 369357 0
Endpoints: Patients positive for influenza-like illness on clinical history
On a weekly basis, patients will receive an SMS asking whether they have experienced ILI. Patients who respond “Yes” will be asked to submit a nasal swab for influenza testing. The proportion of swabs testing positive will be compared by allocated cohort. Participants will be given a swab to use if they develop an ILI. Patients with an ILI (who response “Yes”) will be contacted by study coordinator/research nurse and asked to present for a medical review at PMCC. They will be reviewed by a member of the study team. In conjunction with the treating team, clinical management (e.g treatment, admission) will follow standard of care for all patients with ILI. Education will be provided on the collection and storage of specimens. Swabs will be collected by the study coordinator. The total duration of the weekly SMS messages will be from first vaccine dose until 6 months post first vaccination.
Secondary outcome [3] 369358 0
To determine the number and proportion of patients with laboratory confirmed influenza infections post vaccination
On a weekly basis, patients will receive an SMS asking whether they have experienced ILI. Patients who respond “Yes” will be asked to submit a nasal swab for influenza testing. The proportion of swabs testing positive will be compared by allocated cohort. Participants will be given a swab to use if they develop an ILI. Patients with an ILI (who response “Yes”) will be contacted by study coordinator/research nurse and asked to present for a medical review at PMCC. They will be reviewed by a member of the study team. In conjunction with the treating team, clinical management (e.g treatment, admission) will follow standard of care for all patients with ILI. Education will be provided on the collection and storage of specimens. Swabs will be collected by the study coordinator
Timepoint [3] 369358 0
Patients positive for influenza on PCR testing
On a weekly basis, patients will receive an SMS asking whether they have experienced ILI. Patients who respond “Yes” will be asked to submit a nasal swab for influenza testing. The proportion of swabs testing positive will be compared by allocated cohort. Participants will be given a swab to use if they develop an ILI. Patients with an ILI (who response “Yes”) will be contacted by study coordinator/research nurse and asked to present for a medical review at PMCC. They will be reviewed by a member of the study team. In conjunction with the treating team, clinical management (e.g treatment, admission) will follow standard of care for all patients with ILI. Education will be provided on the collection and storage of specimens. Swabs will be collected by the study coordinator. The total duration of the weekly SMS messages will be from first vaccine dose until 6 months post first vaccination.
Secondary outcome [4] 369359 0
To evaluate factors associated with risk of influenza infection, including antibody titres and previous vaccination history.
Patients will be requested to provide a blood sample at baseline (V1), V2, 21-28 days post-V2 and approximately 6 months post-V1 to assess antibody titres.
Vaccination history will be collected through the questionnaire at the baseline visit. The questionnaire was designed specifically for this study.
Timepoint [4] 369359 0
Endpoints: Proportion of patients positive for influenza. On a weekly basis, patients will receive an SMS asking whether they have experienced ILI. Patients who respond “Yes” will be asked to submit a nasal swab for influenza testing. The proportion of swabs testing positive will be compared by allocated cohort. The total duration of the weekly SMS messages will be from first vaccine dose until 6 months post first vaccination.

Eligibility
Key inclusion criteria
1. Patients aged greater than or equal to 18 years and have received autoHSCT within last 12 months.
2. Willing and able to provide a blood sample just prior to vaccination, 21-28 days post dose (2 doses) and roughly 6 months post-vaccination.
3. Has not received influenza vaccine for the 2019 season following transplantation
4. No known contraindications for influenza vaccination.
5. Not recently (within last 7 days) or currently ill, or has a fever above 38°C.
6. Willing to provide current mobile phone number for SMS reminders
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Known contraindication(s) for TIV (e.g. hypersensitivity to vaccine component (including eggs)).
2. Recent immunosuppressive treatment with anti-CD20 antibody, Bruton’s tyrosine kinase inhibitor (within last 6 months)
3. Recently or currently ill, or has a fever above 38°C

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)
sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
All statistical analyses will be conducted using R version 3.4.3.

