A Phase II Multi-Center Open-Label Clinical Trial to Assess the Prevention of Liver Transplantation and/or Death Among Subjects Treated With Intravenous Silibinin (Legalon® SIL) for Amatoxin Induced Hepatic Failure
Phase: PHASE2
Conditions: Amatoxin Poisoning, Amanita Poisoning, Mushroom Poisoning, Liver Failure
Sponsor: Mylan Specialty, LP

d Mylan-
Protocol SB16A1.07 
Page 1 of 53 
CLINICAL STUDY PROTOCOL 
A Phase II Multi-Center Open-Label Clinical Trial to Assess the Prevention of Liver 
Transplantation and/or Death Among Subjects Treated with Intravenous Silibinin 
(Legalon® SIL) for Amatoxin Induced Hepatic Failure 
Protocol Number 
SB16A1.07 
Product 
Legalon® SIL (Silibinin-C-2', 3-dihydrogensuccinate, 
disodium salt) 
Study Type 
Phase II 
Version 
4.0 
Protocol: Current Version / 
Date 
Version 4.0 dated 
07 Sep 2018 
Revision 
Amendment 4 
Previous version / Date 
Version 3.0 Dated 12 May 2009 
IND no. 
105960 
Legal/Filing Sponsor 
Mylan Specialty LP 
P.O. Box 4310 
781 Chestnut Ridge Road 
Morgantown, WV 26504-4310, USA 
Confidential 
This protocol is the confidential, intellectual property of Mylan Specialty, LP. It should not 
be disclosed to a third party with the exception of regulatory agencies and study audit 
personnel that being Mylan employees, representatives, agents and/or contractors responsible 
for conducting the clinical study, audits. Reproduction, modification, or adaption in part or in 
total is strictly forbidden without prior written approval by Mylan Specialty, LP. 
07 Sep 2018 
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20172934
IRB Conditions 
Satisfied at the Protocol 
Level 
Dec 03, 2018

IwjMyiarv 
Protocol SB16/11.07 
SIGNATURE PAGE 
Page 2 of53 
Protocol Description 
SB16A1.07 
" 
Product 
Logaion® SIL (Silibinm-C-2*, 3-dihydrogensuccinato. 
disodium salt) 
Protocol Version 
4.0 
- 
-
Protocol Version Date 
- . 
.. 
07 Sep 2018 
I tare read this pratocol and afflrn tot the information contained herein is complete and 
dCCUHUC. 
Date: 
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Global Lead, Safety Surveillance & Risk 
Management 
Dhaynl Panchnl, MD 
Date: 
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Senior Director, Qiostatistics & Data 
Management 
Hans-J?ricdrich Koch, PhD 
Senior Director/Clinical Project leader 
Eduardo Pcnuella, MD, MBA 
Date: \ 4-$epkv?nkp r2ol8 
Date: OTAy/3-O'g" 
5r, Global Clinical Operations] 
Kctty Bclizalie 
Head, Global Clinical Research and 
Development 
Abhijit Bnrve, MD, PhD 
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Protocol SB16A1.07 
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PRINCIPAL INVESTIGATOR ACCEPTANCE FORM 
SIGNATURE OF INVESTIGATOR 
I, the undersigned, as Investigator for this study, have read this protocol numbered 
SB16A1.07 and agree to conduct the study as outlined herein and in accordance with all 
applicable requirements of the country where the study is being conducted, the country where 
the study will be submitted, and the Sponsor's requirements. Applicable guidelines and 
regulations include, but are not limited to: 
• 
Permission to allow the Sponsor and/or its agent or regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner that ensures 
subject confidentiality. 
• 
Immediate notification of the Sponsor and/or its agent of any regulatory inspection related to 
this study. 
• Submission of the proposed clinical investigation, including the protocol and consent form, to 
a duly constituted IRB/Ethics Committee for approval, and acquisition of written approval for 
each, prior to study initiation. 
• 
Use of IRB/Ethics Committee-approved written informed consent that is obtained prior to 
study initiation for each subject. 
• Submission of any proposed change in or deviation from the protocol to the IRB/Ethics 
Committee using a signed formal amendment document prepared by the Sponsor and/or its 
agent. Any proposed change(s) or deviation(s) from the protocol require that the informed 
consent also reflect such change(s) or deviation(s), and that the revised informed consent be 
approved by the IRB/Ethics Committee. 
• 
Documentation and explanation of the individual protocol deviations on the appropriate CRF 
page or other Sponsor-approved document. 
• Submission of written reports of serious AEs, as defined in the protocol, to the Sponsor within 
24 hours. 
• 
Adherence to ICH GCP guidelines. 
Signature (Investigator), and Date 
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Investigator Telephone Number (office and mobile) 
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(mobile) 
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SYNOPSIS 
Protocol 
Title 
A Phase II Multi-Center Open-Label Clinical Trial to Assess the 
Prevention of Liver Transplantation and/or Death Among Subjects 
Treated with Intravenous Silibinin (Legalon® SIL) for Amatoxin Induced 
Hepatic Failure 
Product 
Legalon® SIL (Silibinin-C-2 ', 3-dihydrogensuccinate, disodium salt) 
Study Type 
Interventional Clinical Trial 
Protocol 
Version / 
Date 
Version 4.0 dated 07 Sep 2018 
Previous 
version / 
Date 
Version 3.0 dated 
May 12, 2009 
Revision 
Amendment 4 
EudraCT no. 
NA 
IND no. 
105960 
Legal/Filing 
Sponsor 
Mylan Specialty LP 
P.O. Box 4310 
781 Chestnut Ridge Road 
Morgantown, WV 26504-4310 USA 
Background 
and 
Rationale 
Human mushroom poisonings are classified according to clinical 
symptoms. In the case of intoxication with Amanita species - the most 
relevant being Amanita phalloides - the summary of typical clinical 
symptoms is called phalloides syndrome. While severe mushroom 
poisonings are rare, phalloides syndrome is reported to account for about 
90% of fatal mushroom poisonings [5]. 
There are no controlled clinical studies available due to ethical reasons, 
but uncontrolled trials and case reports describe successful treatment with 
intravenous silibinin (Legalon® SIL). In nearly 1,500 documented cases, 
the overall mortality in subjects treated with Legalon® SIL is less than 
10% in comparison to more than 20% when using penicillin or a 
combination of silibinin and penicillin. Silibinin, a proven antioxidative 
and anti-inflammatory acting flavonolignan isolated from milk thistle 
extracts, has been shown to interact with specific hepatic transport 
proteins blocking cellular amatoxin re-uptake and thus interrupting 
enterohepatic circulation of the toxin. The addition of intravenous 
silibinin to aggressive intravenous fluid management serves to arrest and 
allow reversal of the manifestation of fulminant hepatic failure, even in 
severely poisoned subjects . These findings together with the available 
clinical experience justify the use of silibinin as Legalon® SIL in Amanita 
poisoning cases, (la). 
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More than 90% of all fatal mushroom poisonings worldwide are due to 
amatoxin containing species that grow abundantly in Europe, South Asia, 
and the Indian subcontinent. Many cases have also been reported in North 
America (1,2,3). Initial symptoms of abdominal cramps, vomiting, and a 
severe cholera-like diarrhea generally do not manifest until at least six to 
eight hours following ingestion and can be followed by renal and hepatic 
failure. Outcomes range from complete recovery to fulminant organ 
failure and death which can sometimes be averted by liver transplant. 
Epidemiological data on mushroom poisoning, particularly poisoning 
with amatoxin-containing mushrooms, are rare. The true incidence of this 
intoxication is unknown since national data banks maintained at poison 
control centers have only incomplete data of this non-reportable illness 
Uncontrolled European studies and emergency use in the USA, suggest 
that treatment of amatoxin poisoning with Legalon® SIL drug may 
prevent severe morbidity (hepatic failure) and mortality. 
This is a Phase II Multi-Center Open-Label Clinical Trial to Assess the 
Prevention of Liver Transplantation and/or Death Among Subjects 
Treated with Intravenous Silibinin (Legalon® SIL) for Amatoxin Induced 
Hepatic Failure. A total of 139 subjects will be enrolled into this study. 
Legalon® SIL is formulated as a sterile lyophilisate in rubber-stoppered 
vials to be dissolved for intravenous infusion, containing 528.5 mg 
silibinin-C-2',3-dihydrogen succinate, disodium salt which is equivalent 
to 350 mg of silibinin according to DNPH testing or 315 mg of silibinin 
according to HPLC determination. The recommended daily dose is 20 mg 
silibinin/kg via continuous infusion over 24 hours, following a single 
loading dose of 5 mg silibinin/kg on the first day of treatment. 
Subjects will be screened for eligibility and, if confirmed to meet the 
study criteria, will be enrolled to receive treatment of Legalon® SIL. 
The study is comprised of a screening period of up to 24 hours from the 
time a potential study participant is identified. Treatment may be 
administered for up to 96 hours, or longer, following consultation with 
PPI. The final study assessment (Follow-up Visit) is to occur at 10 (+/-2) 
days from the last administered treatment. During screening, treatment 
and follow-up, assessments for medical history (only at screening), vital 
signs, labs and physical examination will be completed. Concomitant 
medications and adverse events will be recorded on every subject from 
the time of consent through the completion of the Follow-up Visit. 
Sponsor should be notified of any SAEs reported to the site and up to 30 
days after discontinuation of study medication. 
[4]. 
Primary 
Objectives 
The primary objective is to evaluate the efficacy of Legalon® SIL in 
preventing hepatic failure and/or death resulting from amatoxin poisoning 
in a phase II clinical trial. 
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Primary 
endpoints 
The primary endpoint is the percentage of subjects treated under this 
clinical trial without morbidity (liver transplantation) and or mortality 
(death). 
Methodology 
and 
treatments 
Legalon® SIL will be administered to subjects with amatoxin poisoning 
diagnosed by medical history, gastrointestinal symptoms, elevated liver 
enzymes (values higher than the upper limit of institution's normal for the 
age/sex at screening). Treatment consists of a 5 mg/kg loading dose 
followed by 20 mg/kg/day via continuous infusion (13). The treating 
physician is expected to administer supportive therapy of his/her choosing 
but consistent with best practices. Other measures to eliminate residual 
toxin, maintain perfusion and vital signs, and prevent coagulopathy will 
be as chosen by the treating physician. 
Legalon® SIL will be discontinued when prothrombin time and/or INR 
have returned to normal range, and when transaminases (AST and ALT) 
both are no more than 2 times the upper limit normal for the institution. 
If treatment is approaching 96 hours and the above criteria for 
discontinuation have not been met, the Primary Principal Investigator 
(PPI) and Onsite Investigator (OSI) must discuss the viability of 
continued study treatment. Upon confirmation of eligibility, subjects will 
receive a loading dose of 5 mg/kg of Legalon SIL intravenously (IV) over 
1 hour via an infusion pump followed by 20 mg/kg continuous IV over 24 
hours. 
Upon discharge from hospital, the subject should be advised to be seen 
for a physical examination and blood work (transaminases and PT/INR) 
approximately 10 days post discharge. The OSI or his designee is 
responsible to follow up with the subject for these results. 
The Protocol requires that the OSI and the PPI engage in daily telephone 
consultations once the subject is enrolled and for the duration of treatment 
with the study drug. All consultations will be documented and maintained 
on file by the PPI and OSI. 
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Inclusion/ 
exclusion 
criteria 
Due to the potential life-threatening nature of Amatoxin poisoning and 
given the safety profile of Legalon® SIL, inclusion and exclusion criteria 
are minimal for the study. 
