Overview

OPAL is a multicenter observational study, following the natural disease trajectory of participants who have permanent damage to their liver caused by scarring, sometimes also referred to as liver cirrhosis. These participants will also have recently had an acute worsening of their liver disease, which is also known as a hepatic decompensating event, which has resulted in them being admitted to hospital or required them to seek medical attention as an outpatient.

Eligibility

Individuals eligible to participate in this study must meet the following criteria:

Inclusion Criteria:

1. Male or female age ≥18-75 years.
2. Patient is willing and able to provide informed consent to participate in the study.
3. Patient confirms willingness/ability to comply with all study procedures.
4. Has a diagnosis of liver cirrhosis determined by a physician based on at least one of the following:
   1. clinical and radiological features that correlate with a diagnosis of cirrhosis;
   2. transient elastography (TE) (FibroscanTM) >15kPa;
   3. previous liver biopsy confirming histological features of cirrhosis.
5. For eligibility at Screen Part 2 - Aetiology of liver disease of pure metabolic

   dysfunction-associated steatotic liver disease (MASLD) or metabolic and alcohol related/associated liver disease (MetALD), or alcohol-related liver disease (ALD) providing no active alcohol misuse (see Exclusion criterion 11) ≥3 months prior to screening, or hepatitis C virus sustained virologic response (HCV SVR) with ongoing cirrhosis.

6. Meets one of the following criteria:
   1. has been hospitalised as an in-patient for the first time for a major hepatic decompensation event (qualifying event) defined as either ascites, hepatic encephalopathy (HE) or variceal bleed, OR
   2. has intractable hepatic decompensation, defined as continuing diuretic resistant ascites requiring frequent paracentesis, or ongoing hepatic encephalopathy despite medical therapy, or medium to large gastrointestinal varices treated with repeated banding, treated only in an out-patient setting.

             NOTE: the study will only screen up to a maximum of 10 patients with intractable
             hepatic decompensation, limited to a maximum of three patients per site.
          7. MELD 3.0 score of 12-20 taken within 2 weeks of qualifying event.
          8. Has stabilised post-hepatic decompensation event, as defined by two MELD assessments
             (within 1 point of each) other taken within 2 weeks, or physician assessed as stable.
             with the ability to safely cell mobilise with GCSF, apherese and received RTX001 treat
             in the interventional Phase 1/2 study.
        Exclusion Criteria:
          1. Liver cirrhosis due to:
               1. any viral hepatitis with the exception of HCV SVR, or
               2. autoimmune and cholestatic aetiologies including, but not limited to, primary
                  biliary cholangitis and primary sclerosing cholangitis.
          2. Acute liver disease in the absence of underlying liver cirrhosis, including, but not
             limited to, drug induced liver injury.
          3. Any prior hospitalisation for or resulting from a decompensation event (unless in the
             intractable hepatic decompensation subgroup).
          4. Any current organ failure requiring more than out-patient non-invasive supportive
             care, and not associated with the patient's qualifying hepatic decompensation event.
          5. Known splenomegaly ≥16cm.
          6. Thrombocytopenia <50,000 mm3.
          7. Sepsis (with positive microbial cultures) or as defined by the PI, within 12 weeks of
             consent.
          8. Presence or suspicion of any of the following co-morbidities:
               1. history of liver transplantation or other organ transplant;
               2. acute on chronic liver failure (ACLF);
               3. spontaneous bacterial peritonitis;
               4. human immunodeficiency virus;
               5. pulmonary embolism;
               6. refractory ascites, with exception of the small group of patients with continuing
                  diuretic resistant ascites requiring frequent paracentesis (see Inclusion
                  criteria 6b);
               7. hepatocellular carcinoma, or active malignant disease within the last 5 years,
                  (excluding non-melanoma skin cancer, cervical carcinoma in situ, superficial
                  bladder cancer, benign polyps etc.);
               8. co-hepatic morbidities e.g., hepatic hydrothorax (refractory to medical
                  management), portal vein thrombosis;
               9. chronic renal impairment (on dialysis) or unresolved acute kidney injury;
              10. acute or chronic heart failure;
              11. porto-pulmonary hypertension;
              12. severe chronic lung disease e.g., chronic obstructive pulmonary disease or
                  interstitial lung disease where the forced expiratory volume (FEV1) is less than
                  50% and/or FEV1/forced vital capacity is less than 60%;
              13. hepatopulmonary syndrome;
              14. history or current treatment with chronic albumin treatment;
              15. significant untreated/unstable psychiatric disease.
          9. Current or planned use of immunosuppressive medication, with the exception of low
             doses up to 10 mg/day prednisone or equivalent, or inhaled steroids to manage an
             asthma, which are permitted.
        9. Current or planned use of immunosuppressive medication, with the exception of low doses
        up to 10 mg/day prednisone or equivalent, or inhaled steroids to manage an asthma, which
        are permitted.
        10. Any other intercurrent illness that is either life-threatening or of clinical
        significance such that it might limit compliance with study procedures, in the
        Investigator's opinion.
        11. Current/recent alcohol misuse ≥ 3 months prior to screening, defined as alcohol intake
        greater than 3 units/day for females and 4 units/day for males, or binge drinking (>14
        units/day) as determined by the Investigator, or intake of non-medically supervised drugs
        of abuse that is judged (by the Investigator) to be a high risk to the patients acute
        health or which makes the patient likely to be non-compliant with follow-up. N.B. One
        alcohol unit is equivalent to14 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125
        mL) of wine or 1 (25 mL) measure of spirits.
        12. Are currently participating in an investigational interventional study. Note:
        concurrent participation in another non-interventional study is permitted.