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The results of this study may be published or presented at scientific meetings. If this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor prior to submission. In accord with standard editorial and ethical practice, the sponsor will generally support publication of multicentre trials only in their entirety and not as individual centre data. Authorship will be determined by mutual agreement.

Appendix 1

AEs Categories for Determining Relationship to Test Drug

Un-Related:

Evidence exists that the adverse event has an etiology other than the study drug. For example a pre- existing condition, underlying disease, intercurrent illness or concomitant medication.

Related:

A temporal relationship exists between the adverse event (AE) onset and administration of the study drug that cannot be readily explained by the subject’s clinical state or concomitant therapies. Furthermore, the AE appears with some degree of certainty to be related, based on the known therapeutic and

pharmacologic actions or adverse event profile of the study drug. In case of cessation or reduction of the dose, the AE abates or resolves and reappears upon rechallenge.

Appendix 2

Child‐Pugh classification of severity of liver disease

1, 2 or 3 points are scored for increasing abnormality of each of the 5 parameters measured.

Grade A: 5 or 6 Grade B: 7 to 9 Grade C: 10 to 15

Appendix 3

ICH Guidelines for Clinical Safety Data management Definitions and Standards for Expedited Reporting

A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution. It is any AE that at any dose fulfills at least one of the following criteria:

 is fatal; [results in death] [NOTE: death is an outcome, not an event]

 is life-threatening [NOTE: the term "life-threatening" refers to an event in which the patient was at immediate risk of death at the time of the event; it does not refer to an event which could hypothetically have caused a death had it been more severe].

 required in-patient hospitalization or prolongation of existing hospitalization;  results in persistent or significant disability/incapacity;

 is a congenital anomaly/birth defect;

 is medically significant or requires intervention to prevent one or other of the outcomes listed above

Medical and scientific judgment should be exercised in deciding whether expedited reporting to the sponsor is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definitions above. These situations should also usually be considered serious.

Examples of such events are intensive treatment in an emergency room or at home for allergic

bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.

An unexpected AE is one, the nature or severity of which is not consistent with the applicable product information.

Causality is initially assessed by the investigator. For Serious Adverse Events, possible causes of the event are indicated by selecting one or more options. (Check all that apply)

– Pre-existing/Underlying disease - specify

– Study treatment – specify the drug(s) related to the event – Other treatment (concomitant or previous) – specify – Protocol-related procedure

The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For example, nausea of several hours duration may be rated as severe, but may not be clinically serious.

A serious adverse event occurring during the study or which comes to the attention of the investigator within 15 days after stopping the treatment or during the protocol defined follow-up period, if this is longer, whether considered treatment-related or not, must be reported. In addition, a serious adverse event that occurs after this time, if considered related to test “drug”, should be reported.

Such preliminary reports will be followed by detailed descriptions later which will include copies of hospital case reports, autopsy reports and other documents when requested and applicable.

For serious adverse events, the following must be assessed and recorded on the AE form of the eCRF: intensity, relationship to test substance, action taken, and outcome to date.

The investigator must notify the Ethics Review Committee/Institutional Review Board of a serious adverse event in writing as soon as is practical and in accordance with international and local laws and regulations.

Appendix 4

Fibrosis Scores (HAI (Ishak) original and modified)

Score Original HAI Modified HAI

0 None None

1 Mild piecemeal _necrosis Mild (focal, few _{portal areas)}

2 Mild/Moderate (focal, most

portal areas) 3 Moderate piecemeal necrosis (involves less than 50% of the circumference of most portal tracts) Moderate (continuous around <50% of tracts or septae) 4 Marked piecemeal necrosis (involves more than 50% of the circumference of most portal tracts) Severe (continuous around >50% of tracts or septae)

[a] The Periportal component of the Knodell HAI has been split into a Periportal piecemeal necrosis and a bridging/confluent necrosis component for better comparison to the other scoring systems. In order to recreate the original scale, the bridging/confluent necrosis component should be added to the Periportal piecemeal necrosis component.

Appendices 8.2

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