APACHE Study (IG1407)(ACLF Plasma Exchange)

Effects of Plasma Exchange with Human Serum Albumin 5% (PE-A 5%) on Short-term Survival in Subjects with “Acute-On-Chronic Liver Failure” (ACLF) at High Risk of Hospital Mortality”

Protocol v. 2.0, Amendment 1, 02-May-2018

SIV Training Presentation

Version n. 1.0_12Feb2019

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Primary Efficacy/Endpoints

• Primary: To evaluate the effect of standard medical treatment (SMT) plus PE-A 5% (SMT+PE-A 5%) on 90-day overall survival

• Secondary:

• To evaluate the effect of SMT+PE-A 5% on 90-day transplant-free survival.

• To evaluate the effect of SMT+PE-A 5% on 28-day overall survival

• Exploratory objectives focusing on survival parameters, organ failures, changes in various scores (CLIF-SOFA, CLIF-C, CPT and MELD), systemic inflammation markers, infections, albumin levels and time to discharge

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Main Inclusion criteria

• Male or female cirrhotic subjects between 18 and 79 years of age

• Subjects with ACLF-1b, ACLF-2, or ACLF-3a detected either at admission or during hospitalization (must be ACLF-1b, -2, or -3a within the Screening Period [a maximum of 10 days])

• In case of HE, informed consent will be provided by a relative or a legally authorized representative (surrogate)

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Main exclusion criteria

• Subjects without ACLF

• Subjects with ACLF-1a or ACLF-3b after the Screening Period

• Subjects fulfilling inclusion criteria that improve to no ACLF or to ACLF-1a or worsen to ACLF-3b during the Screening Period (between initial evaluation and time of randomization)

• Subjects with ACLF for more than 10 days prior to randomization

• Subjects with acute or subacute liver failure without underlying cirrhosis

• Subjects with septic shock lasting >1 hour that does not respond to fluid resuscitation-IV therapy or pharmacologic-pressors

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Main exclusion criteria

• Subjects with active bacterial or fungal infection with hemodynamic instability

• Subjects with acute respiratory distress syndrome with peripheral oxygen saturation (SpO2) ≤89

• Subjects with active or recent bleeding (unless controlled for > 48 hours)

• Subjects with severe thrombocytopenia (≤ 20 × 109/L) (based on local laboratory assessment)

• Subjects with chronic renal failure and currently receiving hemodialysis

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Main exclusion criteria

• Evidence of current locally advanced or metastatic malignancy

Subjects with HCC lesions within Milan criteria , non-melanocytic skin cancer, and controlled breast or prostate cancer can be included

• Subjects with severe chronic heart failure (NYHA Class III or IV)• Subjects with severe pulmonary disease (GOLD stage III or IV)• Subjects with severe myopathy as defined clinically• Subjects with previous liver transplantation• Subjects receiving anti-platelet or anti-coagulant therapy• Subjects with active drug addiction

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ACLF Grading

• Study population: subjects with cirrhosis and ACLF-1b, ACLF-2, or ACLF-3a

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Inclusion Grading At Screening

Exclusion Grading At Screening

ALCF GradingComplete Response (CR)

Resolution of ACLF (no ACLF) or improvement to ACLF-1a

Partial Response (PR)

Partial response is a reduction of 1 organ failure or more to ACLF-1b or ACLF-2.

No Response (NR)

ACLF 3a or deteriorate to ACLF grade 3b

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CR

PR

NR

ACLF Grading

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Illness Severity Scoreing

• Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) will be used for ACLF Grading

• Number of organ failures determines the ACLF Grade

• Local lab results, where applicable, will be used to determine number organ failure as noted below

Shaded are designates areas of organ failure

SMT+PE-A 5% Treatment Group

• The treatment schedule consists of 2 initial PE-A 5% sessions on consecutive days followed by every other day PE-A 5% sessions

• ▲ A minimum of 4 and a maximum of 9 PE-A 5% sessions will be performed in subjects randomized to receive SMT+PE-A 5% (maximum treatment period: 17 days).

• Fresh frozen plasma (FFP) will be given after each PE-A 5% session to prevent coagulopathy

• ■IVIG will be given after every two PE sessions except when odd number of PE sessions occur.

Minimum dosing sequence based on response (Complete Responder)

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SMT+PE-A 5% Treatment Group

SMT+PE-A 5% with maximum 9 doses 17 day treatment period (Partial Responder)

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