Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001365550
Ethics application status
Approved
Date submitted
10/12/2015
Date registered
16/12/2015
Date last updated
24/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Feasibility study looking at the effects of Gut microbiota on adult immune response to the seasonal influenza vaccine
Scientific title
Feasibility study assessing the association between gut microbiota in healthy adults and antibody response to seasonal influenza vaccination
Secondary ID [1] 287934 0
MRINZ/16/01
Universal Trial Number (UTN)
U1111-1174-2870
Trial acronym
N/A
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Immune response to trivalent influenza vaccine 296814 0
Condition category
Condition code
Inflammatory and Immune System 297041 297041 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be vaccinated with a Medsafe approved trivalent influenza vaccine. Participants will be given one dose of the vaccine by intramuscular or deep subcutaneous injection by trained study investigators. The mode of administration will be determined at the discretion of the trained study investigators.
Intervention code [1] 293283 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296641 0
The number needed to participate in the proposed RCT to see a 10% increase in responsiveness to the Medsafe approved annual influenza vaccine in the treated group versus the control group with 90% power and an alpha of 5%. This outcome will be assessed using regression analysis of the immune response rates (which will be analysed using Hemagglutination assays and ELISA testing) and compared to stool community type along with the withdrawal rate calculated at 28 days after Day Zero.
Timepoint [1] 296641 0
28 days after Day Zero.
Primary outcome [2] 296784 0
The proportion of participants (95% CI) who fail to complete the feasibility study to Day 28. This is defined by failure to attend the Day 28 visit.
Timepoint [2] 296784 0
28 days after Day Zero.
Primary outcome [3] 296785 0
The proportion of participants (95% CI) who fail to complete the feasibility study in its entirety.
This is defined by failure to attend the Week 26 visit.
Timepoint [3] 296785 0
26 weeks after Day Zero.
Secondary outcome [1] 318969 0
The proportion of participants (95% CI) who can be mapped to any of the four pre-specified Stool Community Type at Day Zero. Stool Community type will be determined by 16s rRNA analysis.
Timepoint [1] 318969 0
Day Zero.
Secondary outcome [2] 318971 0
The proportion of participants (95% CI) who map to Stool Community Types A, B, C and D respectively at Day Zero using 16s rRNA analysis of stool sample.
Timepoint [2] 318971 0
Day Zero.
Secondary outcome [3] 318972 0
The proportion of participants (95% CI) who can be mapped to any of the four pre-specified Stool Community Type at Day 28. Stool Community type will be determined by 16s rRNA analysis.
Timepoint [3] 318972 0
28 days after Day Zero.
Secondary outcome [4] 318973 0
The proportion of participants (95% CI) who map to Stool Community Types A, B, C and D respectively at Day 28 using 16s rRNA analysis of stool sample.
Timepoint [4] 318973 0
28 days after Day Zero.
Secondary outcome [5] 318974 0
The proportion of participants (95% CI) who have the same Stool Community Type at Day 28 versus Day Zero using 16s rRNA analysis of stool sample.
Timepoint [5] 318974 0
28 Days after Day Zero.
Secondary outcome [6] 318975 0
Identification of proposed supplemental intervention. assessed using observed trends in macro-molecule diet data obtained from the 7-day food diaries, and by assesssment of Day Zero, 3, 7 and 28 blood tests..
Timepoint [6] 318975 0
28 days after Day Zero
Secondary outcome [7] 318976 0
The proportion of participants (95% CI) who take systemic antibiotics within 28 days before Day Zero. Assessed using data obtained from the lifestyle questionnaire created specifically for this study.
Timepoint [7] 318976 0
Day Zero
Secondary outcome [8] 318977 0
The proportion of participants (95% CI) who take systemic antibiotics between Day Zero and the 26 week visit Assessed using data obtained from participant self reporting between Day Zero and Week 26.
Timepoint [8] 318977 0
26 weeks after Day Zero
Secondary outcome [9] 319336 0
The proportion of participants (95% CI) who take systemic corticosteroids within 28 days before Day Zero. Assessed using data obtained from the lifestyle questionnaire created specifically for this study.
Timepoint [9] 319336 0
Day Zero
Secondary outcome [10] 319337 0
The proportion of participants (95% CI) who take systemic corticosteroids between Day Zero and the 26 week visit. Assessed using data obtained from participant self reporting between Day Zero and Week 26.
Timepoint [10] 319337 0
26 weeks after Day Zero
Secondary outcome [11] 319338 0
The proportion of participants (95% CI) who ingest alcohol (in any quantity – as documented in the 7-day food diary) in the 24 hour period prior to supplying faecal samples.
Timepoint [11] 319338 0
28 days after Day Zero.
Secondary outcome [12] 319339 0
The proportion of participants (95% CI) who have had an influenza vaccine in the previous 2 years. Assessed using data obtained from the lifestyle questionnaire created specifically for this study.
Timepoint [12] 319339 0
Day Zero.
Secondary outcome [13] 319340 0
The proportion of participants (95% CI) who are pregnant at Day Zero, or become pregnant during the study. Assessed using data obtained the lifestyle questionnaire created specifically for this study and self reporting by participants between Day Zero and week 26.
Timepoint [13] 319340 0
26 weeks after Day Zero.
Secondary outcome [14] 319341 0
The proportion (95% CI) of participants who complete a minimum of 5 days of the first 7-day diary AND whose reported intake for each day is greater than 1.2 x Basal Metabolic Rate (BMR), using predicted BMR based on sex, age, height and weight. Assessed by the lifestyle questionnaire created specifically for this study and the 7-day food diary.
Timepoint [14] 319341 0
Day Zero.
Secondary outcome [15] 319342 0
The proportion (95% CI) of participants who complete a minimum of 5 days of the second 7-day diary AND whose reported intake for each day is greater than 1.2 x Basal Metabolic Rate (BMR), using predicted BMR based on sex, age, height and weight. Assessed by the lifestyle questionnaire created specifically for this study and the 7-day food diary.
Timepoint [15] 319342 0
28 days after Day Zero.
Secondary outcome [16] 319343 0
The proportion (95% CI) of participants who complete all of the first 3 days of the first 7-day diary AND whose reported intake for each day is greater than 1.2 x Basal Metabolic Rate (BMR), using predicted BMR based on sex, age, height and weight. Assessed by the lifestyle questionnaire created specifically for this study and the 7-day food diary.
Timepoint [16] 319343 0
Day Zero
Secondary outcome [17] 319344 0
The proportion (95% CI) of participants who complete all of the first 3 days of the second 7-day diary AND whose reported intake for each day is greater than 1.2 x Basal Metabolic Rate (BMR), using predicted BMR based on sex, age, height and weight. Assessed by the lifestyle questionnaire created specifically for this study and the 7-day food diary.
Timepoint [17] 319344 0
28 days after Day Zero.
Secondary outcome [18] 319345 0
The proportion (95% CI) of participants who complete a minimum of 90% of the questions in the Lifestyle Questionnaire created specifically for this study.
Timepoint [18] 319345 0
Day Zero.
Secondary outcome [19] 319346 0
The proportion of participants (95% CI) who provide a faecal sample at Day Zero.
Timepoint [19] 319346 0
Day Zero.
Secondary outcome [20] 319347 0
The proportion (95% CI) of Day Zero faecal samples that are adequately dated and time stamped by participants (i.e. can be related back to the food diary).
Timepoint [20] 319347 0
Day Zero.
Secondary outcome [21] 319348 0
The proportion of participants (95% CI) who provide a faecal sample at Day 28.
Timepoint [21] 319348 0
28 days after Day Zero.
Secondary outcome [22] 319349 0
The proportion (95% CI) of Day 28 faecal samples that are adequately dated and time stamped by participants (i.e. can be related back to the food diary).
Timepoint [22] 319349 0
28 days after Day Zero.
Secondary outcome [23] 319350 0
The proportion (95% CI) of blood samples obtained versus plan, and proportion (95% CI) of analysable samples at Day Zero.
Timepoint [23] 319350 0
Day Zero.
Secondary outcome [24] 319351 0
The proportion (95% CI) of blood samples obtained versus plan, and proportion (95% CI) of analysable samples at Day Three.
Timepoint [24] 319351 0
3 days after Day Zero.
Secondary outcome [25] 319352 0
The proportion (95% CI) of blood samples obtained versus plan, and proportion (95% CI) of analysable samples at Day Seven.
Timepoint [25] 319352 0
7 days after Day Zero.
Secondary outcome [26] 319353 0
The proportion (95% CI) of blood samples obtained versus plan, and proportion (95% CI) of analysable samples at Day 28.
Timepoint [26] 319353 0
28 Days after Day Zero.
Secondary outcome [27] 319354 0
The proportion (95% CI) of blood samples obtained versus plan, and proportion (95% CI) of analysable samples at 26 weeks.
Timepoint [27] 319354 0
26 weeks after Day Zero.
Secondary outcome [28] 319355 0
The proportion (95% CI) of participants who seroconvert (pre-vaccination antiviral antibody titre less than 1:10 and a post-vaccination antiviral antibody titre equal to 1:40, OR pre-vaccination antiviral antibody titre equal to 1:10 AND a minimum four-fold increase on post-vaccination antiviral antibody titre) to ALL arms of the influenza vaccine at Day 28 . Assessed by Hemagglutination assay and ELISA.
Timepoint [28] 319355 0
28 days after Day Zero
Secondary outcome [29] 319356 0
The proportion (95% CI) of participants that seroconvert (pre-vaccination antiviral antibody titre less than 1:10 and a post-vaccination antiviral antibody titre equal to 1:40, OR pre-vaccination antiviral antibody titre equal to 1:10 AND a minimum four-fold increase on post-vaccination antiviral antibody titre) to EACH arm of the influenza vaccine at Day 28. Assessed by Hemagglutination assay and ELISA.
Timepoint [29] 319356 0
28 days after Day Zero
Secondary outcome [30] 319357 0
The proportion (95% CI) of participants who undergo a 2.5-fold increase in Geometric Mean Titre to ALL arms of the influenza vaccine at Day 28. Assessed by Hemagglutination assay and ELISA.
Timepoint [30] 319357 0
28 Days after Day Zero.
Secondary outcome [31] 319358 0
The proportion (95% CI) of participants who undergo a 2.5-fold increase in Geometric Mean Titre to EACH arm of the influenza vaccine at Day 28. Assessed by Hemagglutination assay and ELISA.
Timepoint [31] 319358 0
28 days after Day Zero.
Secondary outcome [32] 319359 0
The proportion (95% CI) of participants who achieve seroprotection (antiviral antibody titre greater than 1:10) to ALL arms of the influenza vaccine at Day 28. Assessed by Hemagglutination assay and ELISA.
Timepoint [32] 319359 0
28 days after Day Zero.
Secondary outcome [33] 319360 0
The proportion (95% CI) of participants who achieve seroprotection (antiviral antibody titre greater than 1:10) to EACH arm of the influenza vaccine at Day 28. Assessed by Hemagglutination assay and ELISA.
Timepoint [33] 319360 0
28 days after Day Zero.

