ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618000815268

Ethics application status

Approved

Date submitted

20/04/2018

Date registered

11/05/2018

Date last updated

8/01/2020

Date data sharing statement initially provided

18/01/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

MRGPRX2 in general anaesthetic reactions

Scientific title

Does MRGPRX2 activation produce life-threatening anaphylaxis during anaesthesia and can it be
predicted and avoided?

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1212-6002

Trial acronym

None

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Anaphylaxis

Condition category

Condition code

Inflammatory and Immune System

Allergies

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

General anaesthesia- the study group will comprise patients who have had an allergic reaction during general anaesthesia. Samples will be collected prospectively following the reaction but prior to testing, and participants classified into arm 1 (NMBA implicated) or arm 2 (NMBA not implicated) on the basis of the general anaesthetic testing. The control group will be recruited prior to surgery, and the lack of reaction will be confirmed following the procedure.
The observation period in the patient group will comprise the duration of testing for general anaesthetic allergy (a day procedure). Participants will have blood taken in addition to blood samples for routine testing as part of general anaesthetic testing.

Intervention code [1]

Diagnosis / Prognosis

Comparator / control treatment

Observational study
A control group will be recruited from patients about to undergo surgery, with subsequent confirmation that no allergic reaction has occurred. This group will have blood taken in addition to routine pre-operative blood tests.

Control group

Active

Outcomes

Primary outcome [1]

Change in risk of reaction to NMBAs with specific MRGPRX2 variants. Risk will be determined using clinical determination of anaphylaxis cause as NMBA vs non-NMBA and analysed by chi-square test for each variant.
MRGPRX2 gene variants will be assessed by gene-specific PCR amplification followed by Sanger sequencing. Gene expression will also be quantified from mRNA using Taqman gene expression assays and real time PCR.

Timepoint [1]

All assessment will be performed on samples taken at the single study timepoint, which will be the day of general anaesthetic testing.

Secondary outcome [1]

MRGPRX2 variants associated with non-NMBA anaphylaxis as compared to control group. Techniques for DNA and RNA analysis will be as per the primary outcome. Case definition and analysis as per primary outcome.

As this is primarily an exploratory, hypothesis generating study further analyses will be performed including analysis of genes involved in MRGPRX2 signalling pathways, effects of patient serum on mast cell lines, and investigation of participant-derived mast cell lines, but these analyses and techniques are not pre specified and may vary based on findings, with further studies required to confirm any findings.

Timepoint [1]

All assessment will be performed on samples taken at the single study timepoint, which will be the day of general anaesthetic testing.

Eligibility

Key inclusion criteria

Patients who have been referred and accepted for general anaesthetic allergy testing at the Royal Melbourne Hospital Department of Clinical Immunology and Allergy are eligible for the study. Patients recruited will be 18 years or older. There are no restrictions on gender in the patient group. The volunteer control group should be matched for age and sex.will be patients planned for surgery at the Royal Melbourne Hospital.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Biologically related family members of participants with possible general anaesthetic allergy will not be able to participate as healthy controls.

Exclusion criteria for the control group will be known immunodeficiency, treatment with immunosuppressive medications, and any disease that would compromise the validity of a sample for the trial in the opinion of the investigator.

Study design

Purpose

Screening

Duration

Cross-sectional

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

SAMPLE SIZE ESTIMATION & JUSTIFICATION

This is an exploratory research study, and is expected to generate hypotheses to be tested with follow-up studies.

The cohort size (n=20 per group) was selected based on what is practical in terms of identifying patients in this setting, as general anaesthetic allergy is relatively uncommon.

For the genetic component of the study, sequencing of MRGPRX2, assuming a phenotypic and/or genetic variant (e.g. MRGPRX2 gene polymorphism) that increases the risk of anaphylaxis to rocuronium compared to healthy controls by 10-fold, could be detected with about 20 in each group (80% power and at a 95% confidence). This is a feasible number in our study. A rarer variant (e.g. 1% of the control population) could be detected with similar numbers if the relative risk is higher (50-fold increase). This is an hypothesis-generating study and no specific finding is predicted, but the above calculation indicates that the proposed numbers are adequate to statistically distinguish a strong effect from a common variant, or a very strong effect from a rare variant. Any finding from the proposed study would need to be confirmed by a specific prospective study. (Power calculation at http://www.openepi.com/SampleSize/SSCC.htm).