Inclusion Criteria: 
1. Signed Informed Consent(s) for clinical trial participation (due to 
the potential critical status of the subject upon presentation, 
consent may need to be obtained from Legally Authorized 
Representative (LAR) per sites consenting policy and ICH/GCP 
guidance) Signed Informed Consent for Clinical Trial 
participation 
2. History of eating foraged mushrooms 
3. Gastrointestinal symptoms suggestive of amatoxin poisoning 
(cramping abdominal pain, nausea, vomiting, and / or watery 
diarrhea) usually 24-48 hours after of mushroom ingestion 
4. Liver function tests suggestive of amatoxin poisoning: AST or 
ALT above the institutions upper limit of normal after mushroom 
ingestion 
Exclusion criteria: 
1. Evidence of significant medical illness or any other abnormal 
laboratory finding that, in the Investigator's judgment, will 
substantially increase the risk associated with the subject's 
participation in, and completion of the study or could preclude the 
evaluation of the subject's response. 
Note: There are no adequate data from the use of Legalon® SIL in 
pregnant women and for this reason Legalon® SIL administration during 
pregnancy and lactation is not recommended. Based on the isolated report 
of fetal toxicity, it is recommended that the risks and benefits of 
Legalon® SIL therapy should be discussed with pregnant patients prior to 
use. In pregnant patients with a questionable exposure to amatoxin 
poisoning, it may therefore be reasonable to monitor carefully serial liver 
enzyme tests (e.g. every 4 hours) and defer initiation of Legalon® SIL 
until abnormalities are detected. Diagnosis of liver failure upon 
presentation based upon laboratory values and clinical picture. DIC at 
time of presentation. Evidence of significant medical illness or any other 
abnormal laboratory finding that, in the Investigator's judgment, will 
substantially increase the risk associated with the subject's participation 
in, and completion of, the study, or could preclude the evaluation of the 
subject's response. 
Sample size 
Sample Size: 
A total of 139 enrolled subjects is considered sufficient to show the effect 
of the Legalon® SIL in preventing liver transplantation, and/or death 
resulting from amatoxin poisoning. Using the large sample normal 
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approximation, a sample size of 139, provides a two-sided 95% 
confidence interval for proportion of subjects not meeting the outcome of 
interest (liver transplantation and/or death) within a half width of 5% 
from the observed proportion at an expected proportion of 90%. 
Statistical 
Methods 
Demographic and Anamnestical Data: 
All demographic and anamnestical data will be analyzed descriptively. 
For quantitative variables, the descriptive summary (means, medians, 
standard deviation, minimum and maximum) will be calculated. For 
qualitative data, the corresponding absolute and relative frequencies will 
be determined. 
Efficacy Analysis: 
The primary endpoint is the proportion of subjects treated with Legalon® 
SIL that do not exhibit morbidity (liver transplantation) and/or mortality 
(death). 
Proportion of subjects not meeting outcome of interest (liver 
transplantation and/or death) will be determined. Furthermore, the 
corresponding 95% confidence intervals will be determined. 
Sensitivity Analyses: 
Subject survival rate without hepatic transplantation and/or death will be 
calculated for all subjects and for each stage of disease. Moreover, the 
corresponding 95% confidence intervals for the rate of survival will be 
determined. The survival time will be described by means of Kaplan-
Meier estimates. 
Secondary endpoint (efficacy): 
• All quantitative secondary endpoints will be analyzed 
descriptively. Means, medians, standard deviations, minimum and 
maximum will be calculated as measures of location and 
dispersion. 
• The time to normality for AST, ALT, bilirubin, PT/INR, and 
creatinine, if abnormal at presentation, will be determined for all 
subjects and for each stage of disease by means of Kaplan-Meier 
estimates. 
Additional summaries — Assessment of Emergency Liver Transplantation 
Criteria in ALF due to Amanita Poisoning - using Ganzert's and 
Escudie's criteria. (13a. 
• Number (%) of subjects without hepatic transplantation by 
Ganzert's intoxication (pre-treatment) 
• Elapsed days between amanita poisoning and start of treatment 
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• Number (%) of subjects without hepatic transplantation by 
Ganzert's intoxication (during treatment) 
• Number (%) of subjects without hepatic transplantation by INR 
severity criteria (INR < 2 and >2) 
• Number (%) of subjects without hepatic transplantation by 
Escudie's intoxication grade transplantation criteria (INR < 6 and 
>6) 
• Safety analysis 
Clinical and laboratory adverse events will be analyzed by descriptive 
statistics. Moreover, the absolute and relative frequencies for laboratory 
variables within, above, or below the reference ranges will be determined. 
The frequencies and the corresponding 95% confidence intervals will be 
determined for MedDRA preferred terms and System Organ Classes. 
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TABLE OF CONTENTS 
SIGNATURE PAGE 
2 
PRINCIPAL INVESTIGATOR ACCEPTANCE FORM 
3 
SYNOPSIS 
5 
TABLE OF CONTENTS 
11 
LIST OF TABLES 
14 
1 
STUDY SCHEDULE OF ACTIVITIES 
15 
2 
INTRODUCTION 
17 
2.1 
Indication 
17 
2.2 
Background and Rationale 
17 
2.2.1 
Rationale for Dose Selection 
20 
3 
OBJECTIVES AND ENDPOINTS 
21 
3.1 
Objectives 
21 
3.1.1 Primary objective 
21 
3.2 
Endpoints 
21 
3.2.1 Primary Endpoints 
21 
3.2.1.1 Safety 
21 
3.2.2 Secondary Efficacy 
21 
4 
STUDY POPULATION 
22 
4.1 
Study Population 
22 
4.2 
Sample Size Considerations 
22 
4.3 
Inclusion and Exclusion Criteria 
22 
4.3.1 Inclusion Criteria 
22 
4.3.2 Exclusion Criteria 
22 
4.3.3 Randomization Criteria 
23 
4.3.4 Criteria for study drug termination, withdrawal from the study and study 
termination 
23 
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4.3.5 Females - Childbearing Potential 
23 
4.4 
Pregnancy Testing 
23 
5 
STUDY DRUG 
25 
5.1 
Investigational Drug 
25 
5.1.1 Administration of Study Drugs 
25 
5.2 
Drug Inventory 
26 
5.3 
Study Medication Complaints 
26 
5.4 
Storage, Disposition of Unused Study Drug and Drug Accountability 
27 
5.5 
Concomitant Medications 
27 
6 
STUDY CONDUCT 
28 
6.1 
OSI and Site Requirement for Study Participation 
28 
6.2 
Screening Phase (Screening/Presentation and Pre-first Dose) 
29 
6.2.1 
Required Screening Study Procedures for Assessment and Confirmation of 
Eligibility for Treatment: 
29 
6.3 
Treatment phase 
31 
6.3.1 Required Daily Study Assessments/Procedures While on Study Treatment 
31 
6.3.2 Early Termination of study drug Termination 
32 
6.4 
Follow-up Phase 
32 
6.4.1 Safety Testing 
33 
6.4.1.1 Adverse Event Assessment 
33 
6.4.1.2 Laboratory Safety 
33 
6.4.1.3 Blood Pressure and Pulse Rate 
34 
6.4.1.4 General Physical Examination 
34 
7 
STATISTICAL ANALYSIS 
35 
Published Clinical Experience with Legalon® SIL 
35 
8 
ADMINISTRATIVE PROCEDURES 
42 
8.1 
Final Clinical Study Report and Case Report Forms (CRFs) 
42 
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8.2 
Adherence to Protocol 
42 
8.3 
Data Handling and Record Retention 
42 
8.4 
Confidentiality 
43 
8.5 
Ethics and Regulatory Authorities 
43 
8.5.1 Institutional Review Board/Ethics Committee 
43 
8.5.2 Regulatory Authority 
43 
8.6 
Informed Consent 
43 
8.7 
Disclosure and Publication of Clinical Study Data 
44 
8.8 
End of Trial 
44 
9 
Adverse Event Reporting 
45 
9.1 
Assessment of Safety 
45 
9.1.1 Safety Parameters 
45 
9.2 
Adverse Event Reporting 
45 
9.2.1 
Definitions 
..45 
9.2.2 Documentation of Adverse Events 
46 
9.2.3 Relationship of Adverse Experiences to the Investigational Drug 
46 
9.2.4 Severity of the Event 
47 
9.2.5 Special Situations 
48 
9.2.6 
Exposure to Investigational Drug During Pregnancy: 
48 
9.2.7 Notification - Immediately Reportable Events 
49 
9.2.8 Reporting Timelines for Serious Adverse Events and Follow-up Information.. 50 
10 REFERENCE LIST 
51 
II 
Protocol Amendment Details 
53 
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LIST OF TABLES 
Table 1 
Study Schedule 
15 
Table 2 Laboratory Safety Tests 
33 
Table 3 Summary of Clinical Experience with Legalon® SIL in Amatoxin Poisoning 
36 
LIST OF COMMONLY USED ABBREVIATIONS 
AE 
Adverse event 
ALF 
Acute Liver Failure 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
CRF 
Case Report Form 
DIC 
Disseminated Intravascular 
Coagulation 
D5NS 
5% Dextrose in Normal Saline 
DNPH 
2,4-dinitrophenylhydrazine 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HPLC 
High-performance liquid 
chromatography (formerly referred 
to as high-pressure liquid 
chromatography 
ICF 
Informed Consent Form 
ICH 
International Conference on 
Harmonization 
IEC 
Independent ethics committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram 
LAR 
Legally Authorized Representative 
MedDRA 
Medical dictionary for 
regulatory activities 
mg 
milligram 
mL 
milliliter 
ms 
millisecond 
NA 
Not Applicable 
OATP1B3 
Organic Anion Transporting 
Polypeptide 1B3 
OSI 
Onsite Investigator 
PPI 
Primary Principal Investigator 
PSRM 
Product safety and risk 
management 
PT 
Prothrombin Time 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TEAE 
Treatment emergent adverse 
event 
TNF 
Tumor Necrosis Factor 
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United States 
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2 
INTRODUCTION 
2.1 
Indication 
Ingestion of amatoxin containing mushrooms may account for approximately 95% of deaths 
attributable to mushroom ingestion worldwide. In the United States, European invader 
Amanita phalloides and California native Amanita ocreata account for almost all cases 
reported on the West Coast (during the rainy season from September to April). Amanita 
bisporigera and Amanita virosa are responsible for poisonings in the Midwest and East Coast 
(April to September). 
Amanita mushrooms are often mistaken for nonpoisonous species, even by experienced 
mushroom foragers, particularly immigrants familiar with similarly appearing mushrooms in 
their home environment. They are often described as delicious ("best tasting mushrooms I 
have ever eaten") and the onset of initial GI symptoms can be delayed by six or more hours. 
The principal toxins (amanitins) are not destroyed by cooking, freezing, or drying, however, 
the mushrooms themselves are completely safe to handle (1). Amanitins are processed via 
enterohepatic circulation, are secreted in the bile, taken up by hepatocytes and tightly bound 
to RNA polymerase II, suppressing protein synthesis and resulting in severe acute hepatitis 
and fulminant hepatic failure. It is believed that prevention of the secretion of the toxin from 
the bile, by either gall bladder drainage or inhibition of gall bladder contractility, may help to 
mitigate the magnitude of the amanitins' toxicity. 
