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Clinical Trial Results:
Enhanced Epidermal Antigen Specific Immunotherapy trial -1 (EE-ASI-1): A Phase 1a study of gold nanoparticles administered intradermally by microneedles to deliver immunotherapy with a proinsulin derived peptide in Type 1 diabetes.

Summary
EudraCT number	2015-003934-28
Trial protocol	GB SE
Global end of trial date	30 Dec 2019

Results information
Results version number	v1(current)
This version publication date	01 Jan 2021
First version publication date	01 Jan 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

SPON1455-15

ISRCTN number

ISRCTN16067611

US NCT number

NCT02837094

WHO universal trial number (UTN)

Sponsor organisation name

Cardiff University

Sponsor organisation address

McKenzie House, 36 Newport Rd, Cardiff, United Kingdom, CF24 0DE

Public contact

Professor Colin Dayan, Cardiff University, +44 02920742182, dayancm@cardiff.ac.uk

Scientific contact

Professor Colin Dayan, Cardiff University, +44 02920742182, dayancm@cardiff.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

17 Apr 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

30 Dec 2019

Global end of trial reached?

Yes

Global end of trial date

30 Dec 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to examine the risk of C19-A3 GNP administration in terms of general safety and induction of hypersensitivity.

Protection of trial subjects

N/A

Background therapy

All subjects were patients with type 1 diabetes who received s/c insulin treatment as per clinical indication.

Evidence for comparator

N/A

Actual start date of recruitment

01 Jan 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

United Kingdom: 5

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

There were 2 recruiting sites: Cardiff, UK and Linkoping, Sweden. Between 30/10/2016 and 05/10/2018 , 109 potential participants were referred, 6 were enrolled and received the trial treatment. 103 were excluded.

Screening details

There were six participants enrolled (Cardiff n=5 participants, Linkoping n=1 participant). Data are available for all the six participants. One participant (114) withdrew after receiving the first injection due to competing time commitments but agreed to be contacted to provide information to the study team if needed.

Number of subjects started

Number of subjects completed

Period 1 title

Baseline period (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Blinding implementation details

This was an open label uncontrolled early phase safety study, so no blinding or randomisation were performed. In keeping with standard phase 1 study designs, no placebo or control group were included as the primary aim was to establish whether there are any major unexpected safety issues in the use of the IMP for the first time in man.

Treatment arm

Arm description

IMP

Arm type

Interventional

Investigational medicinal product name

Investigative medicine product comprising proinsulin peptide C19-A3 linked to Gold Nanoparticles

Investigational medicinal product code

C19-A3 GNP

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intradermal use

Dosage and administration details

C19-A3 GNP was administered intradermally via CE marked Nanopass 600nm microneedles. 3 doses were given at 4 weekly intervals. The dose given was equivalent to 10ug of C19-A3 peptide.

Number of subjects in period 1	Treatment arm
Started	6
Completed	4
Not completed	2
Consent withdrawn by subject	1
Halt to dosing	1

Baseline characteristics

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Reporting group title

Baseline period

Reporting group description

Reporting group values	Baseline period	Total
Number of subjects	6	6
Age categorical
Age at consent (years): 28.46 (8.06) Range: 18.29 – 37.34
Units: Subjects
Adults (18-64 years)	6	6
Age continuous
Units: years
arithmetic mean (standard deviation)	28.46 ( 8.06 )	-
Gender categorical
Female (%): 33.3%
Units: Subjects
Female	2	2
Male	4	4
Ethnicity
Units: Subjects
White	6	6
Age at diagnosis of type 1 diabetes
26.16 (9.45) years
Units: Years
arithmetic mean (standard deviation)	26.16 ( 9.45 )	-
Duration of diabetes
Units: Months
arithmetic mean (standard deviation)	27 ( 31.47 )	-

Subject analysis set title

Treatment group

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects are included in this group.

Subject analysis set title

Comparison group

Subject analysis set type

Safety analysis

Subject analysis set description

There is no comparison group as this is open label and not a placebo controlled trial.

