Calf Muscle Perfusion in Patients With Intermittent Claudication by Non-invasive MSOT (MSOT_IC)

Cross-sectional Study of Calf Muscle Perfusion in Patients With Intermittent Claudication by Non-invasive Multispectral Optoacustic Tomography

The objective of the proposed study is to define independent parameters for the diagnostic assessment of the perfusion situation of the calf muscle based on multispectral optoacoustic tomography (MSOT) in a cross-sectional collective of patients with PAD in Fontaine stage II (intermittent claudication) and a healthy control collective (study group 1). The results will be validated using an independent validation group (study group 2).

Study Overview

• Status: Recruiting
• Conditions: Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication
• Intervention / Treatment: Device: Multispectral Optoacoustic Tomography (MSOT)

Detailed Description

PAD is one of the most common diseases of the elderly. As life expectancy increases, there is a growing need for new treatment concepts and new diagnostic procedures.

Up to now, only the measurement of macrocirculation in the form of CCDS, ABI and measurement of the actual walking distance are available as independent validation measures of revascularization methods (endovascular/open). The S3 guideline for diagnosis, therapy and medical aftercare of PAD published in 2015 by DGA (Deutsche Gesellschaft für Angiologie, German Society for Angiology) recommends such aftercare examinations, especially for patients that underwent vascular surgery. However, for the mentioned validation measures there are some patient groups for which these methods provide only insufficient or unusable results (e.g. diabetes mellitus, terminal renal failure). In these cases, independent verification of the success of the chosen therapy would have to be performed using angiography (digital subtraction angiography, CT angiography or MR angiography). However, this is not routinely performed in the respective patient populations due to the associated risks (including radiation exposure, contrast agent administration, invasiveness).

MSOT provides a new non-invasive diagnostic method that may be able to fill this diagnostic gap. A first study (MSOT_PAD, NCT04641091) confirmed the hypothesis that data collected via MSOT examination of the calf muscle can be used for PAD diagnostics. The derived concentration of oxygenated hemoglobin (HbO2) proved to be the most suitable measurement parameter. A connection could be established between the measured HbO2 concentration and the clinical stage of PAD. Differentiation improved after a standardized exercise of a walking distance of 150 meters, with patients in the stage of intermittent claudication (IC, Fontaine stage II) being more difficult to differentiate in comparison to patients in Fontaine stages III and IV.

The aim of this cross-sectional study is to increase the sensitivity and specificity of the procedure for IC patients by using a more suitable exercise between first and second MSOT measurement, namely repeated heel raises until the occurrence of claudication pain. A subgroup of the IC patients having been included in the study will be asked to undergo the study protocol a second time after interventional/ surgical revascularization. This is to investigate whether and how the improved blood flow situation translates to the measured MSOT parameters.

As additional target variables, the relative, absolute and total walking distance in a 6-minute walk test as well as the PAD-specific quality of life will be recorded with the VASCUQOL-6 questionnaire. A healthy control collective is included as a comparison group.

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

Contacts and Locations

• Study Contact: Name: Ulrich Rother, PD Dr. med.; Phone Number: +4991318542028; Email: ulrich.rother@uk-erlangen.de

Study Locations

• Germany
  • Bavaria
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • University of Erlangen-Nuremberg (FAU), Department of Vascular Surgery
      • Contact: Ulrich Rother, Dr. med.; Phone Number: +4991318542028; Email: ulrich.rother@uk-erlangen.de
      • Contact: Werner Lang, Prof. Dr. med.; Phone Number: +4991318532968; Email: werner.lang@uk-erlangen.de
      • Sub-Investigator: Julius Kempf
      • Sub-Investigator: Milenko Caranovic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with

• PAD IIa
• PAD IIb presenting for consultation during consultation hours of the department of vascular surgery.

