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Trial registered on ANZCTR


Registration number
ACTRN12618000112268
Ethics application status
Approved
Date submitted
9/01/2018
Date registered
25/01/2018
Date last updated
23/07/2019
Date data sharing statement initially provided
23/07/2019
Date results information initially provided
23/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Two-part, randomised, double-blind, placebo-controlled study in healthy participants to investigate the skin tolerability of micro-projection array patches coated with inactivated split influenza virus haemagglutinin (HA) from A/Singapore/GP1908/2015 (A/Michigan/45/2015(H1N1)-like) vaccine.

Scientific title
First-in-human study to investigate the skin tolerability of micro-projection array patches coated with inactivated split influenza virus haemagglutinin (HA) from A/Singapore/GP1908/2015 (A/Michigan/45/2015(H1N1)-like) vaccine in healthy volunteers
Secondary ID [1] 293731 0
SP-1207-022
Universal Trial Number (UTN)
U1111-1207-3550
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
prevention of influenza infection 306099 0
Condition category
Condition code
Infection 305223 305223 0 0
Other infectious diseases
Public Health 305321 305321 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is in 2 parts,with 4 parallel treatment groups in Part A and 9 parallel treatment groups in Part B. In both study parts the interventional exposure group being studied is the Micro array projections (MAPs) coated with A/Singapore/GP1908/2015 antigen (A/Sing) in various doses. The comparator products are listed in the section below.

The A/Sing MAP comes in 2 doses; 5mcg Haemagglutinin protein (HA) or 2.5 mcg HA. They are single use. For each subject, a MAP is applied for 2 mins then removed then the next patch is applied for 2 mins then removed etc.
The MAP is applied by a trained medical professional.

Study Part A:
Group 1 subjects will receive 3 x 5mcg A/Sing coated MAPs to the forearm, total dose 15mcg HA.
Groups 2, 3 and 4 will receive comparator products (described in section below)

Study Part B:
Group 1 subjects receive 3 x 5mcg A/Sing coated MAPs to the forearm, total dose 15mcg HA
Group 2 subjects receive 3 x 5mcg A/Sing coated MAPs to the forearm, total dose 15mcg HA and they will undergo additional testing of punch biopsy of application site.
Group 3 subjects receive 2 x 5mcg A/Sing coated MAPs to the forearm plus 1 uncoated (placebo MAP, total dose 10mcg HA
Group 4 subjects receive 1 x 5mcg A/Sing coated MAP to the forearm plus 2 uncoated (placebo MAPs, total dose 5mcg HA
Group 5 subjects receive 1 x 2.5mcg A/Sing coated MAP (2.5mcg HA) plus 2 uncoated (placebo) MAPs to the forearm, total dose 2.5 mcg HA
Group 8 subjects receive 3 x 5mcg A/Sing coated MAPs to the deltoid muscle, total dose 15 mcg HA

The MAP delivery device is a hand-held mechanical, spring loaded, disposable applicator (Vaxxas Clinical Applicator, disposable, CAP) calibrated at a specific speed of 20 m/s. Each MAP will be delivered to the skin and left in situ for 2 minutes. It will then be removed by a gloved finger by gently tensioning the skin around the patch with one hand, whilst pulling the MAP directly up and away from the skin with the other hand.








Intervention code [1] 299983 0
Prevention
Comparator / control treatment
In study Part A:
Group 2 subjects receive single dose intramuscular (IM) Afluria Quadrivalent influenza vaccine, dosage 15mcg HA
Group 3 subjects receive 3 uncoated (placebo) MAPs
Group 4 subjects receive single dose IM A/Sing vaccine, dosage 15mcg HA

The MAPs are applied as per the section above.

In Study part B, the comparator groups are:
Group 6 subjects receive 3 uncoated (placebo) MAPs
Group 7 subjects receive 3 uncoated (placebo) MAPs and undergo additional testing of punch biopsy of application site
Group 9 subjects receive single dose IM Afluria Quadrivalent influenza vaccine, dosage 15mcg HA

Control group
Active

Outcomes
Primary outcome [1] 304383 0
To evaluate the safety and tolerability of A/Singapore/GP1908/2015 antigen delivered by the micro-projection array patch (MAP) in comparison to an uncoated MAP and intramuscular administration of both a quadrivalent seasonal influenza vaccine and a monovalent vaccine delivering approximately the same dose of A/Singapore/GP1908/2015 (A/Sing) HA protein.
Treatment site reaction, pain scores, and skin irritation index will be summarised at each assessment time by treatment group. Comparisons between sites of application and between MAP and intramuscular injection administration and active (A/Sing) versus placebo administrations will be analysed using appropriate statistical tests.
Pain scores will be assessed b a 100 mm visual analogue scale..
Timepoint [1] 304383 0
Skin tolerability will be assessed daily to Day 7 then at Day 22 then fortnightly up to Day 60 or at resolution.
Secondary outcome [1] 341781 0
To evaluate the immune responses to MAP application to the forearm with A/Singapore/GP1908/2015 (A/Sing) at 4 dose levels (0, 2.5, 5, 10 and 15 micrograms) in comparison to IM administration of the standard 15 microgram HA dose per strain.This is measured using the Haemagglutination inhibition (HI) assay.
Immune responses post-treatment will be compared within and between groups. Confidence intervals and p-values will be presented for two-tailed tests, where significance is assumed for p<0.05.
Timepoint [1] 341781 0
Subjects Immune response will be assessed at Day 21.
Secondary outcome [2] 342076 0
To evaluate the skin penetration performance of applied A/Sing MAPs at two sites of application (forearm and upper arm).

Applied MAPs are collected for analysis of penetration performance.
• Uncoated MAPs are analysed using scanning electron microscopy
• A/Sing MAPs are analysed using scanning electron microscopy and / or total protein content.
Timepoint [2] 342076 0
immediately post MAP removal from skin
Secondary outcome [3] 342077 0
In a subset of subjects, to assess further measures of immune response through additional assays or assessment of the local skin response via punch biopsy at the micro-projection array application sites. Such as
• Enzyme linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) in serum.
• Microneutralization (MNT) in serum.
• ELISA for mucosal Immunoglobulin A in saliva.
• Antibody dependent cellular cytotoxicity (ADCC) in serum.
• Cell mediated immunity (CMI) in peripheral blood mononuclear cells (PBMCs).
• Memory B cells in PBMCs
• Assays on biopsy samples for local skin response:
o Flow cytometry
o Immunohistochemistry.
This is an exploratory outcome
Timepoint [3] 342077 0
Punch biopsy performed on Day 4 post application
Saliva assessment done at Days 4, 8 and 22
serum assessments done at Days 4, 8, 22 and 61

Eligibility
Key inclusion criteria
1. Aged 18-50 years (inclusive).
2. Subject has a Body Mass Index (BMI) within the range 18.0–30.0 kg/m²
3. Satisfactory medical assessment, with no clinically significant or relevant abnormalities in medical history, physical examination, vital signs and laboratory evaluation (haematology or biochemistry)
4. Adequate venous access in their left or right arms to allow collection of a number of blood samples.
5. Females of childbearing potential and males should either be sexually inactive (abstinent) for 14 days prior to screening and throughout the study or be using one of the following acceptable birth control methods:
a. Surgically sterile (hysterectomy and/or bilateral oophorectomy);
b. Surgically sterile (bilateral tubal ligation with surgery at least 6 months prior to study initiation);
c. IUD in place for at least 3 months;
d. Stable hormonal contraceptive for at least 3 months prior to study through completion of study;
e. Surgical sterilization (vasectomy) for male participants or for female participant’s partner at least 6 months prior to study
f. Condom for male participant together with effective contraception for their female partner.
6. Postmenopausal women must have had at least 12 months since their last menstrual period
7. Subject is able to communicate effectively with study personnel and is considered reliable, willing and cooperative in terms of compliance with the protocol requirements.
8. Subject is able and willing to provide written, personally signed and dated informed consent to participate in the study.
Minimum age
18 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Subject with birthmarks, tattoos, wounds, scars, moles, blemishes, heavy hair or other skin conditions (such as eczema) on forearms and upper arm regions (both arms) which could reasonably obscure application site reactions.
2. Subject with known chronic spontaneous urticaria / dermographism
3. Known anaphylactic hypersensitivity to a previous influenza vaccination or to eggs, neomycin, polymyxin B sulphate or any of the constituents or trace residues of the study vaccine.
4. Has received an influenza vaccine or has been diagnosed by a doctor as having influenza in the last 12 months.
5. Known history of Guillain-Barré syndrome.
6. Recent vaccination (within 30 days prior to enrolment) with any vaccine.
7. Known predisposition to keloid scar formation.
8. History of granulomatous diseases (especially sarcoidosis and granuloma annulare).
9. History of clinically significant gastrointestinal, hepatic, renal, cardiovascular, dermatological, immunological, respiratory, endocrine, oncological, neurological, metabolic, psychiatric disease or haematological disorders.
10. History of malignancy, other than non-melanoma skin cancer.
11. An active medical condition (which is deemed as clinically significant) that is under evaluation or treatment, or a recent illness, a chronic illness, an autoimmune disease or had major surgery within the last year.
12. History of Hepatitis B, Hepatitis C or HIV infection or clinical laboratory serology is positive for Hepatitis B surface antigen, Hepatitis C or HIV antibodies.
13. History of abnormal bleeding tendencies or thrombophlebitis unrelated to venepuncture or intravenous cannulation.
14. Receiving chronic treatment with immune-suppressive therapy (asthma inhalers and topical corticosteroids are permitted). All medications will be documented and reviewed for acceptance by the Investigator or a medically qualified nominee.
15. History of any psychiatric illness or psychological disorder which may impair the ability to provide written informed consent or participate in the study.
16. Subject has donated blood or plasma or clinically significant blood loss within 60 days prior to screening visit.
17. Subject is pregnant or breast-feeding.
18. A history of alcohol or drug abuse in the last 12 months or current alcohol consumption is >4 standard drinks (or equivalent) per day.
19. Use of any prescription medication (except for contraceptives) within 7 days, unless approved by the PI. All medications will be documented and reviewed for acceptance by the Investigator or a medically qualified nominee.
20. Use of any investigational drug or device within 30 days or 5 half-lives of the drug, whichever is longer, prior to the Day 1.
21. Previous exposure to the Nanopatch and its applicator as a participant in previous clinical studies.