2.2 
Background and Rationale 
The use of Legalon® SIL (silibinin) for amatoxin poisoning has a well-recognized 
biochemical mechanism of action: inhibition of OATP1B3 mediated amanitin uptake by 
hepatocytes (3, 4). This data also suggests that Penicillin G works by the same mechanism, 
although with a much less significant effect, and that combining Penicillin G with silibinin 
may lead to a reduced therapeutic effect. The undesirability of combining Penicillin G with 
silibinin was the subject of a paper published in Germany which suggested less favorable 
outcomes when Penicillin G combination therapy was used in comparison to silibinin 
monotherapy (5). 
A second mechanism of action Legalon® SIL has also emerged. Amatoxin appears to induce 
fulminant hepatic failure via TNF mediated hepatocyte apoptosis. Building on earlier work it 
now appears that silibinin may inhibit TNF release in the injured liver (6, 7, 8, 9). 
Legalon® SIL reduced death in amatoxin-poisoned dogs from 80% to 0% (10). This is the 
only substance that has been shown to be of benefit for post exposure prophylaxis against 
fulminant hepatic failure and death in this species. 
Although there are no controlled studies of Legalon® SIL for amatoxin poisoning, open-label 
treatment in Europe compared to historical controls, suggests that mortality is markedly 
decreased from 22% to 10% among all subjects treated with Legalon® SIL (11, 12). 
Diagnosis 
Amatoxin poisoning is diagnosed by the clinical history and laboratory findings, specifically; 
a. History of eating foraged mushrooms 
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b. Gastrointestinal symptoms consistent with amatoxin poisoning (cramping 
abdominal pain, nausea, vomiting, and / or watery diarrhea) usually 24-48 hours 
after mushroom ingestion 
c. Liver function tests consistent with amatoxin poisoning: AST or ALT above the 
upper limit of normal after mushroom ingestion 
Amatoxin Poisoning Clinical Picture and Laboratory Findings 
Amatoxin Poisoning Clinical Picture and Laboratory Findings 
Patients who consume amatoxin containing mushrooms exhibit signs and symptoms that 
typically occur in a progression through three stages. 
Stage I: 
There is an initial quiescent period (6-24 hours post ingestion) after which cramping 
abdominal pain, nausea, vomiting, and watery "cholera like" diarrhea develop. Routine 
laboratory values may reflect dehydration and electrolyte loss, but they may not accurately 
assess the magnitude of intoxication or predict the eventual outcome. 
Stage II 
The second stage of amatoxin poisoning is characterized by generalized clinical improvement 
(resolution of gastrointestinal symptoms) that begins 24 to 48 hrs after ingestion, albeit 
masking the hepatic deterioration that is occurring at the same time. The liver function tests 
show a progressive elevation of transaminases and an evolving coagulopathy. Early renal 
damage may be reflected by elevations in the serum creatinine and blood urea nitrogen levels. 
Grade 1: Patients develop gastroenteritis-like symptoms several hours (6-36) after ingestion 
but do not develop severe biochemical indications of hepatitis (peak transaminases <1000 
without coagulopathy) or renal dysfunction. 
Grade 2: In addition to GI symptoms patients manifest a moderate (1000-5000 IU/L) rise in 
transaminases and a moderate (peak INR <2.0) coagulopathy. 
Stage III 
Transition into the third stage can occur quite suddenly. Hepatic failure may be fulminant and 
is manifested by a severe increase in serum transaminases and profound coagulopathy. 
Patients may experience a swift progression from Stage I to Stage III or IV. The presence of 
hypoglycemia is a poor prognostic sign reflecting massive hepatic necrosis. Normalization of 
transaminases in the setting of a rising INR, creatinine, ammonia level plus worsening 
symptoms, should be considered to be a sign of fulminant hepatic necrosis and, hence an 
indicator of poor prognosis. Renal failure, due to hepatorenal syndrome and/or direct 
nephrotoxicity of amanitins, may result in severe oliguria or anuria. Fifty percent of patients 
with amatoxin poisoning may also have laboratory evidence of pancreatitis (2). 
Grade 3: Patients develop a marked elevation of transaminases (>5000 IU/L) and significant 
coagulopathy (INR>2.0). Grade 3 is divided into two subgroups according to bilirubin values. 
In Grade 3a: hyperbilirubinemia is mild or absent, while Grade 3b: shows a steep and 
continuous rise in bilirubin (greater than 5 mg/dL). 
Grade 4: A steep rise in transaminases is accompanied by a corresponding steep decline in 
clotting function (INR>3.0) and renal dysfunction. 
Grade 1 and Grade 2 patients have the best chance of surviving amatoxin poisoning and need 
symptomatic treatment only. Grade 3, particularly Grade 3b patients, are at risk and should be 
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transferred to a tertiary care center where liver transplant is available. Grade 4 patients have 
an extremely poor prognosis. There is a 90% probability of death in spite of intensive 
therapy. Survival usually requires a liver transplant. 
Laboratory Abnormalities and Corresponding Prognostic Indication 
Transaminases 
Grade 1 patients show mild elevations of liver enzymes. Grade 2 patients develop a moderate 
rise in transaminases, usually below 5,000 IU/L but sometimes much higher. Grade 3 patients 
show a steep and massive rise in transaminases. There is no significant difference in the 
magnitude of transaminase results in Grade 4 relative to Grade 3, although in fatal cases the 
mean values are generally higher. A decrease of transaminase values on Day 4 is either a sign 
of improvement or a hepatic "bum-out" phenomenon. A massive rise in transaminases 
(Grade 3 and 4) does not necessarily predict a fatal outcome, whereas a mild rise in 
transaminases (Grade 2) generally indicates a good chance for survival. 
Prothrombin Time 
PT/INR is of high prognostic value. An early and steep prolongation of prothrombin time 
values suggests a poor prognosis. In Europe, those patients in whom prothrombin times could 
not be improved to values above 20-30% by substitution of clotting factors on Days 3-4 had 
>90% mortality. From 48 hrs after ingestion onwards, there is a significant difference 
between the prothrombin time of survivors in Grade 3 (>30 %) and non-survivors in Grade 4 
(< 20%). 
Bilirubin 
On admission to the hospital, bilirubin values are normal in 90% of all cases. Elevation at this 
early stage (>3 mg/dL) suggests a poor prognosis. During the course of the intoxication, only 
about 20% of Grade 3 patients (Grade 3b) show a marked rise in bilirubin. It is possible to 
obtain information on the prognosis from the absolute values after Day 3. At that time, 
values < 5 mg/dL indicate a favorable prognosis, even if transaminases are high, while a 
value > 5 mg/dL indicates a severe or fatal course. 
Impairment in kidney function 
Early renal dysfunction signals a poor prognosis. Prerenal azotemia secondary to dehydration 
on initial presentation is a common finding that can usually be reversed by aggressive fluid 
replacement. Acutc tubular necrosis may also occur in severely dehydrated patients and may 
represent a direct cytotoxic effect of amatoxin. A slight elevation of creatinine on Days 1 to 2 
that does not respond to fluid replacement suggests that a direct toxic effect has occurred. 
About 70% of fatal cases show this early increase of creatinine. Hepatorenal syndrome occurs 
later and indicates an extremely poor prognosis. 
In summary, Legalon® SIL will be administered to patients with amatoxin poisoning 
diagnosed by history, gastrointestinal symptoms, elevated liver enzymes. Treatment will 
consist of a 5 mg/kg loading dose followed by 20 mg/kg/day via continuous infusion (13). 
The treating physician is expected to administer supportive therapy of his/her choosing but 
consistent with best practices. Legalon® SIL will be discontinued when coagulopathy is no 
longer present, and when liver function tests have returned to no greater than 2 times the 
upper limit of normal or patient does not respond to treatment with Legalon® SIL. Patients 
will be followed 10 (+/-2) days after the end of Legalon® SIL therapy with follow-up 
laboratory studies and physical exam. If the Follow-up Visit is not feasible due to patient's 
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condition, reason for the missed visit must be clearly documented in the patient' medical 
record. 
Complete information for Legalon® SIL may be found in the Legalon® SIL Investigator's 
Brochure. 
2.2.1 
Rationale for Dose Selection 
A study was conducted aiming at the verification of Legalon® SIL reconstituted solution in 
infusion bags containing 5% glucose solution. The stability was tested up to 30 hours at 
25°C/60% RH. 
The design of the study was as follows: 
> 4 times 35 ml were taken from a 500 ml Glucose (5%) infusion bag 
> 4 vials of Legalon SIL were reconstituted with 35 ml each 
> after reconstitution the 4 solutions were returned into the infusion bag 
> the infusion bag (containing 4 vials of Legalon SIL) was stored under defined 
conditions for min. 24 hrs. (study report number 02VB0164 07/01). 
This kind of preparation was intended to be used for a 24 hrs. infusion. 
A stability of the solution of minimum 30 hrs. could be confirmed. 
Based on the results, it was concluded that, the reconstituted solution of Legalon® SIL is 
stable at 25°C/60% RH, as shown by content of Silibinin mono- and dihydrogensuccinate 
(SHS), sodium salts. 
Although there was a slight increase of the content of SHS, sodium salts, from 1.8% to 3.0% 
of batch number 120204 lnd from 1.3% to 2.4% of batch no. 163601 the values were still far 
below the specification limit of not more than 5.5%. 
Therefore, the study verifies that the reconstituted solution of Legalon® SIL is from the 
analytical point of view stable at 25°C/60% RH for 24 hours. 
No microbiological investigations were performed in this study, because such aspect depends 
more on the GCP application than on the product itself, which is sterile and is to be dissolved 
in sterile media. 
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3 
OBJECTIVES AND ENDPOINTS 
3.1 
Objectives 
3.1.1 
Primary objective 
The primary objective is to evaluate the efficacy of Legalon® SIL in preventing hepatic failure and/or 
death resulting from amatoxin poisoning in a phase II clinical trial 
3.2 
Endpoints 
3.2.1 
Primary Endpoints 
The primary endpoint is the proportion of subjects treated with Legalon® SIL that do not 
exhibit morbidity (liver transplantation and/or mortality (death). 
3.2.1.1 
Safety 
Safety based on the evaluation of changes in baseline laboratory and clinical presentation while on 
study treatment. The laboratory values to be followed are transaminases and renal function tests 
(AST, ALT, bilirubin, PT/INR, creatinine, lactic acid). 
3.2.2 
Secondary Efficacy 
Efficacy as demonstrated by time to normality of the laboratory values from start of treatment 
with Legalon® SIL. The laboratory values to be followed are transaminases and renal 
function tests (AST, ALT, bilirubin, PT/INR, creatinine, lactic acid). 
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4 
STUDY POPULATION 
4.1 
Study Population 
Study will enroll 139 male and female subjects that meet all protocol defined eligibility 
criteria. 
The period from Screening to completion of active treatment will be approximately 5 days. 
Patients will be required to have follow up physical examination and laboratory evaluations 
7-14 days post-is continuation from study drug. 
4.2 
Sample Size Considerations 
A total of 139 enrolled patents is considered sufficient to show the effect of the Legalon® SIL 
in preventing liver transplantation, and/or death resulting from amatoxin poisoning. 
4.3 
Inclusion and Exclusion Criteria 
4.3.1 
Inclusion Criteria 
Subjects' eligibility should be reviewed and documented by the Investigator or a qualified 
designee before subjects are included in the study. 
