ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12622000442707

Ethics application status

Approved

Date submitted

18/12/2021

Date registered

21/03/2022

Date last updated

4/09/2023

Date data sharing statement initially provided

21/03/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

The feasibility of 18F-Fluoromisonidazole (18F-FMISO) imaging for atherosclerotic and non-atherosclerotic intra-arterial hypoxia.

Scientific title

The feasibility of 18F-FMISO imaging for atherosclerotic and non-atherosclerotic intra-arterial hypoxia in the setting of peripheral arterial disease requiring amputation.

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

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

Cardiovascular Disease

Peripheral artery disease

Arterial calcification

Condition category

Condition code

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Cardiovascular

Other cardiovascular diseases

Intervention/exposure

Study type

Observational

Patient registry

False

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

Participants will attend a tertiary hospital for stand-alone 18F-Fluoromisonidazole (18F-FMISO) Positron Emission Tomography Computed Tomography (PET-CT) study acquisition prior to primary below-knee or above-knee amputation. PET-CT imaging will be performed for study/research purposes only.

18F-FMISO
-Prior to undergoing 18F-FMISO imaging, participant heart rate will be optimised using to target a heart rate below 65 beats per minute (bpm), using metoprolol or ivabradine.
-Participants will undergo an intravenous (IV) injection of 300MBq of 18F-FMISO that will be prepared according to site protocol.
-Injection of 18F-FMISO will be performed by trained nuclear medicine staff.
-After the injection, participants will be rested in a quiet environment and undergo frequent oxygen saturation and heart rate monitoring, for a duration of two hours.
-At two hours, 18F-FMISO PET imaging will begin with a low-dose attenuation correction CT scan of the lower limbs and the thorax.
-Following this, PET imaging will be acquired in 3D list mode acquisition from toes to mid-thigh.
-Subsequently, a chest imaging protocol from the upper thorax to diaphragm will be performed in prospective, cardiac gated, list mode acquisition.
- PET/CT imaging will be performed over approximately 45 minutes.
-18F-FMISO PET/CT is to occur up to 30 days prior to primary major limb amputation.

Histological assessment
-Within one hour of primary major limb amputation, lower limb arterial specimens will be salvaged to the best ability of local surgical staff.
-Samples from the anterior tibial, fibular, and posterior tibial artery will be extracted and fixed according to a local protocol for histological analysis.
- Samples will undergo basic histological staining and immunohistochemistry with HIF1-a.
- The remaining arterial samples will be used for biomechanical testing and other imaging with ex-vivo molecular and traditional imaging modalities.

Ex-vivo multi-modality imaging
- Samples not used for histological analysis will undergo ex-vivo 18F-NaF PET imaging, CT imaging and computational biomechanical modeling, and ex-vivo biomechanical testing.
- This will be performed after PET/CT imaging

Intervention code [1]

Diagnosis / Prognosis

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

The burden of HIF-1a (a histological marker for hypoxia) on immunohistochemisty between 18F-FMISO positive segments and 18F-FMISO negative segments, within the same artery.

Timepoint [1]

To be assessed following retrieval of arterial segments post major lower limb amputation, fixation, and staining. Analysis of primary timepoint will take place within 12 months of operation being performed.

Secondary outcome [1]

Arterial wall micro-calcification assessed using ex-vivo 18F-Sodium Fluoride PET activity.

Timepoint [1]

To be assessed following retrieval of arterial segments post major lower limb amputation, freezing, and storage. Analysis of secondary timepoint will take place within 12 months of operation being performed.

Secondary outcome [2]

Ex-vivo markers of calcification on computationally modeled measures of arterial stiffness determined from CT imaging; computational fluid dynamics and finite element analysis.

Timepoint [2]

To be assessed following retrieval of arterial segments post major lower limb amputation, freezing, and storage and after 18F-NaF PET radioactive decay. Analysis of secondary timepoint will take place within 12 months of the operation being performed.

Secondary outcome [3]

Ex-vivo markers of calcification on biomechanical measures of arterial stiffness from Cellscale Biotester; force displacement and stress-strain measurements

Timepoint [3]

To be assessed following retrieval of arterial segments post major lower limb amputation, freezing, and storage and after 18F-NaF PET radioactive decay and CT imaging. Analysis of secondary timepoint will take place within 12 months of the operation being performed.

Secondary outcome [4]

CT coronary calcium score; Agatston units

Timepoint [4]

Analysis of secondary timepoint will take place within 12 months of operation being performed.

Secondary outcome [5]

Measures of arterial lower limb stiffening; tibial calcification score and ankle brachial pulse index

Timepoint [5]

Analysis of secondary timepoint will take place within 12 months of operation being performed.

