Symptomatic and Systemic Atherosclerotic Plaque Activity in Patients With Peripheral Arterial Disease Using Novel Imaging (SISYPHUS)

The goal of this observational study is to characterise the relationships between inflammation, microcalcification and thrombus activity in atherosclerotic plaques in peripheral and systemic vascular territories in patients with symptomatic peripheral arterial disease.

Study Overview

• Status: Recruiting
• Conditions: Peripheral Arterial Disease; Chronic Limb Threatening Ischemia
• Intervention / Treatment: Radiation: Whole body [68Ga]DOTATATE PET-CT; Radiation: Whole body [18F]GP1 PET-CT; Radiation: Whole body [18F]NaF PET-CT; Radiation: Whole body CT angiogram

Detailed Description

In peripheral arterial disease (PAD), arteries in the lower body can become narrowed and develop blockages due to a process called atherosclerosis, leading to reduced blood flow to the lower limbs. Symptoms can range from mild cramping pain in legs on walking, to loss of parts of the leg. Patients with PAD are also at a high risk of blockages in other arteries in the body that can lead to problems such as heart attacks and strokes. Despite improvements in medical treatments and surgery, the outlook for patients with PAD has not improved.

Further information is required to understand the relationships between the processes that lead to narrowing and blockages (atherosclerosis) of the arteries and if they behave the same in different parts of the body. This can help to identify targeted treatments to reduce the risk of the disease getting worse and avoid heart attacks and strokes.

In this study investigators plan to recruit 100 people with symptomatic PAD to undergo a series of whole body PET-CT and CT angiogram scans using different tracers targeting the processes involved in atherosclerosis. Investigators will aim to co-enrol patients taking part in the LEADER-PAD study (NCT04774159).

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Allison c Winarski, MBChB, MRCS(Ed); Phone Number: +447495905258; Email: awinarsk@ed.ac.uk
• Study Contact Backup: Name: Rachael O Forsythe, MBChB, PhD, FRCS (Vascular); Phone Number: +44 01312423585; Email: rachael.forsythe@ed.ac.uk

Study Locations

• United Kingdom
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH16 4SA
      • Recruiting
      • Royal Infirmary of Edinburgh
      • Contact: Allison C Winarski, MBChB MRSC(Ed); Phone Number: +447495905258; Email: awinarsk@ed.ac.uk
      • Contact: Rachael O Forsythe, MBChB, PhD, FRCS (Vascular); Phone Number: 01312423585; Email: rachael.forsythe@ed.ac.uk
      • Sub-Investigator: Allison C Winarski, MBChB MRCS (Ed)
      • Principal Investigator: Rachael O Forsythe, MBChB, PhD, FRCS (Vascular)
      • Sub-Investigator: David E Newby, BSc (Hons)PhD BM DM DSc FRCP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients will be prosectively recruited from vascular outpatient clinics and inpatient wards.

Description

Inclusion Criteria:

• Male or female aged > 18 years

• Symptomatic atherosclerotic peripheral artery disease;

  • Intermittent claudication; with ankle/arm blood pressure ratio <0.90 or artery stenosis >50% in addition to at least one of the following;

    • >1 vascular bed affected by atherosclerosis
    • Diabetes
    • Heart failure
    • Chronic kidney disease (eGFR < 60 mL/min/1.73 m2)
  • Rest pain or necrosis of limb or gangrene of limb
  • Revascularization defined as limb bypass surgery or endovascular revascularization procedures (irrespective of the specific device used), including percutaneous transluminal angioplasty/stent of iliac or infra-inguinal arteries or extra-anatomical bypass surgery
  • Leg or foot amputation for arterial vascular indications
• Ability to give written or verbal informed consent

Exclusion Criteria:

• Contraindication to colchicine or iodinated contrast
• Long term requirement for colchicine for another clinical indication
• Active diarrhoea
• Recent lower limb revascularisation for symptomatic disease (<6 weeks)
• Renal failure (glomerular filtration rate <30 mL/min/1.73 m2)
• Cirrhosis or severe chronic liver disease
• Women who are pregnant or breast-feeding
• Women of child-bearing potential not protected by reliable contraception or is planning conception during the study
• Current or planned long term use of cyclosporine, verapamil, HIV protease inhibitors, azole antifungals, or macrolide antibiotics (apart from azithromycin)
• Patients deemed unlikely to return for follow up
• Life expectancy <1 year
• Inability or unwilling to give informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with symptomatic peripheral arterial disease	Radiation: Whole body [68Ga]DOTATATE PET-CT; Targeting vascular inflammation; Radiation: Whole body [18F]GP1 PET-CT; Targeting thrombus activity; Radiation: Whole body [18F]NaF PET-CT; Targeting vascular microcalcification; Radiation: Whole body CT angiogram; To determine anatomical and morphological atherosclerotic plaque characteristics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of PET tracer uptake of [68Ga]DOTATATE, [18F]GP1 and [18F]NaF in the symptomatic lower limb(s)	The 3 primary endpoints will be the location and degree of: inflammation: uptake of [68Ga]DOTATATE; calcification: uptake of [18F]NaF; thrombus activity: uptake of [18F]GP1 in peripheral arterial disease affecting the lower limbs. This will be determined by the degree of tracer standardised uptake values (SUVs) at the site of the symptomatic atherosclerotic plaque.	From baseline imaging until completion imaging at 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of PET tracer uptake of [68Ga]DOTATATE, [18F]GP1 and [18F]NaF in remote arterial territories	The secondary outcome measures will be the location and degree of inflammation, calcification and thrombus activity in remote arterial territories, including the coronary arteries, cerebral arteries, aorta and mesenteric vessels, as determined by SUVs of [68Ga]DOTATATE, [18F]NaF and [18F]GP1, respectively.	From baseline imaging until completion imaging at 1 year
CT plaque morphology	Investigators will characterise CT plaque morphology (total, calcified, non-calcified and low-attenuation plaque) in peripheral and systemic arterial beds and compare this to areas of [68Ga]DOTATATE, [18F]GP1 and [18F]NaF uptake.	From baseline imaging to completion imaging at 1 year
The association between patient risk factors for cardiovascular disease and PET tracer uptake	Investigators will explore the association between patient risk factors for cardiovascular disease (hypertension, diabetes, smoking) and the degree of [68Ga]DOTATATE, [18F]GP1 and [18F]NaF uptake as quantified by standard uptake values (SUVs). This will be measured by odds ratio (OR) with 95% confidence interval (CI) for each risk factor-tracer combination.	Frome baseline imaging to completion imaging at 1 year
The progression of microcalcification, as defined by [18F]NaF uptake, to macrocalcification.	Investigators will also aim to characterise the relationship between microcalcification progressing to calcification and the uptake of [18F]NaF. This will be assessed using baseline and follow-up [18F]NaF PET-CT SUVs and their correlation with calcified regions on CT angiography.	From baseline imaging to completion imaging at 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major adverse cardiovascular events (MACE) and major adverse limb events (MALE)	Exploratory endpoints will include major adverse cardiovascular events (acute myocardial infarction, stroke or cardiovascular death) and major adverse limb events (revascularisation or lower limb amputation) as well as death from any cause.	From baseline imaging to completion imaging at 1 year

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Principal Investigator: Rachael O Forsythe, MBChB, PhD, FRCS (Vascular), University of Edinburgh

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2025
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: September 15, 2025
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Peripheral arterial disease; cardiovascular diseases; Sodium Fluoride; DOTATATE; PET-CT; Chronic limb threatening ischaemia; GP1
• Additional Relevant MeSH Terms: Vascular Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Ischemia; Pathological Conditions, Signs and Symptoms; Chronic Limb-Threatening Ischemia; Cardiovascular Diseases; Peripheral Arterial Disease
• Other Study ID Numbers: AC25008; BHF PG/24/12097 (Other Grant/Funding Number: British Heart Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No