Subjects must meet all the following inclusion criteria to be eligible for enrolment into the 
study: 
1. Signed Informed Consent(s) for Clinical Trial participation 
2. History of eating foraged mushrooms 
3. Gastrointestinal symptoms consistent with amatoxin poisoning (cramping abdominal 
pain, nausea, vomiting, and / or watery diarrhea) usually 24-48 hours after mushroom 
ingestion 
4. Liver function tests consistent with amatoxin poisoning: AST or ALT above the 
institutions upper limit of normal after mushroom ingestion 
4.3.2 
Exclusion Criteria 
Subjects must not be enrolled in the study if they meet any of the following criteria: 
1. Evidence of significant medical illness or any other abnormal laboratory finding that, in 
the Investigator's judgment, will substantially increase the risk associated with the 
patient's participation in, and completion of, the study, or could preclude the evaluation 
of the patient's response. 
Note: There are no adequate data from the use of Legalon® SIL in pregnant women and 
for this reason Legalon® SIL administration during pregnancy and lactation is not 
recommended. Based on the isolated report of fetal toxicity, it is recommended that the 
risks and benefits of Legalon® SIL therapy should be discussed with pregnant patients 
prior to use. In pregnant patients with a questionable exposure to amatoxin poisoning, it 
may therefore be reasonable to monitor carefully serial liver enzyme tests (e.g. every 4 
hours) and defer initiation of Legalon® SIL until abnormalities are detected. 
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4.3.3 
Randomization Criteria 
This is an open label study and therefore randomization will not occur. 
4.3.4 
Criteria for study drug termination, withdrawal from the study and study 
termination 
Subjects will be free to request termination of study drug or withdrawal from the study at any 
time for any reason. 
Subjects must be withdrawn from the study prior to initiating treatment under the following 
circumstances: 
• Laboratory values indicative of recovery prior to the start of Legalon® SIL 
A subject must terminate study drug for safety reasons under the following circumstances: 
• Development of a SAEs that is deemed attributable to Legalon® SIL by the OSI 
A subject may be required to terminate study drug for other reasons including the following: 
• 
Patients in whom, after 96 hours of starting treatment there is no significant 
improvement in the PT/INR and transaminases, termination of treatment may occur 
following consultation between the OSI and PPI. 
• 
If it is in the subject's best interest based on decision of the OSI or his/her 
Sub-Investigator e.g. due to occurrence of an AE and/or other findings considered to 
present a safety concern to continued dosing with study drug. 
• Despite education/reinforcement, the subject shows persistent inadequate compliance 
with required procedures, potentially compromising safety monitoring while on study 
drug. 
Unless consent is withdrawn, subjects who prematurely terminate study drug and are 
discharged from the hospital, will have PT/INR, liver transaminases collected by local lab 
and have a physical examination performed by local physician 10 days post last dose of study 
drug. The OSI is responsible for obtaining the results of these procedures form the patient. 
The Principal Investigator and/or Mylan reserves the right to terminate the study for any 
reason. 
The study will be terminated early if there are significant safety concerns. 
4.3.5 
Females - Childbearing Potential 
4.4 
If the patient is pregnant appropriate counseling will be provided based on the 
risk/benefit condition. Pregnancy Testing 
Serum or urinary pregnancy testing will be performed on all females of childbearing potential 
as described in the schedule of activities. In the event of a positive test, the patient will be 
informed that systematic data on the use of SIL in pregnancy and lactation are not available. 
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Note: There are no adequate data from the use of Legalon® SIL in pregnant women and for 
this reason Legalon® SIL administration during pregnancy and lactation is not recommended. 
Based on the isolated report of fetal toxicity, it is recommended that the risks and benefits of 
Legalon® SIL therapy should be discussed with pregnant patients prior to use. In pregnant 
patients with a questionable exposure to amatoxin poisoning, it may therefore be reasonable 
to monitor carefully serial liver enzyme tests (e.g. every 4 hours) and defer initiation of 
Legalon® SIL until abnormalities are detected. Any patient found to be pregnant at time of 
initiation of treatment, the pregnancy will be followed up and reported to the sponsor as per 
Section 9.2.6. 
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5 
STUDY DRUG 
5.1 
Investigational Drug 
Legalon® SIL is a fully developed and documented pharmaceutical formulation manufactured 
by Madaus (Cologne, Germany). Its active ingredient is silibinin-C-2',3-dihydrogen 
succinate, disodium salt Fig. (1). It has the molecular formula C33H28016Na2 and a 
molecular mass of 726.56 g/mol. It is a microcrystalline powder that results from the 
esterification of silibinin with succinic anhydride to form its hydrosoluble disuccinic acid 
ester for parenteral application. Silibinin, a flavonolignan obtained by extraction of the seeds 
from milk thistle fruit (Ph. Eur.), is a mixture of two diastereomers, commonly named 
silibinin A and silibinin B. After the reaction of silibinin with succinic anhydride, silibinin-C-
2',3-dihydrogen succinate, disodium salt is obtained as a mixture of cis- and trans 
diastereomers of silibinin A and B dihydrogen succinates. Legalon® SIL is currently 
registered and/or licensed in over a dozen European countries specifically for the treatment of 
Amanita phalloides intoxication. 
Legalon® SIL 
The drug is provided in carton containing four, rubber-stoppered vials. Each vial contains 
528.5 mg of (equivalent to 350 mg of silibinin) powder for solution for infusion. 
One vial contains: 
Drug substance 
Silibinin-C-2',3-dihydrogen succinate, disodium salt, 528.5 mg 
[corresponding to 476 mg mono-, dihydrogensuccinate sodium salts (HPLC)] 
equivalent to 350 mg (315 mg HPLC) of silibinin 
Excipicnts 
Inulin 70 mg USP 
Nitrogen (as inert gas) Ph.Eur. 
Total sum: 598.5 mg 
Manufacturer: Madaus GmbH, Cologne (Germany) 
5.1.1 
Administration of Study Drugs 
Preparation of infusion fluid 
• 
Dissolve each of the 4 vials that are contained in a carton with 35 mL of 5% 
Dextrose or 0.9% sodium chloride solution. Upon reconstitution a total of 140 ml 
will be available across 4 vials. 
• 
Remove 140 ml from a 500 mL IV container of Dextrose and replace with the 
140 ml of reconstituted drug solution 
• 
The initial loading dose is 5 mg/kg for one hour via infusion pump 
• 
After the loading dose, 20 mg/kg/day is infused continuously via infusion pump 
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In the event of any significant dosing errors, the PPI and Mylan should be contacted 
immediately. 
Since Legalon® SIL is potentially life-saving, reduction or elimination of dosing is to be 
avoided unless there is strong reason to think that an adverse event is due to Legalon® SIL, is 
clinically significant, and cannot be managed otherwise. 
5.2 
Drug Inventory 
Legalon® SIL will be dispensed to enrolling sites from an institution/vendor designated by 
Mylan. Legalon SIL should not be stored above 25°C / 77°F. 
The medical community will be alerted to the availability of Legalon® SIL via 
communication with poison control centers, mushroom organizations, and emergency room 
hospitals/physicians. There will be an emergency hotline number which the US physicians 
can call to initiate the process of obtaining Legalon® SIL. 
Because amatoxin poisoning occurs episodically and randomly throughout the USA, most 
physicians wishing to enroll their patients on the study will not have prospective IRB 
approval of this protocol. The OSI will need to supply documentation of approval of this 
protocol from the IRB of his/her respective hospital. 
5.3 
Mylan will be responsible for furnishing study drug supply for distribution. Study 
Medication Complaints 
In the event the patient has a complaint/concern during study participation regarding the 
supplied study medication, they should contact the site. 
In the event of a complaint/concern during study participation, regarding the supplied study 
medication, the site should contact the sponsor. As a minimum the following information 
should be sent by the site as part of the complaint: 
Study number: SB16A1.07 
• OSI name, site address, contact number 
• Subject ID. 
• Date of occurrence of incident/complaint. 
• Description of incident/complaint (facts). 
• Confirmation if the complaint caused or resulted in a SAE? If "Yes", confirmation 
that the SAE has been reported. 
Additional information and potentially the return of study medication may be requested by 
Mylan in order to investigate the complaint. 
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5.4 
Storage, Disposition of Unused Study Drug and Drug Accountability 
The Investigator, or an approved representative, e.g. pharmacist, will ensure that all 
investigational products are stored in a secured area under recommended storage conditions 
and in accordance with applicable regulatory requirements while at the investigator site. 
Study drug should be stored in accordance with the drug label. Storage conditions stated in 
the Investigator's Brochure may be superseded by the label storage. 
Temperature of storage facilities should be monitored and recorded on a daily basis using 
validated devices that record maximum and minimum temperatures. Should the storage 
facility experience any excursion of temperature outside of the labelled storage condition this 
must be reported immediately to Mylan or designee 
The investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. Mylan will supply drug accountability forms for this study, the 
form must be fully completed and identify the study drug, including batch or code numbers, 
and account for its disposition on a subject-by-subject basis, including specific dates and 
quantities. The forms must be signed by the individual who dispensed the drug, and copies 
must be provided to Mylan or designee. 
Upon completion of each patient treatment at site, the site must return all used and unused 
vials as well as drug accountability log and administration records redacted of all personal 
identifiers with subject study identifier added. 
5.5 
Concomitant Medications 
All concomitant medications taken during the study (from signing informed consent to 
discontinuation of study drug) must be recorded with indication, daily dose, and start and stop 
dates of administration in the CRF. 
Medications taken within 28 days prior to screening and prior to dosing with study 
medication will be documented as a prior medication. Medications taken after dosing begins 
with study medication will be documented as concomitant medications. 
There are no prohibited medications for this study. 
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6 
STUDY CONDUCT 
6.1 
OSI and Site Requirement for Study Participation 
Patients will be identified as potential study subject at the medical facility to which they 
present with symptoms. The treating physician at the local medical facility will either reach 
out to a Poison Control Hotline or will call the study designated hotline directly. Upon 
notification of the potential subject to the Mylan designated PPI, the following actions will 
take place: 
• The designated hotline service for the study will contact the assigned coordinator for the 
study and be provided with contact information for immediate follow-up. This 
information includes 
> Treating physician' s name 
> Contact details (telephone number and email) of treating physician 
> Medical facility name and address and phone number 
• The assigned study coordinator will triage the call to assure there is suspicion of amatoxin 
poisoning and direct the case to the PPI 
• The PPI will contact the treating physician to discuss the case(s) of amatoxin poisoning to 
determine eligibility for treatment under the protocol and complete the PPI Eligibility 
Confirmation Form(s). The information on the PPI eligibility confirmation form will 
include: 
> Date/Time of contact 
> Name and institution of referring physician 
> Referring physician contact phone number and email 
> Number of patients in cohort 
> If patient(s) included in study: 
> Written confirmation that the criteria for inclusion have all been met: mushroom 
eating history, Gastrointestinal symptoms, elevated liver function tests 
> If patient(s) excluded from study. 
> Reason for exclusion must be documented. 
• Upon confirmation of eligibility for the subject(s), the treating physician must 
immediately contact the IRB for approval of treatment according to the protocol. At the 
least, an email or a memo with indication of IRB approval for the subject(s)' participation 
in the study must be provided to the PPI/SC prior to drug shipment. 
• Upon receipt of the IRB approval email/memo, the PPI will direct dispatch of the study 
drug to be shipped to the medical facility 
• The assigned SC, in the interim, will send the following documentation to be processed 
by the treating physician, now the prospective On-Site Investigator (OSI), 
> FDA Form 1572 
> OSI Commitment Form 
> OSI Financial Disclosure 
> Protocol 
> Informed Consent Template 
> Case Report Forms (CRFs) and Completion Guidelines 
> SAE Form 
> Drug Accountability Form 
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As soon as possible after enrollment of new patient into the study but no later than 24 hours, 
the Primary Study Coordinator will conduct a study training teleconference with the On-Site 
Investigator (OSI) and his designee(s). Training will include but not limited to the review of 
the protocol, safety reporting, and completion of CRFs. 
6.2 
Screening Phase (Screening/Presentation and Pre-first Dose) 
a) 
Subjects eligible for study recruitment will have the nature, purpose, and risks of 
the study explained to them by the investigator. They will be provided with a 
written copy of the informed consent form (ICF) for the study and given sufficient 
time to consider the study's implications before deciding to participate. Subjects 
agreeing to participate in the study will sign the ICF and be given a duplicate copy 
before undergoing any screening or pre-screening (if required) procedures. Please 
note that due to the potential critical condition of subjects considered for this trial, 
informed consent may need to be obtained from the LAR or other responsible 
party per sites consenting policy and/or ICH GCP guidance. A unique subject 
identifier will be issued at the time of consent. 
b) 
Due to the emergent treatment requirement of the study drug, a signed informed 
consent from the patient may be delayed, as the patient may be incapacitated. 
However, until this is possible, consent from the LAR must be obtained. 
Documentation of the consenting process, including interim consent obtained 
from the LAR, must be documented in the patient's medical record. Signed 
consent from the patient must be obtained at the earliest time possible. A signed 
copy must be given to the patient/LAR as well as sent electronically to the 
assigned SC. The original copy should be kept in the patients' medical record 
along with a copy of the protocol. 
c) 
Once a subject enrolls in this trial the site will make every effort to retain the 
subject for the planned duration of the trial. In cases where the subject does not 
return for the post discharge Follow-up Visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the 
subject so that they can appropriately be withdrawn from the study. All contact 
attempts should be documented in the subject's medical record. Should the subject 
continue to be unreachable, then and only then will he/she be considered to have 
withdrawn from the study with a primary reason of "Lost to Follow-up." For all 
other subjects withdrawing from the study, an alternative reason for 
discontinuation should be recorded in the CRF. Regardless of site plans to support 
and retain subjects within the trial, subjects may voluntarily withdraw from the 
trial for any reason and at any time. 
For a subject that completes the study and all procedures it is anticipated that the 
duration of study would be approximately 20 days, inclusive of follow up visit. 
6.2.1 Required Screening Study Procedures for Assessment and Confirmation of 
Eligibility for Treatment: 
• 
Informed consent 
• 
History 
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• 
Physical 
• 
Vital signs 
• 
Serum HCG in women of child bearing potential 
• 
AST 
• 
ALT 
• 
Bilirubin 
• 
PT 
• 
INR 
• 
BUN 
• 
Creatinine 
• 
Lactate 
• 
Amylase 
• 
Lipase 
• 
Ammonia 
• 
CBC with differential 
• 
Platelet 
• 
Glucose 
• 
Na 
• 
K 
• 
Recovery of toxin (if possible) 
• 
Baseline medical conditions 
• 
Baseline medications 
For details and timings of assessments, refer to Section 6.5. 
The Protocol requires that the OSI contact the PPI for a daily telephone consultation once the 
patient is enrolled and for the duration of treatment with the study drug. All consultations will 
be documented and maintained on file by the PPI and OSI. 
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6.3 
Treatment phase 
Following receipt of study drug, if patient remains eligible for enrollment according to the 
protocol, treatment with Legalon® SIL should begin as soon as possible as a continuous 
infusion until the PT/INR have returned to the normal range set by the institution and 
transaminases have returned to no greater than 2 times the institutions upper limit of normal. 
If the laboratory tests and/or the patient clinical picture is not improving after 96 hours on 
treatment the PPI and OSI must specifically discuss the benefit of continued treatment. Full 
documentation and reason for decision to either continue or discontinue treatment must be 
documented in the patient's medical record as well as on the Daily Communication CRF. 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases, the investigator or designated representative will take all 
steps necessary to ensure the safety and well-being of the subject. When a protocol required 
test cannot be performed the investigator or designated representative will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. The Mylan study team will be 
informed of these deviations in a timely fashion. 
6.3.1 
Required Daily Study Assessments/Procedures While on Study Treatment 
• 
Physical 
• 
Vital signs 
• 
AST 
• 
ALT 
• 
ALP 
• 
Bilirubin 
• 
PT 
• 
INR 
• 
BUN 
• 
Creatinine 
• 
Lactate 
• 
Amylase 
• 
Ammonia 
• 
CBC with differential 
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• 
Platelets 
• 
Glucose 
• 
Na 
• 
K 
• 
AEs 
• 
Concomitant medications 
• 
Infusion of Legalon® SIL 
• 
Other measures to eliminate residual toxin, maintain perfusion and vital signs, and 
prevent coagulopathy will be at the discretion of the OSI. 
6.3.2 
Early Termination of study drug Termination 
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the investigator or sponsor for reasons as 
per Section 4.3.4. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 
return for the follow up visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The investigator will contact Mylan or designee, in the event that a 
subject fails to complete the study or violates the protocol. 
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
return to the clinic for the follow up visit and will have this scheduled within 10 days of 
stopping the study drug. 
6.4 
Follow-up Phase 
Patients will be followed 10 days +/-2 after stopping Legalon® SIL therapy unless they failed 
treatment and proceeded to transplant. Follow up will consist of a physical examination and 
blood work to assure recovery and to assess for any AEs. 
Subjects will be reminded that SAEs should be reported to the study staff up to 30 days after 
the last dose of study medication. 
If the patient recovers from the poisoning, upon discharge from the hospital, they should be 
given a prescription for follow up blood work to include PT/INR and liver function studies as 
well as instructed to follow with their local physician for a physical exam. The OSI or 
designee is responsible for following up with the patient for the results of the exam and blood 
work. 
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6.4.1 
Safety Testing 
6.4.1.1 
Adverse Event Assessment 
If a subject reports any symptoms that could preclude the drug administration before starting, 
they will be evaluated by medical staff and necessary measurements will be performed. The 
OSI will be notified before dosing to determine the course of action. 
Findings from screening procedures, e.g., laboratory tests or physical examinations will be 
recorded as medical history. Clinically significant changes following completion of the 
screening procedures will be recorded as adverse events. 
Subjects will be routinely queried in regards to the presence or absence of adverse events 
using open ended questions. The treating medical staff will provide documentation of any 
adverse events in the subject's CRF. The adverse event source documentation will minimally 
include the following information: date and time of assessment, description of the adverse 
event, date/time of onset, date/time of resolution if applicable, and identification of the staff 
member collecting the information. 
There are no adverse events of special interest for this study. 
6.4.1.2 Laboratory Safety 
6.4.1.2.1 Blood Volume 
Total blood volume collected per patient for this study will vary between treating institutions. 
The blood assessments required per the protocol approximate the sampling that would be 
conducted as standard of care for patients suffering from the effects of amatoxin poisoning 
and as such do not pose any additional risk to the patient. The following safety laboratory 
tests will be performed at times defined in the study schedules in Sections 1 and 6. 
Table 2 
Laboratory Safety Tests 
Hematology 
Chemistry 
Other 
Hemoglobin 
Urea and Creatinine 
Serum Pregnancy in 
Hematocrit 
Glucose (non-fasting) 
women of childbearing 
RBC count 
Sodium 
potential (screening 
Platelet count 
Potassium 
only) 
WBC count 
AST, ALT 
Total neutrophils (Abs) 
Total Bilirubin 
Eosinophils (Abs) 
Alkaline phosphatase 
Monocytes (Abs) 
Lactate 
Basophils (Abs) 
Lipase 
Lymphocytes (Abs) 
Amylase 
Ammonia 
Hematology and chemistry will be analyzed by the local laboratory. 
Any clinically significant findings in laboratory safety data following completion of 
screening should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the Investigator's medical judgment. 
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6.4.1.3 
Blood Pressure and Pulse Rate 
Blood pressure and pulse rate will be measured at times specified in Sections land 6. 
Additional collection times, or changes to collection times of blood pressure and pulse rate 
will be permitted, as necessary, to ensure appropriate collection of safety data. 
Any clinically significant changes in blood pressure and pulse rate following completion of 
screening should be recorded as an AE. Determination of clinical significance and 
seriousness will be based on the OSI's medical judgment. 
6.4.1.4 
General Physical Examination 
At screening, general physical examination will be performed which consists of an 
examination of the abdomen, cardiovascular system, lungs, lymph nodes, musculoskeletal 
and neurological systems, skin, extremities, head, ears, eyes, nose, and thyroid gland by 
trained medical personnel at the site. 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition in the subject's medical history. At the end of the study, any new clinically 
significant findings/abnormalities that meet the definition of an adverse event must also be 
recorded and documented as an adverse event. 
Height and weight will be assessed at screening. Physical examination results will not be 
recorded in the CRFs, but any clinically significant finding at Screening should be recorded 
under medical history and changes between Screening and subsequent examinations should 
be recorded as an AE. Determination of clinical significance and seriousness will be based on 
the OSI's medical judgment. 
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7 
STATISTICAL ANALYSIS 
7.1 
Sample Size Calculations 
The overall mortality rate for Legalon® SIL treated patients, regardless of the severity of liver 
damage, is less than 10%. This represents more than a 50% reduction in the reported 
mortality rate before Legalon® SIL was available.. For ethical and practical reasons there are 
no controlled clinical studies available for any amatoxin treatments but observational studies 
and case reports describe successful treatment with intravenous silibinin (Legalon® SIL). 
A total of 139 enrolled patents is considered sufficient to show the effect of the Legalon® SIL 
in preventing liver transplantation, and/or death resulting from amatoxin poisoning. Using 
the large sample normal approximation, a sample size of 139, provides a two-sided 95% 
confidence interval for proportion of patients not meeting the outcome of interest (liver 
transplantation, and/or death) within a half width of 5% from the observed proportion at an 
expected proportion of 90%. 
Published Clinical Experience with Legalon® SIL 
Between 1982 and 2008, mostly single cases were published by various authors (Table7.1). 
Overall, out of these 1,136 reported patients treated with Legalon® SIL as monotherapy or in 
combination with mostly penicillin G, 1,064 patients (94%) survived. It was further reported 
that the severity of liver damage correlated with the time interval between mushroom intake 
and commencement of silibinin treatment. If silibinin was given within 48 hours after 
intoxication, a light or medium hepatic injury was expected. When silibinin treatment was 
delayed by more than 48 hours, then a severe clinical course with coagulation disorders and 
liver coma was more likely. 
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Table 3 
Summary of Clinical Experience with Legalon® SIL in Amatoxin 
Poisoning 
Reference 
Treatment Regimen 
No. of Patients 
Treated 
Survived 
Lorenz etal, 1983 (unpublished) 
PE + SIL 
201 
181 
Strenge-Hesse et al., 1996 (unpublished) 
PE + SIL 
154 
139 
Floersheim et al., 1982 [29] 
PE + SIL 
16 
16 
Hruby 1983 [30] 
PE + SIL 
15 
14 
Marugg and Reutter 1985 [33] 
PE + SIL 
12 
11 
Smetana et al., 1986 [34] 
PE + SIL 
2 
2 
Schenke et al., 1987 f351 
SIL 
2 
2 
SIL 
17 
16 
Hruby 1987 [36] 
PE + SIL 
TH + SIL 
37 
1 
34 
1 
PE + TH + SIL 
15 
15 
Kelbel and Weilemann 1989 [37] 
PE + SIL 
5 
4 
Nagy et al., 1994 [38] 
PE + SIL 
4 
3 
Kleist-Retzow et al., 1995 [39] 
PE + SIL 
2 
2 
Moiling et al., 1995 [40] 
PE + SIL 
2 
2 
Carducci et al., 1996 [41] 
PE + SIL 
4 
4 
Alves etal., 2001 [42] 
PE + SIL 
4 
4 
Boyer et al., 2001 [43] 
NAC+ SIL 
1 
1 
Enjalbert et al., 2002 [28] 
SIL or PE+SIL 
624 
589 
Ganzert et al., 2008 [31.] 