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.

In Part A, clinical staff and subjects will be blind to treatment for MAPs (A/Sing MAPs or uncoated MAPs) and for IM injections (A/Sing or Afluria Quadrivalent).
In Part B, clinical staff and subjects will be blind to treatment for MAPs applied to the forearm (A/Sing MAPs or uncoated MAPs).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple Randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis
Demographic and clinical measurements will be summarised by frequencies for categorical variables and by mean, standard deviation and range for continuous variables.
No statistical testing between groups for safety endpoints is planned to be performed. Safety endpoints have been identified as being of main interest in this study. Study investigations will be exploratory and conclusions based on the complete set of subject evidence.
Immune responses post-treatment will be compared within and between groups. Skin irritation index scores in response to vaccination or application statistical tests. Confidence intervals and p-values will be presented for two-tailed tests, where significance is assumed for p<0.05.

Recruitment
Recruitment status
Completed
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] 9703 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 18473 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 298345 0
Commercial sector/Industry
Name [1] 298345 0
Vaxxas Pty Ltd
Address [1] 298345 0
Suite 13.02,
Level 13,
179 Elizabeth Street,
Sydney,
NSW 2000
Country [1] 298345 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Vaxxas Pty Ltd
Address
Suite 13.02,
Level 13,
179 Elizabeth Street,
Sydney,
NSW 2000
Country
Australia
Secondary sponsor category [1] 297471 0
None
Name [1] 297471 0
none
Address [1] 297471 0
none
Country [1] 297471 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299338 0
Bellberry Ltd
Ethics committee address [1] 299338 0
129 Glen Osmond Road
Eastwood
South Australia 5063
Ethics committee country [1] 299338 0
Australia
Date submitted for ethics approval [1] 299338 0
20/12/2017
Approval date [1] 299338 0
30/01/2018
Ethics approval number [1] 299338 0

Summary
Brief summary
This study is designed to test the hypothesis that MAP application to the skin using a small number of healthy adult subjects with a well characterised influenza vaccine antigen (A/Singapore/GP1908/2015) results in comparable safety / local skin reaction to conventional intramuscular vaccination. This study represents the first time that polymer MAPs with an active vaccine will be applied to humans. Therefore, this study will assess both systemic and the local reaction to application of the A/Sing MAP delivering a 15 mcg HA intramuscular-equivalent dose with the application of three MAPs, in comparison to uncoated MAPs, intramuscular injection with Afluria Quadrivalent (delivering 15 mcg A/Sing HA) and intramuscular injection with 15 mcg A/Sing HA (as a monovalent antigen). The local skin response will be monitored for up to 60 days. On-site clinic assessments will be performed up to 2 hours post application and at 1, 3, 7, 21 and 60 days (if required) post application. Phone calls will be made at Day 36 and Day 50
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80106 0
Dr Jason Lickliter MBBS, PhD, FRACP
Address 80106 0
Medical Director,
Nucleus Network Pty Ltd
The Burnet Tower,
5th Floor
89 Commercial Rd
Melbourne,
VIC 3004
Country 80106 0
Australia
Phone 80106 0
+61 3 9076 8900
Fax 80106 0
Email 80106 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 80107 0
Dr Angus Forster
Address 80107 0
Vaxxas Pty Ltd
Translational Research Institute
37 Kent Street
Woolloongabba,
QLD 4102
Country 80107 0
Australia
Phone 80107 0
+61 7 3443 7838
Fax 80107 0
Email 80107 0
aforster@vaxxas.com
Contact person for scientific queries
Name 80108 0
Dr Angus Forster
Address 80108 0
Vaxxas Pty Ltd
Translational Research Institute
37 Kent Street
Woolloongabba,
QLD 4102
Country 80108 0
Australia
Phone 80108 0
+61 7 3443 7838
Fax 80108 0
Email 80108 0
aforster@vaxxas.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
sponsor company to decide
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary