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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] 306080 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cardiovascular Disease 324733 0
Peripheral artery disease 324734 0
Arterial calcification 324735 0
Condition category
Condition code
Cardiovascular 322183 322183 0 0
Diseases of the vasculature and circulation including the lymphatic system
Cardiovascular 322184 322184 0 0
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] 322486 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 329950 0
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] 329950 0
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] 404394 0
Arterial wall micro-calcification assessed using ex-vivo 18F-Sodium Fluoride PET activity.
Timepoint [1] 404394 0
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] 404395 0
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] 404395 0
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] 406720 0
Ex-vivo markers of calcification on biomechanical measures of arterial stiffness from Cellscale Biotester; force displacement and stress-strain measurements
Timepoint [3] 406720 0
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] 407384 0
CT coronary calcium score; Agatston units
Timepoint [4] 407384 0
Analysis of secondary timepoint will take place within 12 months of operation being performed.
Secondary outcome [5] 407389 0
Measures of arterial lower limb stiffening; tibial calcification score and ankle brachial pulse index
Timepoint [5] 407389 0
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?
No
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
12
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 21360 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 36252 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 310416 0
Hospital
Name [1] 310416 0
Royal Perth Hospital
Country [1] 310416 0
Australia
Primary sponsor type
Hospital
Name
Royal Perth Hospital
Address
197 Wellington St
Perth, 6000
Western Australia
Country
Australia
Secondary sponsor category [1] 311574 0
None
Name [1] 311574 0
NA
Address [1] 311574 0
NA
Country [1] 311574 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310062 0
Royal Perth Hospital Human Research and Ethics Committee
Ethics committee address [1] 310062 0
197 Wellington St
Perth, 6000
Western Australia
Ethics committee country [1] 310062 0
Australia
Date submitted for ethics approval [1] 310062 0
19/04/2020
Approval date [1] 310062 0
27/07/2020
Ethics approval number [1] 310062 0
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 116358 0
Dr Jamie Bellinge
Address 116358 0
Royal perth Hospital
197 Wellington St
Perth 6000
Western Australia
Country 116358 0
Australia
Phone 116358 0
+61 8 9224 3181
Fax 116358 0
Email 116358 0
[email protected]
Contact person for public queries
Name 116359 0
Jamie Bellinge
Address 116359 0
Royal perth Hospital
197 Wellington St
Perth 6000
Western Australia
Country 116359 0
Australia
Phone 116359 0
+61 8 9224 3181
Fax 116359 0
Email 116359 0
[email protected]
Contact person for scientific queries
Name 116360 0
Jamie Bellinge
Address 116360 0
Royal Perth Hospital
197 Wellington St
Perth 6000
Western Australia
Country 116360 0
Australia
Phone 116360 0
+61 8 9224 3181
Fax 116360 0
Email 116360 0
[email protected]

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; [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14478Study protocol  [email protected]
14479Informed consent form  [email protected]
14480Clinical study report  [email protected]
14481Ethical approval  [email protected]



Results publications and other study-related documents

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