SIL or PE+SIL 
367 
339 
Mitchell and Olson 2008 [32] 
PE+NAC+S1L 
6 
5 
Total 
1,491 
1,384 
PE=penicillin, SIL=Legalon® SIL, NAC=N-acetylcysteine, TH=thioctic acid. 
Based on the available clinical data (unpublished and published), from a total of 1,491 
documented Amanita-poisoned patients treated with Legalon® SIL 1,384 survived, resulting 
in a survival rate of 93% (la). 
7.2 
Analysis Set Definitions 
The following analysis sets will be used for the statistical analyses: 
Full Analysis Set (FAS): Full Analysis Set includes all treatment allocated subjects with least 
one post baseline evaluable efficacy assessment. 
Safety Analysis Set (SAF): Safety Analysis Set includes all subjects who receive the study 
treatment. 
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Per-Protocol Set (PPS): Per-Protocol Set includes all subjects who receive study treatment, 
have evaluable efficacy assessment and have no major protocol deviations. A major protocol 
violation is defined as a protocol deviation that is considered to have an impact on the 
efficacy results. A list of possible major protocol deviations will be identified and 
documented in the SAP and the subjects having major protocol deviation will be finalized 
prior to the data base lock. 
7.3 
Primary Endpoint 
The primary endpoint is the proportion of patients treated with Legalon® SIL that do not 
exhibit morbidity (liver transplantation,) and/or mortality (death) at the end of treatment 
period (96 hours). 
7.4 
Secondary Endpoint (s) 
The secondary endpoints of the study are: 
• 
Proportion of patients not needing liver transplantation 
• 
The time to normality for AST, ALT, bilirubin, PT/INR, and creatinine during the 
treatment period 
• 
Number (%) of patients without hepatic transplantation by Ganzert's intoxication (pre-
treatment) 
• 
Elapsed days between amanita poisoning and start of treatment 
• 
Number (%) of patients without hepatic transplantation by Ganzert's intoxication 
(during treatment) 
• 
Number (%) of patients without hepatic transplantation by INR severity criteria (INR 
< 2 and >2) (during treatment) 
• 
Number (%) of patients without hepatic transplantation by Escudie's intoxicion grade 
transplantation criteria (INR < 6 and >6) (during treatment) 
7.5 
Statistical Analysis Methodology 
In general, data will be summarized using descriptive statistics by treatment group. 
Continuous variables will be summarized using the mean, standard deviation, median, 
minimum value and maximum value. Categorical variables will be summarized using 
frequency counts and percentages. All data will be presented in patient data listings. Any data 
excluded from the summaries and statistical analyses will be flagged accordingly. Baseline 
value is defined as the last valid value prior to the treatment, i.e.in other words, Baseline 
value is treatment specific value. If the data is missing at Baseline, then the Baseline will be 
imputed with the corresponding value at screening. Detailed methodology for summary and 
statistical analyses of the data collected in this study will be documented in a Statistical 
Analysis Plan (SAP). This document may modify the plans outlined in the protocol; however, 
any major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. 
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7.5.1 
Patient Demographics, Patient Disposition and Protocol Deviations 
Descriptive statistics will be presented for continuous demographic variables and number and 
percentage will be presented for categorical demographic variables. Subject's disease 
characteristics will be summarized as applicable. 
Patient accountability will be tabulated for all patients by summarizing the number of patients 
who are assigned to treatment, complete the study, or prematurely discontinue, and the reason 
for early discontinuation by treatment. A listing will be presented to describe dates of 
completion or early withdrawal and the reason for early discontinuation, if applicable, for 
each patient. Listings of data collected during the study, e.g., inclusion/exclusion criteria 
responses, study treatment administration will be provided. 
The protocol deviations in the study will be evaluated on a case to case basis and will be 
categorized as major or minor. A major protocol deviation is defined as any deviation that 
may affect the cfficacy outcome or the treatment of the subject. The number and proportion 
of subjects meeting minor or major protocol deviations will be summarized by treatment 
group. The data will also be listed. The protocol deviation criteria and detailed list of major 
protocol deviations will be mentioned in the statistical analysis plan. 
Treatment duration and compliance will be descriptively summarized. 
7.5.2 Prior and Concomitant Medications 
Concomitant medications will be coded by using WHO dictionary. Concomitant medications 
will be summarized by ATC class and WHO preferred term by treatment, and overall, and 
will be listed for all subjects in the Safety Population 
7.5.3 Analysis of Primary Endpoint 
The primary objective of the study is to compute the survival of the patients without liver 
transplantation, renal failure or death during the treatment period of 96 hours. The number 
and proportion of patients surviving without liver transplantation, renal failure and/or death at 
the end of treatment period will be computed, 95% CI for the proportion of patients surviving 
without liver transplantation, renal failure and/or death will be computed based on 
Newcombc-Wilson score method. 
The analysis of primary endpoint will be performed based on Full Analysis Set. 
7.5.4 Secondary/Sensitivity Analyses for Primary Endpoints 
As a sensitivity analysis, the primary analysis will be repeated using the Per-Protocol Set. 
In addition, the survival rates using Kaplan-Meier estimation method at 96 hours (end of 
treatment period) will be computed for the patients surviving without liver transplantation, 
renal failure or death. 95% CI will be computed for the survival rate by using Greenwoods 
formula. This analysis will be carried out using both Full Analysis and Per-Protocol Analysis 
sets. 
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7.5.5 Missing Data 
In general, missing data will not be imputed. However, more analytical details about handling 
of missing data may be covered in the SAP. 
7.5.6 Sub-Group Analyses 
The primary and sensitivity analyses of primary endpoint will be repeated by the disease 
severity stages. 
7.5.7 Analysis of Secondary Endpoint(s) 
All secondary analysis will be carried out using the Full Analysis Set. 
The endpoints of proportion of patients not needing liver transplantation, without hepatic 
transplantation by Ganzert's intoxication (pre-treatment), without hepatic transplantation by 
Ganzert's intoxication (during treatment), without hepatic transplantation by INR severity 
criteria (INR < 2 and >2) (during treatment), without hepatic transplantation by Escudie's 
intoxicion grade transplantation criteria (INR < 6 and >6) (during treatment) will be analyzed 
in the same way as the analysis of primary endpoint. The number and proportion of patients 
meeting the criteria will be computed and presented along with 95% CI that is computed 
using Newcombe-Wilson score method. 
Elapsed days between amanita poisoning and start of treatment will be summarized 
descriptively. 
The time to normality for AST, ALT, bilirubin, PT/INR, and creatinine will be analyzed 
using Kaplan-Meier estimation method of estimation for the survival time. 95% CI will be 
computed for the survival rate by using Greenwoods formula. The analysis of time to 
normality for AST, ALT, bilirubin, PT/INR, and creatinine will be analyzed by the disease 
severity stages as well. 
7.6 
Interim Analyses 
Interim Clinical Study Report summarizes the data related to the first 50 patients of the 54 
recruited, as of December, 2012 into this study with protocol No. SB16A1.07, entitled 
"Prevention and Treatment of Amatoxin Induced Hepatic Failure with Intravenous Silibinin 
(Legalon® SIL): An Open Multicenter Clinical Trial", which was originally submitted to the 
FDA on 9 July 2009 under IND 105,960 and is being conducted in US investigational sites. 
Study Objectives and Endpoints: This study aims to assess the efficacy and safety of 
Legalon® SIL in the prevention of severe morbidity (defined as liver transplant) and death in 
amatoxin poisoned patients. The primary endpoint is the proportion of enrolled patients 
without liver transplant or death. Secondary assessments include AST, ALT, bilirubin, 
PT/INR, and creatinine as indicators of liver and renal function, adverse events and vital 
signs. 
Design: Multicenter, open, uncontrolled study. 
Study Population: Patients with a clinical diagnosis of amatoxin poisoning based on history, 
gastrointestinal symptoms, elevated liver enzymes. 
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Results: 42 of the 50 poisoned patients (84.0%; 95% CI 70.9% to 92.8%) were discharged 
home from the hospital with complete recovery. Conversely, 8 of the 50 patients (16%) had a 
severe morbidity, resulting in 5 deaths and 3 liver transplants. The negative outcome of these 
8 patients was due to the progression of the liver and renal failure as a consequence of 
Amatoxin intoxication in the absence of an adequate aggressive hydration to preserve renal 
function and when treatment with Legalon® SIL was instituted started >96 hours after 
poisoning. 
A total of 11 patients (22.0%) experienced 20 Adverse Events (AEs) during the course of the 
clinical trial, 11 of which were Serious Adverse Events (SAEs). All SAEs were regarded as 
severe AEs by the on-site investigator (OSI) and all of them were considered not related to 
Legalon® SIL treatment. Indeed, they were all signs of the severe amatoxin intoxication, 
responsible for severe liver failure leading these patients to die or to be liver transplanted. 
Conclusions: Since silibinin strongly inhibits the hepatocyte uptake of amatoxin and the 
survival has been correlated with the time of initiation of therapy, Legalon® SIL treatment 
should be instituted as soon as a diagnosis has been made/suspected. As a matter of fact, all 
the patients who started treatment with the study drug >96 hours after poisoning had a 
negative outcome. 
As long as renal function has been maintained with aggressive intravenous hydration, patients 
who receive intravenous Legalon® SIL appear to recover from amatoxin induced 
hepatotoxicity in a rapid, predictable, and reliable manner. Length of hospitalization for the 
successfully treated patients was relatively short, often well under 8 days. Legalon® SIL was 
not associated with any serious adverse events. It was easy to administer, safe, and was well 
tolerated in this patient population. 
7.7 
Safety Analyses 
The safety analyses will be based on the Safety population. 
The analysis set for safety summaries is defined as all subjects who received at least one dose 
of study medication. 
7.7.1 Adverse events 
Adverse events will be summarized and listed by Preferred Term (PT) and SOC using 
MedDRA vocabulary (most recent) by treatment. All AEs that occur after the first dose of 
study medication through 30 days after the last dose will be considered to be treatment 
emergent AEs. The number and percentage of subjects with at least one treatment emergent 
AE will be presented by treatment group and events further summarized by maximum 
severity and relationship to study medication. The number and percentage of patients with 
SAE, discontinuation of study treatment due to AE (DAE), and AEs of severe intensity will 
be summarized by treatment. The AEs will be summarized by outcome of the event as well. 
Furthermore, listings of SAEs and AEs that lead to withdrawal will be provided. Summary 
statistics (N, %) of AEs of special interest will be also be separately tabulated. 
Descriptive statistics will be provided for the following safety data. No inferential analysis of 
this safety data is planned. Any ECG, BP, and pulse rate abnormalities of potential clinical 
concern will be described. 
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7.7.4 Laboratory Data 
Clinical laboratory data consists of clinical chemistry, hematology, and other parameters. 