Subject analysis sets values	Treatment group	Comparison group
Number of subjects	6	6
Age categorical
Age at consent (years): 28.46 (8.06) Range: 18.29 – 37.34
Units: Subjects
Adults (18-64 years)	6
Age continuous
Units: years
arithmetic mean (standard deviation)	( )	( )
Gender categorical
Female (%): 33.3%
Units: Subjects
Female
Male
Ethnicity
Units: Subjects
White
Age at diagnosis of type 1 diabetes
26.16 (9.45) years
Units: Years
arithmetic mean (standard deviation)	( )	( )
Duration of diabetes
Units: Months
arithmetic mean (standard deviation)	( )	( )

End points

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Reporting group title

Treatment arm

Reporting group description

IMP

Subject analysis set title

Treatment group

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects are included in this group.

Subject analysis set title

Comparison group

Subject analysis set type

Safety analysis

Subject analysis set description

There is no comparison group as this is open label and not a placebo controlled trial.

Primary: Assessment of the safety of C19-A3 GNP

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End point title

Assessment of the safety of C19-A3 GNP

End point description

There were no significant safety concerns.

End point type

Primary

End point timeframe

Treatment and follow-up period.

End point values	Treatment group	Comparison group
Number of subjects analysed	6	6
Units: Subjects	6	6

Attachments

Data Review Report

Statistical analysis pending

Comparison groups

Treatment group v Comparison group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.05

Method

Pending

Parameter type

Pending

Confidence interval

Adverse events

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Timeframe for reporting adverse events

AEs were collected from the time each participant received their first dose of IMP until one month after their last trial visit. At each visit, participants were assessed for AEs. Between 13/10/2016 and 17/04/2020, 48 AEs were reported for 6 participants.

Adverse event reporting additional description

Each participant was given a patient diary and asked to record details of any new illnesses they experienced and any medication taken. The diary was reviewed at each trial visit. At each visit participants were assessed for AE's by the clinical staff and details recorded in the trial CRF.

Assessment type

Systematic

Dictionary name

Dictionary not used.

Dictionary version

Reporting group title

All trial participants

Reporting group description

In total there were 48 adverse events reported for the 6 participants. One was reported as an SAE. Of the six participants, 2 (33.33%) participants experienced moderate AEs but the events were unrelated to the study. All six participants (100%) experienced mild AEs:- 5 very likely related to the trial; 1 possibly related; 3 unlikely to be related; 4 unrelated. All six participants showed skin reactions at injection sites.

Serious adverse events	All trial participants
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 6 (16.67%)
number of deaths (all causes)	0
number of deaths resulting from adverse events	0
Gastrointestinal disorders
Diarrhoea and vomiting
Additional description: Campylobacter infection.
subjects affected / exposed	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 1
deaths causally related to treatment / all	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	All trial participants
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)
Nervous system disorders
Headache
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	4
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Vomiting
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Respiratory, thoracic and mediastinal disorders
Common cold
subjects affected / exposed	2 / 6 (33.33%)
occurrences all number	3
Cold
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Headcold
subjects affected / exposed	2 / 6 (33.33%)
occurrences all number	3
Coryza
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	2
Upper respiratory infection
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Sore throat
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Influenza
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Skin and subcutaneous tissue disorders
Gold hypersensitivity
Additional description: Positive result to gold sensitivity / Gold allergy / Positive gold allergy / Gold hypersensitivity
subjects affected / exposed	5 / 6 (83.33%)
occurrences all number	5
Hyperpigmentation deltoid.
subjects affected / exposed	3 / 6 (50.00%)
occurrences all number	7
Red skin discolouration / Red Skin discolouration deltoid.
subjects affected / exposed	2 / 6 (33.33%)
occurrences all number	6
Skin discoloration at injection site
subjects affected / exposed	2 / 6 (33.33%)
occurrences all number	2
Hyperpigmentation without redness.
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Intermittent Pruritis at injection site.
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Pain at injection site
Additional description: Painful injection site.
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Skin erythema at injection site.
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	2
Reaction at injection site: Red, slightly swollen, itchy when touched.
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Granuloma at injection site
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Musculoskeletal and connective tissue disorders
Pressure in neck and head
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1
Infections and infestations
Insect bite
subjects affected / exposed	1 / 6 (16.67%)
occurrences all number	1

More information

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Were there any global substantial amendments to the protocol? Yes

21 Apr 2016

Amendment to trial protocol, PIS and ICF following review by REC, MHRA and MPA and update of IMPD sections: 2.1.S.5 Validation of Analytical Methods 2.1.P.5.5 Characterisation of Impurities 2.1.P.8.1 Stability Summary and Conclusion 2.1.P.8.2 Post Approval Stability Protocol 2.1.P.8.3 Stability Data

21 Apr 2016

Change of overseeing trials unit. Lengthening of follow up period and addition of follow-up phone call post IMP administration, following advice from competent authorities. Additional exclusion criteria. Reduction in blood draw volume at trial visits. Clarification on "conditions for interruption of dosing to individuals." Additional renal function tests for safety monitoring. Clarification of AE reporting responsibilities with the new trial unit.

23 Jun 2016

To update the protocol and patient information sheet to reflect changes to the trial.

24 Oct 2016

Update of IMPD sections 2.1.P.5.5 Characterisation of Impurities 2.1.P.8.1 Stability Summary and Conclusion 2.1.P.8.3 Stability Data

03 Mar 2017

Addition of information on skin reaction at injection site and addition of optional skin biopsy and blister sample.

16 May 2017

Addition of taking photographs of the injection sites and option of the injecting in the underside of the upper arm instead of the usual deltoid region.

17 Oct 2017

Addition of Patient Identification Centre (PIC).

07 Nov 2017

Request to extend IMP expiry date.

17 Nov 2017

�� Request to extend patient follow-up by adding an optional visit 12 months post first injection to gain more immunological information.��

23 Jul 2018

Addition of optional patch skin test to assess gold hypersensitivity in participants.

26 Nov 2018

Halt to dosing and recruitment.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
22 Nov 2018	Temporary halt of trial due to suspecting that the IMP induced gold hypersensitivity in trial subjects. Recruitment and dosing were halted and participants were followed up as per protocol. 6 subjects were treated with the IMP, 4 received all 3 doses, 1 had 1 dose and then withdrew and 1 had 1 dose and did not proceed to the second due to suspicion of inducing gold hypersensitivity. The 4 subjects who received all 3 doses had gold skin hypersensitivity testing and all 4 tested positive. Dermatologists advised that usually <10% of people have gold hypersensitivity and 4 from 4 testing positive is a higher rate than would be expected and was likely to be related to the IMP. The temporary dosing halt was decided to allow time to gather further information and obtain expert advice following the gold hypersensitivity testing. Following discussions with the DSMB and Trial Management Group, it was decided that the trial would not recruit or dose any further patients but follow-up visits would continue as per protocol. This decision was reached as the study had achieved its aim to assess safety and how well the IMP is tolerated. The timing of IMP expiry and scheduled end of recruitment (Jan 2019) along with the temporary halt in dosing led to the decision that no further IMP would be given and the study end date would be unaffected.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The planned number of subjects for this trial was 8 adults and no adolescents, not 6 and 1 as stated in the "Trial Information" section.

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Clinical trials

Clinical Trial Results:
Enhanced Epidermal Antigen Specific Immunotherapy trial -1 (EE-ASI-1): A Phase 1a study of gold nanoparticles administered intradermally by microneedles to deliver immunotherapy with a proinsulin derived peptide in Type 1 diabetes.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Assessment of the safety of C19-A3 GNP

Primary: Assessment of the safety of C19-A3 GNP

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: Enhanced Epidermal Antigen Specific Immunotherapy trial -1 (EE-ASI-1): A Phase 1a study of gold nanoparticles administered intradermally by microneedles to deliver immunotherapy with a proinsulin derived peptide in Type 1 diabetes.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Assessment of the safety of C19-A3 GNP

Primary: Assessment of the safety of C19-A3 GNP

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Enhanced Epidermal Antigen Specific Immunotherapy trial -1 (EE-ASI-1): A Phase 1a study of gold nanoparticles administered intradermally by microneedles to deliver immunotherapy with a proinsulin derived peptide in Type 1 diabetes.