Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000130662
Ethics application status
Approved
Date submitted
13/01/2023
Date registered
8/02/2023
Date last updated
8/02/2023
Date data sharing statement initially provided
8/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Measuring and strengthening immunity to measles in young adults fully immunised in childhood - a randomised controlled trial (RCT)
Scientific title
Measuring and strengthening immunity to measles in young adults fully immunised in childhood - RCT
Secondary ID [1] 308287 0
None
Universal Trial Number (UTN)
U1111-1283-1406
Trial acronym
MAXXED MeaslesvAXXroutEsofDelivery
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Waning measles immunity in vaccinated young adults 328071 0
Immune health 328776 0
Condition category
Condition code
Public Health 325132 325132 0 0
Other public health
Inflammatory and Immune System 325784 325784 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
NAME
Administration of measles-mumps-rubella (MMR) vaccine by nebulised aerosol or intradermal device compared with intramuscular route in seronegative previously vaccinated young adults.

WHAT
0.3 mL of MMR vaccine (Priorix GSK) https://www.medsafe.govt.nz/profs/Datasheet/p/Priorixvac.pdf)
will be administered using a vibrating mesh nebuliser manufactured by Aerogen Ltd (Ireland) or the MicronJet600 microneedle device (NanoPass Technologies Ltd) to aid delivery of vaccine intradermally in the upper arm deltoid region.
Procedures for use of the Aerogen nebuliser - most commonly used to deliver nebulised drugs - are provided here: https://www.youtube.com/watch?v=3l6yFy0F5zs and for the MicronJet600 microneedle device: https://www.nanopass.com/micronjet-microneedle-device/instructions-for-use/

WHO
MMR vaccine will be administered by nurses who are certified immunisation providers. Use of both the Nanopass MicronJet600 device and the Aerogen nebuliser are well within the scope of practice for trained registered nurses and specific training videos are available, supplemented by tailored instructions from the manufacturers

HOW
Delivery will be during a face-to-face visit using the devices as described above by the staff as described above to individual consenting eligible participants.
For participants randomized to the aerosol study arm a study nurse will prepare the 0.3 mL MMR vaccine dose and prepare the single-use Aerogen ultra device. Following instructions, the participant will inhale the vaccine mist using the mouthpiece via slow, natural breathing. The study nurse will assess appropriate aerosol formation and during administration will monitor for completeness of inhaled dose.
For participants randomized to the intradermal study arm, the study nurse will prepare the 0.3 mL MMR vaccine dose using the provided sterile vaccine diluent and attach the MicronJet600 needle to the syringe. The dose will be administered in the deltoid region precisely according to the device protocol (45 degree angle, correct orientation and consistent pressure when deploying the dose).
For both intervention methods, the participant will be monitored for 30 minutes post-vaccination for any immediate adverse events or reactions.

DOCUMENTATION AND REPORTING
Adherence to the intervention will be recorded by study staff through use of electronic clinical report forms in the secure study database. This includes a data quality check to verify the randomized intervention assigned was received. Post study, data collection will be monitored for participant adherence to study questionnaires electronically delivered at set time points post-intervention and individual participants followed up in cases of missing data.
The receipt of MMR vaccine will also be recorded for each participant in the national immunisation register.

WHERE
The intervention will be delivered in a clinical setting - a student health service in the University of Otago, Dunedin which has all required infrastructure for delivery of vaccines.

TIMING and FREQUENCY of INTERVENTION
Administration of MMR vaccine will occur once with four subsequent study visits over the month post-vaccination for sampling and measurements of immune responses by antibody assays in blood and detection of measles vaccine virus in oral fluid by PCR

TAILORING
For both the aerosol and intradermal intervention study arms, MMR vaccine will be reconstituted to 0.3 mL using the sterile diluent provided with the vaccine, with the only variation being the mode of delivery between the study arms.