These data will be summarized by treatment. For clinical laboratory tests, listings of values 
for each patient will be presented with abnormal or out of range values flagged. The 
laboratory data will be presented in System International (SI) units. Numerical laboratory 
results will be summarized using standard summary statistics by timepoint of collection and 
treatment group. Baseline shift tables will be prepared for the laboratory findings ('Normal', 
'Low' and 'High'). Subject listing will be prepared for the pregnancy test results for female 
patients. 
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8 
ADMINISTRATIVE PROCEDURES 
Access to Data/Source Documentation 
The OSI or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections. 
8.1 
Final Clinical Study Report and Case Report Forms (CRFs) 
A written clinical study report will be provided in accordance with the International 
Conference on Harmonization (ICH) E-3 guidelines including Annex I (Synopsis) 
documenting the clinical execution of the study. This report will include a description of any 
protocol deviations. The final report will also include reasons for withdrawals and any 
necessary treatment(s). The report will also include tables presenting demographics (separate 
summary tables for enrolled and completed subjects), and adverse events recorded during the 
study. In addition, the clinical study report will include a Quality Assurance statement, 
documenting that the report has been reviewed for completeness, accuracy, and compliance 
with the protocol and applicable local and federal regulations. For final clinical reporting 
purposes only, adverse events deemed "definite", "probable" or "possible" will be included in 
the treatment-related summaries/listings. 
Case Report Forms (CRFs) containing data transcribed from subject source documents (as 
appropriate) and copies of other source documents will be supplied by the clinical site. The 
OSI must sign each subject's CRF after completion of data entry, signifying that the data 
entered in the CRF is complete and accurate. 
8.2 
Adherence to Protocol 
Except for an emergency situation, in which proper care for the protection, safety and well-
being of the study subjects requires medical treatment, the study will be conducted as 
described in the approved protocol (and amendments, if applicable), GCP and applicable 
SOPs. In addition, the study will be conducted in accordance with the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. Any deviation(s) from the protocol will be recorded and 
presented in the final report. 
8.3 
Data Handling and Record Retention 
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the trial 
subjects remains protected. 
A set of CRF is required to be completed for each subject receiving study medication. The 
CRF is property of the sponsor and the OSI must review all CRFs prior to submission to the 
sponsor. 
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final CRFs, worksheets, and other pertinent source documents 
must be retained in accordance with ICH-GCP and the applicable regulatory requirements of 
the country where the study is being conducted as well as the country where the study will be 
submitted. 
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The investigator must obtain in writing the sponsor's agreement to dispose of any records, 
even if the retention period has been reached. 
8.4 
Confidentiality 
Information furnished to OSIs and IRBs/Ethics Committees will be maintained in confidence 
by the OSI and IRB/Ethics Committee. By signing this protocol, the OSI affirms to the 
Sponsor that he/she will maintain, in confidence, information furnished to the IRB/Ethics 
Committee relevant to this study under appropriate understanding of confidentiality with such 
IRB/Ethics Committee. 
By signing the protocol, the OSI agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory/X-ray reports, ECG tracings, workbooks, medical records) in 
order to verify CRF data. 
8.5 
Ethics and Regulatory Authorities 
Guidelines will be followed with regards to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use ICH-E6-R2 in addition to the regulatory requirements of the country where the study is 
being conducted as well as the country where the study will be submitted. 
8.5.1 Institutional Review Board/Ethics Committee 
The OSI is responsible for obtaining initial and continuing review (at intervals not more than 
once per year) of the study by an IRB/Ethics Committee, or in accordance with applicable 
government regulations of the country where the study is being conducted as well as the 
country where the study will be submitted. Ideally study will not enroll any subjects until the 
IRB/Ethics Committee provides written approval of the protocol and the informed consent to 
the investigator. Due to the critical condition of subjects with amatoxin poisoning verbal 
approval confirmed via email may suffice until formal written approval can be issued by the 
local IRB. In addition, a copy of the IRB/Ethics Committee approval documents (email 
and/or formal letter) must be provided to the sponsor prior to enrolling any subjects into the 
study. 
8.5.2 Regulatory Authority 
This clinical study protocol, title as well as other relevant documentation will be submitted to 
the local Regulatory Authorities for review and approval prior to trial start. Upon completion, 
the Regulatory Authorities will be notified the study has ended. The study will only be 
undertaken in compliance with the local regulatory requirements. 
8.6 
Informed Consent 
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each patient or their legally authorized 
representative (LAR or next of kin) prior to entering the study. The investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the patient's medical record. 
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8.7 
Disclosure and Publication of Clinical Study Data 
The disclosure and publication of clinical study data will be detailed in the OSI Commitment 
Form. 
8.8 
End of Trial 
The end of trial is considered to be the date of last subject last visit or the date of early 
termination of the study whichever is the later. 
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9 ADVERSE EVENT REPORTING 
9.1 
Assessment of Safety 
9.1.1 Safety Parameters 
Safety will be assessed by the monitoring of adverse clinical events, vital signs, clinical 
laboratory evaluations, and physical examinations. All adverse events occurring during the 
study must be recorded according to Section 9.2.2. 
Findings from screening procedures, e.g., laboratory tests or physical examinations will be 
recorded as medical history. Clinically significant changes following the screening 
procedures will be recorded as adverse events. 
The study period for the purpose of adverse event collection is defined as the period from the 
signing of a study specific informed consent to 30 days after the last dose of study 
medication. All adverse events that occur after the first dose of study medication through 
30 days after the last dose will be considered to be treatment emergent adverse events. Any 
adverse event received by the clinical site for a subject who has previously exited the study 
needs to be forwarded to the sponsor for evaluation if within the aforementioned window. 
9.2 
Adverse Event Reporting 
9.2.1 Definitions 
Adapted from ICH Harmonised Tripartite Guideline: Clinical Safety Data Management 
Definition and Standards for Expedited Reporting: E2A 
Adverse Event 
Any untoward medical occurrence in a subject administered a medicinal product and which 
does not necessarily have to have a causal relationship with this treatment. An adverse event 
can therefore be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
Serious Adverse Event 
An event that is fatal, life-threatening, or leads to persistent or significant disability; one that 
requires or prolongs hospitalization; or one that results in a congenital anomaly, or one that is 
a significant medical event. 
Medical events that are not fatal, life-threatening, or require hospitalization may be 
considered serious when, based on appropriate medical judgment, they jeopardize the subject 
and may require [urgent] medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
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9.2.2 Documentation of Adverse Events 
The investigator or designee must record all adverse events reported by subjects that have 
occurred during the adverse event collection period of the study. In addition, adverse events 
should be solicited from subjects though open-ended questions, and as appropriate, by 
examination. Subjects will be evaluated for adverse events from the time of consent through 
study follow up visit. The subject should also be queried for any previously unreported 
adverse event as part of study exit procedures. All adverse events must be followed until they 
have resolved or stabilized. 
Where possible and appropriate, the investigator should record the most important medical 
event or specific diagnosis rather than individual signs and symptoms (all clearly related 
signs, symptoms, and abnormal diagnostic procedure results should be recorded in the source 
document, but should be grouped under one diagnosis on the AE page). 
All adverse events (including laboratory abnormalities, if they are of clinical concern), 
whether or not thought to be caused by the investigational drug, will be recorded on the CRF. 
The information in the CRF will include: 
• The date/time of onset of any new adverse event or the worsening of a previously 
observed adverse event or worsening of any previously existing disease 
• The event in standard medical terminology 
• The duration of the adverse event 
• The relationship of the adverse event to the investigational drug(s) 
• The severity of the adverse event 
• Seriousness of the adverse event 
• Description of action taken in treating the adverse event and/or change in investigational 
drug administration or dose 
Clinically significant abnormal laboratory values that represent a change from baseline 
should be recorded diagnostically as AEs (e.g. for elevated serum glucose, the AE would be 
described diagnostically as "hyperglycemia"). Determination of clinical significance and 
seriousness is based on the investigator's medical judgment. The following are examples of 
laboratory abnormalities that would normally qualify as adverse events: 
• The abnormality suggests a change in disease severity and/or organ toxicity 
The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
9.2.3 Relationship of Adverse Experiences to the Investigational Drug 
The Investigator is responsible for assessing relationship of adverse events to the 
investigational drug (e.g., causality assessment). Factors that need to be considered when 
making a causality assessment include: the temporal relationship (e.g., time to onset); the 
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clinical and pathological characteristics of the events; pharmacological plausibility; exclusion 
of confounding factors (medical and medication history); drug interactions; 
dechallenge/rechallenge, and dose relationship etc. 
A suspected relationship (definite, probable, possible) between the events and the study 
medication means in general that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. 
The Investigator is responsible for assessing relationship of adverse events to the 
investigational drug in accordance with the following definitions: 
Definite - causal relationship is certain (e.g., the temporal relationship between drug 
exposure and the AE onset/course is reasonable, there is a clinically compatible response to 
dechallenge, other causes have been eliminated and the event must be definitive 
pharmacologically or phenomenologically, using a satisfactory rechallenge procedure if 
necessary). 
Probable - high degree of certainty for causal relationship (e.g., the temporal relationship 
between drug exposure and AE onset/course is reasonable, there is a clinically compatible 
response to dechallenge (rechallenge is not required), and other causes have been eliminated 
or are unlikely). 
Possible - causal relationship is uncertain (e.g., the temporal relationship between drug 
exposure and the AE onset/course is reasonable or unknown, dechallenge information is 
either unknown or equivocal, and while other potential causes may or may not exist, a causal 
relationship to the investigational drug does not appear probable). 
Unlikely - temporal relationship between drug administration and event onset is improbable, 
and/or another explanation is more likely such as disease, environment, other drugs etc. Does 
not represent a known reaction to the investigational drug. 
Unrelated/Not related - no possible relationship (e.g., the temporal relationship between 
drug exposure and the AE onset/course is unreasonable or incompatible, or a causal 
relationship to the investigational drug is implausible). 
9.2.4 Severity of the Event 
Note that 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. Likewise, mild or moderate events could, under some circumstances, 
result in a serious outcome as defined above. 
The intensity or severity of AEs will be graded as follows: 
• Mild - awareness of sign or symptom, but easily tolerated. Not expected to have a 
clinically significant effect on the subject's overall health and well-being. Does not 
affect daily activities. Not likely to require medical attention. 
• Moderate - discomfort enough to cause interference with usual daily activities or 
affects clinical status. May require medical intervention and/or prescription drug 
therapy. 
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• Severe - incapacitating or significantly affecting clinical status. Severely limits daily 
activities. Medical intervention, prescription drug therapy and/or hospitalization 
required. 
9.2.5 Special Situations 
Emergency Room Visits: Post discharge from the hospital and up to 30 days post 
discontinuation of study drug, events that result in emergency room visits that do not result in 
admission to the hospital are not routinely considered to be serious events; however, these 
events should be evaluated for one of the other serious outcomes (e.g., life-threatening, other 
serious [medically significant] events). 
Neoplasms: For this protocol, any diagnosis of cancer or neoplasm is considered serious 
(significant medical event criterion). 
Quality Complaints: Quality complaints related to study drug are not AEs, however, any AE 
or SAE experienced by the subject as a result of these should be documented in the CRF and 
SAEs sent to Mylan on the SAE reporting form. Please see Section 5.3 for further details. 