Healthy volunteers being recruited by notices posted in the clinic with following conditions:

• no PAD previously known
• no diabetes mellitus previously known
• no chronic renal insufficiency previously known
• no symptoms of intermittent claudication
• ABI with values between 0.9 and 1.4 (screening examination before inclusion in the study)
• palpable foot pulses

Description

Inclusion Criteria:

• Patients with manifest PAD in stage II according to Fontaine or categories 1-3 according to Rutherford or healthy volunteers
• Adults (>18 years) who are able to give their consent

Exclusion Criteria:

• Patients with PAD stage I, III and IV according to Fontaine or categories 0, 4, 5 and 6 according to Rutherford or healthy volunteers with diabetes mellitus, chronic renal failure, claudication symptoms, abnormal ABI or non-palpable foot pulses
• Underage persons
• Lack of written consent
• Safety concerns of the study physician (person with physical, mental or psychiatric conditions which, by the judgement of the study physician, would compromise the person's safety or the quality of the data, thereby rendering the person an ineligible candidate for the study)

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Study group 1; Multispectral Optoacoustic Tomography (MSOT) and B-Mode Ultrasound of the Musculus triceps surae of the affected leg in PAD patients in Fontaine stage II (intermittent claudication) or one leg in healthy volunteers (total 1 site) Physical assessment: Pulse status / Color-Coded Duplex Sonography / Ankle-Brachial Index / 6-minute walk test (6MWT) / Continued heel raises for at least 30s	Device: Multispectral Optoacoustic Tomography (MSOT); Non-invasive transcutaneous imaging of subcellular muscle components via infrared and near-infrared laser pulses
Study group 2; Multispectral Optoacoustic Tomography (MSOT) and B-Mode Ultrasound of the Musculus triceps surae of the affected leg in PAD patients in Fontaine stage II (intermittent claudication) or one leg in healthy volunteers (total 1 site) Physical assessment: Pulse status / Color-Coded Duplex Sonography / Ankle-Brachial Index / 6-minute walk test (6MWT) / Continued heel raises for at least 30s	Device: Multispectral Optoacoustic Tomography (MSOT); Non-invasive transcutaneous imaging of subcellular muscle components via infrared and near-infrared laser pulses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optimal diagnostic MSOT thresholds	Optimal diagnostic threshold for hemoglobin-associated MSOT parameters in calf muscle tissue in patients with intermittent claudication before and after exercise	single time point (1 day)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between the corresponding MSOT values before and after exercise	Difference of the values before and after exercise for hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT in patients with IC	single time point (1 day)
Reperfusion profiles for hemoglobin-associated parameters	Curves of hemoglobin-associated MSOT parameters in the first ten minutes after exercise	single time point (1 day)
Correlation of acquired MSOT parameters with the CCDS flow profile and PSV	Hemoglobin-associated MSOT parameters (units: arbitrary units (a.u.)) in patients with IC correlated with the flow profile and PSV of A. femoralis communis and A. poplitea determined by CCDS	single time point (1 day)
Correlation of acquired MSOT parameters with the ABI	Hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT correlated with the ABI	single time point (1 day)
Correlation of acquired MSOT parameters with relative and absolute walking distance	Hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT correlated with relative (until the first occurrence of pain) and absolute walking distance (until the first stopping due to pain) in the 6-minute walk test (6MWT)	single time point (1 day)
Correlation of acquired MSOT parameters with maximum walking distance within 6 minutes	Hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT correlated with the maximum walking distance during the 6 minutes of the 6-minute walk test	single time point (1 day)
Correlation of acquired MSOT parameters with the subjectively perceived maximum walking distance in everyday life	Hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT correlated with the subjectively perceived maximum walking distance in everyday life	single time point (1 day)
Correlation of acquired MSOT parameters with the perceived PAD-specific quality of life (VASCUQOL-6 questionnaire)	Hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT correlated with the perceived PAD-specific quality of life (VASCUQOL-6 questionnaire)	single time point (1 day)
Correlation of the acquired MSOT parameters with the TASC-classification (angiography)	Hemoglobin-associated parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT in patients with IC correlated with the TASC-classification (angiography) [If angiographic imaging is already available due to routine diagnostics independently from this study.]	single time point (1 day)
Subgroup analysis: Difference between the corresponding MSOT values before and after revascularization intervention	Subgroup analysis: Difference of the MSOT values before and after revascularization intervention for hemoglobin-associated parameters derived by transcutaneous MSOT in patients with IC	two time points (2 days)
Subgroup analysis: Reperfusion profiles for hemoglobin-associated parameters after revascularization intervention	Subgroup analysis: Reperfusion profiles of hemoglobin-associated MSOT parameters (i.e. the curves of hemoglobin-associated MSOT parameters in the first ten minutes after exercise) after revascularization intervention	single time point (1 day)
Subgroup analysis: Correlation of acquired MSOT parameters after intervention with the CCDS flow profiles and PSVs after intervention	Subgroup analysis: hemoglobin-associated MSOT parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT in patients with IC after revascularization intervention correlated with the flow profiles and PSVs of A. femoralis communis and A. poplitea determined by CCDS after revascularization intervention	single time point (1 day)
Subgroup analysis: Correlation of acquired MSOT parameters after intervention with the ABI after intervention	Subgroup analysis: hemoglobin-associated MSOT parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT after revascularization intervention correlated with the ABI measurements after revascularization intervention	single time point (1 day)
Subgroup analysis: Correlation of acquired MSOT parameters after intervention with relative (until the first occurrence of pain) and absolute walking distance (until the first stopping due to pain) determined during the 6MWT after intervention	Subgroup analysis: hemoglobin-associated MSOT parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT after revascularization intervention correlated with relative (until the first occurrence of pain) and absolute walking distance (until the first stopping due to pain) in the 6MWT after revascularization intervention	single time point (1 day)
Subgroup analysis: Correlation of acquired MSOT parameters after intervention with maximum walking distance in the 6MWT after intervention	Subgroup analysis: hemoglobin-associated MSOT parameters (units: arbitrary units (a.u.)) derived by transcutaneous MSOT after revascularization intervention correlated with the maximum walking distance in the 6MWT after revascularization intervention	single time point (1 day)

Collaborators and Investigators

• Sponsor: Ulrich Rother
• Collaborators: PD Dr. med. Ferdinand Knieling, Department of pediatrics, University of Erlangen-Nürnberg

Publications and helpful links

General Publications

• Larsen ASF, Reiersen AT, Jacobsen MB, Klow NE, Nordanstig J, Morgan M, Wesche J. Validation of the Vascular quality of life questionnaire - 6 for clinical use in patients with lower limb peripheral arterial disease. Health Qual Life Outcomes. 2017 Sep 22;15(1):184. doi: 10.1186/s12955-017-0760-3.
• Alpert JS, Larsen OA, Lassen NA. Exercise and intermittent claudication. Blood flow in the calf muscle during walking studied by the xenon-133 clearance method. Circulation. 1969 Mar;39(3):353-9.
• Lawall H, Diehm C, Hoffmann U, Reinecke H. [Update PAVK: Epidemiology, comorbidity and prognosis of peripheral arterial obstructive disease]. Dtsch Med Wochenschr. 2015 Dec;140(24):1798-802. doi: 10.1055/s-0041-107064. Epub 2015 Dec 1. German.
• Lawall H, Huppert P, Espinola-Klein C, Zemmrich CS, Ruemenapf G. German guideline on the diagnosis and treatment of peripheral artery disease - a comprehensive update 2016. Vasa. 2017 Mar;46(2):79-86. doi: 10.1024/0301-1526/a000603. Epub 2017 Jan 27.
• Karlas A, Masthoff M, Kallmayer M, Helfen A, Bariotakis M, Fasoula NA, Schafers M, Seidensticker M, Eckstein HH, Ntziachristos V, Wildgruber M. Multispectral optoacoustic tomography of peripheral arterial disease based on muscle hemoglobin gradients-a pilot clinical study. Ann Transl Med. 2021 Jan;9(1):36. doi: 10.21037/atm-20-3321.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 20, 2022
• Primary Completion (Anticipated): September 30, 2022
• Study Completion (Anticipated): September 30, 2022

Study Registration Dates

• First Submitted: May 9, 2022
• First Submitted That Met QC Criteria: May 9, 2022
• First Posted (Actual): May 13, 2022

Study Record Updates

• Last Update Posted (Actual): May 27, 2022
• Last Update Submitted That Met QC Criteria: May 24, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: PAD; Peripheral Artery Disease; 6-minute walk test; Peripheral Arterial Disease; Ankle Brachial Index; Multispectral Optoacoustic Tomography; Claudicatio intermittens; MSOT; CLI; Color-Coded Duplex Sonography; CCDS; ABI; Peripheral Vascular Diseases; Intermittent Claudication; Critical Limb Ischaemia; Critical Limb Threatening Ischemia; CTLI; Heel Raises; 6MWT; Muscle Perfusion; Calf Muscle Perfusion
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Vascular Diseases; Peripheral Arterial Disease; Peripheral Vascular Diseases; Intermittent Claudication
• Other Study ID Numbers: MSOT_IC

Drug and device information, study documents

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