MODIFICATIONS
No modifications are anticipated

HOW WELL
Delivery of vaccine will be monitored for delivery and any subsequent adverse reactions by study staff
Intervention code [1] 324742 0
Treatment: Devices
Comparator / control treatment
Comparator for aerosol and intradermal administration is standard intramuscular administration via a single vial dose, reconstituted in 0.5 mL vaccine diluent.
Control group
Active

Outcomes
Primary outcome [1] 332955 0
Percentage of participants who develop measles antibody above the threshold for measles protection in the serum microimmune assay (MIA) in National Public Health Laboratory Netherlands (RIVM). The established threshold in serum is - 0.12 IU/ml., which is strongly correlated with the Plaque Reduction Neutralisation Titre (PRINT) WHO standard.
Timepoint [1] 332955 0
28 days and 12 months post MMR
Primary outcome [2] 333650 0
Percentage of participants in whom measles vaccine virus is present in oral fluid (by PCR assay)
Timepoint [2] 333650 0
3-4, 7, 14 days post MMR
Secondary outcome [1] 415326 0
Percentage of participants who develop measles antibody in serum above the threshold for measles protection by microimmune assay (MIA) at earlier time points.
Timepoint [1] 415326 0
At 3-4, 7 and 14 days post MMR
Secondary outcome [2] 415327 0
Geometric mean serum antibody titres (GMTs)
Timepoint [2] 415327 0
7, 14, and 28 days post MMR; 12 months post MMR

Eligibility
Key inclusion criteria
* Antibody below threshold for positivity of the Diasorin assay for either or both of measles/mumps antibody and required to have a dose of MMR vaccine by University of Otago Screening and Immunisation Policy
* Capable and willing to give written informed consent
* Residing in Dunedin
* Able and willing to participate for the duration of the study visits and follow-up
* Willing to provide verifiable identification at study entry and follow-up visits
* Daily access to an internet-connected device (smart phone, tablet, laptop or PC) and willing to complete an electronic diary post vaccination.
Minimum age
17 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Contraindications to MMR as specified in the NZ Immunisation Handbook. These include:
• proven anaphylaxis to the vaccine or vaccine component (eg, neomycin or gelatin)
• significant immunocompromise: impaired cell-mediated immunity, including untreated malignancy, type 1 interferon receptor (IFNAR) signalling pathway defects, immunosuppressive drug therapy, including high-dose steroids, receiving high-dose radiotherapy, HIV infection with severely impaired T cell immunity
• another live vaccine, including Bacillus Calmette-Guérin (BCG), within the previous 4 weeks
• pregnant women – pregnancy should be avoided for four weeks after immunization
• participants pregnant during study participation may complete follow-up.
• intravenous immunoglobulin or blood transfusion during the preceding 11 months

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)
Allocation will be by centralised computer-generated means using the REDCap database programme randomisation instrument and thus will only be known to participants at the time of vaccination.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computerised sequence generation in microsoft excel {=RANDBETWEEN(0,2)}.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The statistical analysis will compare antibody responses to three routes of vaccine administration. The primary outcome is the proportion of participants exceeding the threshold of seropositivity for the Microimmune assay (MIA) assay undertaken at RIVM (Bilthoven, Netherlands) who have at least a 4-fold increase in Ab from baseline for measles and mumps (Me and Mu). Aerosol (Ae) vs intramuscular (IM) and Intradermal (ID) vs IM will be compared. We will describe participant characteristics for each route of administration, identify possible confounders (residual of randomisation) and adjust for them in multivariate analyses when comparing vaccine delivery routes. We will tabulate participants for each route of administration. All analyses will be done by a professional statistician using the most recently updated version of Stata software.