Other endpoints (including variations in intracellular signaling, mast cell activation and modulation of mast cell line response with participant serum) will be exploratory in nature and it is acknowledged that the sample size may not provide sufficient power to draw firm conclusions, with results most likely requiring formal follow up studies.

STATISTICAL METHODS TO BE UNDERTAKEN

All data will be expressed as mean +/- SEM and for statistical comparison between
groups, depending on the nature of the comparisons, t-test, ANOVA or non-parametric methods with appropriate post-hoc testing will be applied. Data will be analysed and presented using PRISM (version 7; GraphPad).

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

6/06/2018

Actual

27/06/2018

Date of last participant enrolment

Anticipated

18/12/2020

Actual

Date of last data collection

Anticipated

18/12/2020

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Royal Melbourne Hospital - City campus - Parkville

Recruitment postcode(s) [1]

3050 - Parkville

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Australian and New Zealand College of Anaesthetists

Address [1]

20 Pidgeon Cl, West End QLD 4101

Country [1]

Australia

Primary sponsor type

Hospital

Name

Melbourne Health

Address

Grattan Street, Parkville
VIC 3050

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health HREC

Ethics committee address [1]

Grattan Street,
Parkville VIC 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

31/01/2018

Approval date [1]

20/04/2018

Ethics approval number [1]

Summary

Brief summary

General anaesthesia is a very important component of modern surgery, and is necessary for many procedures ranging from kidney transplantation to total hip replacement. Anaesthesia requires the careful delivery of anaesthetic drugs, with constant monitoring of the patient by specialized doctors. To facilitate effective anaesthesia neuromuscular blocking agents (NMBAs) such as rocuronium are often used. These drugs relax muscle, enabling surgery to be performed without patient movement. In the vast majority of individuals these drugs are effective and safe, but in rare cases they can produce a severe life-threatening reaction. This severe allergy-like reaction can make the circulation fail, and during surgery can have potentially fatal consequences. This severe drug reaction has similar features to the allergic response termed anaphylaxis.

Anaphylaxis can be seen with food allergies, for example in peanut-sensitive individuals, in whom exposure to peanuts can be life-threatening. The similarity of this response seen with neuromuscular blocking drugs suggests a shared common mechanism. In anaphylactic reactions, the body generates an allergic antibody (called IgE) that interacts with the substance to which the patient is allergic to stimulate special immune cells called mast cells and basophils. These cells then release numerous chemicals, such as histamine, that produce the severe symptoms of anaphylaxis. Whilst this IgE mechanism is important to some drug allergy, there are also cases where no specific IgE can be found to explain the reaction. Recently, a new mechanism has been revealed whereby certain drugs, such as rocuronium, can directly stimulate a receptor protein on the surface of mast cells leading to their activation. Despite this advance, key questions remain - why are only some people affected? Secondly, by understanding this new mechanism - can we identify individuals who are likely to suffer these reactions, sparing them from potentially devastating consequences?

This project aims to answer these questions and in so doing provide a more individualised and safer approach to the use of muscle relaxant drugs during surgery.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Jeremy McComish

Address

Department of Clinical Immunology and Allergy
Royal Melbourne Hospital
Grattan Street, Parkville
VIC 3050

Country

Australia

Phone

+61 3 9342 7191

Fax

+61 3 9349 3199

jeremy.mccomish@mh.org.au

Contact person for public queries

Name

Jeremy McComish

Address

Department of Clinical Immunology and Allergy
Royal Melbourne Hospital
Grattan Street, Parkville
VIC 3050

Country

Australia

Phone

+61 3 9342 7191

Fax

+61 3 9349 3199

jeremy.mccomish@mh.org.au

Contact person for scientific queries

Name

Jeremy McComish

Address

Department of Clinical Immunology and Allergy
Royal Melbourne Hospital
Grattan Street, Parkville
VIC 3050

Country

Australia

Phone

+61 3 9342 7191

Fax

+61 3 9349 3199

jeremy.mccomish@mh.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

This information will be made available assuming that it complies with local privacy legislation and policies.

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

No additional documents have been identified.

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