Clinical trial NCT03712280
Conditions: Hepatic Cirrhosis Hepatic Encephalopathy (HE)
Sponsor: Mallinckrodt
Start date: 2018-12-01; Completion date: 2020-07-14
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main reason for this study is to see how the study drug interacts with the body.

It will compare different doses of the study drug with a drug already in use.

Participants will be adults with liver disease that has affected the brain in the past.

Detailed description:

Arms: arm 1: Participants receive 2 tablets of MNK6106 three times daily (tid) for 5 days arm 2: Participants receive 4 tablets of MNK6106 twice daily (bid) for 5 days arm 3: Participants receive 4 tablets of MNK6106 tid for 5 days arm 4: Participants receive 1 tablet of rifaximin bid for 5 days
Interventions: intervention 1: MNK6106 intervention 2: Rifaximin
Intervention descriptions: intervention 1: 1 gram tablet of MNK6106 for oral administration intervention 2: 550 mg tablet of rifaximin for oral administration

Protocol documents:
Prot_SAP_000.pdf: 
Confidential and Proprietary 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Randomized, Open-Label, Phase 2a Comparator Study to Assess 
the Pharmacodynamics, Safety and Pharmacokinetics of Oral Administration 
of MNK6106 (L-Ornithine Phenylacetate) Versus Rifaximin in Subjects With 
Hepatic Cirrhosis and a History of Prior Episodes of Hepatic Encephalopathy 
Regulatory Agency Identification Number: IND #115524 
Protocol Number: MNK61062107 
Date of Original Protocol: 15 October 2018 
Date of Protocol Amendment 1: 18 February 2019 
Date of Protocol Amendment 2: 04 April 2019 
Date of Protocol Amendment 3: 08 October 2019 
Date of Protocol Amendment 4 Version 5.0: 21 April 2020 
Ocera Therapeutics Inc, a Mallinckrodt Company 
1425 US Route 206 
Bedminster, NJ 07921 
United States of America 
NCT03712280


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SPONSOR SIGNATURE 
 
My signature, in conjunction with the signature of the investigator, confirms the agreement of 
both parties that the clinical study will be conducted in accordance with the protocol and 
applicable laws and other regulations including, but not limited to, the International Council for 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the US Code of Federal 
Regulations (CFR) (where applicable), all applicable national and local regulations, protections 
for privacy, and generally accepted ethical principles for human research such as the Declaration 
of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care. 
 
 
Sponsor Signature 
 
Refer to e-signature page 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
Sponsor Name (print) 
 
 
 
 


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INVESTIGATOR SIGNATURE 
My signature confirms that the clinical study will be conducted in accordance with the protocol 
and applicable laws and other regulations including, but not limited to, the International Council 
for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the US Code of Federal 
Regulations (CFR) (where appropriate), all applicable national and local regulations, protections 
for privacy, and generally accepted ethical principles such as the Declaration of Helsinki. 
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care. 
 
 
Investigator’s Signature 
 
Date of Signature 
(DD Month YYYY) 
 
 
 
Investigator’s Name and Title (print) 
 
 
 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR SIGNATURE.....................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
CHANGES TO THE PROTOCOL .................................................................................................8 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
PROTOCOL SUMMARY ..........................................................................................16 
1.1. 
Synopsis ......................................................................................................................16 
1.2. 
Study Schematic .........................................................................................................19 
1.3. 
Schedule of Study Events ...........................................................................................20 
2. 
INTRODUCTION ......................................................................................................24 
2.1. 
Background .................................................................................................................24 
2.1.1. 
Nonclinical Safety Data ..............................................................................................25 
2.1.2. 
Clinical Safety Data ....................................................................................................25 
2.2. 
Study Rationale ...........................................................................................................26 
2.3. 
Assessment of Potential Benefits and Risks ...............................................................26 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................28 
3.1. 
Primary Objective/Endpoint .......................................................................................28 
3.2. 
Secondary Objectives/Endpoints ................................................................................28 
3.3. 
Outcome Measures .....................................................................................................29 
4. 
STUDY DESIGN .......................................................................................................29 
4.1. 
Overall Design ............................................................................................................29 
4.2. 
Study Design Rationale ..............................................................................................30 
4.2.1. 
Dose Rationale ............................................................................................................30 
4.3. 
End of Study Definition ..............................................................................................30 
5. 
STUDY POPULATION .............................................................................................31 
5.1. 
Inclusion Criteria ........................................................................................................31 
5.2. 
Exclusion Criteria .......................................................................................................32 
5.3. 
Lifestyle Considerations .............................................................................................33 
5.4. 
Screen Failures ............................................................................................................33 


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6. 
STUDY TREATMENT ..............................................................................................34 
6.1. 
Treatment Administration ...........................................................................................34 
6.2. 
Study Treatment Preparation/Handling/Storage/Accountability ................................35 
6.3. 
Measures to Minimize Bias ........................................................................................36 
6.4. 
Study Treatment Compliance .....................................................................................36 
6.5. 
Prior and Concomitant Therapy ..................................................................................37 
6.5.1. 
Prohibited Concomitant Therapies .............................................................................37 
6.5.2. 
Other Restricted Substances .......................................................................................38 
6.5.3. 
Meals and Fluids .........................................................................................................38 
7. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................39 
7.1. 
Discontinuation of Study Treatment ...........................................................................39 
7.2. 
Subject Discontinuation/Withdrawal From the Study ................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
8.1. 
Screening (Day -28 to Day -1) ....................................................................................41 
8.2. 
Randomization ............................................................................................................42 
8.3. 
Treatment Period (Week 1; Day 1 to Day 5/ET) and Day 6 (Discharge) ...................43 
8.4. 
Final Visit (Week 2) ...................................................................................................44 
8.5. 
Pharmacodynamic and Pharmacokinetic Assessments ..............................................44 
8.5.1. 
Pharmacodynamic Sampling ......................................................................................44 
8.5.2. 
Pharmacokinetic Sampling (Plasma PAA, ORN and PAGN) ....................................45 
8.5.3. 
Urine Sampling for PAGN Measurement...................................................................46 
8.5.4. 
Bioanalytical Methodology ........................................................................................47 
8.5.5. 
Sample Shipment ........................................................................................................47 
8.6. 
Safety Assessments .....................................................................................................47 
8.6.1. 
Medical and Surgical History .....................................................................................47 
8.6.2. 
Electrocardiogram .......................................................................................................47 
8.6.3. 
Physical Examination .................................................................................................48 
8.6.4. 
Height, Weight and Waist Measurements ..................................................................48 
8.6.5. 
Vital Signs ..................................................................................................................48 
8.6.6. 
Clinical Laboratory Tests ...........................................................................................48 


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8.7. 
Adverse Events ...........................................................................................................49 
8.8. 
Treatment Overdose ....................................................................................................49 
8.9. 
Provisions for Remote Assessment Methods .............................................................50 
9. 
STATISTICAL CONSIDERATIONS .......................................................................50 
9.1. 
Sample Size Determination ........................................................................................50 
9.2. 
Populations for Analysis .............................................................................................50 
9.3. 
Statistical Hypothesis and Analyses ...........................................................................50 
9.3.1. 
Pharmacodynamic Analyses .......................................................................................50 
9.3.2. 
Pharmacokinetic and Pharmacodynamic Analyses ....................................................51 
9.3.3. 
Analysis Methods for C-P, MELD, Conn and HESA Scores .....................................51 
9.4. 
Liver Function Classification .....................................................................................51 
9.5. 
Other Analyses ............................................................................................................51 
9.5.1. 
Safety Analyses ..........................................................................................................51 
9.5.2. 
Treatment Exposure ....................................................................................................52 
9.5.3. 
Interim Analyses .........................................................................................................52 
9.5.4. 
Handling Missing Data ...............................................................................................52 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................52 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................52 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................52 
10.1.2. 
Financial Disclosure ...................................................................................................53 
10.1.3. 
Subject Information and Consent ...............................................................................53 
10.1.4. 
Data Protection ...........................................................................................................54 
10.1.5. 
Dissemination of Clinical Study Data ........................................................................54 
10.1.6. 
Data Quality Assurance ..............................................................................................54 
10.1.7. 
Source Documents ......................................................................................................55 
10.1.8. 
Study and Site Closure................................................................................................55 
10.1.9. 
Publication Policy .......................................................................................................56 
10.2. 
Clinical Laboratory Tests ...........................................................................................57 
10.3. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up and Reporting ...........................................................................................58 


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10.3.1. 
Safety ..........................................................................................................................58 
10.3.2. 
Definitions ..................................................................................................................58 
10.3.3. 
Adverse Event and Serious Adverse Event Classifications ........................................60 
10.3.4. 
Adverse Event and Serious Adverse Event Recording and Reporting .......................61 
10.3.5. 
Adverse Events of Special Interest .............................................................................62 
10.4. 
Pregnancy Reporting ..................................................................................................62 
10.5. 
Liver Safety: Suggested Actions and Follow-up Assessments ...................................63 
10.6. 
Clinical Function Scoring ...........................................................................................63 
10.6.1. 
Conn Score ..................................................................................................................63 
10.6.2. 
HESA Score ................................................................................................................63 
10.6.3. 
MELD Score ...............................................................................................................64 
10.6.4. 
Child-Pugh Score ........................................................................................................64 
10.7. 
Common Terminology Criteria for AEs .....................................................................65 
10.8. 
Stages of Hepatic Encephalopathy According to Hepatic Encephalopathy 
Scaling Algorithm (HESA).........................................................................................65 
11. 
REFERENCES ...........................................................................................................66 
 
List of Tables 
Table 1: 
Schedule of Study Events ...........................................................................................20 
Table 2: 
Summary of Treatment Groups, Frequency and Dose ...............................................34 
Table 3: 
Adverse Event Relationships ......................................................................................60 
Table 4: 
Adverse Event Severity Grades ..................................................................................60 
Table 5: 
Reporting Requirements for Adverse Events .............................................................61 
Table 6: 
C-P Classification for Severity of Liver Disease ........................................................64 
 
List of Figures 
Figure 1: 
Study Schematic .........................................................................................................19 
 


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CHANGES TO THE PROTOCOL 
Protocol Amendment 4 – Summary of Changes: 
The primary purpose of Amendment 4 is to add 14 days to the screening period to give subjects 
more time to complete screening assessments due to extenuating circumstances of the 
COVID-19 pandemic. The changes to the protocol are listed below. 
1. Section 1.2 Study Schematic: the following changes have been made: 
a. Change: The Screening Visit from “Day -14 to Day -1” to read: “Day -28 to Day -1.” 
b. Add footnote “a” to the table heading for Final Visit (7 days post-dosing) (+ 3 daya 
window) that reads: “If circumstances occur such that this visit cannot occur within 
the specified window, the visit window may be extended to 14 days, after discussion 
with the Sponsor.” 
2. Section 1.3 Schedule of Study Events: Change: Screening from “Day -14 to Day -1” to 
read: “Day -28 to Day -1.” 
3. Section 4.1 Overall Design:  
 2nd paragraph, 2nd sentence: Change: “Subjects may participate in the study for a total 
of up to approximately 3 to 4 weeks, including a screening period of up to 14 days” to 
read: “Subjects may participate in the study for a total of up to approximately 
6 weeks, including a screening period of up to 28 days.” 
 Add 3rd paragraph: “The final visit window may be extended, due to extenuating 
circumstances, to 14 days after discussion with the Sponsor.” 
4. Section 5.2: Add exclusion criterion #19: “Has hyponatremia, defined as blood sodium 
level ≤ 125 mmol/L.” Subsequent exclusion criterion renumbered accordingly. 
5. Section 5.4 Screen Failures:  
 2nd paragraph: Change:  “The period from the start of screening related procedures at 
the Screening Visit to randomization must not exceed 14 days, inclusive of any repeat 
screening procedures.” to read: “The period from the start of screening related 
procedures at the Screening Visit to randomization must not exceed 28 days, 
inclusive of any repeat screening procedures.” 
 4th paragraph: Change: “Subjects may be rescreened for a subsequent episode of 
acute HE, provided that the subject was not randomized.” to read: Subjects may be 
rescreened provided that the subject was not randomized. 
6. Section 8.1 Screening: 
 Heading: Change: “Screening (Day -14 to Day -1)” to read: Screening (Day -28 to 
Day -1)” 
 Third bullet: Change: “Record medical/surgical history” to read: Record 
medical/surgical history (including history of exposure to COVID-19). 


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 Last paragraph: Change: “…screening (up to 14 days before Day 1).” to read: 
“…screening (up to 28 days before Day 1).” 
7. Section 8.4 Final Visit (Week 2): 
 2nd paragraph: Add: “The final visit window may be extended, due to extenuating 
circumstances, to 14 days after discussion with the Sponsor.” 
 Add: Section 8.9 Provisions for Remote Assessment Methods  
“For emergency situations where there are extenuating circumstances that prohibit 
physically coming to the clinical site or when the safety of subjects may be 
compromised by physical visits to the site, remote assessments may be considered 
after discussion with the Sponsor.” 
Other minor edits to text (including updating page headers/footers with current protocol 
template) were made to the document that did not affect study conduct. 
Protocol Amendment 3 – Summary of Changes: 
The 3rd amendment was implemented to make minor changes to the inclusion/exclusion criteria 
and prohibited medications to clarify criteria for and required documentation defining HE to 
facilitate enrollment in the study based on investigator observations/input during the trial. 
1. Table 1 (Schedule of Study Events): 
 Clarification that C-P and MELD scores do not need to be repeated at the time of 
confinement (Day -1) as they will be performed at screening (Days -14 to Day -1). 
 Clarification that urinalysis will be performed on Days 1 to 5 (not Days 1 to 6 as for 
chemistry and hematology laboratories). This change was also made to text in 
Section 8.3 (Treatment Period [Week 1; Day 1 to Day 5/ET] and Day 6 [Discharge]). 
 Urine pregnancy test added to Day -1 (first day of confinement) for women of 
child-bearing potential. Text has also been added to Section 8.1 (Screening [Day -14 
to Day -1]), Section 8.6.6, and Section 10.2 (Clinical Laboratory Tests). 
2. Section 3.3 added: Outcome measures are identified to facilitate clinical trial registration 
and patient access to basic results disclosed on public clinical trial registries. 
 Primary: Number of participants with a change in ammonia at Day 5.  
 Secondary: Number of participants with adverse events or deaths during the study. 
3. Section 5.1 Inclusion Criteria: 
 Inclusion criterion #4 was changed from “A history of at least 2 or more documented 
episodes of HE within the last 12 months, with 1 episode within the last 6 months.” 
To read: “A history of at least 1 or more documented episodes of HE within the last 
12 months.” 
 Inclusion criterion #5 was changed from “Hyperammonemia at screening.” To read: 
“Hyperammonemia (defined as an ammonia level ≥ 37 μmol/L) at screening.” 


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4. Section 5.2 Exclusion Criteria: Exclusion criterion #16 (second bullet) was changed from 
“Platelet count no more than 50,000 cells/μL” to read “Platelet count no more than 
25,000 cells/ μL.” 
5. Section 6.5.1 Prohibited Concomitant Therapies (Second bullet) was changed from 
“Current use of drugs whose plasma concentration may be affected by MNK6106, such 
as alfentanel, cyclosporine, midazolam, quinidine, metformin, or cimetidine.” To Read: 
“Current use of drugs whose plasma concentration may be affected by MNK6106, such 
as alfentanil, cyclosporine, midazolam, quinidine, or cimetidine. Metformin use is 
permitted at low doses. Doses of metformin > 1,000 mg should be discussed with the 
medical monitor prior to enrollment.” 
6. Section 10.8 (Stages of Hepatic Encephalopathy According to HESA):  
 Replaced HESA sheet with HESA sheet approved for use in the study and added 
reference (Hassanein et al, 2008).  
 Added a sentence to describe the new HESA scale with respect to the severity as 
follows: “It consists of a 5-point scale (Grade 0 to 4), with 4 indicating most severe.” 
Other minor issues (document conversion to Accenture StartingPoint Authoring Template, 
adding references, removing a web address, etc) were addressed; none affected study conduct. 
Protocol Amendment 2 – Summary of Changes 
The second amendment to the protocol was implemented to clarify and ensure consistency of 
text throughout the protocol. Changes to the protocol are summarized below. 
1. Section 1, Table 1 (Schedule of Study Events): added MELD score and HESA score 
limited physical examination to Day 6 (end of confinement); added complete physical 
examination on Day -1; included collection of concomitant medications/therapies at 
screening (Day -14 to -1) and on Day -1; removed hepatitis and HIV serology from 
Day -1 and added to screening; added weight to be assessed on Day 1; and, added 
footnote f next to “Laboratories: Urinary drug screen” defined below the table as 
“Methadone will be tested at screening only.” All subsequent footnote letters reordered 
accordingly. 
2. Section 1, Table 1, footnote h, Section 8.1 (Screening Day -14 to Day-1), and 
Section 10.2 (Clinical Laboratory Tests): revised the statement regarding FSH testing as 
follows: removed “performed only at screening,” and added “required for 
postmenopausal women.”    
3. Section 3.2 (Secondary Objectives/Endpoints: Removed secondary endpoint “Absolute 
change and percent change in C-P, MELD, Conn, and HESA scores. 
4. Section 8.1 (Screening Day -14 to Day-1), added the following text to Urinary Drug 
Screen: “including a screen for methadone at screening only.”   


