Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001260112
Ethics application status
Approved
Date submitted
9/08/2019
Date registered
11/09/2019
Date last updated
16/12/2020
Date data sharing statement initially provided
11/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Malignant Hyperthermia - A new simple diagnostic test
Scientific title
Assessing Calcium flux in single muscle fibres in response to halothane and caffeine to diagnose Malignant Hyperthermia.
Secondary ID [1] 298988 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Hyperthermia 313982 0
Condition category
Condition code
Anaesthesiology 312380 312380 0 0
Anaesthetics

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
2
Target follow-up type
Weeks
Description of intervention(s) / exposure
Malignant Hyperthermia (MH) is a potentially life threatening event in response to anaesthetic triggering agents – volatile anaesthetics or depolarising muscle relaxants, resulting from alterations in intracellular calcium homeostasis of skeletal muscle cells.
Current diagnosis of MH involves a functional test on a large skeletal muscle biopsy from the leg, obtained under a non-triggering general anaesthetic - the in-vitro contracture test (IVCT). A diagnosis of MH susceptible is determined at a critical threshold of 0.2 g of force at 2 mM or less of caffeine and 2% or less of halothane in each test.

This study will assess intracellular calcium movements in isolated skeletal muscle fibres, to diagnose MH. Force is not used as a measure of responsiveness to RYR1 agonists. In single muscle fibre testing, the Ca2+ waves induced by caffeine or halothane imaged by confocal microscopy are classified by their amplitude and frequency. The amplitude is typically an indicator of the amount of Ca2+ being released through the RyR1s; and the frequency of the waves is indicative of the susceptibility of the RyR1 to opening in the presence of agonist.

Individual testing will occur over 3 hours. Results from the IVCT and the single muscle fibre assay will be collated. Direct comparison of the results will establish the reliability of the new technique, with reference to the current IVCT. We will calculate the proportion of these where the two methods give identical categorization as negative or susceptible using the Wilson method. If 200 out of 200 patients are categorized identically by the two methods then the 95% CI will be 0.981 to 1.00, meaning that the level of disagreement is no more than 1.2%. Recruitment of 200 samples will occur over a two year period.
Intervention code [1] 315254 0
Diagnosis / Prognosis
Comparator / control treatment
Control : the current diagnostic in vitro contracture test (IVCT)
Control group
Active

Outcomes
Primary outcome [1] 321017 0
To confirm that single muscle fibre testing can be used to diagnose Malignant Hyperthermia. This would be assessed by comparison with the IVCT, the current "gold standard" for MH diagnosis.
Timepoint [1] 321017 0
2 years post commencement of study will allow recruitment of 200 participants. Based on discussions with the senior hospital statistician 200 comparable tests will confirm the reliability of the single muscle fibre test.
Secondary outcome [1] 373703 0
Five hundred potential malignant hyperthermia susceptible patients appropriately diagnosed as assessed by intracellular calcium movements in isolated skeletal muscle fibres.
Timepoint [1] 373703 0
5 years. We anticipate that any diagnostic errors or complications of the new diagnostic test would become apparent within 5 years of the commencement of the study.

Eligibility
Key inclusion criteria
Patients who have experienced a MH clinical episode or their relatives have MH susceptibility, or they do not carry the diagnostic family genetic pathogenic variant. These patients display no clinical signs of neuromuscular disease.
Minimum age
18 Years
Maximum age
79 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children will be excluded

