DELIVER Study in a Population With Clinical Suspicion of Liver Cirrhosis

A Case Control Study in a Population With Clinical Suspicion of Liver Cirrhosis to Develop a Risk Model for the Presence of Cirrhosis Using Breath Biomarkers/EVOC Probes

Owlstone Medical has demonstrated that the use of an Exogenous Volatile Organic Compound (EVOC) that targets specific metabolic processes linked to cirrhosis pathophysiology enables identification of subjects with cirrhosis with high accuracy compared to healthy controls. This approach relies on the oral administration of food additives that are metabolized in the liver resulting in volatile end-products exhaled in breath. The presence of liver cirrhosis alters the metabolism of these EVOC-probes altering the breath concentrations of the end-products. These alterations can be used to identify subjects who have a risk of having liver cirrhosis.

The study is designed as a case control study comparing subjects with cirrhosis against controls originating from a group of subjects with clinical suspicion of cirrhosis. Adequate balancing of subjects across definitive, probable, possible, and absent cirrhosis groups will be assured through a recruitment enrichment strategy. The primary output of the study will be an algorithm to calculate a risk score for the presence of cirrhosis. As a secondary objective sensitivity analysis will be performed to assess the impact of subject characteristics and cirrhosis etiology on test performance to assure robustness of the test in a deployment setting. The results of this study will inform test optimization for a prospective clinical validation trial, with the goal of developing a test that is widely applicable and available in primary care centers

Liver disease and cirrhosis specifically is an area of growing public health concern with serious liver disease frequently presenting at advanced stages. Up to 75% of patients with cirrhosis receive their first diagnosis after they arrive at the accident and emergency department with a failing (decompensating) liver. This late diagnosis can lead to poor prognosis as treatments available are less effective at preserving the liver.

At present early detection is difficult as early disease often has few or no symptoms, and current diagnostic methods are either invasive or have limited accuracy. There is therefore an unmet need for easy to use, non-invasive tests that can help to diagnose cirrhosis earlier, when treatments are still effective at preserving liver function and increasing life expectancy. A breath test may fulfil such requirements.

The DELIVER study aims to develop a breath test that can identify cirrhosis at an earlier stage.

Recent research has shown that cells inside the body produce substances that end up in the lungs and are breathed out, or 'exhaled' in breath. These studies have shown that those substances may be different if someone is suffering from a particular disease, including liver cirrhosis.

Research has also shown that when we ingest a certain product (referred to as a 'probe') it may be processed differently in the body if you are healthy, compared to if you have a particular disease. This is very similar to different bodies digesting foods in different ways. This difference in processing leads to different types of chemicals being released by the body which would show up on breath as a sign of the presence or absence of disease.

Inclusion Criteria:

1. Age ≥ 18 years.
2. Able to provide written informed consent.
3. Clinical suspicion of cirrhosis evaluated in the last six months preceding the recruitment into the study.

The presence of clinical suspicion is at the discretion of the (referring) clinician. For reference this will typically be based on (a combination of) the following:

• Risk factors: viral hepatitis, metabolic dysfunction associated steatotic liver disease (MASLD), alcoholic liver disease, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, haemochromatosis or combinations of these diseases
• Symptoms: e.g. fatigue, weakness, abdominal pain, nausea, vomiting, loss of appetite, oedema, jaundice, spider angioma, palmar erythema, clubbing, gastrointestinal bleeding or altered blood parameters in a liver function test.

Exclusion Criteria:

1. Interventional treatment for (underlying cause of) cirrhosis aimed at disease modification during the past six months. Any treatment solely focused on symptom/complications management are permissible.
2. Received an investigational medicinal product in the context of a Clinical Trial (CTIMP) during the 28 days prior to administration of the (first) probe.
3. Women who are pregnant or breastfeeding, for women of childbearing potential a urine pregnancy test can be administered
4. Known allergy/intolerance to any of the constituents of the EVOC-probe cocktail, specifically limonene, 2-butanol, 2-pentanone, polysorbate 80 (aka Tween-80), and sucralose.
5. Subjects on peritoneal- or hemo-dialysis
6. Primary referral for evaluation of the presence of liver cancer (e.g. abnormal findings on imaging).
7. The presence of histopathologically diagnosed liver cancer.
8. (Anticipated) inability to complete the breath sampling procedure due to e.g., inability to maintain adequate ventilation unaided / Inability to comply with the study procedures in the opinion of the investigator.