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5. Section 4.2 (Study Design Rationale), changed text in the study design rationale from 
“…to correlate the plasma AMM reduction with dosing regimen administered…” to 
‘…to characterize the PK/PD of MNK6106 in subjects.”  
6. Section 5.2 (Exclusion Criteria), exclusion criterion #7 replaced “gastrointestinal 
hemorrhage” with “gastrointestinal bleeding.”  
7. Section 5.2 (Exclusion Criteria), exclusion criterion #8: replaced “estimated glomerular 
filtration rate” with “creatinine clearance calculated using the Cockroft-Gault formula.”   
8. Section 5.2 (Exclusion Criteria), exclusion criterion #13, changed ‘psychiatric disorders” 
to psychotic disorders “ 
9. Section 10.2 (Clinical Laboratory Tests), added “FSH test (required for postmenopausal 
women).”  
10. Table 6 (C-P Classification for Severity of Liver Disease), removed incorrect table 
(former Table 10-4) and replaced with the correct table in former Section 10.8 (C-P 
Score).  
Additional changes were made for formatting, spelling, punctuation, and clarification throughout 
protocol. 
Protocol Amendment 1 – Summary of Changes 
The first amendment to the protocol was implemented to incorporate FDA requested changes 
and to correct oversight. Additional changes were made for clarification, to correct typos and 
certain hyperlinks, and for format errors. Detailed protocol changes are summarized below.  
1. Included CTCAE (Common Terminology Criteria for AEs). Section 7.1, pg 36, Section 
10.3.3, pg 58 and Section 10.7, pg 63 were revised. 
2. Included INR as part of the laboratory assessments. Section 10.5, pg 61, Section 10.6.3, 
pg 62, Table 10.4, pg 63 and Section 10.8, pg 64 were revised. 
3. Included the MELD score as part of the daily assessments. Section 8.1, pg 39, Section 
8.3, pg 40 and Section 8.4, pg 41 were revised. 
4. Included the MELD score as part of the exclusion criteria. Section 5.2, pg 28 was revised. 
5. Included waist circumference at screening, Day 1 and last assessment in the clinic on 
Day 6. Table 1-1, pg 16 and Section 8.3, pg 39 were revised. 
6. Added FSH testing for postmenopausal women. Table 1-1, pg 16 and Section 8.1, pg 39 
were revised. 
7. HESA score assessment was added at screening and every day during confinement. 
Table 1-1, pg 16, and Section 8.3, pg 40 were revised. 
8. Child-Pugh and Conn score assessments were added at screening and every day. 
Table 1-1, pg 16, Section 8.1, pg 39, Section 8.3, pg 40 and Section 8.4, pg 41 were 
revised. 


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9. Harmonized all liver and neurological assessments throughout the protocol. 
Former sections 8.5 and 9.4.1 were moved to Section 10.6. 
10. Eliminated the upper limit of ammonia levels in inclusion criterion #5. Section 5.1, pg 27, 
inclusion criterion #5 was revised. 
11. Removed remission of hepatic encephalopathy at enrollment (Conn score 0/1). Section 
5.1, pg 27, former inclusion criterion #8 was deleted. 
12. Added an exclusion criterion for HESA Grade 4. Section 5.2, pg 28, was revised to add 
exclusion criterion #6. 
13. Clarify language of exclusion criterion words "therapy or". Section 5.2, pg 28, exclusion 
criterion #11 was revised. 
14. Added an exclusion criterion of “Has a history of prior cognitive impairment”. 
Section 5.2, pg 28, exclusion criterion #12 was added. 
15. Added an exclusion criterion of: History of psychiatric disorders including but not limited 
to schizophrenia, dementia or other severe psychiatric disorders that would interfere with 
evaluation of HE. Section 5.2, pg 28, exclusion criterion #13 was added. 
16. Added an exclusion criterion of “Positive screening results for drugs and alcohol. (except 
for subjects positive to cannabinoids)”. Section 5.2, pg 28, exclusion criterion #14 was 
added. 
17. Added text under Sedatives, “Any psychoactive agents including strong analgesics, 
antidepressants, and/or anxiolytics should be avoided such as but not limited to 
methadone.” Section 6.5.1.1, pg 34, second paragraph, was revised 
18. Removed text in Meals and Fluids, “Water will be provided ad libitum except for 1 hour 
before and 2 hours after dosing”. Section 6.5.3, pg 35 was revised to delete the sentence. 
19. Changed text in Meals and Fluids to remove “but.” Section 6.5.3, pg 35, third paragraph 
was revised.  
20. Text for HESA Score was revised to add further explanation. Section 9.5, pg 49 was 
revised.  
21. Added prothrombin time/INR to clinical laboratories section. Section 10.2, pg 55 was 
revised. 
22. Added text to clarify CTCAE v5.0. Section 10.7, pg 63 was revised to add a link to 
current CTCAE information. 
23. Added a link under liver function clarification for the previous language for MELD and 
C-P scores. Links to Section 10.6 were added to Section 9.3.4 and Section 9.4, pg 49. 
24. Changed the methadone collection to screening only. Section 8.1, pg 38 was revised 
regarding urinary drug screen for methadone; Section 10.2, Urine Drug of Abuse and 
Alcohol Screen, pg 55 was revised to add methadone at screening. 


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25. Added a new section for AEs of special interest. Section 10.3.5, pg 60 was added as a 
new section. 
26. A new secondary endpoint was added: Absolute change and percent change in C-P, 
MELD, Conn and HESA scores. Section 1.1, Secondary Endpoints, pg 13 and Section 
3.2, Secondary Objectives/Endpoints, pg 24 were revised. 
27. Added “active control” to study design description. Section 1.1, Overall Design, pg 14 
and Section 4.1, Overall Design, pg 24 were revised. 
28. Changed Day 5 to Day 5/ET globally. 
29. Clarified the rescreening text to read “Subjects may be rescreened for a subsequent 
episode of acute HE, provided that the subject was not randomized. All Screening Visit 
procedures must be repeated”. Section 5.4, Screen Failures, pg 30 was revised. 
30. Deleted the PD population since it is included in the mITT population. Section 9.2, 
Populations for Analysis, pg 48 was revised. 
31. Both pretreatment and treatment-emergent periods were added to safety summaries. 
Section 9.3.3, Safety Analyses, pg 49 was revised. 
32. Analysis methods were added for C-P, MELD, Conn and HESA scores. A new section 
9.3.4, pg 49 was created. 
33. Analysis of treatment compliance was added. Section 9.5.1, pg 50 was revised. 
34. Added amendment date to title page and revised the page headers to indicate 
incorporation of amendment #1. 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AMM 
Ammonia 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019 
C-P 
Child-Pugh 
CTCAE 
Common Terminology Criteria for AEs 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ET 
end of treatment 
FDA 
Food and Drug Administration (US) 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practices 
HCV 
Hepatitis C virus 
HE 
Hepatic encephalopathy 
HESA 
Hepatic Encephalopathy Scaling Algorithm  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
hormonal replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IR 
Immediate release 
IRB 
Institutional Review Board 


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Abbreviation 
Term 
IV 
Intravenous 
mITT 
Modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD 
Model for End Stage Liver Disease 
MM 
Medical monitor 
MNK6105 
L-Ornithine phenylacetate intravenous solution 
MNK6106 
L-Ornithine phenylacetate tablets 
ORN 
L-Ornithine 
PAA 
Phenylacetate 
PAGN 
Phenylacetylglutamine 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
QTcF 
QT interval corrected using Fridericia’s formula  
SAE 
Serious adverse event 
ULN 
Upper limit of normal 
US 
United States 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Study Title: A Randomized, Open-Label, Phase 2a Comparator Study to Assess the Pharmacodynamics, Safety 
and Pharmacokinetics of Oral Administration of MNK6106 (L-Ornithine Phenylacetate) Versus Rifaximin in 
Subjects With Hepatic Cirrhosis and a History of Prior Episodes of Hepatic Encephalopathy 
Protocol Number: MNK61062107 
Type: Interventional/Phase 2a 
Condition/Disease: Hepatic Cirrhosis and a History of Prior Episodes of Hepatic Encephalopathy 
Approximate Number of Subjects: 48 
Approximate Duration of Subject Participation: 6 weeks 
Rationale:  
Current treatment strategies for the prevention of overt hepatic encephalopathy (HE) are limited to the correction 
or removal of precipitating factors, as well as the imperfect reduction of circulating ammonia (AMM) levels by 
dietary changes and/or pharmacological approaches. Pharmacological approaches include non-absorbed 
disaccharides (eg, lactulose) and antibiotics (eg, neomycin and rifaximin), which target AMM absorption and 
change the gut microbiome to non-urease-producing bacteria reducing intestinal AMM production, respectively. 
Lactulose is orally/rectally administered, does not directly target AMM metabolism, has limited efficacy in 
subjects with acute episodes of overt HE, is difficult to administer, and requires doses taken frequently 
throughout the day. 
Rifaximin is indicated for reduction in risk of overt HE recurrence in patients at least 18 years of age. 
In the trials of rifaximin for HE, 91% of the subjects were using lactulose concomitantly. Differences in the 
treatment effect of those subjects not using lactulose concomitantly could not be assessed. 
In the Phase 1/2a study OCR002-SP103, which was conducted with the oral formulation of 
MNK6106 (L-Ornithine phenylacetate tablets) although the percentage change in blood AMM concentrations 
was highly variable, MNK6106 dosing of 4 g and 7 g 3 times daily was seen to lower AMM concentrations or at 
least prevent increases in AMM concentrations following the discontinuation of lactulose. 
MNK6105 (Intravenous formulation of L-Ornithine phenylacetate) has been evaluated in 2 Phase 1 studies 
OCR002-HV201 (healthy subjects) and OCR002-HE201 (subjects with Child-Pugh Class A or B cirrhosis and in 
2 investigator initiated Phase 2 studies OP-GIB (subjects with cirrhosis and active gastrointestinal bleeding) and 
OCR002-HE209 (subjects with cirrhosis and HE). In the recently completed OCR002-HE209 study with 
MNK6105 (10 g/day, 15 g/day, and 20 g/day IV for 5 days), data suggested better clinical improvement, plasma 
AMM-lowering/normalizing pharmacodynamics (PD) effects ratio and decrease in AMM concentrations in 
subjects receiving MNK6105 compared to placebo. 
Objectives and Endpoints:  
Primary Objective 
Endpoint 
To evaluate the pharmacological activities 
through plasma AMM concentration as a PD 
marker following oral administration of 
MNK6106 with rifaximin as a comparator in 
subjects with hepatic cirrhosis and a history of 
prior episodes of HE. 
Absolute and percentage change of plasma AMM from 
baseline. 


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Study Title: A Randomized, Open-Label, Phase 2a Comparator Study to Assess the Pharmacodynamics, Safety 
and Pharmacokinetics of Oral Administration of MNK6106 (L-Ornithine Phenylacetate) Versus Rifaximin in 
Subjects With Hepatic Cirrhosis and a History of Prior Episodes of Hepatic Encephalopathy 
Protocol Number: MNK61062107 
Type: Interventional/Phase 2a 
Secondary Objectives 
Secondary Endpoints 
To determine the safety and tolerability of 
MNK6106 following oral administration of 
MNK6106 in subjects with hepatic cirrhosis and 
a history of prior episodes of HE. 
Adverse event (AEs) and serious adverse event (SAEs). 
To evaluate the exposure response (PD and 
safety) relationships following the oral 
administrations of MNK6106 in subjects with 
hepatic cirrhosis and a history of prior episodes 
of HE. 
Plasma exposure of phenylacetate (PAA), L-ornithine 
(ORN) and phenylacetylglutamine (PAGN) with AMM 
reduction, and total renal elimination of PAGN. 
PAA exposure and neurotoxicity. 
Outcome Measures 
Outcome measures are identified to facilitate trial registration and patient access to basic results disclosed on 
public registries. 
 
The primary outcome measure in the study is the number of participants with a change in ammonia 
at Day 5. 
 
The secondary outcome measure in the study is the number of participants with adverse events or 
deaths during the study. 
Overall Design: 
This is a randomized, open-label, parallel group, multiple-dose, dose-ranging, active control, Phase 2a study. The 
objective of the study is to assess the PD, safety and pharmacokinetics (PK) of different doses of MNK6106 (oral 
administration) vs rifaximin in subjects 18 to 80 years of age (inclusive) with hepatic cirrhosis and a history of 
prior episodes of HE. 
Approximately 48 subjects will be randomized to meet the primary objective. Subjects may participate in the 
study for a total of up to approximately 6 weeks, including a screening period of up to 28 days, a treatment period 
of 1 week (5 days), and a final visit 7 days (+ 3 day window) after ending study treatment.  
The final visit window may be extended, due to extenuating circumstances, to 14 days after discussion with the 
Sponsor. 
Subjects will be confined to the study center overnight during the 5-day treatment period and randomly assigned 
to receive 1 of 3 dosing regimens of MNK6106 or the comparator rifaximin for 5 days. 
Approximately 48 subjects will be 1:1:1:1 randomized to 1 of the 4 groups. Subjects will receive either 
1 of 3 MNK6106 dosing regimens (2 g three times daily, 4 g twice daily, or 4 g three times daily) or rifaximin 
(550 mg twice daily) taken orally for 5 days. Samples for plasma AMM levels will be drawn at screening and on 
Days 1, 3 and 5/ET, predose in the morning immediately before breakfast and 4 hours (±15 minutes) after the 
morning dose, as well as at the final visit 1 week (7 days [+ 3 day window] after the last dose). Samples for 
plasma PAA, ORN and PAGN will be drawn prior to the first dose on Day 1 (within 15 minutes prior to the 
morning dose) and then prior to (within 10 minutes) and 1 hour (± 15 minutes) after the last dose on Days 1, 3, 
and 5/ET. Subjects will remain in the clinic overnight during Day 5/ET and be discharged on Day 6 after the last 
24 hour urine collection is completed. 
Approximately 1 week after the end of the treatment period, subjects will complete a final visit. 


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Study Title: A Randomized, Open-Label, Phase 2a Comparator Study to Assess the Pharmacodynamics, Safety 
and Pharmacokinetics of Oral Administration of MNK6106 (L-Ornithine Phenylacetate) Versus Rifaximin in 
Subjects With Hepatic Cirrhosis and a History of Prior Episodes of Hepatic Encephalopathy 
Protocol Number: MNK61062107 
Type: Interventional/Phase 2a 
Number of Subjects: 
Approximately 48 subjects will be randomized to meet the primary objective. Subjects may participate 
in the study for a total of up to approximately 6 weeks, including a screening period of up to 28 days, 
an treatment period of 1 week (5 days), and a final visit to occur 1 week (7 days [+ 3 day window]) 
after ending study treatment. 
Treatment Groups and Duration: 
All treatment groups will be dosed orally as follows: 
Group A: MNK6106 2 g (2 tablets), three times daily for 5 days (6 g daily dose and 30 g total dose). 
Group B: MNK6106 4 g (4 tablets), twice daily for 5 days (8 g daily dose and 40 g total dose). 
Group C: MNK6106 4 g (4 tablets), three times daily for 5 days (12 g daily dose and 60 g total dose). 
Group D: Rifaximin 550 mg tablet (1 tablet), twice daily for 5 days (1.1 g daily dose and 5.5 g total 
 
dose). 