Over the two years 2022-23, we anticipate ~ 1400 students will be screened at UoO Dunedin. For Aim 1, comparing modes of MV delivery, we believe that a difference of >= 15% in seroconversion is clinically significant. In order to detect this difference in
seroconversion with 80% power and a 5% significance level, we need 87 participants students with 1:1 allocation ratio. With 3 arms (SC, ID and AD) this becomes a total of 300 students, after allowing for 10% dropout. We anticipate that we can achieve our recruitment target of 300 participants (100 per arm) in our target cohort over two years and will make appropriate adjustments to study sites and recruitment strategy if review of year 1 results indicates this is necessary.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
23/02/2023
Actual
Date of last participant enrolment
Anticipated
31/07/2024
Actual
Date of last data collection
Anticipated
30/08/2024
Actual
Sample size
Target
300
Accrual to date
Final
Recruitment outside Australia
Country [1] 25090 0
New Zealand
State/province [1] 25090 0
Otago

Funding & Sponsors
Funding source category [1] 312538 0
Government body
Name [1] 312538 0
Health Research Council
Country [1] 312538 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Professor Richard Blaikie
Research and Enterprise
Centre for Innovation
87 St David St
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 314138 0
None
Name [1] 314138 0
Address [1] 314138 0
Country [1] 314138 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311868 0
Health and Disability Ethics Committees (HDECs): Northern A
Ethics committee address [1] 311868 0
Ministry of Health
Health and Disability Ethics Committees
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 311868 0
New Zealand
Date submitted for ethics approval [1] 311868 0
02/11/2022
Approval date [1] 311868 0
10/01/2023
Ethics approval number [1] 311868 0
13681

Summary
Brief summary
In settings such as Australia and New Zealand where measles elimination has been achieved for a decade or more due to sustained high MMR vaccine coverage, cases of measles in young adults who have two documented MMR doses in childhood is increasingly being documented in association with waning measles antibody levels.
This study will evaluate whether alternate routes of MMR administration result in superior antibody responses compared to standard intramuscular at one and 12 months in seronegative young adults. This comparative immunogenicity and reactogenicity trial will have three intervention arms - one each for the three different routes of administration of the Priorix Measles-Mumps_Rubella vaccine (MMR; GSK) routinely used in New Zealand. Administration of MMR by aerosol via a vibrating mesh nebuliser (arm 1) will be compared with administration intradermally using a specifically designed microneedle MicronJet600 device (Nanopass) (arm 2) and both will be compared with standard intramuscular administration (arm 3). The study population is young adults documented to have antibodies to either or both of measles and mumps measured by the Diasorin assay which are below the threshold set by the manufacturer for seropositivity despite a history of two previous MMR doses.
The working hypothesis is that alternate sites of delivery where attenuated measles, mumps and rubella viruses encounter different immune effector cells are likely to result in greater and more sustained antibody responses. The intradermal device will deliver the vaccine to the skin's dermis, where dendritic cells are plentiful, and the aerosol device will deliver the vaccine to airway and pulmonary mucosal tissue. We will also measure local and systemic adverse reactions for the three delivery techniques.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122658 0
Prof Peter McIntyre
Address 122658 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
3rd Floor Children's Pavilion
201 Great King Street
Dunedin 9016
Country 122658 0
New Zealand
Phone 122658 0
+64212814242
Fax 122658 0
Email 122658 0
peter.mcintyre@otago.ac.nz
Contact person for public queries
Name 122659 0
Prof Peter McIntyre
Address 122659 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
3rd Floor Children's Pavilion
201 Great King Street
Dunedin 9016
Country 122659 0
New Zealand
Phone 122659 0
+64212814242
Fax 122659 0
Email 122659 0
peter.mcintyre@otago.ac.nz
Contact person for scientific queries
Name 122660 0
Prof Peter McIntyre
Address 122660 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
3rd Floor Children's Pavilion
201 Great King Street
Dunedin 9016
Country 122660 0
New Zealand
Phone 122660 0
+64212814242
Fax 122660 0
Email 122660 0
peter.mcintyre@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Upon future request we would consider sharing de-identified line-by-line individual participant data but do not wish to make a commitment to this at this stage as it would require specific consultation including with Maori advisory groups


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
17480Ethical approval    384900-(Uploaded-13-01-2023-11-59-19)-Study-related document.pdf



Results publications and other study-related documents

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