Eligibility
Key inclusion criteria
Participant is willing and able to give informed consent for participation in the trial.
Male or Female, aged 18-64 years
In the investigators' opinion, is able and willing to comply with all trial requirements
Minimum age
18 Years
Maximum age
64 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
They have had a known severe reaction or allergy to any components of the influenza vaccine.
They have any contra-indications to vaccination per recommendations of vaccine manufacturer.
They have a history of Guillain-Barre Syndrome within 6 weeks of receiving a previous influenza vaccine.
They have an impaired immune system that may confound immune response testing; i.e. any condition that impairs participant immune response through either the condition itself or through the treatment of the condition.
They have already received the 2016 seasonal influenza vaccine.
They have any other clinical condition which the investigator deems relevant for exclusion from the study.

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)
This is an open label trial, there is no allocation concealment
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
N/A
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
The following table shows the sample size required in the main study to test for the difference between responsiveness to the influenza vaccine between the treated and the untreated group, exclusive of drop-out rates: (Please refer to appendix 1 in the attachments section for these figures)

The sample size will then be adjusted to account for the drop-out rate calculated at Day 28.
For this feasibility study the distribution of the rise of titre of antiviral antibodies against influenza vaccine is not well reported in the literature although we anticipate that it might be logarithm normal distributed. We will explore the distribution of this outcome variable in the feasibility study by ANOVA (a general linear model) of titre against community stool type with residual analysis with an appropriate transformation. If the distributional assumptions are best met on the logarithm normal scale then the difference in titres will be reported as ratio of geometric means.
We will also estimate the proportions of participants with different stool types who have a four-fold titre rise as this is the accepted way of reporting whether seroconversion as has occurred.
For the sample size for the feasibility study having 15 to 20 participants with each stool type should be appropriate to have reasonable precision in the regression estimates.
A sample size of 100 in the Feasibility study gives a margin of error for a proportion of +/- 10%, thus a seroconversion rate in the Feasibility study of 50% will be estimated at 40 to 60%.

Since this study is quite intense in the first week and takes place over a long period we are expecting a withdrawal rate of around 20%. Even though we only need 100 participants for the statistical analysis plan, we will be recruiting 125 participants in order to take into account potential withdrawals. Recruiting 125 participants should leave us with at least 100 participants finishing the study in its entirety ( attendance of week 26 visit).

SAS 9.3 will be used.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/03/2016
Actual
16/03/2016
Date of last participant enrolment
Anticipated
28/06/2016
Actual
18/05/2016
Date of last data collection
Anticipated
Actual
25/11/2016
Sample size
Target
125
Accrual to date
Final
125
Recruitment outside Australia
Country [1] 7344 0
New Zealand
State/province [1] 7344 0
Wellington

Funding & Sponsors
Funding source category [1] 292415 0
Charities/Societies/Foundations
Name [1] 292415 0
The Malaghan Institute of Medical Research
Country [1] 292415 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
The Malaghan Institute of Medical Research
Address
Malaghan Institute of Medical Research
PO Box 7060
Newtown
Wellington 6242
New Zealand
Country
New Zealand
Secondary sponsor category [1] 291105 0
None
Name [1] 291105 0
Address [1] 291105 0
Country [1] 291105 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293880 0
Central Health and Disability Ethics Committee
Ethics committee address [1] 293880 0
Freyberg Building
20 Aitken Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 293880 0
New Zealand
Date submitted for ethics approval [1] 293880 0
11/11/2015
Approval date [1] 293880 0
24/11/2015
Ethics approval number [1] 293880 0

Summary
Brief summary
This is a feasibility study that is looking at the effect of gut bacteria on immune response. Participants will be categorised into one of 4 "stool community types" based on their gut bacteria populations.
Participants will be given a Medsafe approved influenza vaccine which is being used as a proxy for a respiratory tract infection. During the study participants will need to attend 6 visits spread out over 6 months. Participants will attend an information seminar which will explain the study and answer any questions. They will then attend Visit 1. During this visit they will be given a stool sample collection kit, a lifestyle questionnaire and a 7-day food diary. These must be completed and returned to the study investigators for Visit 2. The lifestyle questionnaire can be done online instead of on paper.
Visit 2 will occur 7-14 days after Visit 1. Visit 2 will consist of a blood test, a temperature and general health check and vaccination with the influenza vaccine.
Visit 3 will occur 3 days after vaccination. Visit 3 will just consist of a blood test.
Visit 4 will occur 7 days after vaccination and will be the same format as Visit 3. At the end of Visit 4 participants will be given another stool sample collection kit and another 7-day food diary. These need to be completed and returned during Visit 5.
Visit 5 will occur 28 days after vaccination. Visit 5 will be the same as Visit 3 and 4 with the added step of collecting the stool sample and food diary.
The final visit (Visit 6) will occur 6 months after vaccination and will just consist of a blood test. Participants will also have the option to sign an optional consent form for future unspecified research,
If they choose to sign this form the samples that remain after testing will be stored for future research at the Malaghan Institute of Medical research.
Trial website
Trial related presentations / publications
Shortt, N. , Poyntz, H. , Young, W. , Jones, A. , Gestin, A. , Mooney, A. , Thayabaran, D. , Sparks, J. , Ostapowicz, T. , Tay, A. , Poppitt, S. , Elliott, S. , Wakefield, G. , Parry-Strong, A. , Ralston, J. , Gasser, O. , Beasley, R. , Weatherall, M. , Braithwaite, I. and Forbes-Blom, E. (2018), A feasibility study: association between gut microbiota enterotype and antibody response to seasonal trivalent influenza vaccine in adults. Clin Transl Immunol, 7: e1013. doi:10.1002/cti2.1013
Public notes
Attachments [1] 662 662 0 0
/AnzctrAttachments/369652(v07-12-2015-08-46-34)-Malaghan Study Protocol V1.3 TC accept.pdf
Attachments [2] 668 668 0 0
/AnzctrAttachments/369652-Appendix 1.pdf

Contacts
Principal investigator
Name 61666 0
Dr Irene Braithwaite
Address 61666 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand

Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand
Country 61666 0
New Zealand
Phone 61666 0
+64 4 805 0245
Fax 61666 0
Email 61666 0
irene.braithwaite@mrinz.ac.nz
Contact person for public queries
Name 61667 0
Mr Nick Shortt
Address 61667 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand

Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand
Country 61667 0
New Zealand
Phone 61667 0
+64 4 805 0236
Fax 61667 0
Email 61667 0
nick.shortt@mrinz.ac.nz
Contact person for scientific queries
Name 61668 0
Mr Nick Shortt
Address 61668 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand

Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand
Country 61668 0
New Zealand
Phone 61668 0
+64 4 805 0236
Fax 61668 0
Email 61668 0
nick.shortt@mrinz.ac.nz

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
Dimensions AIA feasibility study: association between gut microbiota enterotype and antibody response to seasonal trivalent influenza vaccine in adults2018https://doi.org/10.1002/cti2.1013
N.B. These documents automatically identified may not have been verified by the study sponsor.