Overdose: The protocol specified dose should not be exceeded. Overdose will be 
documented as a deviation in the source and communicated to the sponsor Clinical Scientist 
or designee. The subject should be monitored appropriately by the investigator for latent 
adverse effects. Any adverse event occurring as a result of overdose or medication error will 
be recorded as an AE in the CRF and if serious (per definition, Section 9.2.1) reported 
immediately to sponsor as per Section 9.2.7. Please see Section Error! Reference source not 
found, for further details. 
9.2.6 Exposure to Investigational Drug During Pregnancy: 
Pregnancy in a female subject is to be reported on the Pregnancy Report Form within 
24 hours of awareness starting from first dose of study medication. The pregnancy should be 
followed to term or termination and updates submitted during the pregnancy at 3-monthly 
intervals via the Pregnancy Report Form. 
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of pregnancy for medical reasons will be recorded as an AE or a SAE 
depending upon the Investigator's medical judgment. 
If a pregnancy occurs in a female partner of a male subject that has received at least one dose 
of investigational drug, the site should contact Mylan (or designate) to obtain a partner 
pregnancy informed consent form. While the occurrence of a partner pregnancy must be 
communicated to Mylan Product Safety & Risk Management, consent of the pregnant partner 
must be obtained before the site can collect any details of the pregnancy or share personal 
medical information of the partner with the sponsor. If the pregnant partner provides consent 
to have the pregnancy followed, the site should collect the information specified on the 
Pregnancy Report Form and forward the completed form to Mylan Product Safety & Risk 
Management in 3-monthly intervals until the pregnancy outcome has been obtained. No entry 
into the male subject's CRF is required for the partner pregnancy including adverse events 
experienced by the mother, fetus, or neonate. 
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A spontaneous abortion is always considered to be a SAE. Furthermore, any SAE occurring 
as a result of a post-study pregnancy AND considered reasonably related in time to receipt of 
the investigational product by the investigator, will be reported to the sponsor. Serious 
pregnancy-related medical events and congenital anomalies are to be reported on the SAE 
Report Form. 
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered to be an elective procedure and not an adverse event; nevertheless, Mylan requests 
that the outcome (e.g. elective termination) be reported within 24 hours and sent as a 
follow-up on the Mylan Delivery and Infant Follow-up Form. 
9.2.7 Notification - Immediately Reportable Events 
In addition to standard documentation of adverse events in the CRF, serious adverse events 
and pregnancies require immediate notification to Mylan Product Safety and Risk 
Management Department (PSRM) on the Mylan Clinical Trials Serious Adverse 
Event/Pregnancy Reporting Fonns. "Immediate" is defined as within 24 hours of the 
investigator's or site staffs knowledge of the event. 
The SAE and Pregnancy Report Forms are to be completed for all serious AEs and 
pregnancies, signed by the Investigator, and emailed with supporting documentation (e.g. 
case report forms, hospital records, laboratory reports). Subject identity details (such as but 
not limited to name or clinic/hospital number) must not be visible on the forms or any 
supporting documentation provided by the Investigator. These should be "blacked out", 
signed and dated before submission to Mylan. The subject ID is to be provided on every 
document. 
All SAEs/Pregnancies must be sent within 24 hours of awareness to: 
Mylan Global Product Safety & Risk Management at: 
pvclinicalfeftmylan.coin 
Note: Email is the preferred method of communication 
If an acknowledgment is not received from Mylan PSRM within 24 hours, report the 
SAE via: 
Tel: +1.304.285.6409 
The investigator will include a narrative description of the serious adverse event(s) that 
discusses: 
• Investigational drug(s) administered, including dates 
• Date and time of the onset of the adverse event 
• Description of the reaction in standard medical terminology 
• Date the event resolved or outcome of the event at last observation 
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• Investigator's assessment - the attribution of the adverse event to the 
investigational drug(s) or possible alternative etiologies for the event 
• Description of action taken in treating the adverse event and/or change in 
investigational drug administration or dose 
Follow-up information to a safety report shall be submitted to Mylan's Product Safety and 
Risk Management Department by the investigator as soon as the relevant information is 
available. Relevant information such as discharge summaries, autopsy reports, and medical 
consultations shall be reviewed in detail by the Investigator. The Investigator shall comment 
on any event, abnormal laboratory result, or any other finding, noting whether it shall be 
considered a serious or non-serious AE or considered part of the subject's history. In addition, 
the Investigator shall report on an SAE form all subsequent events or other findings 
determined to be relevant and shall state for each event or finding whether it is related to the 
investigational drug. All events determined to be non-serious shall be reported on the relevant 
CRF page and entered into the clinical database by the CRO or others as agreed in their 
contractual obligations. 
Reconciliation of SAEs will be performed periodically (quarterly) or at the end of the trial, 
depending upon the duration of the study to ensure both the number of cases and information 
is consistent between both the Clinical Database and the Global Safety Database. 
9.2.8 Reporting Timelines for Serious Adverse Events and Follow-up Information 
The Principal Investigator (or designee) will report any AE classified as serious or pregnancy 
via email or telephone within 24 hours but no later than 1 calendar days after becoming 
aware. A complete description of the event (i.e. completed SAE or Pregnancy Report form) 
must be transmitted to the Sponsor, as follow-up data, in writing as soon as possible, but in 
any case, not later than 2 calendar days for all serious events after first knowledge of the SAE 
or pregnancy. The Investigator should also be aware of any special reporting requirements, 
such as institutional review boards or ethics committees. The Sponsor has strict regulatory 
reporting time lines for safety related information. Therefore, the above-mentioned reporting 
timeframes must be adhered to by the OSIs. 
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10 REFERENCE LIST 
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with Acute Hepatotoxicity from Amatoxin Poisoning. Curr Pharm Biotechnol, 2012 
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3. Koppel C. Clinical symptomatology and management of mushroom poisoning. 
Toxicon. 1993;12:1513-1540. r PubMed! 
4. Blackman J R. Clinical approach to toxic mushroom ingestion. J. Am. Board Fam. 
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5. Bresinsky A, Besl H. Giftpilze. Stuttgart, Wiss. VerlagsgesellschafL 1985. pp. 18-35. 
6. Ellenhorn MJ, Barceloux DG. Medical Toxicology, Diagnosis and Treatment of 
Human Poisoning. New York: Elsevier; 1988. pp. 1324-1351. 
7. Meunier B, Messner M, Bardaxoglou E, Spiliopoulos G, Terblanche J, Launois B. 
Liver transplantation for severe Lepiota helveola poisoning. Liver. 1994;14:158-160. 
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8. Enjalbert F, Cassanas G, Rapior S, Renault C, Chaumont J-P. Amatoxins in wood-
rotting Galerina marginata. Mycologia. 2004;96 (4 ):720-729. [PubMed] 
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1152. [PubMed] 
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polymerization of muscle actin. Biochemistry. 1981;20:708-712. [PubMed] 
11. Beer JH. Derfalsche Pilz. Schweiz. Med. Wschenschr. 1993;123:892-905. [PubMed] 
12. Bodenmuller H, Faulstich H, Wieland T. In: Amanita Toxins and Poisoning. Faulstich 
H, Kommerell B, Wieland T, editors. Verlag Witzstrock, Baden-Baden, Koln, New 
York; 1980. pp. 18 -20. 
13. Faulstich H, Talas A, Wellnoner HH. Toxicokinetics of labelled amatoxins in the dog. 
Arch. Toxicol. 1985;56:190 -194. [PubMed] 
13a. Ferreira R, Romaozinho JM, Amaro P, Ferreira M, Sofia C. Assessment of 
emergency liver transplantation criteria in acute liver failure due to Amanita 
phalloides. Eur J Gastroenterol Hepatol. 2011 Nov;23(12): 1226-32. doi: 
10.1097/MEG.0b013e32834c7b8f. 
14. Jaeger A, Jehl F, Flesch F, Sauder P, Kopferschmitt J. Kinetics of amatoxins in 
human poisoning: Therapeutic implications. Clin. Toxicol. 1993 ;31:63 -80. 
TPubMedl 
15. Kroncke KD, Flicker G, Meiers PJ, Gerok W, Wieland T, Kurz G. Alpha-amanitin 
uptake into hepatocytes. J. Biol. chem. 1986; 261:1252-1256. [PubMed] 
16. Wieland T, Faulstich H. Fifty years of amanitin. Experientia. 1991 ;47:1186-1193. 
[PubMed] 
17. Fiume L, Maritozzi V, Nardi F. The effect of amanitin poisoning on mouse kidney. 
Br. J. Exp. Pathol. 1969;50:270-276. [PMC free article] [PubMed] 
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18. Zilker TR. Klinische Toxikologie fur die Notfall- und Intensivmedizin,. In: Zilker 
TR, editor. Uni-Med Verl. Bremen-London- Boston: Uni-Med Verlag AG; 2008. pp. 
257-265. 
19. Letschert K, Faulstich H, Keller D, Keppler D. Molecular Characterization and 
Inhibition of Amanitin Uptake into Human Hepatocytes. Toxicological. Sciences. 
2006;91 (1 ): 140-149. fPubMedl 
20. Magdalan J, Piesniewska M, Gliniak H. The Inhibition of alpha- Amanitin Uptake in 
Perfused Rat Liver. Adv. Clin. Exp. Med . 2007; 16(3 ):353-360. 
21. Al-Anati L, Essid E, Reinehr R, Petzinger E. Silibinin protects OTA-mediated TNF-
alpha release from perfused rat livers and isolated rat Kupffer cells. Mol. Nutr. Food 
Res. 2009;53:460-466. [PubMed] 
22. Sonnenbichler J, Zetl I. In: Progress in Clinical and Biological Research. Cody V, 
Middleton E, Harborne JB, EDs Alan R, editors. Vol 213. New York: Alan R. Liss, 
Inc; 1986. pp. 319-331. fPubMed] 
23. Floersheim GL, Eberhard M, Tschumi P, Duckert F. Effects of penicillin and 
silymarin on liver enzymes and blood clotting factors in dogs given a boiled 
preparation of Amanita phalloides. Toxicol. Appl. Pharmacol. 1978;46:455-462. 
[PubMed] 
24. Vogel G, Tuchweber B, Trost W, Mengs U. Protection by silibinin against Amanita 
phalloides intoxication in beagles. Toxicol. Appl. Pharmacol. 1984;73:355-362. 
[PubMed] 
25. Sailer R, Melzer J, Reichling J, Meier R. An updated systematic review of the 
pharmacology of silymarin. Forsch. Komplement med. 2007; 14:70-80. [PubMed] 
26. Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, Novo E, di 
Manzano C, Marra F, Loguercio C, Pinzani M. Silybin a component of sylimarin, 
exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. J. 
Hepatol. 2009;50:1102-1 111. [PubMed] 
27. Faulstich H, Jahn W, Wieland T. Silybin inhibition of amatoxin uptake in the perfused 
rat liver. Arzneim. Forsch./Drug Res. 1980; 30 0(3 ):452-454. [PubMed] 
28. Enjalbert F, Rapior S, Nouguier-Soule J, Guillon S, Amouroux N, Cabot C. Treatment 
of Amatoxin Poisoning: 20-Year Retrospective Analysis. Journal of Toxicology 
CLINICAL TOXICOLOGY. 2002;40(6):715-757. [PubMed] 
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11 PROTOCOL AMENDMENT DETAILS 
Any significant changes in the study procedure or study design will only be affected upon 
mutual agreement between the sponsor and CRO and after obtaining a favorable opinion 
from the Ethics Committee and Regulatory Agency (if applicable). All such changes will be 
documented in the amended version of the protocol and a list of changes with reference to 
previous will be generated and submitted to the IEC/IRB along with amended version of the 
protocol. 
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