Study design
Purpose
Screening
Duration
Cross-sectional
Selection
Defined population
Timing
Prospective
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/11/2019
Actual
10/03/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
200
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 14508 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 14509 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 27520 0
2145 - Westmead
Recruitment postcode(s) [2] 27521 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 303527 0
Charities/Societies/Foundations
Name [1] 303527 0
The Pickles Foundation
Country [1] 303527 0
Australia
Funding source category [2] 307438 0
Charities/Societies/Foundations
Name [2] 307438 0
Australian & New Zealand College of Anaesthetists
Country [2] 307438 0
Australia
Primary sponsor type
Individual
Name
Dr Margaret Perry
Address
The Malignant Hyperthermia Unit, Sydney
Anaesthetic Department
The Children's Hospital, Westmead
Locked Bag 4001 Westmead NSW 2145
Country
Australia
Secondary sponsor category [1] 303592 0
Individual
Name [1] 303592 0
Dr Robyn Gillies
Address [1] 303592 0
The Malignant Hyperthermia Unit, Melbourne
Anaesthetic Department
Royal Melbourne Hospital
300 Grattan Street (corner of Royal Parade)
Parkville, Victoria 3050
Country [1] 303592 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304054 0
The Sydney Children's Hospitals Network Human Research Ethics Committee
Ethics committee address [1] 304054 0
Corner Hawkesbury Road and Hainsworth Street
Locked Bag 4001
Westmead NSW 2145
Ethics committee country [1] 304054 0
Australia
Date submitted for ethics approval [1] 304054 0
Approval date [1] 304054 0
01/07/2019
Ethics approval number [1] 304054 0
2019/ETH08726

Summary
Brief summary
Title: Malignant Hyperthermia - A new simple diagnostic test

Malignant Hyperthermia is a life threatening uncommon complication associated with having an anaesthetic. It may be passed down through families from one generation to the next. Many people at risk of Malignant Hyperthermia may be confirmed by a simple genetic test. However all other patients require a sample of muscle (muscle biopsy) taken from the leg, to have special functional testing to confirm they are at risk of Malignant Hyperthermia – the in-vitro contracture test (IVCT). The muscle biopsy is taken from the leg, requiring a surgical operation and a general anaesthetic that is known to be safe with MH.

Technical advancements have enabled the design of a new test on a very small component of the muscle obtained from a minor needle biopsy, under local anaesthetic. Through this project we will show this simple less invasive technique is a reliable test to determine a patient’s potential risk of malignant hyperthermia.

On the east coast of Australia, we have two Malignant Hyperthermia testing units. The Malignant Hyperthermia Units at The Royal Melbourne Hospital (RMH), Victoria and The Children’s Hospital, Westmead, NSW have been established for more than 15 years, and offer assessment of malignant hyperthermia risk through consultation, the muscle biopsy test and genetic analysis. The Muscle Research Laboratory, The University of Queensland, has extensive experience and understanding of skeletal muscle functioning. We will combine the excellence of all departments to improve our understanding of malignant hyperthermia and develop this simple, cheaper less invasive testing for malignant hyperthermia risk.

This study will have implications for providing a clear diagnosis for patients at risk of malignant hyperthermia, while being significantly less invasive than the current muscle biopsy test. A simple investigation acceptable to the general population will increase the number of patients agreeing to define their risk of malignant hyperthermia and thus contribute to safer anaesthesia for our community.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95662 0
Dr Margaret Perry
Address 95662 0
The Malignant Hyperthermia Unit
Anaesthetic Department
The Children's Hospital, Westmead
Locked Bag 4001
Westmead, 2145 Sydney NSW
Country 95662 0
Australia
Phone 95662 0
+61 2 98452367
Fax 95662 0
Email 95662 0
[email protected]
Contact person for public queries
Name 95663 0
Dr Margaret Perry
Address 95663 0
The Malignant Hyperthermia Unit
Anaesthetic Department
The Children's Hospital, Westmead
Locked Bag 4001
Westmead, 2145 Sydney NSW
Country 95663 0
Australia
Phone 95663 0
+61 2 98452367
Fax 95663 0
Email 95663 0
[email protected]
Contact person for scientific queries
Name 95664 0
Dr Margaret Perry
Address 95664 0
The Malignant Hyperthermia Unit
Anaesthetic Department
The Children's Hospital, Westmead
Locked Bag 4001
Westmead, 2145 Sydney NSW
Country 95664 0
Australia
Phone 95664 0
+61 2 98452367
Fax 95664 0
Email 95664 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not supported by the Ethics approval


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
3948Study protocol  [email protected]



Results publications and other study-related documents

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