Eligibility

Key inclusion criteria

- Male or post-menopausal female (defined as the absence of menses of >12 months in the absence of pathology) above the age 40 who have undergone a clinical decision to proceed to below knee or above knee amputation
- A lower limb computed-tomography angiography performed in the last 18 months and performed exclusively for clinical purposes
- Have some evidence of arterial disease on lower limb computed-tomography angiography

Minimum age

40 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Inability to provide informed consent
- A diagnosis of chronic obstructive pulmonary disease or other respiratory disease that currently requires home oxygen therapy
- A resting oxygen saturation (measured at time of screening and in the absence of oxygen therapy) below 92%
- eGFR less than or equal to 30 at time of screening
- Symptomatic heart failure impairing an ability to lie flat on for imaging purposes or requiring supplemental oxygen therapy
- A prior below knee, above knee or higher, lower limb amputation of the other limb
- Acute lower limb ischemia requiring urgent revascularisation or emergent amputation
- Prior orthopaedic surgery of the lower limb with foreign material remaining in-situ
- In-patients requiring nurse escort for inter-hospital transport
- Recent or current lung cancer or cancer of the lower limb (excluding Non-melanoma skin cancer)
- Known cardiac arrhythmia that precludes ECG gating

Study design

Purpose

Natural history

Duration

Cross-sectional

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

Descriptive statistics will be used for the histological analyses. Correlations will be used to describe the relationship between PET activities (measured as a continuous variable; Tissue-to-background ratio or SUVmax) and other continuous variables. T-tests and Mann-Whitney U tests will be used to compare features of 18F-FMISO positive regions with 18F-FMISO negative regions. More advanced statistical methods will be used as required

Based on prior studies, we expect 60% of all 18F-FMISO positive lesions to stain positive for HIF-1 alpha . We may expect somewhere between 13% – 30% of 18F-FMISO negative lesions to stain positive for HIF-1 alpha, based on extrapolations from other observations. With an alpha of 0.05 and a power of 0.8, we would need 25 samples for each group to achieve significance. Assuming an intra-artery case-control like analysis, we would need 25 arteries in total. Each participant has three lower limb arteries of which we can expect a successful extraction 70% of the time, averaging 2.1 arteries per patient. This would require 12 patients to be enrolled in this study assuming no drop-outs.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

4/04/2022

Actual

15/08/2023

Date of last participant enrolment

Anticipated

1/12/2023

Actual

Date of last data collection

Anticipated

1/01/2024

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Royal Perth Hospital - Perth

Recruitment postcode(s) [1]

6000 - Perth

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Royal Perth Hospital

Address [1]

197 Wellington St
Perth, 6000
Western Australia

Country [1]

Australia

Primary sponsor type

Hospital

Name

Royal Perth Hospital

Address

197 Wellington St
Perth, 6000
Western Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Perth Hospital Human Research and Ethics Committee

Ethics committee address [1]

197 Wellington St
Perth, 6000
Western Australia

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

19/04/2020

Approval date [1]

27/07/2020

Ethics approval number [1]

RGS0000003977

Summary

Brief summary

Cardiovascular disease remains a leading cause of death. The burden of arterial calcifications remains an important predictor of cardiovascular disease events and deaths, however, predicting those who will eventually develop a large arterial calcification burden is difficult. Recently, lab studies have suggested that a low level of oxygen within the arterial wall, and plaque, may predispose to increasing calcification in the same region. 
18F-Fluoromisonidazole (18F-FMISO) Positron Emission Tomography (PET) is a novel molecular imaging modality that can detect areas of low oxygen in the arterial wall and plaque and may be a suitable imaging tool to predict where calcification develops. 
In a prospective arm, we aim to determine if regions of low oxygen in the vessel wall, detected with 18F-FMISO PET, in patients undergoing lower limb amputation, is associated with other markers of hypoxia (in-vitro hypoxia inducible factor 1-alpha) and calcification (ex-vivo 18F-Sodium Flouride PET) in the same anatomical region.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Jamie Bellinge

Address

Royal perth Hospital
197 Wellington St
Perth 6000
Western Australia

Country

Australia

Phone

+61 8 9224 3181

Fax

Jamie.Bellinge@health.wa.gov.au

Contact person for public queries

Name

Jamie Bellinge

Address

Royal perth Hospital
197 Wellington St
Perth 6000
Western Australia

Country

Australia

Phone

+61 8 9224 3181

Fax

Jamie.Bellinge@health.wa.gov.au

Contact person for scientific queries

Name

Jamie Bellinge

Address

Royal Perth Hospital
197 Wellington St
Perth 6000
Western Australia

Country

Australia

Phone

+61 8 9224 3181

Fax

Jamie.Bellinge@health.wa.gov.au

Data sharing statement

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

Yes

What data in particular will be shared?

De-identified IPD may be shared (PET data, clinical information) on specific request

When will data be available (start and end dates)?

Data may be available for request from January 2023 - coinciding with expected publication date of primary outcome. Data will be available for 15 years according to local data safety and storage requirements.

Available to whom?

Researchers in the area of arterial calcification, after specific request

Available for what types of analyses?

Meta-analyses

How or where can data be obtained?

Data may be provided after a reasonable request to the PI via email; Jamie.Bellinge@health.wa.gov.au

What supporting documents are/will be available?

Doc. No.	Type	Email
14478	Study protocol	Jamie.Bellinge@health.wa.gov.au
14479	Informed consent form	Jamie.Bellinge@health.wa.gov.au
14480	Clinical study report	Jamie.Bellinge@health.wa.gov.au
14481	Ethical approval	Jamie.Bellinge@health.wa.gov.au

Results publications and other study-related documents

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