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1.3. 
Schedule of Study Events 
Table 1: 
Schedule of Study Events 
Assessment/Procedure 
Screening 
Begin Confinement 
(Day -1) 
Treatment Period 
(Days) 
End Confinement  
(Day 6) 
Final Visit 
(7 days post-
dosing) 
(+ 3 daya 
window) 
Week 
 
 
1 
 
2 
Day 
-28 to -1 
-1 
1 
2 
3 
4 
5/ET 
6b 
12 
Study Visit Number 
1 
 
2 
3 
4 
5 
6 
 
7 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
 
 
 
 
 
 
 
 
Child-Pugh (C-P) score 
X 
 
X 
X 
X 
X 
X 
X 
X 
Model for End Stage Liver Disease 
(MELD) score 
X 
 
X 
X 
X 
X 
X 
X 
X 
Conn score  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatic Encephalopathy 
Scaling Algorithm (HESA) score 
X 
X 
X 
X 
X 
X 
X 
X  
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/surgical history (including history of 
exposure to COVID-19) 
X 
 
 
 
 
 
 
 
 
Prior medication/therapies 
X 
X 
 
 
 
 
 
 
 
Complete physical examination 
X 
X 
 
 
 
 
 
 
X 


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Table 1: 
Schedule of Study Events (Continued) 
Assessment/Procedure 
Screening 
Begin Confinement 
(Day -1) 
Treatment Period 
(Days) 
End Confinement  
(Day 6) 
Final Visit 
(7 days post-
dosing) 
(+ 3 daya 
window) 
Week 
 
 
1 
 
2 
Day 
-28 to -1 
-1 
1 
2 
3 
4 
5/ET 
6b 
12 
Study Visit Number 
1 
 
2 
3 
4 
5 
6 
 
7 
Limited physical examination 
 
 
X 
 
 
 
 
X 
 
Height and weight
c 
X 
 
X 
 
 
 
 
X 
X 
Waist circumference 
X 
 
X 
 
 
 
 
X 
 
Vital signs
d 
X 
 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
 
Xe 
 
X 
 
X 
 
 
Laboratories: PD plasma AMM
f 
X 
 
X 
 
X 
 
X 
 
X 
Laboratories: PK plasma PAA, ORN, PAGN
g 
 
 
X 
 
X 
 
X 
 
 
Laboratories: PK urine PAGN
h 
 
 
X 
X 
X 
X 
X 
X 
 
Laboratories: safety (chemistry and hematology) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Laboratories: safety (urinalysis) 
 
 
X 
X 
X 
X 
X 
 
 
Laboratories: Urinary drug screen
i 
X 
X 
 
 
 
 
 
 
 


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Table 1: 
Schedule of Study Events (Continued) 
Assessment/Procedure 
Screening 
Begin Confinement 
(Day -1) 
Treatment Period 
(Days) 
End Confinement  
(Day 6) 
Final Visit 
(7 days post-
dosing) 
(+ 3 daya 
window) 
Week 
 
 
1 
 
2 
Day 
-28 to -1 
-1 
1 
2 
3 
4 
5/ET 
6b 
12 
Study Visit Number 
1 
 
2 
3 
4 
5 
6 
 
7 
Laboratories: hepatitis and human 
immunodeficiency virus (HIV) serology
j 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test/FSH
k 
X 
 
 
 
 
 
 
 
X 
Urine pregnancy testl 
 
X 
 
 
 
 
 
 
 
Concomitant medications/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events
m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dosing
n 
 
 
X 
X 
X 
X 
X 
 
 
Subject confinement 
 
X 
X 
X 
X 
X 
X 
 
 
ET = end of treatment; FSH = follicle stimulating hormone; ORN = Ornithine; PAA = Phenylacetate; PAGN = Phenylacetylglutamine; PD = pharmacodynamics; 
PK = pharmacokinetics. 
a If circumstances occur such that this visit cannot occur within the specified window, the visit window may be extended to 14 days, after discussion with the 
sponsor. 
b Subjects may be discharged from the clinic after the final PK samples are obtained. Subjects will be instructed to return for the final visit (7 days [+ 3 day 
window] after the last dose is administered). 
c Height at screening only. 
d Blood pressure, respiratory rate, pulse rate, and body temperature. 


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e ECGs on Days 1, 3, and 5/ET should be recorded one hour after last dose (± 15 minutes). Complete ECG prior to PK sample collection if the timing is the 
same. Subject needs to be supine for greater than 10 min prior to ECG. 
f Samples for plasma AMM levels will be drawn at screening and on Days 1, 3 and 5/ET, predose in the morning immediately before breakfast 
and 4 hours (± 15 minutes) after the morning dose, as well as at the final visit. 
g Samples for plasma PAA, ORN and PAGN will be drawn prior to the first dose on Day 1 (within 15 minutes prior to morning dose) and then 
prior to (within 10 min) and 1 hour (± 15 minutes) after the last dose on Days 1, 3, and 5/ET. 
h Urine collection with start/end time and volume recorded for measurement of PAGN concentration will be collected daily. The 24 hour interval will start 
following the first dose of the day, eg, if the first dose of the day is given at 8 AM, urine will be collected starting at 8 AM and continue until 8 AM of the next 
day. A predose urine sample will be collected on Day 1. 
i Methadone will be tested at screening only. 
j Hepatitis B surface antigen, Heptatitis B core antibody, HCV antibody and HIV. HCV polymerase chain reaction testing will be performed only for subjects 
positive for HCV. 
k FSH test is required for postmenopausal women. 
l A urine pregnancy test will be performed on women of child-bearing potential on Day -1 to ensure that pregnancy did not occur since the time of screening. 
mAEs will be assessed on an ongoing basis; all AEs (serious and non-serious) occurring from the time of signing informed consent until completion of the Final 
Visit will be recorded in the electronic case report form (eCRF) (refer to Section 8.7; full details provided in Section 10.3 and its subsections). 
nStudy drug/formulation will be administered under fed (30 minutes after start of meal) conditions. Lunch and dinner will be served at approximately 30 minutes 
prior to dosing. 
 


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2. 
INTRODUCTION 
MNK6106 is a novel ammonia (AMM)-lowering agent that uses pathways of AMM removal to 
reduce plasma AMM concentration in subjects with varying degrees of hepatic encephalopathy 
(HE). 
MNK6106 (ornithine phenylacetate), in the form of the L-ornithine (ORN) salt of phenylacetate 
(PAA), is a single new chemical entity that allows for alternative pathways for the excretion of 
AMM in the setting of cirrhosis through the enhanced elimination of AMM (Jalan et al, 2007). 
L-ornithine stimulates the activity of glutamine synthetase, inducing body muscle to trap 
circulating AMM in the form of glutamine, which is a nontoxic carrier of AMM. Glutamine is 
then conjugated with PAA to form PAGN, which is excreted in urine. This strategy prevents the 
eventual recirculation and degradation of glutamine by glutaminase and avoids re-formation of 
AMM. 
L-Ornithine phenylacetate was granted orphan drug status in 2010 by the US Food and Drug 
Administration (FDA); for the treatment of hyperammonemia and associated hepatic 
encephalopathy in patients with acute liver failure or acute or chronic liver disease. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of products 
containing L-Ornithine phenylacetate is provided in the Investigator’s Brochure (Mallinckrodt, 
2019). 
2.1. 
Background 
Although the onset of HE can rarely be pinpointed clinically, it is a landmark in patients with 
advanced liver disease (Wijdicks, 2016). An estimated 60% to 70% of cirrhotic patients have at 
least subtle signs of neurocognitive impairment. Overt HE has a prevalence of approximately 
30% in patients with end-stage liver disease, and accounts for about 150,000 hospitalizations 
annually in the United States (Al Sibae et al, 2009). Severe HE in patients with cirrhosis is 
associated with a mortality of more than 50% in the first year alone (Wijdicks, 2016). 
HE is a neuropsychiatric disorder that occurs when gut derived toxins, primarily AMM, bypass a 
failing liver, which would normally detoxify such agents. These toxins enter the circulation and 
cross the blood brain barrier, resulting in impairment of neurotransmission and central nervous 
system (CNS) function. HE can arise in the setting of acute liver failure, chronic progressive 
liver disease in the context of advanced liver cirrhosis (overt HE), and/or as a result of portocaval 
shunting with or without liver disease. The pathogenesis of HE has been incompletely 
understood but the increase in plasma AMM levels remains central to the understanding of HE 
(Wijdicks, 2016), supporting the need for novel, safe, and effective AMM lowering therapies to 
treat as well as to prevent episodes of HE. 
Dietary protein restriction had long been advocated as a strategy to reduce circulating AMM in 
patients with cirrhosis. However, recent data have shown that this strategy is not effective in 
preventing HE and may harm these patients by making them more prone to muscle wasting 
(Cordoba et al, 2004). 


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Current treatment guidelines for episodic overt HE recommend lactulose, a non-absorbed 
disaccharide, at a dose of 25 mL twice daily as first line agent, adjusted for the production of 
3 bowel movements daily (American Association for the Study of Liver Diseases, 2014). 
Rifaximin, which alters gut microbiota, is recommended as an add-on therapy to lactulose for 
prevention of HE recurrence (American Association for the Study of Liver Diseases, 2014); 
(Wijdicks, 2016). However, recent data suggest that a significant number of patients receiving 
lactulose and rifaximin are hospitalized with a recurrence of HE (Kulkarni et al, 2018). 
MNK6106 (L-Ornithine phenylacetate), in the form of an orally administered ORN salt of PAA, 
is a single new chemical entity that allows for alternative pathways for the excretion of AMM in 
the setting of cirrhosis through the enhanced elimination of AMM. 
2.1.1. 
Nonclinical Safety Data 
The nonclinical safety of L-Ornithine phenylacetate was evaluated in a series of in vitro and 
in vivo studies which included evaluation of the potential undesirable pharmacodynamic (PD) 
effects of L-Ornithine phenylacetate on physiological functions in relation to exposure in the 
therapeutic range and above (safety pharmacology core battery), evaluation of the mutagenic and 
clastogenic potentials of L-Ornithine phenylacetate (in vitro and in vivo test battery for 
genotoxicity), evaluation of the short- and longer-term functional and morphologic effects 
associated with L-Ornithine phenylacetate exposure in whole animal models (mammalian 
toxicology program), evaluation of the effects of L-Ornithine phenylacetate on fertility and 
embryo-fetal development, and evaluation of local intravenous (IV) and gastrointestinal tract 
effects of L-Ornithine phenylacetate administration. The results of the toxicology program 
indicate that L-Ornithine phenylacetate does not present a genotoxic hazard and is associated 
with a low potential for local (oral/IV) and systemic toxicity in humans. Potential adverse effects 
of L-Ornithine phenylacetate on sperm parameters (count and morphology) and embryo-fetal 
development were noted at high doses/systemic exposures. 
2.1.2. 
Clinical Safety Data 
Safety data from completed sponsor and investigator-initiated clinical studies demonstrated that 
a single IV dose of 20 g L-Ornithine phenylacetate IV solution (MNK6105) infused over 4 hours 
or daily 20 g IV doses infused over 24 hours for up to 5 days, were generally well tolerated. 
Regarding oral administration with MNK6106 (L-Ornithine phenylacetate tablets), Study 
OCR002-SP103 was an open-label Phase 1/2a, 2-part crossover study in 30 adult subjects with 
varying degrees of cirrhosis, who received oral administration of MNK6106. The safety 
conclusions were that MNK6106 was safe and well-tolerated when administered at doses up to 
21 g/day for 5 days. There were no deaths, 1 serious adverse event (SAE) was reported during 
Part 2 of the study (SAE of urinary tract infection in a subject while receiving 21 g/day; the event 
was considered not related to study drug treatment). In addition, safety data from completed 
Phase 1/2a clinical studies with a single IV dose of 5 g given as an oral solution, as well as oral 
administration of MNK6106 tablets (6 g, 12 g, and 21 g per day for 3 periods, 5 days per period 
with a minimum 4-day washout in between) indicate that both IV and oral administration of L-


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Ornithine phenylacetate were generally well tolerated. No Phase 2/3 studies of MNK6106 have 
been initiated. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of L-Ornithine 
phenylacetate is provided in the Investigator’s Brochure (Mallinckrodt, 2019). 
2.2. 
Study Rationale 
Current treatment strategies for the prevention of overt HE are limited to the correction or 
removal of precipitating factors, as well as the imperfect reduction of circulating AMM levels by 
dietary changes and/or pharmacological approaches. Pharmacological approaches include 
non-absorbed disaccharides (eg, lactulose) and antibiotics (eg, neomycin and rifaximin), which 
target AMM absorption and change the gut microbiome to non-urease-producing bacteria 
reducing intestinal AMM production, respectively. 
Lactulose is orally/rectally administered, does not directly target AMM metabolism, has limited 
efficacy in subjects with acute episodes of overt HE, is difficult to administer, and requires doses 
taken frequently throughout the day. 
Rifaximin is indicated for reduction in risk of overt HE recurrence in patients at least 18 years of 
age. 
In the trials of rifaximin for HE, 91% of the patients were using lactulose concomitantly. 
Differences in the treatment effect of those patients not using lactulose concomitantly could not 
be assessed (American Association for the Study of Liver Diseases, 2014); (Wijdicks, 2016); 
(Horizon Therapeutics, 2017). 
In a Phase 1/2a Study OCR002-SP103, dosing of 4 g or 7 g 3 times daily lowered AMM 
concentrations or prevented increases in AMM concentrations following the discontinuation of 
lactulose, although the percentage change in blood AMM concentrations was highly variable. 
MNK6106 dosing of 4 g and 7 g 3 times daily was seen to lower AMM concentrations or at least 
prevent increases in AMM concentrations following the discontinuation of lactulose. 
MNK6105 has been evaluated in two Phase 1 studies: OCR002-HV201 (healthy subjects) and 
OCR002-HE201 (subjects with Child-Pugh [C-P] Class A or B cirrhosis) and in two investigator 
initiated Phase 2 studies: 
 OP-GIB study (in subjects with cirrhosis and active gastrointestinal bleeding) and  
 OCR002-HE209 (in subjects with cirrhosis and HE). 
The OCR002-HE209 study with MNK6105 (10 g/day, 15 g/day, and 20 g/day IV for 5 days) 
data suggested better clinical improvement, plasma AMM-lowering/normalizing PD effects ratio 
and decrease in AMM concentrations in subjects receiving MNK6105 compared to placebo.  
2.3. 
Assessment of Potential Benefits and Risks  
The results of nonclinical pharmacological studies support the clinical use of L-Ornithine 
phenylacetate in the treatment of hyperammonemia and acute HE. The studies demonstrated 


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AMM reduction in pig (Ytrebo et al, 2009) and rat models (Davies et al, 2009) - effects not seen 
with anti-inflammatory therapy (with a tumor necrosis factor alpha antagonist) if 
hyperammonemia remained untreated (Wright et al, 2011). Significant reduction in AMM levels 
was replicated in 2 other studies using L-Ornithine phenylacetate in a bile duct ligated cirrhotic 
rat model (Mookerjee et al, 2009);(Vairappan et al, 2009). 
L-Ornithine phenylacetate increases AMM elimination by upregulating ORN aminotransferase 
and glutamine synthetase (action of ornithine) and its excretion as PAGN (action of PAA). L-
Ornithine phenylacetate also reduces AMM production by normalizing gut glutaminase activity 
(action of ORN), demonstrating the synergistic effect of the 2 pharmacophores (Jover-Cobos et 
al, 2014). 
L-Ornithine phenylacetate prevented neurophysiological abnormalities in a portacaval shunted 
rat model following a simulated gastrointestinal bleed. L-Ornithine phenylacetate treatment 
significantly blunted the rise in AMM generated by a simulated gastrointestinal bleed. The 
reduction in plasma AMM was associated with normalization of neurophysiologic function as 
assessed by motor evoked potential. These studies provide the pharmacological rationale for 
using L-Ornithine phenylacetate in cirrhotic patients to prevent hepatic encephalopathy 
precipitated by gastrointestinal bleeding (Oria et al, 2012). 
The conclusion, based on the adverse event (AE) data from the nonclinical pharmacological 
studies supporting the clinical use of L-Ornithine phenylacetate in the treatment of 
hyperammonemia and acute HE, is that a 20 g dose infused over 24 hours, appears to be well 
tolerated. 
In aggregate, the clinical data presented provide assurance of appropriate benefit/risk for the 
administration of MNK6105 in patients hospitalized with HE in acute need of intervention. The 
safety and PK data collected to date from completed studies OCR002-HV201, OCR002-HE201, 
OCR002-HE209 along with the information supplied in the product label for RAVICTI® 
(glycerol phenylbutyrate) and similar other products, support the selection of MNK6105 infused 
up to 20 g/24 hours for 5 days in subjects with acute overt HE. 
The individual components of L-Ornithine phenylacetate, namely ORN and PAA, have been 
used in the treatment of hyperammonemia for over 20 years; ORN as an over the counter 
nutritional supplement and PAA to treat hyperammonemia in patients with urea cycle disorders. 
Substantial data therefore exists on the safety of both L-ornithine, sodium PAA and 
phenylbutyrate; albeit PAA data supports the use of the compound in the treatment of urea cycle 
disorders. 
Toxicity with sodium PAA has been observed in PK studies in both healthy volunteers and 
patients with cancer. In these studies, the drug was administered rapidly over 90 minutes with 
resultant high peak plasma concentrations of PAA. 
Side effects have been reported to generally correlate with PAA maximum plasma concentration. 
Dose-related adverse effects in these studies were gastrointestinal (eg, nausea and vomiting) and 
CNS (eg, somnolence, fatigue, and headache) in nature. 


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Concentrations over 400 μg/mL of PAA have been associated with nausea and vomiting 
[Summary Basis of Approval for AMMONUL®] and concentrations over 490 μg/mL have been 
associated with CNS-related AEs when administered in bolus doses in prior PK studies in 
healthy adult volunteers and in patients with cancer. 
Some cancer patients treated with sodium phenylacetate had signs and symptoms of PAA 
neurotoxicity including somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, 
disorientation, impaired memory, and exacerbation of preexisting peripheral neuropathy. In this 
study, these adverse effects were reported to be generally transient and reversible (Thibault et al, 
1994); (Thibault et al, 1995). 
Some patients with urea cycle disorders treated in clinical trials with RAVICTI have experienced 
headache, fatigue, symptoms of peripheral neuropathy, seizures, tremor and/or dizziness. No 
correlation between PAA levels and neurotoxicity symptoms was identified but PAA levels were 
generally not measured at the time of neurotoxicity symptoms (Horizon Therapeutics, 2017). 
Appropriate dosing for MNK6106 has not yet been determined. 
More detailed information about the known and expected benefit, risks, and reasonably expected 
AEs associated with L-Ornithine phenylacetate can be found in the Investigator’s Brochure 
(Mallinckrodt, 2019). 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Primary Objective/Endpoint 
Primary Objective 
Endpoint 
To evaluate the pharmacological activities 
through plasma AMM concentration as a PD 
marker following oral administration of 
MNK6106 with rifaximin as a comparator in 
subjects with hepatic cirrhosis and a history 
of prior episodes of HE. 
Absolute and percentage change of plasma AMM from 
baseline. 
3.2. 
Secondary Objectives/Endpoints 
Secondary Objectives 
Secondary Endpoints 
To determine the safety and tolerability of 
MNK6106 following oral administration of 
MNK6106 in subjects with hepatic cirrhosis 
and a history of prior episodes of HE. 
AEs, SAEs. 
 
To evaluate the exposure response (PD and 
safety) relationships following oral 
administration of MNK6106 in subjects with 
Plasma exposure of PAA, ORN and PAGN with AMM 
reduction, and total renal elimination of PAGN. 
PAA exposure and neurotoxicity. 


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Secondary Objectives 
Secondary Endpoints 
hepatic cirrhosis and a history of prior 
episodes of HE. 
3.3. 
Outcome Measures 
Outcome measures are identified to facilitate clinical trial registration and patient access to basic 
results disclosed on public clinical trial registries. 
The primary outcome measure in the study is the number of participants with a change in 
ammonia at Day 5. 
The secondary outcome measure in the study is the number of participants with adverse events or 
deaths during the study. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, open-label, parallel group, multiple-dose, dose-ranging, active control, 
Phase 2a study. The objective of the study is to assess the PD, safety and PK of different doses of 
MNK6106 (oral administration) vs rifaximin in subjects 18 to 80 years of age (inclusive) with 
hepatic cirrhosis and a history of prior episodes of HE. 
Approximately 48 subjects will be randomized to meet the primary objective. Subjects may 
participate in the study for a total of up to approximately 6 weeks, including a screening period 
of up to 28 days, a treatment period of 1 week (5 days), and a final visit 1 week (7 days [+ 3 day 
window]) after ending study treatment.  
The final visit window may be extended, due to extenuating circumstances, to 14 days after 
discussion with the Sponsor. 
Subjects will be confined to the study center overnight during the 5-day treatment period and 
randomly assigned to receive 1 of 3 dose regimens of MNK6106 or the comparator rifaximin for 
5 days. 
Approximately 48 subjects will be 1:1:1:1 randomized to 1 of the 4 groups. Subjects will receive 
either 1 of the 3 MNK6106 dosing regimens (2 g three times daily, 4 g twice daily, or 4 g three 
times daily) or rifaximin (550 mg twice daily) taken orally for 5 days. Samples for plasma AMM 
levels will be drawn at screening and on Days 1, 3 and 5/ET, predose in the morning 
immediately before breakfast and 4 hours (± 15 minutes) after the morning dose as well as at the 
final visit. Samples for plasma PAA, ORN and PAGN will be drawn prior to the first dose on 
Day 1 (within 15 minutes prior to the morning dose) and then prior to (within 10 minutes) and 1 
hour (± 15 minutes) after the last dose on Days 1, 3, and 5/ET. Subjects will remain in the clinic 
overnight during Day 5/ET and be discharged on Day 6 after the last 24 hour urine collection is 
completed. 


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All treatment groups will be dosed orally as follows: 
 Group A: MNK6106 2 g (2 tablets), three times daily for 5 days 
(6 g daily dose and 30 g total dose). 
 Group B: MNK6106 4 g (4 tablets), twice daily for 5 days 
(8 g daily dose and 40 g total dose). 
 Group C: MNK6106 4 g (4 tablets), three times daily for 5 days (12 g daily dose and 
60 g total dose). 
 Group D: Rifaximin 550 mg tablet (1 tablet), twice daily for 5 days  
(1.1 g daily dose and 5.5 g total dose). 
Approximately 1 week after the end of the treatment period, subjects will complete a final visit. 
4.2. 
Study Design Rationale 
This Phase 2a dose-ranging safety study will be the first to evaluate the oral administration of 
MNK6106 tablets vs rifaximin 550 mg tablets twice daily as well as to characterize the PK/PD of 
MNK6106 in subjects. 
4.2.1. 
Dose Rationale 
In Study OCR002-SP103 with, oral administration of MNK6106 at dose levels of 2 g, 4 g and 
7 g three times daily (total 6 g, 12 g, and 21 g daily), the reduction in AMM concentrations 
appeared to be similar at the doses of 12 g and 21 g daily, with 6 g being able to prevent 
increases in AMM concentrations. This observation was consistent with MNK6105 (L-Ornithine 
phenylacetate IV formulation), where the effect of L-Ornithine phenylacetate was maximized at 
a dose of 15 g/day. Given the fact that MNK6106 (L-Ornithine phenylacetate oral formulation) 
has demonstrated excellent absolute bioavailability (greater than 95%), the 12 g oral formulation 
is expected to achieve comparable exposure as MNK6105 15 g. Therefore, the high dose in this 
study was selected as 12 g/day (4 g three times daily). The low dose of 6 g/day was chosen 
because it was able to prevent an increase in AMM concentrations. 
Since a twice daily dose is favorable for compliance, a 4 g twice a day (8 g daily) regimen was 
selected, to maximize the reduction in AMM following each administration. 
4.3. 
End of Study Definition 
A subject will have completed the study if the final visit at Week 2/Visit 7 is completed or if the 
subject dies or is otherwise lost to follow- up. 
The end of the study is defined as the completion of the final assessment for the last subject 
enrolled in the study. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations in recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
To be eligible to participate in the study, at the Screening Visit each subject must:  
1. Be adequately informed and understand the nature and risks of the study and must be able 
to provide a signature and date on the informed consent form (ICF). 
2. Be at least 18 and no more than 80 years of age at the Screening Visit. Subjects may be 
male or female. 
3. Have known or evident liver cirrhosis. Diagnosis of liver cirrhosis may be based on 
clinical, radiological, and or histological criteria, including 1 or more of the following: 
a. Liver biopsy (documented by histology); 
b. Clinical evidence of cirrhosis, defined as aspartate aminotransferase greater than 
alanine aminotransferase, platelet count less than 150,000 µL, and nodular liver 
surface on computed tomography scan or magnetic resonance imaging; 
c. Clinical evidence of significant portal hypertension, based on current or history of 
gastroesophageal varices on endoscopy, evidence of portosystemic collaterals (on 
contrast computed tomography or magnetic resonance imaging with contrast), and/or 
presence of ascites; 
d. Transient elastography consistent with cirrhosis, ie, a result of greater than 13.0 kPa. 
4. A history of at least 1 or more documented episodes of HE within the last 12 months. 
5. Hyperammonemia (defined as an ammonia level ≥ 37 μmol/L) at screening. 
6. Currently using lactulose (minimum of 5 days prior to Day -1). 
7. If using rifaximin at the Screening Visit, it must be discontinued at least 5 days before the 
first dose of study drug. 
8. If female, be of non-childbearing potential (history of hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation; or postmenopausal with no history of menstrual flow 
in the 12 months prior to the Screening Visit); or, if of childbearing potential, be non-
pregnant, non-lactating and agree to use 2 forms of effective contraception when with a 
male partner for the duration of the study and for 28 days after any active treatment 
period. Acceptable forms of contraception include hormonal measures (oral contraceptive 
pills, contraceptive patch, contraceptive ring, injections), intrauterine devices, double 
barrier method (condom plus diaphragm, condom or diaphragm plus spermicidal gel or 
foam, surgical sterilization of the male partner), and abstinence. 
9. If male with reproductive potential, agree to use 2 forms of effective contraception 
(abstinence, surgical sterilization [vasectomy], or condom with spermicide) with a female 
partner for the duration of the study and for 28 days after any active treatment period. 


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10. Be able to communicate effectively with study personnel. 
11. Be able and willing to follow all protocol requirements and study restrictions. 
12. Be able and willing to return for all study visits. 
5.2. 
Exclusion Criteria 
A subject is ineligible for study participation if, at the Screening Visit, the subject: 
1. Is from a vulnerable population, as defined by the US Code of Federal Regulations (CFR) 
Title 45, Part 46, Section 46.111(b) and other local and national regulations, including 
but not limited to, employees (temporary, part-time, full time, etc.) or a family member of 
the research staff conducting the study, or of the sponsor, or of the contract research 
organization, or of the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC). 
2. Has a history of sensitivity or allergy to MNK6106, ORN, PAA, L-ornithine L-aspartate, 
phenylbutyrate or rifaximin. 
3. Has expectation of liver transplantation within 1 month after the Screening Visit. 
4. Had placement of a portosystemic shunt or transjugular intrahepatic portosystemic shunt 
within 3 months before the Screening Visit. 
5. Has a Model for End Stage Liver Disease (MELD) score greater than 25. 
6. Has HESA score Grade 4. 
7. Had gastrointestinal bleeding within 3 months of the Screening Visit. 
8. Has severe renal impairment (Creatinine Clearance rate no more than 30 mL/min) 
calculated using the Cockroft-Gault formula. 
9. Has intercurrent infection or active spontaneous bacterial peritonitis. 
10. Has known immune compromised status (not related to disease/condition under study), 
including but not limited to individuals who have undergone organ transplantation or who 
are known to be positive for the human immunodeficiency virus (HIV). 
11. Has any solid tumor malignancy currently diagnosed or undergoing therapy or has received 
therapy for any solid tumor malignancy in the 5 years prior to the Screening Visit; with the 
exception of treated and cured basal cell carcinoma, treated and cured squamous cell 
carcinoma of the skin, and treated and cured carcinoma in situ of the cervix. 
12. Has a history of prior cognitive impairment. 
13. Has a history of psychotic disorders including but not limited to schizophrenia, dementia, 
or other severe psychotic disorders that would interfere with evaluation of HE. 
14. Has a positive screening result for drugs and alcohol (except for subjects positive to 
cannabinoids). 


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15. Has a QT interval corrected using Fridericia’s Formula (QTcF) of at least 500 msec at 
screening. 
16. Has any of the following laboratory abnormalities at the Screening Visit: 
 Hemoglobin < 8.0 g/dL. 
 Platelet count < 25,000 cells/µL. 
 Absolute neutrophil count < 1000 cells/µL. 
17. Has any other clinically significant disease, disorder or laboratory abnormality, which, in 
the opinion of the investigator, might put the subject at risk due to participation in the 
study, or may influence the results of the study or the subject’s ability to complete the 
study. 
18. Inability to swallow the study drug whole. 
19. Has hyponatremia, defined as blood sodium level ≤ 125 mmol/L. 
20. Is participating in or plans to participate in any other interventional research study from 
the time of screening and throughout this study. 
5.3. 
Lifestyle Considerations 
Subjects should not donate blood or plasma for the duration of this study and for 28 days after 
study exit. 
Subjects will be instructed to refrain from strenuous exercise from 48 hours prior to 
randomization through to 24 hours after the final PK sample is taken. 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the study but are not 
subsequently randomized. 
The period from the start of screening related procedures at the Screening Visit to randomization 
must not exceed 28 days, inclusive of any repeat screening procedures. 
Subjects who do not meet all of the eligibility criteria at the end of the screening period will be 
deemed a screen failure, and the following information must be recorded for all subjects who are 
screen failures: 
 Demography (age, gender, race/ethnicity). 
 Reason for screen failure. 
 Eligibility criteria. 
 Any AE/SAE experienced by the subject. 
Subjects may be rescreened provided that the subject was not randomized. All Screening Visit 
procedures must be repeated. 


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Subjects may be rescreened only once. Subjects who are re-screened should not be assigned a 
new subject number. The original subject number should be retained. 
6. 
STUDY TREATMENT 
Study treatment is defined as any investigational treatment, marketed products, placebo, or 
device intended to be administered to a study subject according to the study protocol. Subjects 
enrolled in this study will receive study treatment under open-label conditions. 
The study treatments will be dispensed by the investigator or investigator’s designee. 
The treatment groups, frequency and dose are summarized in Table 2.  
6.1. 
Treatment Administration 
The following treatments will be administered: 
Product 
Supplied as: 
MNK6106 
1 g immediate release (IR) MNK6106 tablet 
Rifaximin 
550 mg tablet 
MNK6106 tablets, 1 g, are supplied as white, film coated immediate release tablets for oral 
administration. Each tablet contains 1 g of L-Ornithine phenylacetate. The inactive ingredients 
include 
 
 
Rifaximin tablets, 550 mg, are supplied as a pink-colored, oval, biconvex tablet with “rfx” 
debossed on 1 side and plain on the other. 
Table 2: 
Summary of Treatment Groups, Frequency and Dose 
Treatment 
Frequency 
Dose 
Total Daily Dose 
Total Dose (5 
days) 
MNK6106 
tid 
2 g 
6 g 
30 g 
MNK6106 
bid 
4 g 
8 g 
40 g 
MNK6106 
tid 
4 g 
12 g 
60 g 
Rifaximin 
bid 
550 mg 
1.1 g 
5.5 g 
Note: bid = twice daily; tid = 3 times daily. 
For the 3 times daily dosing regimen, the doses will be given at 8 AM, 1 PM, and 6 PM 
(± 60 minutes); for twice daily dosing, the doses will be given at 8 AM and 6 PM (± 60 minutes). 
Each dose will be administered with an 8 oz glass of room temperature water, and the subject 
will be required to swallow the tablet whole without chewing or crushing it, and to drink all the 
water. The date and actual (clock) time that the subject receives the MNK6106 study drug and 
the dose amount administered will be recorded on the electronic case report form (eCRF). Any 


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deviations from the dosing schedule and instructions described in this protocol will also be 
recorded. Each subject will be closely supervised for ingesting each of the doses and the required 
amount of water. The entire dose must be administered within 15 minutes. 
Any loss of the study drugs will be documented and reported to Mallinckrodt Clinical Supply 
Management, with the approximate amount lost estimated and recorded. Replacements will be 
made accordingly. 
The study drugs will be administered under fed (30 minutes after start of meal) conditions. 
Lunch and dinner will be served at approximately 30 minutes prior to dosing. 
After each dose, the subjects will be required to remain in an upright position for at least 2 hours 
after dosing. In addition, subjects will also be required to refrain from anything more than light 
exercise while confined at the study site. 
6.2. 
Study Treatment Preparation/Handling/Storage/Accountability 
MNK6106 tablets are packed into high-density polyethylene bottles with child-resistant caps, 
60 tablets per bottle. 
The bottles of MNK6106 and rifaximin should be stored at room temperature 20°C to 25°C 
(68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). 
The sponsor will supply MNK6106 and rifaximin. The investigator or investigator’s designee 
will maintain the following records: receipt of shipments, dispensation to subjects, and return of 
empty, partially used, and unopened bottles. Reasons for departure from the expected dispensing 
regimen must also be recorded. 
Study drug should not be returned before the designated study monitor has checked the drug 
accountability records with the study site personnel after database lock. 
Upon receipt of the study drug supplies, the investigator or investigator’s designee will conduct 
an inventory, follow the process for acknowledging receipt of the study drug, and complete 
appropriate form(s). One copy of the receipt and the packing slip must be retained. 
At the completion of the study, to satisfy regulatory requirements regarding drug accountability, 
all study treatments will be reconciled and retained or destroyed according to applicable 
regulations. 
The investigator or designee will confirm that appropriate temperature control conditions have 
been maintained during transit for all study treatments received and confirm that any 
discrepancies are reported and resolved prior to study treatment administration. 
The study treatment will be maintained in a monitored, environmentally controlled 
(in accordance with treatment labeling), secure, locked area with restricted access at the 
study site. 
Only subjects enrolled in the study will receive study treatment and only authorized study staff 
will dispense study treatment. 


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In accordance with the International Council for Harmonisation (ICH) requirements, at all times 
the investigator will be able to account for all study treatment furnished to the study site. 
An accountability record will be maintained for this purpose. The investigator must maintain 
accurate records indicating dates and quantity of study treatment received, to whom it was 
administered (subject-by-subject accounting) and accounts of any study treatment accidentally or 
deliberately destroyed. All unused study treatment not involved in immediate subject treatment 
will be maintained under locked, temperature-controlled storage at the study site. 
6.3. 
Measures to Minimize Bias 
This is an open-label study. Subjects will be randomized according to a pre-specified, validated 
computer-generated allocation scheme to receive the 4 treatments described above based on a 
1:1:1:1 ratio. 
Each subject will be assigned a unique identification (ID) number. The subject ID number will 
be assigned electronically by the INFORM database system when the study site staff enters the 
required information into the INFORM system. The subject ID number will be used to identify 
the subjects for the duration of the study within all systems and documentation. A subject with a 
signed ICF in place will be assigned a 4-digit sequential subject number preceded by the 4-digit 
study site number with a “dash” in between (ie, XXXX-XXXX). Each part must start with a 
non-zero number. 
If the subject is not eligible to receive study treatment, or should discontinue from the study, the 
subject ID number will not be reassigned to another subject.  
In the event that a subject repeats any evaluation during the screening window, they will not 
receive a new ID number. In addition, subjects who fail screening and are rescreened will not 
receive a new subject ID number. Qualified subjects who meet all of the eligibility criteria will 
be randomized into the study.  
The investigator must maintain a subject master log linking the subject ID to the subject’s name. 
The investigator must follow all applicable privacy laws in order to protect a subject’s privacy 
and confidentiality. Information that could identify a subject will be masked on material received 
by the sponsor. 
Subjects will be randomized according to a treatment allocation scheme that will be sent to each 
site. The treatment assigned will be recorded in the source documentation. 
Based on the randomized treatment assignment, the investigator or investigator’s designee will 
dispense the study treatment tablets (MNK6106 or rifaximin) for each subject. 
6.4. 
Study Treatment Compliance 
Treatment compliance will be determined by drug accountability and dosing information 
recorded in the eCRF. 


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6.5. 
Prior and Concomitant Therapy 
Use of all relevant concomitant medications/therapies will be recorded in the subject’s eCRF. 
The start and stop date, dose, unit, frequency, route of administration, and indication for all prior 
(taken within the 30 days prior to the Screening Visit) and concomitant (taken from the 
Screening Visit through to the Final Visit) medications and nondrug therapies (eg, blood 
transfusions, oxygen supplementation, physical therapy, etc.) received will be recorded.  
6.5.1. 
Prohibited Concomitant Therapies 
The following treatments will not be permitted during the study (from Randomization through to 
the Final Visit): 
 Current use of drugs that could potentially interfere with renal excretion of PAGN, 
such as corticosteriods, haloperidol, valproic acid probenecid, estrone sulfate, 
ibuprofen, cimetidine, or diclofenac. Use of L-ornithine L-aspartate is prohibited. 
 Current use of drugs whose plasma concentration may be affected by MNK6106, 
such as alfentanil, cyclosporine, midazolam, quinidine,  or cimetidine. Metformin use 
is permitted at low doses. Doses of metformin > 1,000 mg should be discussed with 
the medical monitor prior to enrollment. 
 Current use of AMMONUL® (sodium benzoate with sodium PAA), BUPHENYL® 
(sodium phenylbutyrate), RAVICTI, or other medications containing sodium 
benzoate or sodium phenylbutyrate. 
 Current use of rifaximin (except for subjects randomized to rifaximin), oral 
neomycin, oral vancomycin or any other oral or parenteral antibiotic that could 
potentially alter gut flora. There should be a 5-day washout period for rifaximin use 
prior to the first dose of study drug. 
 Current use of repaglinide. 
 Receipt of an investigational product or device, or participation in a drug research 
study within a period of 30 days (or 5 half-lives of the drug, whichever is longer) 
before the first dose of study treatment. 
 Any investigational drug, device, or procedure administered as part of a research 
study.  
Exceptions to these restrictions during the subject selection process must be approved by the 
investigator and sponsor and will be discussed on a case-by-case basis. Once the study has 
started, if a subject is unable to comply with the restrictions described above, their participation 
in the study will be re-evaluated by the investigator, again in consultation with the sponsor. The 
decision to continue a subject who has received a concomitant medication as directed by the 
investigator for the treatment of an AE will also be made mutually between the investigator and 
sponsor. 


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If any prohibited medication is taken during the study, all pertinent information will be recorded 
in source documents and the eCRF. The designated study medical monitor (MM) must be 
informed immediately so the sponsor may determine whether to continue the subject in the 
study. 
6.5.1.1. 
Sedatives 
Due to the importance of accurately measuring mental status during the treatment period of this 
study, sedation is an important potential confounder, and thus, sedatives should not be used 
during the study period. Sedatives such as benzodiazepines (eg, alprazolam, alcyon, midazolam, 
oxazepam, triazolam, lorazepam, estazolam, temazepam, diazepam, chlordiazepoxide, 
clonazepam, flurazepam, clorazepate) and sleep aids (eg, haloperidol, zolpidem, Midol PM®, 
Sominex®, trazodone [Desyrel®], Sleep-eze®), are not allowed during the treatment period 
through completion of the final visit and, if applicable, + 24 hours after final visit assessments. 
Any psychoactive agents including strong analgesics, antidepressants, and/or anxiolytics should 
be avoided. Narcotic use should be avoided due to subject sensitivity to these agents. Any use of 
sedation must be consistent with standard medical therapy. If sedation is unavoidable, use drugs 
with a short half-life (eg, diprivan) as well as drugs that do not have synergistic effects with 
endogenous promoters of HE (eg, avoid benzodiazepines). 
Mind-altering agents (such as barbiturates, opioids, or benzodiazepines) should be avoided 
during the treatment period through completion of the final visit and, if applicable, + 24 hours 
after final visit assessments. 
6.5.1.2. 
Neuroactive Agents 
Avoid agents that can precipitate confusion or neurological changes or cause central nervous 
system disturbances, such as prochlorperazine (Compazine®), promethazine (Phenergan®), 
trimethobenzamide (Tigan®), dronabinol (Marinol®), metoclopramide (Reglan®), or any of the 
benzodiazepines. These drugs are not allowed during the treatment period until after completion 
of all assessments at the final visit and, if applicable, + 24 hours after final visit assessments. 
6.5.2. 
Other Restricted Substances 
Subjects should refrain from consumption of food and beverages containing alcohol from 
72 hours prior to dosing until completion of the last PK sample collection. The use of drugs of 
abuse and legal narcotic agents is not permitted while subjects are enrolled in this study. If a 
subject is unable to comply with the restrictions described above, their continued participation in 
the study will be re-evaluated by the investigator, in consultation with the sponsor. Subjects must 
abstain from tobacco products, including vaping, during confinement at the study center. 
6.5.3. 
Meals and Fluids 
The study drugs will be administered under fed conditions (30 minutes after the start of a 
standardized meal). Lunch and dinner will be served at approximately 30 minutes prior to 
dosing. 


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For all subjects, standardized, balanced meals will be provided while subjects are confined at the 
research unit. The meals will be nutritionally balanced and will contain sufficient fiber/roughage 
to maintain normal bowel activity. 
Snacks are permitted throughout the day, except on Day 1, Day 3, and Day 5/ET beginning 
8 hours before the breakfast dose until 2 hours after the lunch dose. Snacks must be captured in 
the eCRF. 
The total amount of protein per subject per day (including all meals and snacks) should not 
exceed 1.5 g/kg body weight per day. 
In order to facilitate urine production, subjects will be encouraged to drink fluids frequently 
throughout the confinement period. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
The duration of the study is defined for each subject as the date that signed written informed 
consent is provided until completion of the final visit or until premature withdrawal from the 
study for any other reason (eg, death, physician decision, subject/caregiver withdraws consent, 
lost to follow-up). 
Subjects (or their caregivers) may withdraw consent from the study at any time and for any 
reason, without prejudice to their future medical care by the investigator or others at the study 
site. Every effort should be made to keep subjects in the study. The reason for study treatment 
discontinuation or subject withdrawal from the study will be recorded in the subject’s eCRF. 
7.1. 
Discontinuation of Study Treatment 
Subjects who discontinue, or are withdrawn from study treatment for any reason, will be 
encouraged to complete the final visit and provide any additional follow-up information as 
required by the study, unless the subject specifically indicates that they will not participate in any 
further evaluations. 
Permanent study treatment discontinuation is required for any of the following: 
 A ‘serious’ adverse reaction (ie, an SAE considered at least possibly related to the 
study treatment administration) in 1 subject. 
 Grade 4 AEs as per Common Terminology Criteria for AEs (CTCAE) v5.0 that are 
not expected in the context of underlying medical conditions. 
 The investigator considers study treatment discontinuation to be in the subject’s best 
interest for any other reason. 
 Major protocol violation. 
 Symptoms of an intercurrent illness not consistent with the protocol requirements or 
that justify withdrawal. 


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 The subject becomes pregnant. 
Discontinuation of study treatment for abnormal liver function should be considered by the 
investigator when a subject meets one of the conditions outlined in Section 10.5. 
Additional reasons for permanent study treatment discontinuation include, but are not limited to, 
the following:  
 Subject/caregiver withdraws consent to receive study treatment. 
 Death. 
If a clinically significant cardiac finding is identified (including but not limited to changes from 
baseline in QTcF) after the start of study treatment, the investigator or a qualified designee will 
determine if the subject can continue in the study and if any change in management is needed.  
The reason for study treatment discontinuation will be recorded. 
No dose modifications or temporary treatment discontinuations are permitted in this study. 
7.2. 
Subject Discontinuation/Withdrawal From the Study 
Subjects may withdraw from the study at any time at their own (or per caregiver’s) request or 
may be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 
If the subject/caregiver withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such withdrawal of consent. If a 
subject/caregiver withdraws from the study, the subject/caregiver may request destruction of any 
samples taken and not tested, and the investigator must document this in the study site study 
records. 
The reason for study discontinuation/withdrawal will be recorded. A subject may be 
discontinued from the study for the following medical or administrative reasons including, (but 
not limited to) the following: 
Noncompliance 
The subject is noncompliant with the protocol. 
Intercurrent Illness 
The subject has symptoms or an intercurrent illness that is not consistent with the protocol 
requirements or that justify withdrawal. 
Withdrawal by Subject 
Subjects will be free to discontinue from the study at any time. 


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Adverse Event 
If a dosed subject suffers an AE that, in the judgment of the investigator, sponsor, or MM; 
presents an unacceptable consequence or risk to the subject, the subject will be discontinued 
from study treatment.  
Death 
In the event that a subject dies during the study, death will be the reason for discontinuation. 
Lost to Follow-up 
Every effort should be used to maintain contact with subjects during their participation in the 
study. A subject may be considered lost to follow-up if there is no response to at least 3 attempts 
to reach the subject by telephone and no response to a certified letter (or equivalent) sent to the 
last known address of the subject, if possible. Efforts to contact the subject should be noted in the 
source documentation. 
Met Withdrawal Criteria 
Discontinuation for safety and/or tolerability issues as outlined in Section 7.1. 
Other 
If the above reasons are not applicable, please use the “Other” option in the eCRF and provide 
the appropriate reason for subject withdrawal. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Screening (Day -28 to Day -1) 
Subjects should be screened within 28 days prior to administration of the first dose of study 
treatment on Day 1. Written consent must be obtained from each subject before the initiation of 
any screening procedure. A sufficient number of subjects will be screened to identify 48 subjects 
fulfilling all entry criteria. 
Once written consent has been obtained, the following procedures will be performed at the 
Screening evaluation: 
 Review inclusion/exclusion criteria. 
 Record demographics. 
 Record medical/surgical history (including history of exposure to COVID-19). 
 Record all prior medication/therapies. 
 Record concomitant medications/therapies 
 Perform a complete physical examination. 
 Measure the subject’s height, weight and waist circumference. 


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 Measure the subject’s vital signs. 
 Record an electrocardiogram (ECG). 
 Collect a blood sample for plasma AMM. Results will be used to determine eligibility 
for Inclusion Criterion #5.  
 Collect samples for chemistry, hematology, and urinalysis. 
 Perform a urinary drug screen including a screen for methadone at screening only.  
 Collect blood samples for hepatitis and HIV serology. 
 Record the Conn, MELD, HESA and C-P scores. 
 Record/collect AEs/SAEs (including AEs of special interest [AESI]) after the consent 
process is completed. 
 Perform a serum pregnancy test/follicle stimulating hormone (FSH) test (FSH is 
required for postmenopausal women).  
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range (greater than 40 
mIU/mL) may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). However, in the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Eligible subjects will be instructed about the restrictions on concomitant medication usage and 
other substances (see Section 6.5) and will be asked to return to the clinic for dosing. If deemed 
necessary, additional subjects may be requested to report to the clinic to serve as possible 
replacements for any subject(s) who become unavailable or who are later deemed ineligible to 
participate. 
Subjects will be confined to the study site from Day -1. On Day -1, a urine pregnancy test will be 
performed on women of child-bearing potential to confirm that the subject did not become 
pregnant since the time of screening (up to 28 days before Day 1). 
8.2. 
Randomization 
After confirming that the inclusion and exclusion criteria are satisfied and after the screening 
visit procedures are completed, subjects will begin the study. 


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8.3. 
Treatment Period (Week 1; Day 1 to Day 5/ET) and Day 6 
(Discharge) 
After randomization, subjects will enter the study, and receive active treatment (1 of 3 
MNK6106 dose regimens or rifaximin) for 5 days. Subjects will be confined to the study center 
overnight during the treatment period and discharged on Day 6. The following procedures will 
be carried out on Days 1, 2, 3, 4 and 5 unless otherwise stated: 
 Perform a limited physical examination (Day 1 only). 
 Record the subject’s weight and waist circumference (Day 1 and Day 6 only). 
 Record the subject’s vital signs (Day 1 through Day 6). 
 Record ECG (Days 1, 3 and 5/ET only) at 1 hour after the last dose (± 15 minutes). 
Complete the ECG prior to the PK sample collection if the timing is the same. 
 Collect blood samples for plasma AMM (to be drawn on Days 1, 3 and 5/ET only, 
predose in the morning immediately before breakfast and 4 hours (± 15 minutes) after 
the morning dose), as well as on the day of the final visit. 
 Collect a blood sample for plasma PAA, ORN and PAGN (to be drawn on Days 1, 3 
and 5/ET only). A baseline sample will be drawn prior to the first dose on Day 1 
(within 15 minutes prior to the morning dose) and then prior to (with 10 minutes) and 
1 hour (± 15 minutes) after the last dose on Days 1, 3, and 5/ET. 
 Collect a urine sample for PAGN. For each 24-hour collection following the first dose 
of the day, all urine will be collected during the specified intervals, with the last 
collection for Day 5/ET being collected on Day 6. A baseline urine sample will also 
be collected predose on Day 1. 
 Collect samples for chemistry, hematology, (Days 1 through 6) and urinalysis (Days 1 
through 5 only).  
 Record the Conn, MELD, HESA and C-P scores (Days 1 through 6). 
 Perform study drug dosing. 
 Record all concomitant medications/therapies (Days 1 through 6). 
 Record and assess AEs/SAEs, including AESI (Days 1 through 6). 
On the Day 6 visit (discharge): 
If no clinical or laboratory abnormalities are observed, subjects will be discharged from the study 
on the morning of Day 6. The 24-hour urine collection for PAGN will be completed on Day 6 at 
the end of confinement. 
Additional follow-up visits will be scheduled if a subject shows any clinical or laboratory 
abnormalities at this visit, as deemed appropriate by the investigator/designee (classified as 
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Generally, clinically significant abnormal laboratory values will be monitored periodically until 
resolution or until they are considered irreversible. If a subject discontinues from the study 
prematurely, then every attempt will be made to conduct all the above evaluations at the time of 
discontinuation and at the final visit (approximately 7 days after the last dose of study drug). 
8.4. 
Final Visit (Week 2) 
Subjects will return to the clinic site for the final visit. The final visit will be conducted 
approximately 7 days (+ 3 day window) after the end of the active treatment period. 
The final visit window may be extended, due to extenuating circumstances, to 14 days after 
discussion with the sponsor. 
The following procedures will be carried out at the final visit: 
 Perform a complete physical examination. 
 Record the subject’s weight. 
 Record the subject’s vital signs. 
 Collect a blood sample for plasma AMM. 
 Collect samples for chemistry, hematology, and urinalysis. 
 Perform a serum pregnancy test. 
 Record the Conn, MELD, HESA and C-P scores. 
 Record all concomitant medications/therapies. 
 Record and assess AEs (including AESI) 
 
8.5. 
Pharmacodynamic and Pharmacokinetic Assessments 
8.5.1. 
Pharmacodynamic Sampling 
Plasma AMM data are extremely important, but these samples are exquisitely sensitive. For this 
reason, great care must be taken with the collection, handling, processing, and storage of plasma 
AMM samples. 
Samples for plasma AMM levels will be drawn at screening, on Days 1, 3 and 5/ET predose in 
the morning immediately before breakfast and 4 hours (± 15 minutes) after the morning dose, 
and at the final visit. 
Before the blood draw to collect a sample for venous AMM, place the collection tube on ice for 
at least 10 minutes. Immediately after drawing blood, gently invert the specimen approximately 
8 to 10 times, place the specimen on wet ice, separate the plasma by refrigerated centrifugation 
as soon as possible, and freeze the plasma specimen for analysis at -70°C or colder immediately 
after centrifugation. This specimen will be processed by the laboratory or by trained personnel 


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per facility standard operating procedures. All plasma for AMM testing must be prepared and 
stored in a -70°C or colder freezer with the greatest speed feasible. All frozen samples will be 
transported to a laboratory testing site. Review the Laboratory Manual/sample handling guide for 
complete information. 
Venous AMM draws are predicated on timing, which is of paramount importance; however, for 
subjects able to eat, it is preferable to obtain the blood sample prior to food intake (if feasible). 
Because of the exquisite delicacy of this analyte stringent before drawing, blood draw and 
specimen processing parameters must be adhered to; documentation of each step of preanalytic 
specimen preparation and processing is required for each time point inclusive of date and time 
for each step recorded on the laboratory requisition and source documentation. It is essential 
that venous AMM plasma samples be correctly prepared to avoid spurious results; if the 
specimen integrity is compromised by inappropriate handling, it would be preferable not to send 
that sample to the laboratory for analysis. 
8.5.2. 
Pharmacokinetic Sampling (Plasma PAA, ORN and PAGN) 
8.5.2.1. 
Blood Sampling for Plasma PAA, ORN and PAGN Measurement 
Blood samples for analysis of PAA, ORN, and PAGN will be collected on the days and within 
the time windows specified below and in the Schedule of Study Events (Table 1) and shipped to 
the designated bioanalytical laboratory for analysis. 
Blood samples for plasma concentration of PAA, ORN, and PAGN will be drawn prior to the 
first dose on Day 1 (within 15 minutes prior to morning dose) and then prior to (within 10 
minutes) and 1 hour (± 15 minutes) after the last dose on Days 1, 3, and 5/ET. The date and time 
of each sample collection will be recorded. 
Peripheral venous blood samples (3 mL each) for analysis of plasma PAA concentrations will be 
drawn into prelabeled VACUTAINER® tubes containing spray-dried potassium ethylene 
diaminetetraacetic acid by individual venipuncture (if possible) or a peripheral venous catheter. 
If a peripheral catheter is used, the catheter should be kept patent using a diluted heparin or 
saline drip; and prior to drawing each blood sample, a small volume of blood (~1 mL) should be 
withdrawn from the catheter using a syringe and then discarded so that an undiluted blood 
sample will be collected into the VACUTAINER® tube. The date and exact (clock) time that 
each blood sample is drawn will be recorded on the eCRF. 
Immediately after collection, the blood collection tubes will be gently inverted 8 to 10 times to 
allow mixing with the anticoagulant and then kept on wet ice or refrigerated until centrifugation. 
Each blood sample will be centrifuged within 1 hour after blood collection in a refrigerated 
centrifuge at the following approximate parameters to separate the plasma: 4°C, 1000 × times 
gravity, and 15 minutes to separate the plasma. All the plasma for each sample will be equally 
divided and transferred to 2 storage tubes of adequate capacity and appropriately pre-labeled. 
Note that 4 mL NUNC CRYOVIAL® polypropylene biofreeze tubes (3.6 mL fill) with screw cap 
(Order # 366524) are preferred. The storage tubes will be labeled, at a minimum, with the 
sponsor company, protocol number, subject number, sample matrix, study day, scheduled sample 


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time and tube number (eg, #1 or #2). The tubes will be stored in an upright position in a non-self-
defrosting freezer with the temperature maintained at approximately -80°C until shipment to the 
designated bioanalytical laboratory where samples will be stored at approximately -80°C. 
Samples should be placed into the freezer within 2 hours of blood collection. 
Every attempt will be made to collect samples at the protocol-specified times. The time of each 
sample will be recorded to the nearest minute. 
8.5.3. 
Urine Sampling for PAGN Measurement 
Urine collection (with start/end time and volume recorded) for measurement of PAGN, the study 
drug metabolite excreted in urine, will be collected for 24 hour intervals following the first dose 
of the day. Collect a baseline sample prior to initial dosing on Day 1. 
 Urine collection will start at the initiation of study drug (predose urine sample). 
 The next collection interval time starts immediately following the first dose 
administration of the day. For example, if the first dose of the day is administered at 8 
AM, all urine volume will be collected through the following morning at 
approximately 8 AM. 
 Measure total volume during each time interval, document collection start/stop times, 
obtain 2 aliquots and freeze immediately as per Laboratory Manual instructions. 
 The final urine collection time interval on Day 5/ET is from the first dose on Day 
5/ET until the following day, Day 6 (24 hour interval). 
Urine samples for analysis of PAGN elimination will be collected into pre-labeled polyethylene 
containers for each collection interval. For each 24-hour collection, all urine will be collected 
during the specified intervals in the Schedule of Study Events (Table 1). Subjects will be asked 
to void at the end of each collection interval, but if a subject voids more than once in a single 
collection interval, each void will be added to the collection container for that interval and 
thoroughly mixed. The start and stop time of each collection will be recorded on the eCRF. Care 
should be taken to avoid spillage of urine outside of the collection vessel. 
Once the collection for a time interval is complete, the container (with cumulative urine) will be 
gently shaken (for at least 30 seconds) to mix the urine thoroughly. The total urine volume in 
each collection interval will be measured and recorded. Two 5 mL aliquots of well-mixed urine 
from each collection (including the predose void) will then be transferred to 2 pre-labeled storage 
tubes of adequate capacity with screw caps. The storage tubes will be stored in an upright 
position in a freezer set at approximately –80°C until shipment to the designated bioanalytical 
facility, where samples will be stored at approximately -80°C. All storage tubes should be 
labeled with a preprinted label displaying, at a minimum, the sponsor company, protocol 
number, subject number, sample matrix, study day, scheduled collection interval and aliquot 
number (eg, #1 or #2). Samples should be placed into the freezer within 2 hours from the end of 
each collection interval. 


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8.5.4. 
Bioanalytical Methodology 
Plasma samples will be analyzed for concentrations of ORN, PAA, and PAGN using a validated 
liquid chromatography–tandem mass spectrometry method. Urine samples will be analyzed for 
concentrations of PAGN using a validated liquid chromatography-tandem mass spectrometry 
method. In addition, plasma samples will be also analyzed for AMM concentrations. Please refer 
to the Bioanalytical Report for more direction. 
8.5.5. 
Sample Shipment 
Contact and shipping information for PK samples will be provided by the sponsor. 
Following completion of the treatment period, the plasma and urine samples collected for PK 
assessments will be shipped to laboratories designated by Mallinckrodt for analysis. The first 
aliquot of each plasma and/or urine sample will be shipped together to the sponsor’s designated 
bioanalytical or central laboratory, while the second aliquot of each sample will be retained at the 
investigator site until further instruction for shipment. The samples to be shipped will be clearly 
labeled for sample identification, inventoried and organized in sample boxes. A copy of the 
inventory documentation must accompany each shipment. The original inventory documentation 
will be kept at the study site. The sample boxes should be placed in a Styrofoam (1.5 inch-thick) 
shipping box with sufficient dry ice to maintain the samples in a frozen state for at least 2 days. 
Shipment will be made on Monday, Tuesday, or Wednesday to ensure weekday receipt by the 
sponsor’s designated bioanalytical laboratory. Contact information will be provided to address 
any questions concerning the collection, handling or packaging of the samples. It is the 
responsibility of the investigator to ensure that all samples for interstate transport are 
appropriately handled (packaged and shipped). Failure to comply with these regulations can 
result in imprisonment and/or fines. 
8.6. 
Safety Assessments 
All safety assessments will be performed at times outlined in the Schedule of Study Events 
(Table 1). Additional (unscheduled) safety assessments may be performed as needed. 
8.6.1. 
Medical and Surgical History 
Medical and surgical history will be obtained at screening. Medical history will include a review 
of the following systems: general, dermatological, respiratory, cardiovascular, 
gastrointestinal/hepatobiliary (including history of ascites and episodes of hepatic 
encephalopathy), genitourinary, gynecological, endocrine, musculoskeletal, hematological, 
neuropsychological, immune (allergies), and head, eyes, ears, nose, and throat. Historical and 
current medical conditions including date of last menstrual period for female subjects will be 
recorded.  
8.6.2. 
Electrocardiogram 
A 12-lead ECG will be obtained at screening and on Days 1, 3 and 5/ET at 1 hour after the last 
dose (± 15 minutes). Complete the ECG prior to PK sample collection if the timing is the same. 


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Subject needs to be supine for greater than 10 minutes prior to ECG. The investigator (or 
investigator’s designee who is a physician) will interpret the ECG and will record a global 
interpretation of the ECG (ie, "Normal" or "Abnormal") on the tracing. 
Each ECG tracing must also include the signature of the investigator and the date that the ECG 
was interpreted. If the global interpretation is abnormal, the investigator will indicate on the 
tracing whether the abnormality is clinically significant or not clinically significant. A copy of 
each ECG and the physician’s assessment will be filed with the source documents. 
8.6.3. 
Physical Examination 
The complete physical examination will be performed at screening and the final visit and will 
include evaluation of the head, eyes, ears, nose, throat, neck (including thyroid), cardiovascular 
system (including assessment of heart, peripheral pulses, presence or absence of edema), lungs, 
abdomen (including liver and spleen, bowel sounds), lymph nodes, musculoskeletal system 
(including spine, joints, muscles) neurological system (including cranial nerves, reflexes, 
sensation, strength), skin, extremities, and other conditions of note. 
A limited physical examination will be performed during the treatment period (Day 1 and Day 6) 
and will include evaluation of lungs, cardiovascular system, abdomen, and extremities. 
The findings of the physical examinations will be recorded. Any change from the screening 
physical examination that is considered clinically significant by the investigator will be recorded 
as an AE. 
8.6.4. 
Height, Weight and Waist Measurements 
The subjects’ height, body weight and waist measurement will be collected as outlined in the 
Schedule of Study Events (Table 1). Height may be measured with or without shoes. Any change 
from screening in a subject’s body weight or waist measurement that is considered by the 
investigator to be clinically significant will be recorded as an AE. 
8.6.5. 
Vital Signs 
Vital signs will be obtained after the subject has been seated for 5 minutes (minimum) and will 
include systolic and diastolic blood pressures, pulse rate, respiratory rate, and body temperature. 
The results, date, and time for all vital sign assessments will be recorded. Any change from the 
screening vital signs measurements considered clinically significant by the investigator will be 
recorded as an AE. 
8.6.6. 
Clinical Laboratory Tests 
Required clinical laboratory tests are listed in Section 10.2. Specific instructions for collection, 
processing, storage, and shipment of clinical laboratory samples will be provided in a separate 
laboratory manual. 
Samples for laboratory testing at all visits may be collected under fasted or nonfasted conditions. 
Fasting early morning samples are preferred, but a random daytime sample is acceptable. The 


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date and time of the sample collection must be documented on the laboratory report. 
Investigators must review and sign laboratory reports and document the clinical significance of 
each laboratory abnormality. New clinically significant laboratory abnormalities or clinically 
significant changes in laboratory values will be reported as AEs. 
Hematology, serum chemistry, and urinalysis samples will be collected at the specific times 
starting at screening and throughout the study. 
Samples will be taken for hepatitis and HIV serology at the time point outlined in the Schedule 
of Study Events (Table 1). 
Subjects will also be screened for alcohol and a urinary drug screen will be performed at the time 
points outlined in the Schedule of Study Events (Table 1). 
In addition, all female subjects of childbearing potential will have serum and urine pregnancy 
tests at the time points outlined in the Schedule of Study Events (Table 1). Results must be 
available prior to protocol mandated study treatment. Subjects with positive results at screening 
will be ineligible for study entry. Any female subject that becomes pregnant during the study will 
be immediately withdrawn and will have the pregnancy reported as per Section 10.4. 
8.7. 
Adverse Events 
AEs will be recorded from signing of the ICF through the final visit and will be followed by the 
investigator until the AE is resolved or stabilized. All safety measures (which includes standard 
of care activities) should be provided by the study site to the subject. Any study site follow-up 
should be documented. 
Refer to Section 10.3 for additional details on the handling of AEs and SAEs. 
8.8. 
Treatment Overdose 
For this study, any dose of greater than 40 g within a 24-hour (± 1 hour) time period will be 
considered an overdose. 
MNK6106 should only be administered in accordance with the individual study protocol being 
conducted. There is the possibility that overdosage of MNK6106 can result in obtundation, 
hyperventilation, metabolic acidosis, large anion gap, progressive encephalopathy, 
cardiovascular collapse, and death. In the event of a suspected overdose, discontinue study 
treatment immediately and institute appropriate emergency medical monitoring and procedures. 
Consider hemodialysis in severe cases. 
In the event of an overdose, the investigator or designee should perform the following: 
 Contact the MM immediately. 
 Closely monitor the subject for any AEs/SAEs and laboratory abnormalities until the 
treatment can no longer be detected (at least 3 days). 
 Obtain a blood sample for PK analysis, if requested. 


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 Document the quantity of the excess dose, as well as the duration of the overdose. 
8.9. 
Provisions for Remote Assessment Methods 
For emergency situations where there are extenuating circumstances that prohibit physically 
coming to the clinical site or when the safety of subjects may be compromised by physical visits 
to the site, remote assessments may be considered after discussion with the Sponsor. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Sample Size Determination 
A total of 48 subjects will be randomized 1:1:1:1 to receive 1 of the 3 dosing regimens of 
MNK6106 or the comparator rifaximin for 5 days. This study is exploratory in nature. 
Prematurely discontinued subjects will not be replaced. 
9.2. 
Populations for Analysis 
For the purposes of analysis, the following populations are defined 
 The Modified Intent-to-Treat (mITT) Population will include all randomized subjects 
who receive at least 1 study treatment and who contribute any postbaseline PD data to 
the study. 
 The Safety Population will include all subjects who receive 1 or more study 
treatments. 
 The PK population will consist of all subjects in the Safety Population with at least 
1 evaluable plasma concentration following treatment with MNK6106. 
9.3. 
Statistical Hypothesis and Analyses 
This is an exploratory study and so there is no statistical hypothesis to test. 
9.3.1. 
Pharmacodynamic Analyses 
The descriptive statistics for PD variables, which are the plasma AMM level and the change of 
the plasma AMM level from baseline, will be used by treatment and by visit. The Mallinckrodt 
treatments will also be combined for display. The summaries will be based on the mITT 
population. 
For continuous variables, descriptive statistics will include the following: the number of subjects 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. 
The 95% confidence intervals will be presented. 
The graphic for PD variables by treatment and by visit will also be provided. 


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9.3.2. 
Pharmacokinetic and Pharmacodynamic Analyses  
The descriptive statistics for concentrations of PAA, ORN and PAGN will be used by treatment 
and by PK sampling time. Urinary recovery of PAGN will be summarized by treatment and 
study day. Descriptive statistics will include the following: the number of subjects reflected in 
the calculation (n), mean, median, standard deviation, minimum, and maximum. The 95% 
confidence interval will be presented. 
Population PK modeling will be developed with the PK data obtained from the study such as 
concentration of PAA, ORN and PAGN. Sources of variability contributing to the PK will be 
identified. Exposure response relationships describing the safety and AMM levels following 
treatment with MNK6106 will be explored. 
9.3.3. 
Analysis Methods for C-P, MELD, Conn and HESA Scores 
Details of C-P, MELD, Conn and HESA scores are provided in Section 9.5. 
9.4. 
Liver Function Classification 
Liver function classification details are provided in Section 10.6. 
9.5. 
Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, physical 
examination, social history, and risk factor variables at baseline. 
For C-P, MELD, Conn, and HESA scores: 
 The change and percent change of C-P, MELD, Conn, and HESA scores by visit will 
be summarized and analyzed using multiple imputation with an analysis of 
covariance model, respectively. 
 The percent of subjects with C-P (A, B, C), MELD ( 40+, 30-39,20-29,10-19, <9), 
Conn (0,1,2,3,4) and HESA (0,1,2,3,4) will be provided by treatment group and by 
visit, respectively. 
 The percent of subjects with improvement vs no change from baseline in the C-P 
category, MELD category based on category of 40+, 30 to 39, 20 to 29, 10 to 19, < 9, 
Conn and HESA will be analyzed by the Cochran–Mantel–Haenszel test stratified by 
baseline category, respectively. 
The graphics for the 4 scores by treatment and by visit will be presented. 
9.5.1. 
Safety Analyses 
For safety variables, 2 observation periods are defined:  
 The pretreatment period is defined as the time from signing the ICF until 
administration of the first dose of study drug. 


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 The treatment-emergent period is defined as the time from administration of the first 
dose of study drug to the end of the study. 
Treatment-emergent AEs are defined as those that are not present at start of study drug dosing or 
that represent the exacerbation of a pre-existing condition during the treatment-emergent period. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by 
preferred term within system organ class. The number of AEs and the number of subjects 
reporting AEs will be listed and summarized descriptively by body system, preferred term, 
severity, and causality for each treatment group. Both pretreatment and treatment-emergent AEs 
(events that are new in onset or aggravated in severity following treatment) will be included in 
all summaries. SAEs (including death) will be summarized. Treatment-emergent AEs leading to 
permanent treatment discontinuation will be listed and summarized by treatment group. 
9.5.2. 
Treatment Exposure 
The duration of drug exposure during the study will be summarized by treatment and calculated 
as: (Date of last dose – date of first dose). 
The number (%) of subjects randomized and exposed to drug will be presented by specific time 
periods for each treatment group. The time periods of interest will be specified in the statistical 
analysis plan. 
Treatment compliance = (the number of doses of study drug taken during the exposure 
period)/(the number of planned study drug doses during the exposure period) × 100%. 
A summary of the treatment compliance by treatment group will be provided. 
9.5.3. 
Interim Analyses 
No interim analyses are planned for this study. 
9.5.4. 
Handling Missing Data 
There is no imputation for missing PD data. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
The study will be conducted in full compliance with applicable international, national and local 
regulatory requirements; FDA regulations including 21 CFR 314.106 and 312.120, (where 
applicable), ICH guidelines for Good Clinical Practice (GCP), in accordance with the ethical 
principles that have their origins in the Declaration of Helsinki, and European regulation 
536/2014/EU (where applicable). 


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It is the responsibility of the investigator to obtain the approval of the IRB/IEC before the start of 
the study. A copy of the approval letter along with a roster of IRB/IEC members and compliance 
letter and/or the US Department of Health and Human Services general assurance number 
(if applicable) will be provided to the sponsor and retained as part of the study records. During 
the course of the study, the investigator will provide timely and accurate reports to the IRB/IEC 
on the progress of the study at appropriate intervals (not to exceed 1 year) and at the completion 
of the study. The investigator will notify the IRB/IEC of SAEs or other significant safety 
findings per IRB/IEC guidelines. The study protocol, ICF, advertisements (if any), and 
amendments (if any) will be approved by the IRB/IEC in conformance with international, 
national and local regulatory requirements. 
Any change in the study plan requires a protocol amendment. An investigator must not make any 
changes to the study without IRB/IEC and sponsor approval except when necessary to eliminate 
apparent immediate hazards to the subjects. A protocol change intended to eliminate an apparent 
immediate hazard to subjects may be implemented immediately, but the change must then be 
documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to 
the appropriate regulatory agency in the required time frame, if appropriate. 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after the 
end of the study. 
10.1.3. 
Subject Information and Consent 
The ICF must be approved by the sponsor and the IRB/IEC before any subject provides consent. 
The investigator will provide Mallinckrodt with a copy of the IRB/IEC-approved ICF and a copy 
of the IRB/IEC’s written approval before the start of the study. 
At screening (and at other times as may be required by the study or when changes are made to 
the consent form), subjects will read the consent form(s) and any privacy authorization as 
required by local and national regulations (such as the Health Insurance Portability and 
Accountability Act [HIPAA] authorization form), if applicable after being given an explanation 
of the study. Before signing the consent form(s) and the privacy authorization form (if 
applicable), subjects will have an opportunity to discuss the contents of these forms with study 
site personnel. 
Subjects must assent understanding of and voluntarily sign these forms in compliance with ICH 
GCP and all applicable national and international regulations, before participating in any 
study-related procedures. Subjects will be made aware that they may withdraw from the study at 
any time. Subjects unable to give written informed consent must orally assent to the procedures 
and written informed consent must be obtained from a legally authorized representative in 
accordance with national and local laws, as applicable. 


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The ICF must contain all applicable elements of informed consent and the mandatory statements 
as defined by national and local regulations including confidentiality. All versions of each 
subject's signed ICF must be kept on file by the study site for possible inspection by regulatory 
authorities and/or authorized Mallinckrodt personnel. Signed copies of the consent form(s) and 
the HIPAA authorization form, if applicable, will be given to the subject. 
The subjects will be made aware of their right to see and copy their records related to the study 
for as long as the investigator has possession of this information. If the subject withdraws 
consent and/or HIPAA authorization, the investigator can no longer disclose health information, 
unless it is needed to preserve the scientific integrity of the study. 
10.1.4. 
Data Protection 
Study subjects will be assigned a unique identifier by the sponsor or designee. Any subject 
records or datasets that are transferred to the sponsor will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
The subjects must be informed that their personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure (in accordance with local 
and/or national law) must also be explained to the subject.  
The subjects must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Data 
Aggregate results data will be provided to the study sites that actively enrolled subjects into this 
study after the clinical study report is finalized. 
Study results and de-identified individual subject data will be released as required by local and/or 
national regulation. 
10.1.6. 
Data Quality Assurance 
The sponsor performs quality control and assurance checks on all clinical studies that it sponsors. 
Before enrolling any subjects in this study, sponsor personnel and the investigator review the 
protocol, the Investigator’s Brochure, the eCRF and instructions for their completion, the 
procedure for obtaining informed consent, and the procedure for reporting AEs and SAEs. A 
qualified representative of the sponsor will monitor the conduct of the study. 
The investigator will permit study-related monitoring, audits, IRB/IEC review, and regulatory 
inspections by providing direct access to original source data and documents. 
Each subject’s eCRF should be fully completed and submitted to the sponsor in a timely fashion. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the sponsor to agree upon an acceptable storage solution. Regulatory 
agencies will be notified with the appropriate documentation. 


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Any significant changes in study personnel will require an updated statement of investigator 
(ie, FDA Form 1572) to be filed with the sponsor. 
The investigator must notify their IRB/IEC of protocol deviations in accordance with local 
regulatory and IRB/IEC requirements. 
The eCRF data are stored in a database and processed electronically. The sponsor’s MM reviews 
the data for safety information. The data are reviewed for completeness, and logical consistency. 
Automated validation programs will identify missing data, out-of-range data, and other data 
inconsistencies. In addition, clinical laboratory data will be processed electronically. Requests 
for data clarification are forwarded to the study site for resolution. 
10.1.7. 
Source Documents 
All subject information recorded in the eCRF will be attributable to source data from the study 
site. 
The investigator shall retain and preserve one copy of all data collected or databases generated in 
the course of the study, specifically including but not limited to those defined by GCP as 
essential. Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational medicinal product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. Prior to 
destruction of any study essential documents, the investigator must first obtain written approval 
from the sponsor. 
10.1.8. 
Study and Site Closure 
The sponsor may suspend or terminate the study or part of the study at any time for any reason. 
If the investigator suspends or terminates the study, the investigator will promptly inform the 
sponsor and the IRB/IEC and provide them with a detailed written explanation. Upon study 
completion, the investigator will provide the sponsor, IRB/IEC, and regulatory agency with final 
reports and summaries as required by regulations. Study termination and follow-up will be 
performed in compliance with the sponsor or designee standard operating procedures. 
The sponsor, investigator, or local and national regulatory authorities may discover conditions 
during the study that indicate that the study or study site should be terminated. This action may 
be taken after appropriate consultation between the sponsor and investigator. 
Conditions that may warrant termination of the study/study site include, but are not limited to: 
 The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled 
in the study. 


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 The decision on the part of the sponsor to suspend or discontinue testing or evaluation 
of the study treatment. 
 Failure of the investigator to enroll subjects into the study at an acceptable rate. 
 Failure of the investigator to comply with pertinent regulations. 
 Submission of knowingly false information from the study site to the sponsor, study 
monitor, or local and national regulatory authorities. 
 Insufficient adherence to protocol requirements. 
10.1.9. 
Publication Policy 
The sponsor’s decision to publish or otherwise publicly communicate the results of this study 
will be made in accordance with all applicable laws, regulations, and sponsor policies regarding 
publication and communication of clinical study results. 
Terms and provisions of the investigator’s publication rights are governed by the Publication 
Section in the Clinical Trial Agreement. 
 
 


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10.2. 
Clinical Laboratory Tests 
Serum Biochemistry 
Alanine aminotransferase 
Creatinine 
Albumin (total) 
Gammaglutamyltransferase  
Alkaline phosphatase  
Phosphorus 
Aspartate aminotransferase 
Lactate dehydrogenase  
Bicarbonate (or CO2) 
Potassium 
Bilirubin (total, conjugated [direct], and unconjugated [indirect]) Protein (total) 
Blood urea nitrogen 
Serum glucose  
Calcium 
Sodium  
Chloride 
Uric acid 
Hematology 
Absolute differential count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) 
Hematocrit 
Platelet count  
Hemoglobin 
Red blood cell count  
Mean corpuscular hemoglobin  
Reticulocyte count  
Mean corpuscular hemoglobin concentration 
White blood cell count 
Prothrombin time/INR 
Mean corpuscular volume 
Urinalysis 
Blood 
pH 
Glucose 
Protein 
Ketones 
Specific gravity 
Leukocyte esterase 
Nitrites 
Other Analyses 
Serum pregnancy tests (females) 
FSH test (required for postmenopausal women) 
Urine pregnancy test (females of childbearing potential) 
 
Serology 
Hepatitis B surface antigen 
Hepatitis B core antibody 
HIV 
Hepatitis C virus (HCV) antibody 
HCV polymerase chain reaction testing will be performed only for subjects positive for HCV. 
Urine Drugs of Abuse and Alcohol Screen (local laboratory only) 
Amphetamines 
Alcohol  
Barbiturates 
Methadone (at screening only) 
Benzodiazepines 
Opiates 
Cannabinoids 
Cocaine 


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10.3. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up and Reporting 
10.3.1. 
Safety 
For safety information about MNK6106, refer to the most recent version of the Investigator’s 
Brochure. 
10.3.2. 
Definitions 
Adverse Event 
An AE is any untoward or undesirable medical occurrence in a subject who is administered a 
study treatment, which does not necessarily have to have a causal relationship with this 
treatment. Examples of AEs include but are not limited to: 
 Clinically significant laboratory findings. 
 Clinically significant changes in physical examination findings. 
 An AE occurring due to study treatment overdose whether accidental or intentional. 
 An AE occurring from study treatment abuse. 
 An AE associated with study treatment withdrawal. 
 Unexpected AE. 
An unexpected AE is defined as an AE, the nature and severity of which is not consistent with 
the applicable product information in the most recent version of the Investigator’s Brochure. 
Serious Adverse Event  
An SAE is defined as any untoward medical occurrence that at any dose results in any of the 
following outcomes: 
 Death. 
 Life-threatening AE. 
 Inpatient hospitalization or prolongation of existing hospitalization. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 Results in a congenital anomaly/birth defect. 
 Other serious (important medical events). 
Death 
Death is an outcome of an event. The cause of death should be recorded and reported on the SAE 
form. All causes of death must be reported as SAEs. The investigator should make every effort to 


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obtain and send death certificates and autopsy reports to the sponsor or designee, or state not 
available. 
Life-Threatening Event 
An AE or suspected adverse reaction is considered "life-threatening" if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. For example, hepatitis that resolved without evidence of hepatic failure 
would not be considered life threatening, even though hepatitis of a more severe nature can be 
fatal. Similarly, an allergic reaction resulting in angioedema of the face would not be life 
threatening, even though angioedema of the larynx, allergic bronchospasm, or anaphylaxis can 
be fatal. 
Hospitalization  
Hospitalization is defined as an official admission to a hospital. Hospitalization or prolongation 
of a hospitalization constitutes a criterion for an AE to be serious. The following situations 
should not be reported as SAEs: 
 A hospitalization or prolongation of hospitalization is needed for a procedure required 
by the protocol. 
 A hospitalization or prolongation of hospitalization is part of a routine procedure 
followed by the center (eg, stent removal after surgery). This should be recorded in 
the study file. 
 A hospitalization for a pre-existing condition that has not worsened. 
Important Medical Events 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency department or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
AEs (serious or non-serious) that commonly occur in the study population or background 
regimen will be considered anticipated events. Such events include known consequences of the 
condition under investigation (eg, symptoms, disease progression) and other events that may be 
common in this study population. Anticipated events are to be recorded on the eCRF and 
reported as SAEs when serious. These SAEs will not be expedited to health authorities, but 
rather, included in aggregate safety reports. 


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10.3.3. 
 Adverse Event and Serious Adverse Event Classifications 
The descriptions and grading scales found in CTCAE v5.0 (U.S. HHS CTCAE Version 5.0, 
2017) will be utilized for AE reporting.  
Study Drug Relatedness 
The following classifications should be used when evaluating the relationship of AEs or SAEs to 
study treatment (Table 3). 
Table 3: 
Adverse Event Relationships 
Relationship 
Definition 
Not Related 
No relationship between the AE and the administration of study treatment; the AE 
cannot be explained by other etiologies such as concomitant medications or 
subject’s clinical state. 
Unlikely Related 
The current state of knowledge indicates that a relationship to study treatment is 
unlikely. 
Possibly Related 
An AE that follows a plausible temporal sequence from administration of the study 
treatment to the start of the AE and follows a known response pattern to the 
suspected study treatment. The reaction might have been caused by the subject’s 
clinical state or concomitant medications. 
Related 
The AE that follows a plausible temporal sequence from administration of the 
study treatment to the start of the AE and follows a known response pattern to the 
study treatment. The suspected causality can be confirmed with a positive re-
challenge test or supporting laboratory data. 
 
Severity Assessment 
For purposes of consistency, if required, the investigator may use the severity grades presented in 
Table 4. 
Table 4: 
Adverse Event Severity Grades 
Grade 
Definition 
Grade 1 
Mild AE 
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening AE 
Grade 5 
Death 
Not all grades are appropriate for all AEs. In particular, Grade 5 (Death) is not appropriate for all 
AEs and therefore will not be considered an option for grading severity of AEs; instead, death, if 
it occurs, should be recorded as the outcome of a serious AE. 


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To ensure there is no confusion or misunderstanding of the difference between the terms 
“serious” and “severe,” which are not synonymous, the following note of clarification is 
provided: 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical importance (such as a severe headache). This is not the same as “serious,” which is 
based on the subject/event outcome or action criteria usually associated with events that pose a 
threat to a subject's life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
If an AE increases in severity (eg, from moderate to severe); decreases in severity (eg, changes 
from moderate to mild); or if there is a change in seriousness, a new AE will be opened, and the 
original AE will be closed. If an AE is still ongoing at the time of a subject’s completion of the 
Final Visit, the resolution/stop date and time is left blank. 
10.3.4. 
Adverse Event and Serious Adverse Event Recording and Reporting 
AEs and SAEs will be recorded from signing of the ICF through completion of the final visit. 
The investigator is required to record the AE or SAE regardless of the severity of the event or its 
relationship to study treatment. The investigator must follow up on all AEs and SAEs reported to 
have occurred through the final visit until the event has resolved or stabilized or at such time the 
investigator refers the subject to a nonstudy physician. The investigator will document the further 
follow-up information in the subject’s source document. 
During the period specified above, the investigator will: 
 Record all AEs and SAEs from the signing of the ICF through the completion of the 
final visit. 
 Report all SAEs on an SAE Report Form to Mallinckrodt Global Pharmacovigilance 
or designee. 
 Report all pregnancies to Mallinckrodt Global Pharmacovigilance or designee on the 
appropriate form. 
 Submit any Expedited Safety Report or Suspected Unexpected Serious Adverse 
Reaction from Mallinckrodt Global Pharmacovigilance or designee to the IRB/IEC. 
The reporting requirements for AEs are summarized in Table 5.  
Table 5: 
Reporting Requirements for Adverse Events 
Seriousness 
Reporting Time 
Type of Report 
All Serious 
Within 24 hours of first knowledge 
of event 
Initial report on the SAE Form, appropriate 
eCRF, and source document 
Within 24 hours of receipt of follow-
up information 
Follow up report on the SAE Form, 
appropriate eCRF, and source document 


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Table 5: 
Reporting Requirements for Adverse Events (Continued) 
Seriousness 
Reporting Time 
Type of Report 
Nonserious 
Per case report form submission 
procedure 
Appropriate eCRF and source document 
10.3.5. 
Adverse Events of Special Interest 
An AESI is an event of scientific and medical concern specific to the sponsor’s product or 
program, for which ongoing monitoring and rapid communication by the investigator to the 
sponsor can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it. These will be reported on the AE form including start date and 
time, stop date and time, severity, relation to study drug, any action taken with the study drug, 
and outcome of the event. 
CNS or abuse-related AEs will also be considered as AESIs for this study, based on the 
recommendation of the FDA to closely monitor these events and report time of onset, duration of 
the event, dose of drug taken, severity, and outcome. The eCRF page for these AESIs will be 
designed to capture the above data points. Narratives for all AESIs will be prepared from the 
data reported on the eCRFs. PK values for each individual subject who experienced these AEs 
will be provided to understand if there is a temporal correlation between drug plasma levels and 
AEs. 
CNS AESIs include somnolence, fatigue, lightheadedness, headache, dysgeusia, hypoacusis, 
disorientation, impaired memory, peripheral neuropathy, euphoria, impaired cognition, attention, 
mood, psychomotor effects, inappropriate affect, and aberrant behavior. 
The following are the abuse-related AESIs: abuse, overuse, lost/stolen/missing or unaccounted 
product, any aberrant behavior in subjects who drop out of the study supposedly due to lack of 
efficacy, lost to follow-up, noncompliance or overcompliance. Also, any use of a study treatment 
by individuals other than enrolled subjects need to be reported, if any. 
10.4. 
Pregnancy Reporting 
Certain information regarding pregnancy, although not considered an SAE, must be recorded, 
reported, and followed up as indicated. This includes the following: 
Subjects should not become pregnant during the study. If a female subject, or the female partner 
of a male subject, becomes pregnant during any active treatment period, study treatment must be 
discontinued immediately and the investigator must report the pregnancy by submitting the 
appropriate form to Mallinckrodt Global Pharmacovigilance, or designee, within 24 hours of 
confirmation of a pregnancy (ie, positive serum pregnancy test result). The outcome of 
pregnancy (eg, spontaneous abortion, live birth, still birth, congenital anomalies, birth defects) 
must be reported by submitting the appropriate form to Mallinckrodt Global Pharmacovigilance, 
or designee, within 24 hours of the pregnancy outcome being submitted to the study site. If the 
pregnancy results in a live birth, a post-delivery follow-up will be performed at least 28 days 


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after the baby is born and must be reported to Mallinckrodt Global Pharmacovigilance, or 
designee, within 24 hours of the study site becoming aware of the follow-up information. 
10.5. 
Liver Safety: Suggested Actions and Follow-up Assessments 
All events of alanine aminotransferase at least 3 × the upper limit of normal (ULN) and with 
total bilirubin at least 2 × ULN (greater than 35% direct bilirubin) or alanine aminotransferase at 
least 3 × ULN and INR greater than 1.5 (if INR is measured) which may indicate severe liver 
injury must be reported as an SAE as outlined in Section 10.3.4 (excluding studies of hepatic 
impairment or cirrhosis). 
In subjects with cirrhosis and elevated transaminases and bilirubin at baseline, subjects should be 
discontinued if their alanine aminotransferase or total bilirubin level doubles, or if they develop 
new symptoms suggestive of drug induced liver injury (jaundice, malaise, abdominal pain, 
unexplained nausea and anorexia) or decompensation events during the study. 
10.6. 
Clinical Function Scoring 
10.6.1. 
Conn Score 
Subjects will be assessed at screening and every day using the Conn score, to determine if they 
have a worsening in HE, indicated as an increase in their score by 1 or more grades. The Conn 
score (also known as the West Haven Criteria) is an extensively used grading scale for 
assessment of HE severity. It consists of a 5-point scale (Grade 0 to 4) as follows: 
 Grade 0: no apparent personality or behavioral abnormality; 
 Grade 1: trivial lack of awareness, euphoria or anxiety; shortened attention span; 
impairment of addition or subtraction; 
 Grade 2: lethargy; disorientation for time; obvious personality change; inappropriate 
behavior; 
 Grade 3: somnolence to semi-stupor, responsive to stimuli; confused; gross 
disorientation; bizarre behavior; 
 Grade 4: coma; unable to test mental state. 
10.6.2. 
HESA Score 
The HESA score will be assessed at the screening visit to assess study eligibility, and will also be 
assessed on Days 1 through 5/ET, to determine if subjects have a worsening in their condition. 
The HESA implements objective ways of measuring the parameters of the West Haven scale. 
The HESA utilizes clinical indicators combined with validated neuropsychological tools and 
well-defined criteria for each stage (see HESA algorithm in Section 10.8). The use of the HESA 
is still limited and its metric characteristics have not been fully analyzed. One favorable 
characteristic of the HESA is that it identifies low grades of HE precisely. It consists of a 5-point 
scale (Grade 0 to 4), with 4 indicating most severe (Hassanein et al, 2008). 


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10.6.3. 
MELD Score 
Subjects will be assessed at the screening visit to assess eligibility into the trial. Additionally, 
subjects will be assessed at each visit using the MELD score, to determine if they have a 
worsening in their condition. MELD is a scoring system for assessing the severity of chronic 
liver disease. It was initially developed to predict mortality within 3 months of surgery in 
patients who had undergone a transjugular intrahepatic portosystemic shunt procedure and was 
subsequently found to be useful in determining prognosis and prioritizing for receipt of a liver 
transplant. MELD uses the patient’s values for serum bilirubin, serum creatinine, and the INR for 
prothrombin time to predict survival. It is calculated using the following formula:  
MELD = 3.78 × ln[serum bilirubin (mg/dL)] + 11.2 × ln[INR] + 9.57 × ln[serum creatinine 
(mg/dL)] + 6.43 
10.6.4. 
Child-Pugh Score 
Subjects will be assessed at screening and every day using the C-P score, in order to assess the 
prognosis and liver safety evaluations. The C-P score (or the Child–Turcotte–Pugh score or 
Child Criteria) is used to assess the prognosis of chronic liver disease, mainly cirrhosis. Although 
it was originally used to predict mortality during surgery, it is now used to determine the 
prognosis, as well as the required strength of treatment and the necessity of liver transplantation. 
The score employs 5 clinical measures of liver disease. Each measure is scored 1 to 3, with 3 
indicating the most severe damage. 
The C-P classification scheme shown in Table 6 will be used to define 3 subgroups of subjects 
based on their liver function. Each subject will be included in one of the following liver function 
subgroups based on observations and laboratory values at the baseline evaluation: 
 C-P Class A (5-6 points):  
mild liver disease. 
 C-P Class B (7-9 points):  
moderate liver disease. 
 C-P Class C (10-15 points): 
severe liver disease. 
Table 6: 
C-P Classification for Severity of Liver Disease 
Measure 
1 point 
2 points 
3 points 
Encephalopathy 
None 
Minimal 
Advanced (coma) 
Ascites 
Absent 
Controlled 
Refractory 
Total bilirubin (μmol/L) 
Total bilirubin (mg/dL) 
< 34 
< 2 
34 to 50 
2 to 3 
> 50 
> 3 
Albumin (g/dL) 
> 3.5 
2.8 to 3.5 
< 2.8 
Prothrombin time (sec) 
INR equivalent (approximate) 
< 4 
< 1.7 
4 to 6 
1.7 to 2 
> 6 
> 2 


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Table 6: 
C-P Classification for Severity of Liver Disease (Continued) 
Measure 
1 point 
2 points 
3 points 
References: 
Pugh, R.N.H; Murray-Lyon, I.M.; Dawson, J.L.; Pietroni, M.C; Williams, R. Transection of the 
oesophagus for bleeding oesophageal varices. 
Br J Surg. 1973, 60(8),646-649. 
Durand, F.; Valla, D. Assessment of prognosis of cirrhosis. Semin Liver Dis. 2008,28(1), 110-122. 
10.7. 
Common Terminology Criteria for AEs 
CTCAE v5.0 will be used to report adverse events in this study (U.S. HHS CTCAE Version 5.0, 
2017). 
10.8. 
Stages of Hepatic Encephalopathy According to Hepatic 
Encephalopathy Scaling Algorithm (HESA) 
 
Reference: Hassanein et al, 2008. 


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11. 
REFERENCES 
1. Al Sibae, M.R.; McGuire, B.M. Current trends in the treatment of hepatic 
encephalopathy. Ther Clin Risk Manag. 2009, 5, 617 626. 
2. American Association for the Study of Liver Diseases; European Association for the 
Study of the Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice 
guideline by the European Association for the Study of the Liver and the American 
Association for the Study of Liver Diseases. J Hepatol. 2014, 61, 642-659. 
3. Córdoba, J.; López Hellín, J.; Planas, M.; Sabín, P.; Sanpedro, F.; Castro, F.; et al. 
Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J 
Hepatol. 2004, 41, 38 43. 
4. Davies, N.; Wright, G.; Ytrebø, L.M.; et al. L-ornithine and phenylacetate synergistically 
produces sustained reduction in ammonia and brain water in cirrhotic rats. Hepatology. 
2009, 50, 155-164. 
5. Hassanein TI, Hilsabeck RC, Perry W. Introduction to the Hepatic Encephalopathy 
Scoring Algorithm (HESA). Disgestive Diseases and Sciences 2008 53(2):529-38. 
6. Horizon Therapeutics, LLC. RAVICTI; Package Insert: Lake Forest, IL, 2017. 
7. Jalan, R.; Wright, G.; Davies, N.A.; Hodges, S.J. L Ornithine phenylacetate (OP): a novel 
treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses. 2007, 69, 
1064 1069. 
8. Jover-Cobos, M.; Jalan, R.; et al. Ornithine phenylacetate targets alterations in the 
expression and activity of glutamine synthase and glutaminase to reduce ammonia levels 
in bile duct ligated rats. Journal Hepatology. 2014, Mar, 60(3), 545-53. 
9. Kulkarni, A.A.; Arif, H.; Pronesti, V.M.; Frank, E.; Babich, M.; Kapetanos, A. Mo1489   
Evaluation of patients hospitalized with hepatic encephalopathy and prescribed rifaximin 
therapy at a single multi-disciplinary center. Gastroenterology. 2018, 154(6), Supplement 
1, S-730.Kulkarni 
10. Mallinckrodt Inc. MNK6105; Investigator’s Brochure Edition Number 12, 2019: 
Bedminster, NJ. 
11. Mookerjee, R.P.; et al. Treatment of hyperammonaemia with OCR-002 (L-ornithine 
phenylacetate) reduces portal pressure by modulating hepatic Nfkb and hepatic eNOS 
activity in cirrhotic rats. BASL British Association For Study Of The Liver 2009. 
12. Oria, M.; Romero-Giménez, J.; Arranz, J.A.; Riudor, E.; Raguer, N.; Córdoba, J. 
Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by 
intestinal blood in rats with portacaval anastomosis. J Hepatology. 2012, 56(1), 109-14. 
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Ascending Dose Study to Evaluate the Safety and Pharmacokinetics of OCR-002 in 


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Patients with Stable Hepatic Cirrhosis, submitted to IND 107870 in SN0010 on July 12, 
2011. 
14. Study OCR002-HE209. Phase 2B Efficacy/Safety of Ornithine Phenylacetate in 
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ClinicalTrials.gov Identifier: NCT01966419. 
15. Study OCR002-HV201, A Randomized Double-Blind, Placebo-Controlled, Single and 
Multiple Ascending Dose Study to Evaluate the Safety and Pharmacokinetics of OCR-
002 in Healthy Volunteers, submitted to IND 107870 in SN009 on May 24, 2011. 
16. Thibault, A.; Cooper, M.R.; Figg, W.E.; et al. A Phase I and pharmacokinetic study of 
intravenous phenylacetate in patients with cancer. Cancer Res. 1994, 54(7), 1690-1694. 
17. Thibault, A.; Samid, D.; Cooper, M.R.; et al. Phase I study of phenylacetate administered 
twice daily to patients with cancer. Cancer. 1995, 75(12), 2932-8.  
18. U.S. Department of Health and Human Services (HHS). Common Terminology Criteria 
for Adverse Events (CTCAE) Version 5.0. November 27, 2017. 
19. Vairappan, B.; et al. Reduction in hyperammonemia with L-ornithine phenylacetate 
(OCR-002) in bile duct-ligated (BDL) cirrhotic rats restores brain eNOS activity by 
modulating the DDAH - ADMA pathway. AASLD 2009: Boston. 
20. Wijdicks, E.F. Hepatic Encephalopathy. N Engl J Med. 2016, 375, 1660-1670. 
21. Wright, G.; Vairappan, B.; et al. Reduction in hyperammonaemia by ornithine 
phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic 
rats. Liver International 2011 ISSN, 1478-3223. 
22. Ytrebø, L.M.; Kristiansen, R.G.; Maehre, H.; et al. L-ornithine phenylacetate attenuates 
increased arterial and extracellular brain ammonia and prevents intracranial hypertension 
in pigs with acute liver failure. Hepatology. 2009, 50(1), 165-74. 
 


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Approval
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