Baseline comparisons: Baseline data will be summarised by disease group, with both arms compared using a X2 test for categorical variables or a t-test for continuous variables.
Analysis of antibody titres: The change in pre-/post-V2 geometric mean titres (GMT) by vaccination regimen will be compared by: 1) post-V2 seropositivity (titre >40) analysed using chi-square or fisher’s exact test; and 2) seroconversion rate at 21-28 days post-vaccination (4-fold rise in titre) using logistic chi-square or fisher’s exact test; 3) difference of differences in V2, post-V2 GMT, analysed using mixed-effects linear regression.
Risk of influenza infection: The risk of ILI will be evaluated using logistic regression. GMTs and demographic factors that may be associated with risk of infection will also be included in the model. A similar model will be constructed to examine the risk of confirmed influenza infection.

We reasonably expect to recruit around 70 autoHSCT patients. With 70 patients randomised 1:1 to Arm 1 or Arm 2, for influenza A(H3N2) the minimum effect size we will be able to power for is 0.67, with a power of 0.8 and two sided type 1 error rate of 0.05 (i.e. if proportion achieving seropositivity in Arm 2 is 36%, then the minimum detectable seropositivity for Arm 1 is 69%).We would be underpowered to detect a statistically significant difference in sero-positivity for A(H1N1)pdm09 or influenza Type B. Given that influenza A(H3N2) is associated with increased mortality, a significant improvement in immunogenicity against this subtype could have a clinically meaningful impact on patient outcomes.

Recruitment
Recruitment status
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)
VIC
Recruitment hospital [1] 13616 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 26278 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 302461 0
Commercial sector/Industry
Name [1] 302461 0
Sanofi
Address [1] 302461 0
14 Espace Henry Vallée 69007, Lyon
Country [1] 302461 0
France
Primary sponsor type
Hospital
Name
Peter MacCullum Cancer Institute
Address
305 Grattan Street, Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 302365 0
None
Name [1] 302365 0
Address [1] 302365 0
Country [1] 302365 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303129 0
PETER MACCALLUM CANCER CENTRE HUMAN RESEARCH ETHICS COMMITTEE [EC00235]
Ethics committee address [1] 303129 0
305 Grattan Street
Melbourne Victoria 3000 Australia
Ethics committee country [1] 303129 0
Australia
Date submitted for ethics approval [1] 303129 0
Approval date [1] 303129 0
05/04/2019
Ethics approval number [1] 303129 0
HREC/50288/PMCC-2019

Summary
Brief summary
This study will compare the level of protection afforded by two different influenza vaccination strategies in patients who have undergone autologous haematopoietic stem cell transplantation.

Who is it for?
You may be eligible to join this study if you are aged at least 18 years, have received an autologous haematopoietic stem cell transplantation (autoHSCT) within the last 12 months, and have not received an influenza vaccine for the 2019 season following your transplant.

Study details
Participants in this study will be randomly allocated (by chance) to one of two groups. Participants in one group will receive a new two dose strategy, which consists of the trivalent high dose influenza vaccine followed by a second dose of quadrivalent standard dose influenza vaccine one month later. Participants in the other group will receive the current standard two dose strategy of quadrivalent influenza vaccine one month apart. All vaccines will be administered by injection into the muscle.

All participants will be required to provide blood samples at four time points: 1) before first influenza vaccination, 2) before second influenza vaccination; 3) 21-28 days post-second-vaccination; and 4) approximately 6 months post-vaccination. They will also be asked to provide information on vaccination history, side effects and occurrence of influenza-like illnesses (ILI). Participants who develop respiratory symptoms during the study period will be asked to provide a nasal swab.

Findings may assist in improving vaccine responses and protection from influenza in a highly vulnerable patient group
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92574 0
Dr BENJAMIN TEH
Address 92574 0
Peter MacCullum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 92574 0
Australia
Phone 92574 0
+61 3 85597994
Fax 92574 0
Email 92574 0
ben.teh@petermac.org
Contact person for public queries
Name 92575 0
Ms Sharon Carvalho
Address 92575 0
Peter MacCullum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 92575 0
Australia
Phone 92575 0
+61 3 85597994
Fax 92575 0
Email 92575 0
sharon.carvalho@petermac.org
Contact person for scientific queries
Name 92576 0
Dr BENJAMIN TEH
Address 92576 0
Peter MacCullum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 92576 0
Australia
Phone 92576 0
+61 3 85597994
Fax 92576 0
Email 92576 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
What supporting documents are/will be available?
No other documents available
Summary results
No Results