Enhancing Ultrasound & Photoacoustic for Recognition of Intestinal Abnormalities (EUPHORIA)

• ClinicalTrials.gov Identifier: NCT04456400
• Recruitment Status: Recruiting
• First Posted: July 2, 2020
• Last Update Posted: June 28, 2022
• Sponsor: iThera Medical GmbH
• Collaborator: European Commission
• Information provided by (Responsible Party): iThera Medical GmbH

Study Description

Brief Summary:

The clinical investigation aims to generate clinical data to support the use of Multispectral Optoacoustic Tomography (MSOT) in clinical practice, its inclusion in diagnostic guidelines and to support its reimbursement, specifically to

• Further validate the application with respect to including ulcerative colitis patients
• Prepare a study protocol for large-scale clinical validation study in inflammatory bowel disease (IBD)
• Successfully execute the clinical validation study

Condition or disease	Intervention/treatment
Inflammatory Bowel Diseases; Ulcerative Colitis; Crohn Disease	Diagnostic Test: Multispectral Optoacoustic Tomography (MSOT)

Detailed Description:

The clinical investigation, EUPHORIA, will pave the way to establish Multispectral Optoacoustic Tomography (MSOT) technology for the non-invasive assessment of intestinal inflammation in patients. EUPHORIA will enable commercialization of the technology by finalizing technical improvements that will increase diagnostic outcome beyond what has been shown in a first feasibility study, will improve usability, prepare CE marking for the new device and validate clinical results in a large clinical investigation.

Inflammatory bowel disease (IBD) is a chronic condition, posing significant burden to patients and health care systems. Patients suffer from a relapsing course of intestinal inflammation, and to date, there is no satisfying noninvasive diagnostic modality for monitoring disease activity. In a recent clinical study conducted by University Hospital Erlangen, MSOT, a technology developed by iThera Medical (ITM), has proven to be superior in diagnostic performance to other procedures.

Study Design

• Study Type: Observational
• Estimated Enrollment: 540 participants
• Observational Model: Cohort
• Time Perspective: Cross-Sectional
• Official Title: Enhancing Ultrasound & Photoacoustic for Recognition of Intestinal Abnormalities (EUPHORIA)
• Actual Study Start Date: February 3, 2021
• Estimated Primary Completion Date: February 2023
• Estimated Study Completion Date: April 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Derivation cohort; The derivation sub-cohort will be used to derive optimum reconstruction algorithm parameters of MSOT images. Primary objective of the derivation cohort is to derive Multispectral Optoacoustic Tomography (MSOT) thresholds maximizing receiver operating characteristic (ROC) to distinguish endoscopic remission from active disease. As secondary objective, performance of the Multispectral Optoacoustic Tomography (MSOT) device will be analyzed.	Diagnostic Test: Multispectral Optoacoustic Tomography (MSOT); cMSOT-2 system is indicated for measurement of the Multispectral Optoacoustic Tomography (MSOT) values in the bowel wall of patients with an established diagnosis of inflammatory bowel disease (IBD), specifically Crohn's Disease (CD) and Ulcerative Colitis (UC). The MSOT values provided may be used as an aid to the assessment of inflammatory disease activity in the bowel wall.
Validation cohort; Objective of the validation cohort is to confirm the performance of Multispectral Optoacoustic Tomography (MSOT) using prescribed thresholds from the derivation cohort.	Diagnostic Test: Multispectral Optoacoustic Tomography (MSOT); cMSOT-2 system is indicated for measurement of the Multispectral Optoacoustic Tomography (MSOT) values in the bowel wall of patients with an established diagnosis of inflammatory bowel disease (IBD), specifically Crohn's Disease (CD) and Ulcerative Colitis (UC). The MSOT values provided may be used as an aid to the assessment of inflammatory disease activity in the bowel wall.

Outcome Measures

Primary Outcome Measures :

1. Derivation Cohort: derive optimum diagnostic MSOT thresholds [ Time Frame: 5-10 days ]
   Derivation cohort: The primary endpoint of the derivation cohort is to derive optimum diagnostic MSOT thresholds based on receiver operating characteristics (ROC) analysis to distinguish endoscopic active disease from remission in Crohn's Disease (CD) or Ulcerative Colitis (UC) patients.
2. Validation cohort: re-assess the diagnostic accuracy of MSOT [ Time Frame: 5-10 days ]

   Validation cohort:

   The primary endpoint of the validation cohort is to re-assess the diagnostic accuracy of MSOT to distinguish endoscopic active disease from remission in an independent cohort. It will be considered successful if a lower 90% confidence of limit at least 75% of area under curve (AUC) is reached

Secondary Outcome Measures :

1. Derivation Cohort: MSOT thresholds [ Time Frame: 9-10 months ]
   Derive MSOT thresholds using histology as a reference: receiver operating characteristics (ROC) analysis to distinguish histologic active disease from remission.
2. Derivation Cohort: MSOT performance, diagnostic accuracy measures [ Time Frame: 9-10 months ]
   Diagnostic accuracy measures (area under curve (AUC), sensitivity, specificity) of MSOT to distinguish endoscopic active disease from remission.
3. Derivation Cohort: MSOT performance, diagnostic accuracy [ Time Frame: 9-10 months ]
   Diagnostic accuracy of MSOT to distinguish histologic active disease from remission
4. Validation Cohort: MSOT performance, diagnostic accuracy measures [ Time Frame: through study completion, an average of 1 year ]
   Further diagnostic accuracy measures (sensitivity, specificity, predictive values) of MSOT to distinguish endoscopic active disease from remission using the MSOT thresholds from the derivation cohort
5. Validation Cohort: MSOT performance, diagnostic accuracy [ Time Frame: through study completion, an average of 1 year ]
   Diagnostic accuracy (area under curve (AUC), sensitivity, specificity, predictive values) of MSOT to distinguish histologic active disease from remission using the MSOT thresholds from the derivation cohort.
6. Both cohorts: diagnostic accuracy [ Time Frame: through study completion, an average of 1 year ]
   Diagnostic accuracy of MSOT to distinguish clinical active disease from remission.
7. Both cohorts: performance of other non-invasive diagnostic modalities [ Time Frame: through study completion, an average of 1 year ]
   Assess performance of other non-invasive diagnostic modalities in order to allow for comparison to MSOT performance. Diagnostic accuracy of each of the various non-invasive tests (CRP, fCal, US, MRI) with respect to the endoscopy (reference test) and histology will be calculated using standard techniques for diagnostic studies. This includes cross tabulation of the index test results by the results of the reference standard, as well as plots of their distribution and ROC curves. Area under the Curve (AUC) estimates and confidence intervals (DeLong) will be calculated. Score confidence intervals (Wilson) will be calculated for proportions such as sensitivity, specificity, and predictive values at the predefined thresholds.
8. Both cohorts: likelihood ratios and predictive values for active inflammation [ Time Frame: through study completion, an average of 1 year ]
   Assess the likelihood ratios and predictive values for active inflammation after MSOT examination.
9. Both cohorts: performance of MSOT in combination with other modalities [ Time Frame: through study completion, an average of 1 year ]
   Explore performance of MSOT in combination with other modalities, e.g. in combination with ultrasound (US) or laboratory. AUC will be estimated for all non-invasive tests with a 95% confidence interval (DeLong) both from the derivation cohort and from the pooled cohorts (derivation + validation) for increased precision. Cohen's κ will be used as a measure of overall agreement. Results will be presented in three-way tables, comparing the new test (MSOT), the non-reference standard (non-invasive modalities), and the reference standard (endoscopy).
10. Both cohorts: discriminate different grades of disease activity [ Time Frame: through study completion, an average of 1 year ]
    Investigate ability of MSOT and other non-invasive diagnostic modalities, i.e. ultrasoiund (US), fecal calprotectin (fCal), clinical scores to discriminate different grades of disease activity (remission, mild, moderate, high according to endoscopy, histology or clinical scores; for cut-offs.
11. Both cohorts: interobserver variability [ Time Frame: through study completion, an average of 1 year ]
    Explore variations in MSOT diagnostic accuracy between sites and operators (interobserver variability).
12. Both cohorts: patient preference [ Time Frame: 5-10 days ]
    Evaluate patient preference for different tests using a patient survey
13. Derivation cohort: MSOT thresholds using clinical scores as a reference [ Time Frame: through study completion, an average of 1 year ]
    Derive MSOT thresholds using clinical scores as a reference: ROC analysis to distinguish clinical active disease from remission (only derivation cohort).

Biospecimen Retention:   Samples Without DNA

Endoscopic histology

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Patients with confirmed diagnosis of CD or UC in whom endoscopy is indicated

Criteria

Inclusion Criteria:

1. Established diagnosis of UC or CD for at least three months prior to enrollment
2. Age ≥ 18 years
3. Indication for endoscopy according to institutes routine care
4. Written informed consent

Exclusion Criteria:

1. Stoma independent of localization, ileoanal pouch
2. Prior bowel surgery other than ileocecal resection, which potentially affects the study procedure by fundamentally changing bowel anatomy by removing the ROI (e.g. (partial) resection of the sigmoid, left sided colon) or repositioning the ROI to an inaccessible location (e.g. right-sided colectomy with transversostomy)
3. Indeterminate Colitis, irritable bowel syndrome (IBS)
4. Involvement of the upper gastrointestinal (GI) track only
5. Isolated proctitis
6. Complications, such as infectious enteritis, infectious colitis and infectious enterocolitis, abscess formation, intestinal obstruction, toxic megacolon
7. Tattoo in skin area of interest
8. Skin lesions, scar tissue or skin diseases affecting the area of imaging
9. Highly pigmented skin in the area of imaging (e.g. Fitzpatrick skin type V and VI)
10. The bowel wall is invisible in the Ultrasound image of the MSOT system
11. Medication leading to increased light sensitivity
12. Pregnant and breastfeeding women
13. Mental retardation of the patient with restriction of general judgment and awareness
14. Exclusion due to safety concerns of investigator (subject who has any condition, including any physical, psychological, or psychiatric condition, which in the opinion of the Investigator, would compromise the safety of the subject or the quality of the data and renders the subject an unsuitable candidate for the study)

Contacts and Locations

Contacts

Contact: Claudia Jendrewski, MSc; +49 89 700744913; claudia.jendrewski@ithera-medical.com

Contact: Philipp Bell, Dr. rer.pol.; +49 89 700744911; philipp.bell@ithera-medical.com

Locations

Germany

Charité- Universitätsmedizin Berlin, Campus Benjamin Franklin, Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30; Not yet recruiting

Berlin, Germany, 12203

Contact: Britta Siegmund, Prof. Dr. +49 30 450 514 ext 342 britta.siegmund@charite.de

Contact: Patricia Schaafs +49 30 450 614 ext 876 patricia.schaafs@charite.de

Universitätsklinikum Erlangen Medizinische Klinik 1; Recruiting

Erlangen, Germany, 91054

Contact: Maximilian Waldner, Prof. +49913185 ext 35000 Maximilian.Waldner@uk-erlangen.de

Contact: Daniel Klett, Dr. med. +49913185 ext 35204 Daniel.Klett@uk-erlangen.de

Universitätsklinikum Jena; Recruiting

Jena, Germany, 07747

Contact: Andreas Stallmach, Prof. +49 3641 9-324582 andreas.stallmach@med.uni-jena.de

Contact: Philipp Grunert, Dr. med. +49 3641 9-324582 Philip.Grunert@med.uni-jena.de

Italy

Policlinico Tor Vergata; Suspended

Roma, Lazio, Italy, 00133

Centro per la Ricerca e la Cura delle Malattie Infiammatorie Croniche Intestinali IRCCS Humanitas; Not yet recruiting

Rozzano, Lombardia, Italy, 20133

Contact: Mariangela Allocca, MD, PhD +39022643 ext 2069 ibd@hsr.it

I.R.C.C.S.San Raffaele, Gastroenterology and Gastrointestinal Endoscopy, Via Olgettina 60; Recruiting

Milan, Italy, 20132

Contact: Mariangela Allocca, Dott. ssa +39 2264 312 069 allocca.mariangela@hsr.it

Contact: Carmen di Matteo +39 2264 394 94 dimatteo.carmen@hsr.it

Sponsors and Collaborators

iThera Medical GmbH

European Commission

Investigators

• Principal Investigator: Maximilian Waldner, Prof. Dr.; Universitätsklinikum Erlangen Medizinische Klinik 1

More Information

• Responsible Party: iThera Medical GmbH
• ClinicalTrials.gov Identifier: NCT04456400
• Other Study ID Numbers: cMSOT-2
• First Posted: July 2, 2020
• Last Update Posted: June 28, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by iThera Medical GmbH:

IBD; UC; CD

Additional relevant MeSH terms:

Crohn Disease; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases