Clinical trial NCT05638737
Conditions: Non-Cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
Keywords: NASH Non-Cirrhotic Steatohepatitis
Sponsor: AstraZeneca
Start date: 2022-10-26; Completion date: 2024-04-04
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Participants will be in the trial for up to 24 weeks, including a screening period lasting up to 8 weeks, a 12-week treatment period, and a 4-week safety follow-up period

Participants are not expected to directly benefit from treatment during this trial. Participants will help researchers learn more about and how to develop AZD4831 to treat NASH.

Detailed description:
A randomized, double blind, placebo-controlled, parallel-group, multicenter study including a maximum of approximately 90 randomized adult participants with biopsy-proven non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis (NAS ≥ 4, fibrosis stages F1, F2, F3). The study will be conducted at approximately 48 sites across approximately 9 countries.

During screening, the participants will be checked for eligibility and enrolled in the study. Following a 8-week screening period, approximately 90 participants will be randomized in a 1:1 ratio to once daily dosing of AZD4831 or placebo. All participants will be treated once daily with AZD4831 or placebo for 12 weeks. The safety, tolerability, and pharmacodynamics will be evaluated at 12 weeks. This is the first clinical study to test AZD4831 in participants with non-cirrhotic NASH with fibrosis.

Arms: arm 1: AZD4831 arm 2: Placebo
Interventions: intervention 1: AZD4831 intervention 2: Placebo
Intervention descriptions: intervention 1: AZD4831 intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol - 2.0
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Clinical Study Protocol 
Study Intervention
AZD4831 (mitiperstat)
Study Code
D6581C00001
Version
2.0
Date
20 March 2023
A Phase IIa, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate Safety, Tolerability, and Pharmacodynamics of 
AZD4831 (mitiperstat) in Participants with Non-cirrhotic 
Non-alcoholic Steatohepatitis (NASH) with Fibrosis (COSMOS)
Sponsor Name: AstraZeneca AB
Legal Registered Address: SE-15185 Södertälje  Sweden 
Regulatory Agency Identifier Number(s): 
EU CT: 2022-500594-13-00
IND: 158550
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D6581C00001
Amendment Number: 1
Study Intervention: AZD4831 (mitiperstat)
Study Phase: Phase IIa
Short Title: A Phase IIa Study to Assess Safety, Tolerability, and Pharmacodynamics of 
AZD4831 (mitiperstat) in Adult Participants with Non-cirrhotic NASH with Fibrosis 
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(COSMOS)
Study Physician Name and Contact Information will be provided separately
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
20 March 2023
Original Protocol
10 May 2022
Amendment 1: 20 March 2023
Overall Rationale for the Amendment:
The main reasons for this amendment include: 
1
Extension of the Screening period to 8 weeks to allow sufficient time for biopsy 
scheduling and results. 
2
Clarifications to allow shortening of the Screening period for participants with historical 
biopsies and elevated ALT.
3
Inclusion of participants with fibrosis stage F1.
4
Addition of study stopping criteria.
5
Removal of exclusion for women of childbearing potential from the study.
6
Revision of text to align with updated EU CTR guidelines. 
7
Removal of exclusions/restrictions for CYP3A4 perpetrators.
8
Addition of guidelines for handling of skin reactions.
9
Minor revision of several sections for clarification, typographical errors, and 
harmonization across all amendments. 
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Throughout CSP
Added ‘(mitiperstat)’ to 
study intervention name 
Addition of international 
non-proprietary name
Non-substantial
Title page, full title and 
short title; and Section 1.1 
(Synopsis), full title and 
short title
Added ‘COSMOS’ to 
study name
Addition
Non-substantial
Section 1.1 (Synopsis); 
Section 1.2, Figure 1 
(Study Design); Section 
Revised Screening period 
from 6 weeks (42 days) to 
8 weeks (56 days); 
Screening period 
lengthened to allow 
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.2, Table 1 (Study 
Endpoint Assessment); 
Section 1.3, Table 2 
(Schedule of Activities); 
and Section 4.1 (Overall 
Design)
Revised total study 
duration from 
approximately 22 weeks to 
approximately 24 weeks
additional time for biopsy 
scheduling and results
Section 1.1 (Synopsis) and 
Section 4.1 (Overall 
Design
Added ‘Participants, 
including participants who 
are rescreened, can be 
randomized anytime within 
the screening period 
outlined in the SoA 
(Table 2) once all 
inclusion/exclusion criteria 
have been fulfilled. For 
participants who have a 
historical biopsy and 
elevated alanine 
aminotransferase (ALT), 
the screening period can be 
shortened.’
Addition to allow Screening 
period to be shortened for 
participants who do not 
require a fresh biopsy
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Removed ‘Drugs of abuse 
and alcohol screening 
(Section 8.2.5)’ and 
‘Exploratory fasting 
biomarker sampling 
(optional)’ from Visit 3
Reduction of samples taken 
to streamline screening 
period and reduce patient 
burden 
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added footnote ‘a
Participants, including 
participants who are 
rescreened, can be 
randomized anytime within 
the screening period 
outlined in the SoA once all 
inclusion criteria have been 
fulfilled.’
Addition to allow Screening 
period to be shortened for 
participants who do not 
require a fresh biopsy
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added footnote ‘b
Participants with historical 
biopsy and meeting all 
inclusion criteria are not 
required to have Visit 2. All 
participants must have Visit 
1 and 3 prior to 
randomization.’
Addition to allow Screening 
period to be shortened for 
participants who do not 
require a fresh biopsy
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Removed from footnote c
‘other’
Added ‘Visit 1’
Clarification
Non-substantial
Section 5.4 (Screen 
Failures)
Added ‘Participants who 
are rescreened do not need 
to complete the full 
8-week screening period, 
if all inclusion/exclusion 
criteria have been fulfilled. 
However, they must 
complete Visit 1 and Visit 
3, following Table 2.’
Addition to allow Screening 
period to be shortened for 
participants who do not 
require a fresh biopsy
Non-substantial
Section 1.1 (Overall 
Design); Section 2.1 
(Study Rationale); Section 
2.3.3 (Conclusion); 
Section 4.1 (Overall 
Design); Section 4.2 
(Scientific Rationale for 
Study Design); Section 5.1 
(Inclusion Criteria, 
Criterion 2b); Section 8.5.1 
(Liver Biopsy)
Added ‘F1’
Addition to expand 
potential participant 
population
Substantial
Section 1.1 (Synopsis), 
Section 1.2, Table 1 
(Study Endpoint 
Assessment); Section 4.1 
(Overall Design); and 
Section 9.6 (Data 
Monitoring Committee)
Added ‘and study stopping 
criteria’
Clarification to the remit of 
the Data Review Committee
Substantial
Section 7.4 (Study 
Stopping Criteria)
Added Section 7.4, Study 
Stopping Criteria
Addition
Substantial
Section 1.3, Table 2 
(Schedule of Activities)
Removed row ‘FSH’ 
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 5.1 (Inclusion 
Criteria, Criterion 7)
Removed ‘of non-
childbearing potential’
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 5.1 (Inclusion 
Criteria, Criterion 8)
Removed ‘men or’
Revised to allow women of 
childbearing potential into 
the study
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 5.1 (Inclusion 
Criteria, Criterion 8a)
Removed ‘(a) Male 
participants: 
•
Male participants 
must be surgically 
sterile or using an 
acceptable method of 
contraception 
(defined as barrier 
methods in 
conjunction with 
spermicides) during 
treatment and until 
the end of relevant 
systemic exposure in 
the male participant, 
plus a further 90-day 
period. Male study 
participants must not 
donate or bank sperm 
during this same time 
period.’
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 5.1 (Inclusion 
Criteria, Criterion 8b)
Removed ‘(b) For a non-
pregnant woman of 
childbearing potential 
partner, contraception 
recommendations should 
also be considered. 
Acceptable methods of 
contraception include birth 
control pills, injections, 
implants, or patches, 
intrauterine devices, and 
tubal ligation/occlusion. A 
barrier method is not 
necessary if the female 
partner is sterilized.’
Clarification to allow 
women of childbearing 
potential into the study
Substantial
Section 5.1 (Inclusion 
Criteria, Criterion 8c)
Removed ‘and must be of 
non-child-bearing 
potential’
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 5.1 (Inclusion 
Criteria, Criterion 8c)
Added ‘Females of 
childbearing potential who 
are sexually active with a 
non-sterilized male partner 
must agree to use an 
acceptable method of birth 
control, from enrolment 
throughout the study and 
Revised to allow women of 
childbearing potential into 
the study
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
until at least 4 weeks after 
last dose of study 
intervention. Acceptable 
methods of contraception 
include birth control pills, 
injections, implants or 
patches, intrauterine 
devices, and tubal 
ligation/occlusion. The 
following are not 
acceptable methods of 
contraception: periodic 
abstinence (calendar, 
symptothermal, post-
ovulation methods), 
withdrawal (coitus 
interruptus), spermicides 
only, and lactational 
amenorrhoea. Female 
condom and male condom 
should not be used 
together.’
Section 5.1 (Inclusion 
Criteria, Criterion 8c)
Removed ‘Women not of 
childbearing potential are 
defined as women who are 
either permanently 
sterilized (hysterectomy, 
bilateral oophorectomy, or 
bilateral salpingectomy 
[but not tubal ligation]), or 
who are postmenopausal. 
Women will be considered 
postmenopausal if they 
have been amenorrhoeic 
for 12 months prior to the 
planned date of 
randomization without an 
alternative medical cause. 
The following age-specific 
requirements apply:  
- Women < 50 years old 
would be considered 
postmenopausal if they 
have been amenorrhoeic 
for 12 months or more 
following cessation of 
Revised to allow women of 
childbearing potential into 
the study
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
exogenous hormonal 
treatment and follicle-
stimulating hormone 
levels in the 
postmenopausal range.
- Women ≥ 50 years old 
would be considered 
postmenopausal if they 
have been amenorrhoeic 
for 12 months or more 
following cessation of 
all exogenous hormonal 
treatment.’
Section 8.2.5, Table 8 
(Other Clinical Safety 
Labs--Screening Only)
Removed ‘FHS (female 
participants only)’ 
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added row ‘Urine 
pregnancy test’ at Visit 1
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 8.2.5, Table 7 
(Laboratory Safety 
Variables)
Added ‘Pregnancy test (for 
WOCBP only)’
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 8.3.9.1 (Maternal 
Exposure)
Removed ‘Women of 
childbearing potential are 
not allowed to be included 
in this study.  Should a 
pregnancy still occur, the 
IP should be discontinued 
immediately and the 
pregnancy reported to 
AstraZeneca.’
Added ‘Should a 
pregnancy occur, the IP 
should be discontinued 
immediately and the 
pregnancy reported to 
AstraZeneca.’
Revised to allow women of 
childbearing potential into 
the study
Substantial
Section 1.3, Table 2 
(Schedule of Activities)
Removed row 
‘COVID-19 enquiry’
Clarification 
Non-substantial
Section 5.2 (Exclusion 
Criteria; Criterion 15)
Added ‘if clinically 
indicated, based on 
investigator discretion.’
Addition
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 8.2.5, Table 8 
(Other Clinical Safety Labs-
Screening Only)
Added superscript ‘c’ for 
‘COVID-19 testing c’ 
Added footnote ‘c If 
clinically indicated, based 
on investigator discretion’
Addition
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Removed ‘height only 
taken at Screening Visit 
1)’
Clarification 
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added row ‘HbA1c 
testing (Section 8.2.5)’
Added footnote ‘m HbA1c 
results needed to determine 
eligibility.’
Clarification 
Non-substantial
Section 8.2.5, Table 7 
(Laboratory Safety 
Variables)
Added ‘HbA1c’
Clarification 
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added footnote ‘e If 
positive for HIV at Visit 1, 
a reflex test will be 
performed on the remaining 
sample. Further 
confirmation is available 
with optional HIV RNA 
test, available in retest kit. 
If positive for hepatitis C at 
Visit 1, a hepatitis C RNA 
test will be triggered to 
confirm the result.’
Clarification
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added footnote ‘f Urine 
pregnancy test required for 
WOCBP only. If there is a 
suspicion of pregnancy, 
urine pregnancy test 
should be repeated prior to 
first dosing.’
Addition
Substantial
Section 1.3, Table 2 
(Schedule of Activities)
Added footnote ‘k Visit 3 
clinical safety laboratory 
evaluations (chemistry, 
hematology, and urinalysis)
are only required for 
participants who require a 
fresh liver biopsy.’
Clarification
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.3, Table 2 
(Schedule of Activities)
Removed from footnote l 
‘based on investigator 
discretion’
Clarification
Substantial
Section 4.4 (End of Study 
Definition)
Removed ‘A participant is 
considered to have 
completed the study if 
he/she has completed all 
phases of the study 
including the final follow-
up Visit 9, regardless of the 
number of doses of study 
medication they have 
received. Participants who 
have died during the study 
are also considered to have 
completed the study.
The end of the study is 
defined as the date of the 
last expected visit of the last 
participant in the study 
globally.
Guidelines for the 
dissemination of study 
results are provided in 
Appendix D 5.’
Revision of text to align 
with updated EU CTR 
guidelines
Substantial
Section 4.4 (End of Study 
Definition)
Added ‘For the purpose of 
Clinical Trial Transparency 
(CTT) the definition of the 
end of the study differs 
under FDA and EU 
regulatory requirements:
European Union 
requirements define study 
completion as the last visit 
of the last subject for any 
protocol related activity.
Food and Drug 
Administration 
requirements defines two 
completion dates:
Primary Completion Date –
the date that the final 
participant is examined or 
receives an intervention for 
the purposes of final 
Revision of text to align 
with updated EU CTR 
guidelines
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
collection of data for the 
primary outcome measure, 
whether the clinical study 
concluded according to the 
pre-specified protocol or 
was terminated. In the case 
of clinical studies with 
more than one primary 
outcome measure with 
different completion dates, 
this term refers to the date 
on which data collection is 
completed for all of the 
primary outcomes.
Study Completion Date –
the date the final participant 
is examined or receives an 
intervention for purposes of 
final collection of data for 
the primary and secondary 
outcome measures and AEs 
(for example, last 
participant’s last visit), 
whether the clinical study 
concludes according to the 
pre-specified protocol or is 
terminated.
A participant is considered 
to have completed the study 
if they have completed all 
phases of the study 
including the last visit.’
Section 5.1 (Inclusion 
Criteria; Criteria 3, 5, and 
6) and Section 5.2 
(Exclusion Criteria; 
Criterion 20)
Removed ‘prior to 
screening’ 
Added ‘prior to 
randomization’ 
Clarification
Non-substantial
Section 5.1 (Inclusion 
Criteria; Criterion 3)
Removed ‘screening’ 
Added ‘Visit 1’ 
Clarification
Non-substantial
Section 5.1 (Inclusion 
Criteria; Criterion 4)
Removed ‘Increased 
serum ALT level (> ULN 
[41 U/L for men and 
31 U/L for women] but 
< 300 U/L) at screening, 
with historical local serum 
Revised to harmonize 
across local amendments
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
ALT levels > ULN on ≥ 1 
occasion in the 6 months 
prior to screening.’
Added ‘Two increased 
serum ALT measurements 
(ALT > ULN); one 
historical local ALT within 
6 months prior to screening 
and one at screening.’
Section 5.2 (Exclusion 
Criteria, Criterion 2)
Added ‘or hepatitis B core 
antibody’
Clarification
Non-substantial
Section 8.2.5, Table 8 
(Other Clinical Safety Labs-
Screening Only)
Added ‘Hepatitis B core 
antibody’
Clarification
Non-substantial
Section 5.2 (Exclusion 
Criteria; Criterion 12)
Removed
‘allergy/hypersensitivity’
Added ‘drug allergies or 
hypersensitivity’
Clarification
Non-substantial
Section 5.2 (Exclusion 
Criteria, Criterion 13)
Removed ‘Participants with 
hyperthyroidism, 
uncontrolled 
hypothyroidism (including 
but not limited to TSH ≥ 10 
mIU/mL), or any clinically 
significant thyroid disease 
as judged by the 
investigator.’ 
Added ‘Participants with 
hyperthyroidism, 
uncontrolled 
hypothyroidism, or any 
clinically significant thyroid 
disease as judged by the 
investigator. Patients with 
TSH ≥ ULN should be 
excluded.’
Clarification
Substantial
Section 5.2 (Exclusion 
Criteria; Criterion 19)
Removed ‘History of 
substance dependence or 
positive screen for drugs 
of abuse at screening.’
Added ‘Positive screen 
for drugs of abuse at 
screening or admission to 
the study site prior to the 
Clarification
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
administration of the study 
intervention. Note: 
participants who test 
positive for drugs (ie, 
opioids) that are 
prescribed for appropriate 
medical use are eligible to 
participate in the study.’
Section 5.2 (Exclusion 
Criteria; Criterion 22)
Removed ‘Strong 
CYP3A4 inducers or 
inhibitors within 28 days 
prior randomization
(Table 5).’
The co-administration of 
itraconazole (strong 
CYP3A4 inhibitor) with 
AZD4831 (mitiperstat) 
(Clinical DDI study 
D6580C00013) resulted in 
higher exposure of 
AZD4831 (mitiperstat) by 
approximately 30% 
Substantial
Section 5.3.1 (Meals and 
Dietary Restrictions)
Removed ‘Participants 
must refrain from 
consumption of grapefruit 
juice from the start of study 
intervention until the final 
dose.’ 
The co-administration of 
itraconazole (strong 
CYP3A4 inhibitor) with 
AZD4831 (mitiperstat) 
(Clinical DDI study 
D6580C00013) resulted in 
higher exposure of 
AZD4831 (mitiperstat) by 
approximately 30%
Substantial
Section 6.5 (Concomitant 
Therapy)
Removed ‘Cytochrome 
P450-related restricted 
medications are described 
in Table 5. Table 5 is not a 
complete list of potent 
CYP3A4 
inhibitors/inducers. Refer to 
concomitant medications 
summary of product 
characteristics for further 
information and 
clarification.’
The co-administration of 
itraconazole (strong 
CYP3A4 inhibitor) with 
AZD4831 (mitiperstat) 
(Clinical DDI study 
D6580C00013) resulted in 
higher exposure of 
AZD4831 (mitiperstat) by 
approximately 30%
Substantial
Section 6.5 (Concomitant 
Therapy, Table 5)
Removed Table 5, 
Cytochrome P450 -related 
Restricted Medications
Table numbering updated
The co-administration of 
itraconazole (strong 
CYP3A4 inhibitor) with 
AZD4831 (mitiperstat) 
(Clinical DDI study 
D6580C00013) resulted in 
higher exposure of 
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
AZD4831 (mitiperstat) by 
approximately 30%
Section 5.2 (Exclusion 
Criteria, Criterion 29f)
Removed ‘25 μmol/L’
Added ‘ULN’
Clarification
Substantial
Section 5.2 (Exclusion 
Criteria, Criterion 29g)
Removed ‘100000/mm3’ 
Added ‘150000/mm3’
Clarification
Substantial
Section 5.2 (Exclusion 
Criteria; Criterion 30)
Removed ‘seated’ 
Added ‘supine’
Correction 
Non-substantial
Section 5.2 (Exclusion 
Criteria; Criterion 32)
Removed ‘Day’ 
Added ‘Week’
Typographical error
Non-substantial
Section 6.5.1 (Rescue 
Medicine)
Removed section. The 
text in this section has 
been added to section 
8.3.6.1
Sponsor does not consider 
this study to include rescue 
medicines. The protocol has 
been amended to suggest 
treatment for 
maculopapular rash is in 
line with standard treatment 
guidelines.
Non-substantial
Section 8.2.3 (Vital Signs)
Removed ‘3 
measurements’
Added ‘2 measurements’
Correction
Non-substantial
Section 8.2.5, Table 8 
(Other Clinical Safety Labs-
Screening Only)
Added footnote ‘b For 
European countries, alcohol 
urine test will be used.’
Clarification
Non-substantial
Section 8.3.6.1 (Skin 
Reactions, Including 
Maculopapular Rash) and 
Appendix E 5 (Guide to 
Skin Reaction Assessment)
Removed ‘Upon 
investigator discretion, a 
clinical dermatologist can 
be consulted and a skin 
biopsy considered.’
Added ‘Patients should be 
referred to a dermatologist 
if they experience a skin 
reaction or rash that is 
considered severe, serious, 
persists ≥ 7 days, continues 
worsening after 
discontinuing the 
investigational agent, or if 
the investigator deems it 
otherwise necessary. It 
would be recommended that 
the dermatologist determine 
whether the individual 
Clarification to further 
monitor, characterize and 
treat if necessary potential 
skin reactions
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
subject will benefit with 
additional treatment and 
recommended that a biopsy 
is performed if deemed 
necessary by the 
dermatologist in these 
scenarios.’
Appendix E 5 (Guide to 
Skin Reaction Assessment)
Added ‘Photos taken by the 
investigator and participant 
should avoid identifying 
features like the face, use 
adequate lighting, and 
capture both a close-up 
photo(s) of the affected skin 
and photo(s) from farther 
away to give context to the 
size of the affected area and 
the location of the skin 
reaction/rash. Face, tattoos, 
piercings and other 
identifiers must not be seen 
in the photo(s) to avoid 
identification of the 
participant (participant can 
cover them when making 
photo, or these can be 
masked/edited afterwards 
by investigator).’
Clarification
Non-substantial
Appendix E 5 (Guide to 
Skin Reaction Assessment)
Added ‘Participant must 
not send any photo(s) to 
investigator via SMS, e-
mail or in any other way in 
order to keep the data 
privacy and anonymity. 
Investigator may take a 
photo of participant’s 
photo(s) showed on digital 
device (phone, tablet, etc). 
Alternatively, participant 
can print out photo(s) at the 
site visit and give them to 
the site staff for scanning.’
Clarification
Non-substantial
Section 8.3.10 (Medication 
Error, Drug Abuse, and 
Drug Misuse) and 
Added sub-section 
headings in Section 8.3.10 
Revision of text to align 
with updated EU CTR 
guidelines
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix E 4 (Medication 
Error, Drug Abuse, and 
Drug Misuse)
Revised text with minor 
clarifications in Section 
8.3.10 and Appendix E 4 to 
align with EU CTR 
guidelines
Section 8.5 (Human 
Biological Samples)
Removed 
‘Pharmacokinetic samples 
will be disposed of after 
the Bioanalytical Report 
finalization or 6 months 
after issuance of the draft 
Bioanalytical Report 
(whichever is earlier), 
unless consented for future 
analyses.’
Added ‘after the 
Bioanalytical Report 
finalization or 6 months 
after issuance of the draft 
Bioanalytical Report 
(whichever is earlier), 
unless consented for future 
analyses’
Clarification
Non-substantial
Section 8.5.1 (Liver 
Biopsy)
Removed ‘procedure are 
described in the 
Histopathology Manual’ 
Added ‘should follow local 
procedures’
Correction
Non-substantial
Section 8.6.1.1 (Collection 
of Mandatory Sample for 
Genetic Analysis)
Removed ‘PNPLA2’
Added ‘PNPLA3’
Typographical error
Non-substantial
Section 8.6.1.1 (Collection 
of Mandatory Sample for 
Genetic Analysis)
Added ‘or entire gene 
sequencing’ and ‘and 
NASH associated genes’
Clarification
Non-substantial
Section 9.3.1 (Full 
Analysis Set)
Removed ‘the secondary 
pharmacodynamics 
variables as well as for the 
exploratory 
pharmacodynamics 
variables’ 
Added ‘all 
pharmacodynamics 
variables’
Clarification of the analysis 
set (FAS) for all 
pharmacodynamic variables
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 9.4.1 (General 
Considerations)
Removed ‘Baseline will be 
defined as the last non-
missing value on or before 
the day of first dose and on 
or before dose the day of 
randomization (whatever 
occurs first), individually 
for each participant and 
endpoint. The baseline 
value for safety analyses is 
the last non-missing value 
prior to administration of 
the first dose of IP.’ 
Added ‘For analyses both 
on the FAS and on the SAS, 
baseline is defined as the 
last non-missing value prior 
to first dose including 
unscheduled assessments 
that occurs prior to first 
dose.’
Clarification to align 
definition for FAS and SAS 
and have a more clear 
description
Non-substantial
Section 9.4.2.1 (Primary 
Endpoint)
Removed ‘data will also be 
analyzed as relative 
differences, that is (value at 
time t – value at 
baseline)/(value at 
baseline), in a similar mixed 
effects model but without 
log transformation of data.’
Added ‘data will also be 
analyzed as individual 
percental change, that is 
(value at time t – value at 
baseline)/(value at 
baseline)100%, in a similar 
mixed effects model but 
without log transformation 
of data.’
Clarification to present 
results in percent scale 
rather than as relative 
differences
Non-substantial
Section 9.4.2.1 (Primary 
Endpoint) and Section 
9.4.2.2 (Secondary 
Endpoint)
Removed ‘Participant that 
fulfills all of the inclusion 
and none of the exclusion 
criteria’
Added ‘FAS’
Clarification of the analysis 
set (FAS) for all 
pharmacodynamic variables
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix D 6 (Data 
Quality Assurance)
Added clarifying text 
about details found in the 
Monitoring Plan and the 
AstraZeneca Global 
retention and Disposal 
(GRAD) Schedule
Revision of text to align 
with updated EU CTR 
guidelines
Non-substantial
Appendix F 1 
(Introduction)
Added ‘and in possible 
cholestatic DILI’
Clarification to harmonize 
across local amendments
Substantial
Appendix F 8 
(Recommended Stopping 
Criteria)
Added ‘Table F10 Stopping 
Criteria for Possible 
Cholestatic DILI’
Clarification to harmonize 
across local amendments
Substantial


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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE......................................2
TABLE OF CONTENTS......................................................................................................18
LIST OF TABLES................................................................................................................20
LIST OF FIGURES ..............................................................................................................21
LIST OF APPENDICES.......................................................................................................21
1
PROTOCOL SUMMARY ................................................................................ 22
1.1
Synopsis ........................................................................................................... 22
1.2
Schema............................................................................................................. 25
1.3
Schedule of Activities ....................................................................................... 26
2
INTRODUCTION............................................................................................ 30
2.1
Study Rationale ................................................................................................ 30
2.2
Background ...................................................................................................... 30
2.2.1
Disease Background ......................................................................................... 30
2.2.2
MPO and AZD4831 (mitiperstat) Background .................................................. 31
2.3
Benefit/Risk Assessment................................................................................... 32
2.3.1
Risk Assessment ............................................................................................... 32
2.3.2
Benefit Assessment........................................................................................... 35
2.3.3
Conclusion........................................................................................................ 36
3
OBJECTIVES AND ENDPOINTS................................................................... 37
4
STUDY DESIGN ............................................................................................. 39
4.1
Overall Design.................................................................................................. 39
4.2
Scientific Rationale for Study Design ............................................................... 39
4.3
Justification for Dose........................................................................................ 40
4.4
End of Study Definition.................................................................................... 41
5
STUDY POPULATION.................................................................................... 42
5.1
Inclusion Criteria .............................................................................................. 42
5.2
Exclusion Criteria ............................................................................................. 43
5.3
Lifestyle Considerations ................................................................................... 46
5.3.1
Meals and Dietary Restrictions ......................................................................... 47
5.4
Screen Failures ................................................................................................. 47
6
STUDY INTERVENTION ............................................................................... 47
6.1
Study Intervention(s) Administered................................................................... 47
6.1.1
Investigational Products.................................................................................... 47
6.2
Preparation/Handling/Storage/Accountability ................................................... 48
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 49
6.4
Study Intervention Compliance......................................................................... 50


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6.5
Concomitant Therapy........................................................................................ 50
6.6
Dose Modification ............................................................................................ 52
6.7
Intervention After the End of the Study............................................................. 52
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 52
7.1
Discontinuation of Study Intervention............................................................... 52
7.1.1
Temporary Discontinuation............................................................................... 53
7.1.2
Rechallenge ...................................................................................................... 53
7.2
Participant Withdrawal from the Study.............................................................. 54
7.3
Lost to Follow Up............................................................................................. 54
7.4
Study Stopping Criteria..................................................................................... 55
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 55
8.1
Efficacy Assessments........................................................................................ 56
8.2
Safety Assessments........................................................................................... 56
8.2.1
Medical History................................................................................................ 56
8.2.2
Physical Examinations...................................................................................... 57
8.2.3
Vital Signs ........................................................................................................ 57
8.2.3.1
Orthostatic Blood Pressure Measurements and Follow-up of Confirmed 
Orthostatic Hypotension ................................................................................... 57
8.2.4
Electrocardiograms........................................................................................... 58
8.2.5
Clinical Safety Laboratory Assessments............................................................ 59
8.3
Adverse Events and Serious Adverse Events..................................................... 60
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 60
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 61
8.3.3
Causality Collection.......................................................................................... 62
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 62
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 62
8.3.6
Adverse Events of Special Interest.................................................................... 63
8.3.6.1
Skin Reactions, Including Maculopapular Rash ................................................ 63
8.3.6.2
Infection ........................................................................................................... 64
8.3.7
Hy’s Law.......................................................................................................... 64
8.3.8
Reporting of Serious Adverse Events................................................................ 64
8.3.9
Pregnancy......................................................................................................... 65
8.3.9.1
Maternal Exposure............................................................................................ 65
8.3.10
Medication Error, Drug Abuse, and Drug Misuse.............................................. 66
8.3.10.1
Timelines.......................................................................................................... 66
8.3.10.2
Medication Error............................................................................................... 66
8.3.10.3
Drug Abuse....................................................................................................... 66
8.3.10.4
Drug Misuse ..................................................................................................... 66
8.4
Overdose .......................................................................................................... 66
8.5
Human Biological Samples............................................................................... 67
8.5.1
Liver Biopsy..................................................................................................... 67


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8.5.2
Pharmacokinetics.............................................................................................. 68
8.5.2.1
Determination of Drug Concentration ............................................................... 68
8.5.3
Pharmacodynamics........................................................................................... 69
8.6
Human Biological Sample Biomarkers ............................................................. 69
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 69
8.6.1.1
Collection of Mandatory Sample for Genetic Analysis ...................................... 70
8.6.2
Optional Collection of Human Biological Samples for Future Use.................... 70
8.7
Optional Genomics Initiative Sample................................................................ 71
8.8
Medical Resource Utilization and Health Economics ........................................ 71
9
STATISTICAL CONSIDERATIONS................................................................ 71
9.1
Statistical Hypotheses....................................................................................... 71
9.2
Sample Size Determination............................................................................... 71
9.3
Populations for Analyses................................................................................... 72
9.3.1
Full Analysis Set............................................................................................... 72
9.3.2
Safety Analysis Set ........................................................................................... 72
9.3.3
PK Analysis Set ................................................................................................ 72
9.4
Statistical Analyses ........................................................................................... 72
9.4.1
General Considerations..................................................................................... 72
9.4.2
Pharmacodynamics........................................................................................... 73
9.4.2.1
Primary Endpoint.............................................................................................. 73
9.4.2.2
Secondary Endpoint.......................................................................................... 74
9.4.2.3
Exploratory Endpoints ...................................................................................... 74
9.4.3
Safety ............................................................................................................... 74
9.4.4
Analysis of Pharmacokinetic Data..................................................................... 75
9.5
Interim Analysis—Not Applicable .................................................................... 76
9.6
Data Monitoring Committee ............................................................................. 76
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 76
11
REFERENCES............................................................................................... 117
LIST OF TABLES
Table 1
Study Endpoint Assessment..................................................................... 25
Table 2
Schedule of Activities.............................................................................. 26
Table 3
Risk Assessment...................................................................................... 32
Table 4
Investigational Products........................................................................... 47
Table 5
NASH-related Prohibited and Restricted Medications.............................. 51
Table 6
Orthostatic Blood Pressure Criteria and Management .............................. 58
Table 7
Laboratory Safety Variables..................................................................... 59
Table 8
Other Clinical Safety Labs--Screening Only ............................................ 60


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Table 8
Non-invasive Biomarker Assessments ..................................................... 69
Table F9
Recommended Stopping Criteria and Dose Adaptations for Possible 
Hepatocellular DILI in Phase II-III NASH Clinical Trials in Participants 
with Normal or Elevated Baseline ALT (> 1.5 × ULN)a......................... 107
Table F10
Stopping Criteria for Possible Cholestatic DILI ..................................... 109
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 25
Figure F2
Recommended Stopping Criteria and Dose Adaptations for Possible 
Hepatocellular DILI in Participants with Normal/Near Normal ALT at 
Baseline................................................................................................. 110
Figure F3
Recommended Stopping Criteria and Dose Adaptations for Possible 
Hepatocellular DILI in Participants with Elevated ALT at Baseline ....... 111
LIST OF APPENDICES
Appendix A
Optional Genomics Initiative Sample....................................................... 77
Appendix B
Alcohol Use Disorder Identification Test (AUDIT).................................. 80
Appendix C
COVID-19............................................................................................... 82
Appendix D
Regulatory, Ethical, and Study Oversight Considerations......................... 85
Appendix E
Adverse Events Definitions and Additional Safety Information................ 91
Appendix F
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 101
Appendix G
Handling of Human Biological Samples ................................................ 112
Appendix H
Abbreviations ........................................................................................ 114




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Overall Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study 
including a maximum of approximately 90 randomized adult participants with biopsy-proven 
non-cirrhotic non-alcoholic steatohepatitis (NASH) with fibrosis (NAS ≥ 4, fibrosis stages F1, 
F2, F3). The study will be conducted at approximately 48 sites across approximately 
9 countries. 
During screening, the participants will be checked for eligibility and enrolled in the study. 
Following an 8-week screening period, approximately 90 participants will be randomized at 
Visit 4 in a 1:1 ratio to once daily dosing of 5 mg AZD4831 (mitiperstat) or placebo. 
Participants, including participants who are rescreened, can be randomized anytime within the 
screening period outlined in the SoA (Table 2) once all inclusion/exclusion criteria have been 
fulfilled. For participants who have a historical biopsy and elevated alanine aminotransferase 
(ALT), the screening period can be shortened.
All participants will be treated once daily with 5 mg AZD4831 (mitiperstat) or placebo for 12 
weeks. The safety, tolerability, and pharmacodynamics will be evaluated at 12 weeks.
This is the first clinical study to test AZD4831 (mitiperstat) in participants with non-cirrhotic 
NASH with fibrosis.
Disclosure Statement: This is a parallel group treatment study with 2 arms that is participant 
and investigator blinded. 
Number of Participants:
Approximately 300 participants will be screened/enrolled to achieve approximately 
90 participants randomly assigned to study intervention or placebo. 
Note: “Enrolled” means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned/assigned in the study, are considered “screen failures”, unless 
otherwise specified by the protocol. 
Intervention Groups and Duration:
Participants will be randomized to once daily dosing of 5 mg AZD4831 (mitiperstat) or 
placebo. Dosing should be supervised and documented by study staff when study intervention 
is administered in the clinic. 
The study will comprise 3 periods totaling approximately 24 weeks:
!
A screening period of up to 8 weeks


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!
A total treatment period of 12 weeks
!
A safety follow-up period of 4 weeks
Data Review Committee: An unblinded safety data review committee consisting of 
AstraZeneca personnel and an external dermatologist will be set up for ongoing, periodic 
safety monitoring, with a focus on skin reactions and study stopping criteria.
Statistical Methods
The primary pharmacodynamic endpoint of this study is change from baseline to Week 12 in 
alanine aminotransferase (ALT), and it will be assessed through a treatment policy estimand.
This approach will assess the effect of the treatment policy of AZD4831 (mitiperstat) and 
placebo regardless of discontinuation of study medication. The main analysis will be using a 
mixed effects linear model with participant as random effect, treatment, visit, and treatment-
by-visit interaction as fixed effects, and baseline as covariate, including all participants in the 
full analysis set (FAS). Data will be log-transformed before analyses, and results will be back-
transformed to describe relative change versus placebo in value at end of treatment relative to 
baseline.
The null hypothesis of no decrease in ALT comparing AZD4831 (mitiperstat) to placebo will 
be tested versus the alternative hypothesis of a decrease in ALT in favor of AZD4831 
(mitiperstat) to placebo using a one-sided test at 5% significance level. 
The secondary endpoint Pro-C3 will be analyzed in the same way as ALT.
The study has been powered to have at least 80% power to detect a 25% decrease in ALT level 
at end of treatment relative to baseline for AZD4831 (mitiperstat) treated versus placebo 
treated in a one-sided test at 5% significance level, based on the FAS population. ALT 
measurements will be log-transformed before analysis. Under the assumption of a standard 
deviation of 0.50 for change from baseline in log-transformed ALT, and allowing for 10% 
missing data, 45 participants per arm would render the desired power.
Safety analyses will be performed using the safety analysis set, which includes all participants 
who receive at least 1 dose of randomized AZD4831 (mitiperstat) or placebo. Safety data will 
be presented using descriptive statistics unless otherwise specified and will not be formally 
tested.
No multiplicity adjustment for alpha is planned.
All personnel involved with the conduct of the study will remain blinded until database lock at 
12 weeks and protocol violations have been identified and documented. Analyses will be 
performed by AstraZeneca or its representatives.




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1.3
Schedule of Activities
Table 2
Schedule of Activities
Assessment and sampling time points may 
be adjusted based on emerging data.
Screening a
Treatment
Final 
Follow-up
Visit 1
Visit 2 b,c
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8/EDV
Visit 9
Week -8 to -1
Week 0
Week 2
Week 4
Week 8
Week 12
Week 16
Day 1
Day 15
(± 2 d)
Day 29
(± 2d)
Day 57
(± 2 d)
Day 85
(± 2 d)
Day 113
(± 5 d)
Informed consent, including consent for 
genetic testing d
X
Enrollment in RTSM
X
Optional informed consent for Genomics 
Initiative research (Section 8.7, Appendix A)
X
Inclusion/exclusion criteria (Section 4.4)
X
X
Liver Biopsy (Section 8.5.1)
X b,c
Hepatitis B and C and HIV screening
(Section 8.2.5) e
X
Urine pregnancy test (Section 8.2.5) f
X
COVID-19 tests (Section 8.2.5)
X
Demographic data
X
Medical history
X
Concomitant medication
X
X
X
X
X
X
X
X
Drugs of abuse and alcohol screening 
(Section 8.2.5)
X
AUDIT questionnaire (Appendix B)
X
Randomization
X






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c
Visit 2 and the fresh liver biopsy screening are only required if there is no histologically confirmed NASH as diagnosed by liver biopsy within 12 months of 
provision of written informed consent. For participants without a historical biopsy, the screening liver biopsy will be scheduled after all Visit 1 screening 
procedures and once it has been confirmed that the participant meets all other inclusion/exclusion criteria and safety laboratory assessments are available. 
d
Consent and sample collection for mandatory genetic testing will only be conducted in countries where genetic testing is allowed in this study. 
e
If positive for HIV at Visit 1, a reflex test will be performed on the remaining sample. Further confirmation is available with optional HIV RNA test, 
available in retest kit. If positive for hepatitis C at Visit 1, a hepatitis C RNA test will be triggered to confirm the result.
f
Urine pregnancy test required for WOCBP only. If there is a suspicion of pregnancy, urine pregnancy test should be repeated prior to first dosing.
g
Participants will receive study intervention at the site on Day 1, Day 29, and Day 85 and at home once daily on other days. Study intervention will be 
administered after PK sampling. At Visit 4 and Visit 6, study intervention will be administered from a newly dispensed bottle. At Visit 8, study intervention 
will be administered from the previously dispensed bottle (brought from home). 
h
AEs will be collected from the time of first dose (the only exception is related to the predose orthostatic test at Visit 4: if orthostatic hypotension is 
confirmed, it should be reported as an AE, and symptoms related to the measurement of orthostatic vitals if present should also be reported as an AE). SAEs 
will be collected from signing of ICF. 
i
Orthostatic BP will be measured at Visit 4 and at Visit 8 prior to any required blood draw and study intervention and 1-2 hours post dose at Visit 4. 
Orthostatic BP will be measured 1 and 3 minutes after the participant stands.
j
Blood draws for clinical safety, 
 and exploratory fasting biomarker sampling will be drawn predose (where applicable). 
k
Visit 3 clinical safety laboratory evaluations (chemistry, hematology, and urinalysis) are only required for participants who require a fresh liver biopsy.
l
The ANCA sample collected at baseline is to only be tested upon requirement ie, 
 An additional sample should be 
collected if clinically indicated.
m
HbA1c results needed to determine eligibility.
n
If for any reason the sample is not drawn at Visit 4, it may be taken at any visit until the last study visit.
o
In a subset of participants (approximately 20%), 2 additional postdose samples will be collected at Visit 6. Visit 6 sample collection times are: predose, and 
0.5 to 1.5 h and 1.5 to 3 h, with a minimum of 1 hour between the postdose sampling occasions. Once approximately 20% of participants have been tested, 
no further participants would need this additional post dose sampling. 
AE, adverse event; ANCA, antineutrophil cytoplasmic antibody; AUDIT, Alcohol Use Disorder Identification Test; BP, blood pressure; COVID-19, coronavirus 
disease 2019; ECG, electrocardiogram; EDV, early discontinuation visit; HbA1c, hemoglobin A1c; HIV, human immunodeficiency virus; ICF, informed consent 
form; NASH, non-alcoholic steatohepatitis; PCR, polymerase chain reaction; PK, pharmacokinetic(s); RNA, ribonucleic acid; RTSM, randomization and trial 
supply management; SAE, serious adverse event; SoA, schedule of activities; 
CCI
CCI
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2
INTRODUCTION
AZD4831 (mitiperstat) is a highly potent MPOi that is being developed for the management 
of cardiovascular and metabolic disease. AZD4831 (mitiperstat) is hypothesized to delay 
disease progression and potentially reverse disease in NASH with fibrosis through direct 
disease-modifying effects.
2.1
Study Rationale
This Phase IIa study will evaluate the safety and pharmacodynamics of 5 mg AZD4831 
(mitiperstat) in adults with biopsy-proven non-cirrhotic NASH with fibrosis stage F1, F2, or 
F3. 
MPOi AZD4831 (mitiperstat) is a low molecular weight, selective, and irreversible inhibitor 
of MPO that has been associated with improvement in liver inflammation and fibrosis in an 
animal model of NASH. 
2.2
Background
2.2.1
Disease Background
NASH is part of the spectrum of liver diseases known as NAFLD, ranging from simple 
steatosis or non-alcoholic fatty liver to NASH. NAFLD is the most common cause of chronic 
liver disease in Western industrialized countries, and it has an estimated prevalence of 
approximately 6% to 35% worldwide (Bellentani 2017, Younossi et al 2016). NASH is the 
progressive form of the disease with a prevalence of approximately 2% to 3% of the general 
population. NASH can lead to cirrhosis and its complications, hepatocellular carcinoma, and 
end stage liver disease (Bellentani et al 2010). NASH is expected to become the leading 
reason for liver transplantation over the next decade and is an important etiology driving the 
burden of hepatocellular carcinoma (Cholankeril et al 2017, Wong et al 2014, Pais et al 2016).
NASH is closely associated with metabolic risk factors including obesity, T2DM, and 
dyslipidemia. Epidemiological studies have demonstrated the prevalence of comorbid obesity 
and T2DM in approximately 80% and 45% of patients with NASH, respectively (Younossi et 
al 2016). Pathophysiologically, NASH is frequently associated with a hyperinsulinemic or 
insulin resistant state, leading to adipose tissue dysfunction and increased hepatic de novo 
lipogenesis. Therefore, it is believed that both increased adipose tissue lipolysis and hepatic de 
novo lipogenesis contribute to increased liver fat and formation of lipid metabolites causing 
lipotoxicity. Lipotoxicity, oxidative stress, and mitochondrial dysfunction are believed to 
contribute to the hallmarks of NASH including signs of cell death or hepatocyte ballooning, 
lobular or portal inflammation, and ultimately in some patients, liver fibrosis (Marra et al 
2013, Neuschwander-Tetri 2017).
NASH is defined histologically as a multicomponent condition composed of hepatic steatosis, 


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inflammation, and hepatocyte ballooning in varying proportions. NASH differs from steatosis 
alone by the presence of hepatic cell inflammation and injury in response to lipotoxic 
intermediates that are accumulated and metabolized in the steatotic liver. Approximately 25% 
to 35% of patients with NASH develop liver fibrosis (Mishra and Younossi 2012). Fibrosis 
stage (F1 to F4) has been shown to have significant prognostic value in NASH correlating 
with liver-related outcomes and mortality (Angulo et al 2015, Dulai et al 2017). Several 
factors have been shown to increase the risk of liver fibrosis progression to cirrhosis including 
presence of comorbid T2DM, increasing age, hypertension, and high BMI (Angulo 2007, 
Angulo et al 2015).
There are currently no approved pharmacological therapies for NASH, with lifestyle 
modifications being the mainstay of treatment. Many patients do not achieve or maintain 
dietary goals and weight loss. Consequently, the development of new therapies for NASH 
would address a high unmet medical need, particularly given the expected increasing burden 
of this disease in parallel with the rising global prevalence of obesity and especially T2DM 
(Estes et al 2018).
2.2.2
MPO and AZD4831 (mitiperstat) Background
A detailed description of the chemistry, pharmacology, pharmacodynamics, and safety of 
AZD4831 (mitiperstat) is provided in the IB.
MPO is a highly abundant protein mainly present in azurophilic granules of neutrophils, 
constituting 5% of the dry weight of the cells. In addition to neutrophils, there are also data 
suggesting the presence of MPO in monocytes and macrophages. MPO can be secreted and is 
unique in its ability to generate reactive chlorinating species such as hypochlorous acid, the 
active component of bleach, which possesses potent bactericidal and viricidal activities. In 
addition, hypochlorous acid reacts with electron-rich moieties of a large range of biomolecules 
(Nicholls and Hazen 2005).
MPO is deposited and active in the livers of patients with NASH (Rensen et al 2009, Pulli et 
al 2015, Pulli et al 2017). Neutrophils, the principal cell type expressing MPO, are elevated in 
patients with NASH and a high neutrophil to lymphocyte ratio is associated with advanced 
fibrosis (Alkhouri et al 2012). MPO has been identified as part of a proapoptotic and 
profibrotic pathway of progression in NASH via activation of inflammatory myeloid cells, 
hepatocytes, and hepatic stellate cells, with nonclinical studies indicating that MPO knockout 
reduces NASH-induced fibrosis (Pulli et al 2015, Rensen et al 2012). As such, MPO has been 
identified as a potential therapeutic target to ameliorate this disease.
In a diet-induced mouse model of NASH, the MPOi AZD4831 (mitiperstat) at a dose 
providing a plasma exposure predicted to achieve approximately 
 
 (estimated based on PK-pharmacodynamics modeling using data 
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from study 
), demonstrated significant improvement in histological scoring of 
liver inflammation and fibrosis while not affecting steatosis (study
 data on file: 
Study report to be finalized by pre-IND submission). It is hypothesized that AZD4831 
(mitiperstat) will similarly reduce inflammation and fibrosis in patients with NASH, thereby 
limiting progression of the disease and leading to NASH resolution and fibrosis reversal.
AZD4831 (mitiperstat) is a potent inhibitor of extracellular MPO in the micro- and macro-
vasculature but has minimal effect on intracellular MPO activity, thus is expected to have a 
low risk of decreasing host-defense against infections. 
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD4831 (mitiperstat) may be found in the IB.
2.3.1
Risk Assessment
Identified and potential risks of AZD4831 (mitiperstat) along with mitigation strategies are 
shown in Table 3.
Table 3
Risk Assessment
Risk of clinical 
significance
Summary of data/rationale for risk 
Mitigation strategy
AZD4831 (mitiperstat) - Identified Risk
Maculopapular
rash
Generalized maculopapular rash has been observed 
in healthy volunteers in completed global SAD/MAD 
studies at single doses of 45 mg and above and at 
repeated doses of 15 mg and above, at 7-10 days post 
dose. In the Phase IIa study in participants with 
HFpEF, one participant (of 27) had generalized 
maculopapular rash CTCAE Grade 3 at 5 mg 
AZD4831 (mitiperstat) occurring 5 days after up-
titration from 2.5 to 5 mg. In a single-blind multiple-
ascending dose study in healthy Japanese and 
Chinese participants, maculopapular rash CTCAE 
Grade 1 was reported in one Japanese participant (of 
6) on 5 mg AZD4831 (mitiperstat), and 
maculopapular rash Grade 2 was reported in one 
Chinese participant (of 6) on 5 mg AZD4831 
(mitiperstat) and in in 3 Japanese participants (of 6) 
on 10 mg AZD4831 (mitiperstat). See IB Section 6.3 
for further information. 
•
Exclusion of participants 
with ongoing 
allergy/hypersensitivity 
reaction to drugs 
(Section 5.2) 
•
Specific discontinuation 
criteria (Section 7.1)
•
AESI with special data 
collection/eCRF. 
(Section 8.3.6)
•
DRC oversight (Section 9.6)
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2.3.3
Conclusion
The study design aims to minimize potential risks to participants based on the protocol 
inclusion and exclusion criteria, safety monitoring, and other measures (Table 3). Taking into 
account the measures to minimize risk to participants in this study, the potential and identified 
risks associated with AZD4831 (mitiperstat) are justified by the anticipated benefits that may 
be afforded to participants with non-cirrhotic NASH with stage F1-F3 fibrosis.






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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study 
including a maximum of approximately 90 randomized adult participants with biopsy-proven 
non-cirrhotic NASH with fibrosis (NAS ≥ 4, fibrosis stages F1, F2, F3). The study will be 
conducted at approximately 48 sites across approximately 9 countries. 
During screening, the participants will be checked for eligibility and enrolled in the study. 
Following an 8-week screening period, approximately 90 participants will be randomized at 
Visit 4 in a 1:1 ratio to once daily dosing of 5 mg AZD4831 (mitiperstat) or placebo. 
Participants, including participants who are rescreened, can be randomized anytime within the 
screening period outlined in the SoA (Table 2) once all inclusion/exclusion criteria have been 
fulfilled. For participants who have a historical biopsy and elevated ALT, the screening period 
can be shortened.
All participants will be treated once daily with 5 mg AZD4831 (mitiperstat) or placebo for 12 
weeks. The safety, tolerability, and pharmacodynamics will be evaluated at 12 weeks.
An unblinded safety DRC consisting of AstraZeneca personnel and an external dermatologist 
will be set up for ongoing, periodic safety monitoring, with a focus on skin reactions and 
study stopping criteria. Additional details will be contained in the safety DRC charter.
Participants will be in the study for up to 24 weeks, including a screening period of up to 
8 weeks, a 12-week treatment period, and a 4-week safety follow-up period. 
4.2
Scientific Rationale for Study Design
This is the first study to test AZD4831 (mitiperstat) in participants with non-cirrhotic NASH 
with fibrosis.
This is a double-blind, randomized, placebo-controlled, parallel-group, multicenter study. In 
order to focus on the patient population with the greatest need and potential effect on health 
(currently identified as the target population within NASH with fibrosis who warrant 
pharmacologic intervention), this study will be conducted in participants with non-cirrhotic 
NASH with liver fibrosis. Participants with biopsy-proven non-cirrhotic NASH with fibrosis 
(NAS ≥ 4 with a component score of ≥ 1 for steatosis, lobular inflammation, and ballooning, 
as well as liver fibrosis stage F1, F2, F3) will be enrolled. Participants with stage F4 fibrosis 
(cirrhosis, compensated and decompensated) will not be included. 
The study will evaluate safety, tolerability, PK, and pharmacodynamic effects of 1 dose level 
of AZD4831 (mitiperstat) versus placebo, administered once daily for a total of 12 weeks. The 
control group will receive matching placebo; there are no approved pharmacological 


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treatments for NASH that could be used as a comparator. All participants will be treated 
according to local guidelines on standard of care treatment, focusing on treatment of NASH 
symptoms and comorbidities.
The primary endpoint is change from baseline to Week 12 in log-transformed ALT, an 
indicator of hepatocellular injury. The secondary endpoints are Pro-C3 (measured to assess 
extracellular matrix formation) and PK. The study will also assess the safety and tolerability 
of AZD4831 (mitiperstat), including hepatic safety, at 12 weeks compared with placebo, with 
special focus on the incidence of AESIs related to skin reactions (including maculopapular 
rash) and infection, vital signs, clinical laboratory parameters, and ECG. 
The exploratory endpoints include additional non-invasive assessments of
 
which is a composite measure of 
 Additional markers 
 
 will be measured. 
 will be measured to 
assess 
 will be measured to assess 
. Other tools that leverage
 
s an index of NASH 
disease activity and fibrosis. Various non-invasive indices such as 
, and 
have been reported to have value for monitoring of disease and treatment response. 
These indices leverage routinely measured parameters and will be assessed in the current trial.
4.3
Justification for Dose
To date, 4 Phase I clinical studies have been completed in which a total of 36 healthy 
volunteers have been exposed to AZD4831 (mitiperstat) at doses of 5 to 405 mg as single 
doses and 53 healthy volunteers at doses 2.5 to 45 mg as multiple doses. In healthy volunteers, 
AZD4831 (mitiperstat) was generally well tolerated with the exception of generalized 
maculopapular rash seen around 7 to 10 days after the first dose: in the single ascending dose 
study (D6580C00001), 1 out of 6 receiving 45 mg, 1 out of 6 receiving 135 mg, and 2 out of 6 
receiving 405 mg; in the MAD study (D6580C00004), 2 out of 8 receiving 15 mg and 2 out of 
5 receiving 45 mg.
In a single-blind MAD study in Japanese and Chinese healthy volunteers 
(Study D6580C00008), maculopapular rash was reported in 5 of 24 Japanese and Chinese 
healthy volunteers who received AZD4831 (mitiperstat). Maculopapular rash CTCAE Grade 1 
was reported in one of 6 Japanese healthy volunteers on 5 mg AZD4831 (mitiperstat), and 
maculopapular rash Grade 2 was reported in 1 of 6 Chinese healthy volunteers on 5 mg 
AZD9831 and in 3 of 6 Japanese healthy volunteers on 10 mg AZD4831 (mitiperstat).
A Phase IIa study intended to assess target engagement, safety, and tolerability of AZD4831 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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CCI


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(mitiperstat) in participants with HFpEF was prematurely terminated during the COVID-19 
pandemic after meeting predefined target engagement, safety, and tolerability criteria (Study 
D6580C00003). One participant out of 27 receiving 5 mg AZD4831 (mitiperstat) was 
discontinued from study treatment due to CTCAE Grade 3 generalized maculopapular rash.
The dose selection for this study is based on data from the Phase I MAD study (healthy 
volunteers), the Phase II study (HFpEF), and data from the MAD study in Japanese and 
Chinese healthy volunteers. One dose level is being investigated (5 mg) based on expected 
pharmacodynamics and safety. The 5 mg dose is predicted to result in approximately 60% 
MPO inhibition and is the upper safety dose since no rash was observed at doses below 15 mg 
AZD4831 (mitiperstat) in the Phase I MAD study (healthy volunteers), in 1 of 27 participants 
at 5 mg AZD4831 (mitiperstat) in the Phase IIa study (HFpEF), and in 2 of 12 healthy 
volunteers on 5 mg AZD4831 (mitiperstat) in the Japanese and Chinese MAD study. Doses of 
2.5 and 5 mg are currently being investigated in an ongoing Phase IIb/III study 
(D6580C00010) in heart failure with left ventricular ejection fraction > 40%. 
4.4
End of Study Definition
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity.
Food and Drug Administration requirements defines two completion dates:
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated.
A participant is considered to have completed the study if they have completed all phases of 
the study including the last visit. 


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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each participant should meet all the inclusion criteria and none of the exclusion criteria to be 
assigned/randomized to a study intervention. Under no circumstances can there be exceptions 
to this rule. Participants who do not meet the entry requirements are screen failures 
(Section 5.4).
In this protocol, “enrolled” participants are defined as those who sign informed consent. 
“Randomized” participants are defined as those who undergo randomization and receive a 
randomization number.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥ 18 to ≤75 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Participants with histologically confirmed NASH as diagnosed by liver biopsy within 
12 months of provision of written informed consent fulfilling all of the following 
histological criteria and in accordance with the NASH CRN NAFLD Activity Score 
(NAS).
(a) NAS ≥4 with a score of at least 1 in each of the 3 histological components (ie, 
steatosis, lobular inflammation, and ballooning)
(b) Presence of fibrosis stage F1, F2, or F3
Participants without a historical biopsy that meets the above histological criteria should 
be willing to undergo a liver biopsy at screening, result of which subsequently fulfills the 
criteria.
3
Hemoglobin A1c ≤  9.5% (inclusive) at Visit 1  if T2DM present, managed by a stable 
medication (ie, no major dose adjustments in prior 3 months to randomization).
4
Two increased serum ALT measurements (ALT > ULN); one historical local ALT within 
6 months prior to screening and one at screening.
5
Participants with or without diabetes. If participants are on GLP-1 receptor agonists, 
SGLT2 inhibitors, or pioglitazone, the medication has to be stable for at least 6 months 
prior to randomization.


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6
Stable weight for at least 3 months prior to randomization. Stable weight is defined as 
≤5% change.
Reproduction
7
Male and/or female. Contraceptive use by women should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies.
(a) Criterion not applicable to this CSP version.
(b) Criterion not applicable to this CSP version.
(c) Female participants:
!
Female participants must not be pregnant or lactating. 
!
Females of childbearing potential who are sexually active with a non-sterilized 
male partner must agree to use an acceptable method of birth control, from 
enrolment throughout the study and until at least 4 weeks after last dose of study 
intervention. Acceptable methods of contraception include birth control pills, 
injections, implants or patches, intrauterine devices, and tubal ligation/occlusion. 
The following are not acceptable methods of contraception: periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea. Female condom and 
male condom should not be used together.
Informed Consent
9
Capable of giving signed informed consent as described in Appendix D 3, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol 
(including use of sample for genetic testing where allowed).
10 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative.
5.2
Exclusion Criteria
Participants will be excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of, or any existing condition that, in the opinion of the investigator, would 
interfere with evaluation of the study intervention, put the participant at risk, influence the 
participant’s ability to participate or affect the interpretation of the results of the study.
2
Any positive results for HIV infection or positive results for hepatitis B surface antigen or 
hepatitis B core antibody or hepatitis C antibody test.


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3
Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral, or 
autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis; 
hemochromatosis; alpha 1 antitrypsin deficiency; Wilson’s disease).
4
History of cirrhosis and/or hepatic decompensation, including ascites, hepatic 
encephalopathy, or variceal bleeding.
5
Prior or planned liver transplantation.
6
Clinically significant cardiovascular or cerebrovascular disease within the past 3 months, 
including but not limited to, myocardial infarction, acute coronary syndrome, unstable 
angina pectoris, transient ischemic attack, or stroke, or participants who have undergone 
percutaneous coronary intervention or a coronary artery bypass graft within the past 
6 months or who are due to undergo these procedures at the time of screening.
7
Clinically significant inflammatory bowel disease, gastroparesis, or other severe disease 
or surgery affecting the upper gastrointestinal tract (including bariatric surgery) that may 
affect gastric emptying or could affect the interpretation of the safety and tolerability data.
8
Severe congestive heart failure (New York Heart Association Class IV).
9
History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal) or 
uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter or sinus 
node dysfunction with clinically significant pause or second to third degree AV-block 
untreated with pacemaker.
10 History of malignant neoplasms within 5 years prior to screening, except for adequately 
treated basal cell, squamous cell skin cancer, or in situ cervical cancer.
11 Prolonged QT interval (Fridericia-corrected QT interval > 470 ms) on ECG at screening 
(Visit 1), known congenital long QT syndrome, or family history of cardiac sudden death 
at age < 40 years.
12 History or ongoing drug allergies or hypersensitivity reactions to drugs (including but not 
limited to rash, angioedema, acute urticaria).
13 Participants with hyperthyroidism, uncontrolled hypothyroidism, or any clinically 
significant thyroid disease as judged by the investigator. Patients with TSH ≥ULN should 
be excluded.
14 History of psychosis or bipolar disorder. History of major depressive disorder within the 
past year with the participant being clinically unstable, or any history of suicide attempt 
or history of suicidal ideation within the past year at the discretion of the investigator.
15 Participants with a positive SARS-CoV-2 infection test at screening (Visit 1), if clinically 
indicated, based on investigator discretion.
16 Participants with a significant COVID-19 illness within 6 months of enrollment: 
(a) Participants with a diagnosis of COVID-19 pneumonia based on radiological 
assessment.


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(b) Participants with diagnosis of COVID-19 with significant findings from pulmonary 
imaging tests.
(c) Participants with a diagnosis of COVID-19 requiring hospitalization and/or oxygen 
supplementation therapy.
17 History of excessive alcohol consumption, defined as an average weekly intake of 
> 21 drinks/week for males or > 14 drinks/week for females. One drink is equivalent to 
14 g alcohol.
18 Evidence of alcohol dependence as assessed by the AUDIT questionnaire at screening 
(Appendix B).
19 Positive screen for drugs of abuse at screening or admission to the study site prior to the 
administration of the study intervention. Note: participants who test positive for drugs (ie, 
opioids) that are prescribed for appropriate medical use are eligible to participate in the 
study.
20 Recent (within 3 months of randomization) use of drugs approved for weight loss (eg, 
orlistat, bupropion/naltrexone, phentermine-topiramate, phentermine, lorcaserin), as well 
as those drugs used off-label.
21 Participants planning to make significant lifestyle changes to their diet or exercise 
regimen during the conduct of the study.
Prior/Concomitant Therapy
22 Criterion not applicable to this CSP version.
23 High dose vitamin E (> 400 IU) unless on a stable dose within 6 months of screening.
Prior/Concurrent Clinical Study Experience
24 Participation in another clinical study with an IP administered in the last 3 months or 
5 half-lives of the therapy (whichever is longer) at the time of screening.
25 Participation in a clinical study testing anti-obesity medications within 12 months of 
screening. 
26 Recent (within 6 months of screening) use of therapies associated with development of 
NAFLD (eg, systemic corticosteroids, methotrexate, tamoxifen, amiodarone, or long-term 
use of tetracyclines) (Table 5).
27 Recent (within 6 months of screening) use of obeticholic acid or other therapy under 
investigation for NASH (Table 5).
28 Severe allergy/hypersensitivity to any of the proposed study treatments or excipients.
Diagnostic Assessments
29 Abnormal laboratory values including any of the following:
(a) AST or ALT > 5 × ULN.
(b) ALP ≥1.5 × ULN, unless not of hepatic origin.


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(c) Impaired renal function defined as estimated glomerular filtration rate 
≤30 mL/minute/1.73 m2 at screening (estimated according to chronic kidney disease 
epidemiology collaboration) (Inker et al 2021).
(d) Albumin < 35 g/L.
(e) International normalized ratio > 1.3.
(f) TBL > ULN in the absence of known Gilbert’s disease.
(g) Platelets < 150000/mm3.
(h) MELD score ≥ 12.
(i)
Any other clinically significant abnormalities in clinical chemistry, hematology, or 
urinalysis results as judged by the investigator.
30 Severely uncontrolled hypertension defined systolic BP ≥ 180 mmHg and/or diastolic BP 
≥110 mmHg on the average of 2 supine measurements after being at rest for at least 
10 minutes at screening or randomization.
31 Heart rate > 110 bpm or < 50 bpm at randomization.
32 Any clinically significant abnormalities in rhythm, conduction, or morphology of the 
resting ECG, as considered by the investigator at the screening visit (Visit 1) and/or on 
Week −1.
Other Exclusions
33 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
34 Vulnerable participants, eg, kept in detention, protected adults under guardianship, 
trusteeship, or committed to an institution by governmental or juridical order.
35 Judgment by the investigator that the participant should not participate in the study if they 
have any ongoing or recent (ie, during the screening period) minor medical complaints 
that may interfere with the interpretation of study data or are considered unlikely to 
comply with study procedures, restrictions, and requirements.
36 Previous randomization in the present study.
Participants may be rescreened once if the reason for screen failure was transient (including 
but not limited to study-supplied equipment failure or unforeseen personal events that 
mandate missed screening visits) (Section 5.4). Rescreened participants should be assigned the 
same participant number as for the initial screening. Individuals who do not meet a specific 
criterion may have this parameter retested if the investigator determines there is a reason to 
believe that this was caused by a temporary/transient reason.
5.3
Lifestyle Considerations
No restrictions on lifestyle are required.


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5.3.1
Meals and Dietary Restrictions
Participants should fast overnight for at least 8 hours, ie, no food or beverage except water, 
prior to study site visits according to Table 2.
Study intervention can be taken with or without food.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized into the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the investigator’s discretion. Participants that previously withdrew from the 
study are not permitted to be rescreened. Rescreened participants should be assigned the same 
participant number as for the initial screening, and all enrollment assessments and procedures 
(including signing ICF) should be performed again, except the biopsy. Participants who are 
rescreened do not need to complete the full 8-week screening period, if all inclusion/exclusion 
criteria have been fulfilled. However, they must complete Visit 1 and Visit 3, following 
Table 2. Individuals who do not meet a specific criteria may have this parameter retested if the 
investigator determines there is a reason to believe that this was caused by a 
temporary/transient reason. 
Rescreening should be documented so that its effect on study results, if any, can be assessed. 
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s) (including marketed 
product(s) and placebo) intended to be administered to or medical device(s) utilized by a study 
participant according to the study protocol. Study intervention in this study refers to AZD4831 
(mitiperstat) or matching placebo.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
Table 4
Investigational Products
Study Intervention 
Name 
AZD4831 (mitiperstat)
Matching placebo
Dosage level(s)
5 mg
N/A


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Table 4
Investigational Products
Study Intervention 
Name 
AZD4831 (mitiperstat)
Matching placebo
Dosage formulation
Plain, round, biconvex, white, film-coated 
tablet
Plain, round, biconvex, white, film-coated 
tablet placebo
Route of 
administration 
Oral
Oral
Dosing instructions
Once daily
Once daily
Use
Experimental
Placebo-comparator
IMP and NIMP
IMP
IMP
Packaging and 
labeling
Investigational Product will be provided 
in bottles. Labels of bottles with 
AZD4831 (mitiperstat) 5 mg will have 
white background and black description. 
Each bottle will be labeled in accordance 
with Annex VI to CTR 536/2014 and per 
country regulatory requirements.
Investigational Product will be provided 
in bottles. Labels of bottles with 
AZD4831 (mitiperstat) PTM 5 mg will 
have white background and black 
description. Each bottle will be labeled in 
accordance with Annex VI to CTR 
536/2014 and per country regulatory 
requirements.
Sourcing
Provided centrally by AstraZeneca
Provided centrally by AstraZeneca
CTR, clinical trial regulation; IMP, investigational medicinal product; N/A, not applicable; NIMP, non-
investigational medicinal product; PTM, Placebo to Match
6.2
Preparation/Handling/Storage/Accountability
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Study medication will be dispensed to participants in a bottle with a white label. 
Participants will be instructed to take one tablet per day. Each bottle contains 35 tablets, 
and the participant will receive enough bottles to last until the next resupply visit. 
5
The AstraZeneca representative or delegate is responsible for confirming the investigator 
or delegate has recorded the quantities of returned and unused tablets at a participant level 
before the study intervention is destroyed. 


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6
Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual.
6.3
Measures to Minimize Bias: Randomization and Blinding
All participants will be blinded with respect to active or placebo treatment. 
All participants will be centrally assigned to randomized study intervention using an 
IRT/RTSM. This computerized randomization procedure will ascertain allocation concealment 
and will assign the participants 1:1 to AZD4831 (mitiperstat) (5 mg) or placebo. The 
randomization codes will be computer generated and loaded into the IRT/RTSM database. 
Before the study is initiated, the log-in information and directions for the IRT/RTSM will be 
provided to each site. 
The study will be blinded to both participants and investigators/site staff as well as to the 
sponsor (designated sponsor personnel will be unblinded as part of the DRC as described in 
Section 9.6). The IRT/RTSM will provide to the investigator(s) the kit identification number 
to be allocated to the participant at the dispensation visit. Study intervention will be dispensed 
at the study visits summarized in Table 2. Routines for this will be described in the IRT/RTSM 
user manual that will be provided to each center.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The investigator documents and reports the action to AstraZeneca, without 
revealing the treatment given to the participant to the AstraZeneca staff. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented.
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention will affect the 
immediate management of the participant’s condition (eg, antidote available), the investigator 
has the sole responsibility for determining if unblinding of a participants’ intervention 
assignment is warranted. Participant safety must always be the first consideration in making 
such a determination. If a participant’s intervention assignment is unblinded, the sponsor must 
be notified within 24 hours after breaking the blind. The investigator documents and reports 
the action to AstraZeneca, without revealing the treatment given to participant to the 
AstraZeneca staff.


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The randomization list should be sent to the personnel analyzing the PK samples. PK samples 
will be analyzed by the bioanalytical laboratory performing the bioanalyses only for 
participants on active treatment, as referenced in Section 8.5.2.1. To allow for the appropriate 
selection of samples, the bioanalytical laboratory will, therefore, have access to the treatment 
codes but will not share the codes with the sponsor or others involved in the study until the 
blinding is broken for the study.
6.4
Study Intervention Compliance
Study intervention will be administered in clinic on the day of randomization (Day 1, Visit 4), 
Day 29 (Visit 6), and Day 85 (Visit 8). Participants will self-administer study intervention at 
home on other days.
At Visit 8, a new bottle will not be dispensed at the site, and the participant will receive study 
intervention from the bottle they have brought from home. When participants are dosed at the 
site, they will receive study intervention directly from the investigator or designee, under 
medical supervision, after checking treatment was not taken at home before coming to the 
study site. The date, and time if applicable, of dose administered in the clinic will be recorded 
in the source documents and recorded in the eCRF. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention.
When participants self-administer study intervention at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning 
and counting returned tablets during the site visits and documented in the source documents 
and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
Participants will be provided with a dosing card to record the dose intake information (date 
and time) for each dose.
A record of the number of AZD4831 (mitiperstat)/placebo tablets dispensed to and taken by 
each participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays will also be 
recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be evaluated by the investigator/sponsor and recorded along 
with:
!
Decision to keep taking or abstain from the medication
!
Reason for use




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NAFLD, non-alcoholic fatty liver disease; NASH non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-
activated receptor; SGLT2, sodium glucose co-transporter 2
    
6.6
Dose Modification
No dose modifications are allowed during the study.
6.7
Intervention After the End of the Study
There is no planned intervention following the end of the study.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. Participants who permanently discontinue study intervention prior to 
Week 12 will have an EDV as described in Table 2. If study intervention is permanently 
discontinued, the participant should remain in the study, ie, continue to participate in 
scheduled study visits and evaluations. 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. 
At each visit, participants will be instructed to contact the investigator immediately if rash or 
skin reaction has developed. If maculopapular rash CTCAE Grade 1, 2, or 3 has developed, 
the participant must be permanently discontinued from study intervention and AstraZeneca 
medical staff must be informed.
!
CTCAE Grade 1: Macules/papules covering < 10% body surface area with or without 
symptoms (eg, pruritus, burning, tightness)
!
CTCAE Grade 2: Macules/papules covering 10% to 30% body surface area, with or 
without symptoms (eg, pruritus, burning, tightness); limiting instrumental activities of 
daily living (refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc); rash covering > 30% body surface area with or without 
mild symptoms
!
CTCAE Grade 3: Macules/papules covering > 30% body surface area, with moderate or 
severe symptoms; limiting self-care activities of daily living (refer to bathing, dressing 
and undressing, feeding self, using the toilet, taking medications, and not bedridden)
If the participant develops a rash or skin reaction that is not considered a maculopapular rash 
but is a generalized rash/skin reaction or is considered to be an SAE, the participant must be 
permanently discontinued from the study intervention and AstraZeneca medical staff should 


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be informed.
Further information and rash/skin reaction evaluation guidance is provided in Appendix E 5. 
Participants may also be discontinued from the study intervention in the following situations: 
!
Participant decision - The participant is at any time free to discontinue treatment, without 
prejudice to further treatment
!
Lost to follow-up
!
Pregnancy in a female participant
!
AE or other safety reasons as judged by the investigator and/or sponsor, where continued 
treatment may put the participant at undue risk
!
Development of uncontrolled and clinically significant 
 as judged by 
the investigator
!
Severe non-compliance with the CSP 
!
Elevations in liver tests corresponding to possible DILI (Appendix F 8 for details)
Data to be collected at the time of intervention discontinuation and follow-up and any further 
evaluations that need to be completed are noted in Table 2. 
7.1.1
Temporary Discontinuation
Every attempt should be made to maintain participants on the study intervention during the 
course of the study. If the study intervention has been interrupted, it should be re-introduced as 
soon as, in the opinion of the investigator, the participant is able to re-start study treatment. 
Note related to AESI skin reactions (including maculopapular rash): In the event of 
maculopapular rash CTCAE Grade 1, 2, or 3, or any other generalized rash/skin reaction or 
serious rash/skin reaction, study intervention should be permanently discontinued. At each 
visit, participants will be instructed to stop the study intervention and contact the investigator 
immediately if rash or skin reaction has developed. After the participant has been seen by the 
study doctor or designee and the skin reaction is not considered a maculopapular rash CTCAE 
Grade 1, 2, or 3, or any other generalized rash/skin reaction or serious rash/skin reaction, the 
study treatment can be restarted.
7.1.2
Rechallenge
Participants who have temporarily discontinued study intervention can resume treatment as 
soon as, in the opinion of the investigator, the participant is able to re-start study treatment and 
the participant wishes to resume. No minimum time period is necessary before treatment can 
resume.
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If a participant develops maculopapular rash CTCAE Grades 1, 2, or 3 or any other 
generalized rash/skin reaction or serious rash/skin reaction, study intervention should be 
permanently discontinued.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).
!
At the time of withdrawal from the study, if possible, an EDV should be conducted, as 
shown in Table 2 for data to be collected at the time of study withdrawal and follow-up 
and for any further evaluations that need to be completed. 
o
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
!
The reason for participant withdrawal should be recorded in the eCRF.
7.3
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
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!
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
!
Site personnel, or delegated third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get IP. Public sources may be searched for vital status information. If 
vital status is determined as deceased, this will be documented and the participant will not 
be considered lost to follow-up. Sponsor personnel will not be involved in any attempts to 
collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix D.
7.4
Study Stopping Criteria
In the event of any of the following criteria being met, the clinical trial would be stopped if 
confirmed with the DRC.
!
Any one death considered related to AZD4831 (mitiperstat) by the DRC.
!
A difference of 2 patients experiencing SAEs considered related to AZD4831 
(mitiperstat) by the DRC as compared to placebo.
!
One Hy’s Law case on AZD4831 (mitiperstat) (That is: AST or ALT ≥ 3× ULN together 
with Total Bilirubin ≥ 2× ULN, where no other reason, other than the IMP, can be found 
to explain the combination of increases).
!
Five patients who experience the following categories of rash/skin reaction leading to 
permanent discontinuation: CTCAE Grade 2 maculopapular rash, CTCAE Grade 3 
maculopapular rash, other generalized rash/skin reaction not considered maculopapular, 
or other rash/skin reaction not considered maculopapular that is considered as an SAE; 
these would also need to be considered related to AZD4831 (mitiperstat) by the DRC.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in Table 2. Protocol waivers or 
exemptions are not allowed.


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!
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in Table 2, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in Table 2.
!
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 300 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Efficacy Assessments
ALT will be used as a surrogate non-invasive biomarker of hepatocellular injury (Table 8). 
The primary endpoint is change in ALT from baseline and over placebo to Week 12. 
8.2
Safety Assessments
Planned time points for all safety assessments are provided in Table 2. AEs based on 
examinations and tests are described in Section 8.3.5.
8.2.1
Medical History
Complete medical history will include history and current medical conditions past or present 
cardiovascular disorders; respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, 
lymphatic, hematologic, immunologic, dermatological, psychiatric, genitourinary, or any other 
diseases or disorders; drug and surgical history; and history of alcohol and tobacco use.
The AUDIT questionnaire to assess alcohol use habits will be completed at screening only 
(Table 2). The AUDIT questionnaire should be administered by the investigator using the 
latest version, downloaded from https://auditscreen.org. A sample is provided in Appendix B. 
The results will be used for determining participant eligibility (Section 4.4).


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8.2.2
Physical Examinations
!
A complete physical examination will include assessments of the following: general 
appearance; respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 
eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal (including spine and 
extremities) and neurological systems.
!
A brief physical examination will include, at a minimum, assessments of general 
appearance and skin, abdomen, musculoskeletal, cardiovascular, and respiratory systems.
Physical examination will be performed at timepoints as specified in Table 2. 
8.2.3
Vital Signs
Vital signs (supine BP [average of 2 measurements], pulse rate, height, weight, and body 
temperature) will be performed in-clinic at timepoints as specified in Table 2. Vital sign 
assessments are to be collected using equipment supplied by the investigator.
At Visits 4 and Visit 8, the vital signs BP measurements can be used for the predose supine 
measurements for the orthostatic test, if taken after being supine for at least 10 minutes and as 
long as the standing BP measurements are taken after these supine measurements at the time 
intervals described below for the orthostatic BP measurement.
The measurements should be done before any blood sampling. The measurements should be 
preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
8.2.3.1
Orthostatic Blood Pressure Measurements and Follow-up of Confirmed 
Orthostatic Hypotension 
Orthostatic BP measurements will be obtained using a standard sphygmomanometer after 
scheduled supine measurements (1 and 3 minutes after the participant stands) and prior to any 
required blood draw:
!
At baseline (Visit 4, Day 1), orthostatic BP should be measured predose and 1 to 2 hours 
post‑dose.
!
At Week 12 (Visit 8) orthostatic BP should be measured predose.
To minimize chances of orthostatic hypotension related to volume depletion, participants 
should be well hydrated when they come to the clinic for study visits. Supine BP measures 
will be collected after participants have been lying down for at least 10 minutes. To ensure 
that a stable supine BP is obtained, at least 2 systolic and 2 diastolic BP measurements will be 
obtained. If the replicate measurements differ by no more than 10 mmHg and 5 mmHg, 
respectively, the supine BP will be considered stable. The mean value of each replicate (mean 
systolic and mean diastolic value) will represent the baseline BP for that visit. After stable BP 


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is achieved, the participant will stand, and BP measurements will be taken at 1 and 3 minutes 
after the participant stands. If the BP measurements do not meet the criteria for orthostatic 
hypotension, no additional measurement is needed. If the BP measurement meets the criteria 
shown in Table 6, investigators will repeat the supine and standing measurements up to 
2 additional times. The exception is for participants with orthostatic hypotension symptoms: 
In this situation, the orthostatic hypotension AE should be reported based on a single 
orthostatic test sequence.
When evaluating orthostatic vitals, record any symptoms of dizziness or light headedness. 
Record on the AE page in the eCRF. At Visit 4, if orthostatic hypotension is confirmed 
predose and postdose, the orthostatic hypotension AE should be reported twice (predose and 
postdose). The same applies to symptoms related to the measurement of orthostatic vitals: if 
present predose and postdose, it should also be reported as an AE twice (predose and 
postdose).
Table 6
Orthostatic Blood Pressure Criteria and Management
Decrease in BP Indicative of 
Orthostatic Hypotension
Actions
≥ 20 mmHg systolic or 
≥ 10 mmHg diastolic
Repeat the BP measurements (supine and standing) up to 2 additional times, 
unless orthostatic hypotension is present in association with symptoms 
related to the measurement of orthostatic vitals: in such a case the test 
doesn't need to be repeated and the orthostatic hypotension AE and 
symptoms related to the measurement of orthostatic vitals AE should be 
reported based on a single sequence.
If either the 1-minute or 3-minute standing BP meets the orthostatic 
(postural) hypotension criteria, then the sequence is considered indicative of 
orthostatic hypotension. 
If 2 of 2 or 2 of 3 sequences are positive, then orthostatic hypotension is 
confirmed, and an AE of orthostatic hypotension will be reported.
AE, adverse event; BP, blood pressure
For participants with orthostatic hypotension, individualized treatment should be prescribed at 
the investigator’s discretion following local guidelines, including pharmacological (eg, down 
titration of nitrates) or non-pharmacological (eg, hydration) treatments.
8.2.4
Electrocardiograms
Single 12-lead ECG will be obtained after the participant has been resting in a supine position 
for at least 10 minutes, at the visits outlined in Table 2. A digital ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals will be 
used. Interpretation of the clinical safety digital ECG findings will be reviewed and confirmed 
by the investigator and recorded in the eCRF. 


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8.2.5
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken as the visits indicated in Table 2.
AEs based on laboratory tests should be recorded and reported as described in Section 8.3.5.
Additional safety samples, including antineutrophil cytoplasmic antibodies samples, may be 
collected if clinically indicated at the discretion of the investigator. The date and time of 
collection will be recorded on the appropriate eCRF.
The clinical chemistry, hematology, and urinalysis will be performed at a central laboratory.
Table 7
Laboratory Safety Variables
Hematology/Hemostasis (whole blood)
Hemoglobin
Leukocyte differential count (absolute count and 
percent differential)
Leukocyte count
Platelet count
Hematocrit
MCV
MCHC
MCH
RDW
Reticulocyte 
HbA1c
Clinical Chemistry (serum)
Creatinine
Albumin
Bilirubin, total
Potassium
Bilirubin, direct
Calcium, total
Bilirubin, unconjugated, ie, indirect (total – direct)
Sodium
ALP
Creatine kinase
AST
Glucose
ALT
Chloride
Bicarbonate
Phosphorus
Magnesium
Urine
Hb/Erythrocytes/Blood
Glucose
Protein/Albumin
Pregnancy test (for WOCBP only)
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ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Hb, hemoglobin; 
HbA1c, hemoglobin A1c; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin 
concentration; MCV, mean corpuscular volume; RDW, red cell distribution width; 
 
 WOCBP, women of childbearing potential.
Note, in case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, 
refer to Appendix F “Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law,” for further instructions.
Table 8
Other Clinical Safety Labs--Screening Only
Panel Name
Markers
Serology
•
HIV I and II
•
Hepatitis B surface antigen
•
Hepatitis B core antibody
•
Hepatitis C antibody
Immunology a
•
c-ANCA
•
p-ANCA
Substance use
•
Blood alcohol (screening only; whole blood) b
•
Drugs of abuse, standard panel (screening only; urine)
Other
•
COVID-19 (local assessment) c
a
The ANCA sample collected at baseline is to only be tested upon requirement ie, 
 
 based on investigator discretion. An additional sample should be collected if clinically 
indicated.
b
For European countries, alcohol urine test will be used.
c
If clinically indicated, based on investigator discretion.
c-ANCA, cytoplasmic staining antineutrophil cytoplasmic antibodies; p-ANCA, perinuclear-anti-neutrophil 
cytoplasmic antibodies
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix E.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
Adverse events will be collected from time of first dose throughout the treatment period and 
including the follow-up period. The only exception is related to the predose orthostatic test at 
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Visit 4: If orthostatic hypotension is confirmed, it should be reported as an AE, and symptoms 
related to the measurement of orthostatic vitals if present should also be reported as an AE.
Serious adverse events will be recorded from the time of signing of the informed consent 
form.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
sponsor.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
AE Variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date and time when the AE started and stopped
!
Maximum intensity
!
Maximum CTCAE grade for maculopapular rash
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
In case of fatality:


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o
Probable cause of death
o
Date of death
o
Autopsy performed
!
Causality assessment in relation to study procedure(s) 
!
Causality assessment to other medication
8.3.3
Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question “Do you consider that there is a reasonable possibility 
that the event may have been caused by the IP?” 
For SAEs, causal relationship should also be assessed for other medication. Note that for 
SAEs that could be associated with any study procedure the causal relationship is implied as 
‘yes’.
A guide to the interpretation of the causality question is found in Appendix E to the CSP.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit?”, or 
revealed by observation will be collected and recorded in the eCRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated measurements should therefore 
only be reported as AEs if they fulfill any of the SAE criteria, are the reason for 
discontinuation of treatment with the IP or are considered to be clinically relevant as judged 
by the investigator (which may include but not limited to consideration as to whether 
treatment or non-planned visits were required or other action was taken with the study 
intervention, eg, dose adjustment or drug interruption). 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 


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the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6
Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and collection of additional information by the investigator. An AESI 
may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of 
these events in order to characterize and understand them in association with the use of this IP. 
Adverse events of special interest for this study include:
!
Skin reactions, including maculopapular rash
!
Infections
These AESIs are to be reported as described in Section 8.3.1 and Section 8.3.2. 
8.3.6.1
Skin Reactions, Including Maculopapular Rash
If the rash is considered maculopapular, it will be evaluated using CTCAE Grades 1-3 for rash 
maculopapular; if not considered maculopapular, severity will be captured as 
mild/moderate/severe, along with data element components generally used for CTCAE 
grading of other skin reactions, given that CTCAE grading is specific to the particular type of 
skin lesion. For all rashes, various aspects of the rash will be documented, including start/end 
date, morphology of lesions (maculopapular vs other morphologies), body surface area 
impacted, anatomical site(s), symptoms, effect on participant (including ADL impacted), 
concomitant medications, medication administered, and specific rash diagnosis, if available. 
Photos (overview and detailed) should be taken.
Refer Appendix E 5 for further guidance in rash assessment and reporting. 
At all visits, participants will be instructed to contact the investigator immediately if rash or 
skin reaction has developed at any time point during the study. 
Participants who develop skin reactions, including rash, will be asked to return to the clinic for 
an additional visit that will include a full physical exam and collection of blood samples for 
safety, hs-CRP, and PK. If a participant is discontinued from IP and proceeds to the EDV, an 
exploratory biomarker sample and blood and urine samples for metabolite analysis will also 
be collected. The genetic sample should also be collected at the EDV if not previously 
collected from the participant. It is suggested to start with treatment for maculopapular rash, 


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per local standard treatment guidelines (which may include, but not be limited to, a topical 
steroid and/or oral antihistamine). The treatment should be individualized per participant and 
based on investigator discretion. The participant can be provided with a treatment for the skin 
rash, according to clinical management standard. 
Patients should be referred to a dermatologist if they experience a skin reaction or rash that is 
considered severe, serious, persists ≥ 7 days, continues worsening after discontinuing the 
investigational agent, or if the investigator deems it otherwise necessary. It would be 
recommended that the dermatologist determine whether the individual subject will benefit 
with additional treatment and recommended that a biopsy is performed if deemed necessary 
by the dermatologist in these scenarios.
Blood samples should be drawn prior to treatment, if possible, and without delaying treatment.
8.3.6.2
Infection
Infections will be considered AESI in this study. Local laboratory testing for microorganisms 
per local guidelines is requested for serious infections (those that meet SAE criteria) and 
results documented.
8.3.7
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. Refer to Appendix F for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
8.3.8
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 


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aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. If the EDC system 
is not available, then the investigator or other study site staff reports a SAE to the appropriate 
AstraZeneca representative by telephone. The AstraZeneca representative will advise the 
investigator/study site staff how to proceed.
Further guidance on the definition of a SAE is provided in Appendix E.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug.
8.3.9
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
!
If the pregnancy is discovered before the study participant has received any study 
intervention.
8.3.9.1
Maternal Exposure
Should a pregnancy occur, the IP should be discontinued immediately and the pregnancy 
reported to AstraZeneca.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly/birth defect) should be followed up and documented even 
if the participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (Section 8.3.8) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 


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PREGOUT module is used to report the outcome of the pregnancy.
8.3.10
Medication Error, Drug Abuse, and Drug Misuse
8.3.10.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of 
it.  
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow up 
fatal/life-threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the event of medication error, drug abuse or misuse (Section 8.3.8) and 
within 30 days for all other events.
8.3.10.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix E 4.
8.3.10.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix E 4.
8.3.10.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
The full definition and examples of drug misuse can be found in Appendix E 4.
8.4
Overdose
For this study, any dose of study intervention greater than those specified in this protocol 
within the same day will be considered an overdose.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module


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!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (Section 8.3.8) and within 30 days for 
all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. Further details on Handling of Human Biological 
Samples are provided in Appendix G. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.
!
Pharmacokinetic samples may be disposed of or anonymized by pooling, after the 
Bioanalytical Report finalization or 6 months after issuance of the draft Bioanalytical 
Report (whichever is earlier), unless consented for future analyses. Additional analyses 
may be conducted on the anonymized, pooled PK samples to further evaluate and validate 
the analytical method. Any results from such analyses may be reported separately from 
the CSR.
8.5.1
Liver Biopsy
Liver biopsy samples taken at baseline (either historical [collected within 12 months of 
screening] or taken during the screening period) will be assessed locally by a qualified 
pathologist. Details of the liver biopsy should follow local procedures.
Participants must have histologically confirmed NASH as diagnosed by liver biopsy 
(historical or screening) fulfilling the following histological criteria:
!
NAS ≥4 with a score of at least 1 in each of the 3 histological components (ie, steatosis, 
lobular inflammation, and ballooning)
!
Presence of fibrosis stage F1, F2 or F3


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8.5.2
Pharmacokinetics
!
Blood samples will be collected for measurement of concentrations of AZD4831 
(mitiperstat) in plasma as specified in Table 2. 
!
Pharmacokinetic samples will be collected predose; thus, participants should be reminded 
not to take their study medication at home on the day of their clinic visit as they will 
receive study medication in clinic on these days. Therefore, study medication 
administration at Visit 4, Visit 6, and Visit 8 will be in clinic.
!
Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor, eg, for safety reasons. 
!
Plasma samples will be used to analyze the PK of AZD4831 (mitiperstat). Samples 
collected for analyses of AZD4831 (mitiperstat) plasma concentration may also be used 
to evaluate safety or pharmacodynamics aspects related to concerns arising during or after 
the study.
!
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory 
Manual.
!
Dosing cards will be given to the participants at the randomization visit and the 
participants will be asked to fill in the dose intake information (date and time) at home. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files but will not constitute a protocol amendment. The IRB/IEC will be 
informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF.
8.5.2.1
Determination of Drug Concentration
Samples for determination of drug concentration in plasma will be analyzed by or on behalf of 
AstraZeneca, using an appropriately validated bioanalytical method and only for participants 
on active treatment. Only samples from participants on active treatment will be analyzed 
(Section 6.3), unless there is a need to confirm that correct treatment has been given to study 
participants. Full details of the analytical method used will be described in a separate 
Bioanalytical Report. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will not be reported in the 


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CSR, but in a separate Bioanalytical Report. Pharmacokinetic concentrations may be assessed 
during the study for evaluation of the exposure levels.
8.5.3
Pharmacodynamics
Samples for pharmacodynamic assessments will be collected according to the Laboratory 
Manual at timepoints described in Table 2. Non-invasive biomarker assessments are described 
in Section 8.6.1.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Samples for biomarker research are required and will be collected from all participants in this 
study as specified in Table 2. 
Table 8 presents protocol-defined non-invasive biomarker assessments that are part of the 
primary, secondary, or exploratory objectives. 
Table 8
Non-invasive Biomarker Assessments
Assessment
Biomarker
 
ALT
 
Pro-C3, 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI




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defined in the CSP and may include multiplex analysis using biomarker panels.
Samples will be collected, handled, labeled, stored, and shipped as detailed in the Laboratory 
Manual. Storage, re-use, and destruction of exploratory samples are described in Section 8.5
and Appendix F.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in Table 2 and is subject to agreement in the ICF addendum. A blood sample for 
DNA isolation will be collected from participants who have consented to participate in the 
genetic analysis component of the study. Participation is optional. Participants who do not 
wish to participate in the genetic research may still participate in the study. Appendix A for 
information regarding the Genomics Initiative genetic sample. Details on processes for 
collection and shipment and destruction of these samples can be found either in the 
appendices or in the Laboratory Manual. Information on storage and destruction of genetic 
samples is provided in Appendix A.
8.8
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary hypothesis of the study is that once daily dosing of 5 mg AZD4831 (mitiperstat) 
will result in a significant decrease versus once daily dosing of placebo in ALT at end of 
treatment relative to ALT at baseline in a NASH patient population. The safety hypothesis is 
that once daily dosing of 5 mg AZD4831 (mitiperstat) will be safe and tolerable in a NASH 
patient population.
Statistical hypotheses for secondary endpoints are described in Section 9.4, and further details 
will be provided in the SAP. 
No multiplicity adjustment for alpha is planned.
9.2
Sample Size Determination
The study has been powered to have at least 80% power to detect a 25% decrease in ALT level 
at end of treatment relative to baseline for AZD4831 (mitiperstat) treated versus placebo 
treated in a one-sided test at 5% significance level, based on the FAS population. Alanine 
aminotransferase measurements will be log-transformed before analysis. Under the 
assumption of a standard deviation of 0.50 for change from baseline in log-transformed ALT, 


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and allowing for 10% missing data, 45 participants per arm would render the desired power.
9.3
Populations for Analyses
9.3.1
Full Analysis Set
All participants who have been randomized to the study intervention will be included in the 
FAS irrespective of their protocol adherence and continued participation in the study. 
Participants will be analyzed according to their randomized study intervention irrespective of 
whether or not they have prematurely discontinued and irrespective of the treatment they 
actually received. Participants who withdraw consent to participate in the study are included 
up to the date of their study termination. The FAS will be considered the primary analysis set 
for all pharmacodynamics variables.
9.3.2
Safety Analysis Set
All participants who received at least 1 dose of randomized AZD4831 (mitiperstat) or placebo 
will be included in the safety analysis set. Throughout the safety results sections, erroneously 
treated participants (eg, those randomized to AZD4831 (mitiperstat) but actually given 
placebo) will be accounted for in the actual treatment group. A participant who had received 
any dose of the experimental study intervention will be classified as in the experimental IP 
group.
9.3.3
PK Analysis Set
The PK analysis set will consist of all participants in the FAS who have received at least one 
dose of AZD4831 (mitiperstat) and who have at least one PK sample post dose. 
9.4
Statistical Analyses
The SAP will be finalized prior to database lock, and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and secondary endpoints.
9.4.1
General Considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violations have been identified and documented. Analyses will be performed by 
AstraZeneca or its representatives.
Nominal significance will be 5% and all tests will be one-sided. All confidence intervals will 
be 2-sided and 95%. 
No multiplicity adjustment for alpha is planned.


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For analyses both on the FAS and on the SAS, baseline is defined as the last non-missing 
value prior to first dose including unscheduled assessments that occurs prior to first dose.
All summary statistics will be presented in total, divided by fibrosis stage, and divided by 
T2DM status. 
9.4.2
Pharmacodynamics
9.4.2.1
Primary Endpoint
The primary pharmacodynamic endpoint for this study is change from baseline to Week 12 in 
log-transformed ALT. 
The null hypothesis of no decrease in ALT comparing AZD4831 (mitiperstat) to placebo will 
be tested versus the alternative hypothesis of a decrease in ALT in favor of AZD4831 
(mitiperstat) to placebo using a one-sided test at 5% significance level, assessed through a 
treatment policy estimand. The endpoint will be analyzed in a mixed effects linear model with 
participant as random effect, treatment, visit and treatment-by-visit interaction as fixed effects, 
and baseline as covariate. Data will be log-transformed before analyses, and results will be 
back-transformed to describe relative change versus placebo in value at end of treatment 
relative to baseline. Furthermore, data will also be analyzed as individual percental change, 
that is (value at time t – value at baseline)/(value at baseline)100%, in a similar mixed effects 
model but without log transformation of data.
!
Treatment: Treatment with 5 mg AZD4831 (mitiperstat) compared to placebo, 
administered in addition to optimal background therapy for co-morbidities
!
Population: FAS
!
Endpoint: Change from baseline in log-transformed ALT
!
Intercurrent events: Intercurrent events will be ignored (treatment policy strategy) 
and potential missing data imputed
!
Population-level summary: Relative change versus placebo in value at end of 
treatment relative to baseline
Any missing baseline ALT values will be imputed based on existing baseline values of FAS 
participants using PROC MI MCMC, disregarding the treatment group. For postbaseline 
missing ALT values, a distinction in the imputation will be made between non-monotone and 
monotone missing data. Monotone missing data are defined as missing data that constitute the 
end participant follow-up, while non-monotone missing data means that there are observations 
made after the missing time point. Any non-monotone missing data will be replaced using 
PROC MI MCMC while monotone missing data will use PROC MI regression. The 
imputation model will include timepoint, baseline value, and treatment group. More details 
will be described in the SAP.


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9.4.2.2
Secondary Endpoint
For Pro-C3 the null hypothesis of no decrease comparing AZD4831 (mitiperstat) to placebo 
will be tested versus the alternative hypothesis of a decrease in favor of AZD4831 
(mitiperstat) to placebo in the same way as for ALT. Missing observations will be imputed 
using the same method as for missing ALT observations.
Estimand for Pro-C3:
!
Treatment: Treatment with 5 mg AZD4831 (mitiperstat) compared to placebo, 
administered in addition to optimal background therapy for co-morbidities
!
Population: FAS
!
Endpoint: Change from baseline in log-transformed Pro-C3
!
Intercurrent events: Intercurrent events will be ignored (treatment policy strategy) and 
potential missing data imputed
!
Population-level summary: Relative change versus placebo in value at end of treatment 
relative to baseline
Furthermore, all pharmacodynamics data collected will be listed for each participant and 
summarized descriptively (including, but not limited to, mean, SD, minimum, median, 
maximum, geometric mean, geometric coefficient of variation) by treatment and time 
point/visit. Figures of the mean response (absolute change from baseline, and value relative to 
baseline where appropriate) will be used to visualize the average response over time.
It is important to distinguish between non-adherence with, or withdrawal from, randomized 
treatment and discontinuation from the trial. A randomized participant can withdraw from the 
study but not from the analysis. The potential impact of intercurrent events (events that occur 
after treatment initiation and either preclude observation of the variable or affect its 
interpretation [eg, discontinuation of treatment, switching treatment, severe adverse and 
clinical events, lost to follow-up, or withdrawn consent]) apart from rash leading stop of study 
treatment, potential intercurrent events are anticipated to have even distribution between the 
treatment arms.
9.4.2.3
Exploratory Endpoints
Analysis of exploratory endpoints will be described in the SAP. 
9.4.3
Safety
The safety endpoint for this study is safety and tolerability, including hepatic safety, during 
treatment with AZD4831 (mitiperstat) (5 mg) compared with placebo. Safety analyses will be 
performed using the safety analysis set. Safety data will be presented using descriptive 
statistics unless otherwise specified.


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Adverse Events
Adverse events will be coded using the most recent version of the MedDRA that will have 
been released for execution at AstraZeneca. Adverse events will be presented for each 
treatment group by System Organ Class and/or Preferred Term covering number and 
percentage of participants reporting at least one event and number of events where 
appropriate. An overview of AEs will present for each treatment group the included number 
and percentage of participants with any AE, AEs with outcome of death, serious AEs, and AEs 
leading to discontinuation of IP. Separate AE tables will be provided taking into consideration 
seriousness, death, and events leading to discontinuation of IP. An additional table will present 
number and percentage of participants with most common AEs. Most common (eg, frequency 
of > x%, ≥x%) will be defined in the SAP. In accordance with the requirements of the FDA, a 
separate table will present nonserious AEs occurring in more than 5% of participants in any 
treatment group. Key participant information will be presented for participants with AEs with 
outcome of death, serious AEs, and AEs leading to discontinuation of IP. An AE listing for the 
safety analysis set will cover details for each individual AE. Adverse events of special interest 
related to skin reactions, including maculopapular rash, and infection will be presented. Full 
details of AE analyses will be provided in the SAP.
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, min, Q1, median, Q3, and max. For each scheduled 
postbaseline visit, descriptive statistics for all vital sign parameters will be presented for 
observed values and change from baseline. Details of vital sign analyses will be provided in 
the SAP.
Laboratory
Laboratory parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, min, Q1, median, Q3, and max. For each scheduled 
postbaseline visit, descriptive statistics for all clinical chemistry and hematology parameters 
will be presented for observed values and change from baseline. A frequency table presents 
number of participants reporting at least one treatment emergent change in selected laboratory 
parameters. Details of laboratory analyses will be provided in the SAP.
Electrocardiogram
Electrocardiogram evaluation will be summarized and presented by treatment group for 
baseline and for each scheduled postbaseline assessment. More details of ECG analyses will 
be provided in the SAP.
9.4.4
Analysis of Pharmacokinetic Data
Plasma concentrations of AZD4831 (mitiperstat) will be summarized by timepoints and 


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presented in the CSR. If PK data permit, a population PK model may be developed, possibly 
with the support of PK data from other studies, using nonlinear mixed effects regression 
analysis in the NONMEM program. Furthermore, if data allows, the population PK model 
may be coupled with separate pharmacodynamics models. All PK/pharmacodynamics 
modeling will be described in a separate data analysis plan. Moreover, the derived PK 
parameters and the results of any such modeling will be provided in a separate PK and 
population PK/pharmacodynamics report (as an appendix to the CSR or as a stand-alone 
report).
9.5
Interim Analysis—Not Applicable
9.6
Data Monitoring Committee
There will be no data monitoring committee in this study. An unblinded safety DRC consisting 
of AstraZeneca personnel and an external dermatologist will be set up for ongoing, periodic 
safety monitoring, with a focus on skin reactions and study stopping criteria. Additional 
details will be contained in the safety DRC charter. 
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Optional Genomics Initiative Sample
A 1
Use/Analysis of DNA
!
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments, or medications. Therefore, where local regulations and 
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) allow, a blood 
sample will be collected for DNA analysis from consenting participants.
!
This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 
!
The results of genetic analyses may be reported in a separate study summary.
!
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
A 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
!
All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criterion
!
For inclusion in this genetic research, participants must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent 
for the Genomics Initiative sampling and analyses.
Exclusion Criteria
!
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:
o
Previous allogeneic bone marrow transplant
o
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection


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Withdrawal of Consent for Genetic Research: 
!
Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main Clinical Study Protocol.
Collection of Samples for Genetic Research
!
The blood sample for this genetic research will be obtained from the participants at 
Visit 4 randomization. Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding participants who may withdraw due to an AE. If 
for any reason the sample is not drawn at Visit 4, it may be taken at any visit until the last 
study visit. Only one sample should be collected per participant for genetics during the 
study. 
Coding and Storage of DNA Samples
!
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.
!
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA).
!
The link between the participant enrollment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements
!
The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix D.


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Informed Consent
!
The genetic component of this study is optional, and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study center. The principal investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time.
Participant Data Protection
!
AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.
!
Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data Management
!
Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
!
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organizations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers. 
!
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.




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never) scoring 0, the second (eg, less than monthly) scoring 1, the third scoring 2, the fourth 
scoring 3, and the last response (eg, 4 or more times a week) scoring 4. For questions 9 and 
10, which only have 3 responses, the scoring is 0, 2, and 4. A score of 8 or more is associated 
with harmful or hazardous drinking, a score of 13 or more in women, and 15 or more in men, 
is likely to indicate alcohol dependence.


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Appendix C
COVID-19
C 1
Background to COVID-19
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel 
SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new 
virus has rapidly spread across the globe causing the WHO to declare a pandemic situation on 
12 March 2020. The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new 
clinical studies. As the threat of pandemic burden including new outbreaks, locally or globally, 
will impact the further conduct of clinical studies, appropriate risk assessments and mitigation 
measures will need to be taken into consideration in all clinical studies to protect participants, 
site staff, and society as a whole.
Both EMA and FDA as well as national health authorities in Europe have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during COVID-19 pandemic. Since the pandemic situation is evolving, 
guidelines, recommendations, national laws, and local restrictions may change at high pace. 
Given the circumstances of potentially relapsing pandemic or epidemic situation with regard 
to the spread of COVID-19 in future, special attention will be paid to protect participants 
participating in the study and site staff involved in the investigations against infection with 
SARS-CoV-2 as requested by the newly issued EMA guideline.
C 2
Risk Assessment for COVID-19 Pandemic
While there is a theoretical risk that treatment with a myeloperoxidase inhibitor could impair 
host-defense mechanisms, an increased incidence of infection has not been seen in limited 
clinical data with AZD4831 (mitiperstat). Therefore, the risk to participants exposed to SARS-
CoV-2 or to those who suffer from COVID-19 is expected to be similar to the background 
population with the same co-morbidities as those in the study, in particular non-cirrhotic non-
alcoholic steatohepatitis (NASH) with fibrosis. The risk of exposure to infected people cannot 
be completely excluded as the participants may need to expose themselves to public areas (eg, 
commute to the site) and have additional human contact (eg, with site staff and other 
participants of the clinical study).
AstraZeneca has no data on the co-administration of AZD4831 (mitiperstat) and COVID-19 
vaccines being approved. Potential AZD4831 (mitiperstat) vaccine interactions affecting 
patient safety or IMP and vaccine efficacy are therefore unclear.
Measures to mitigate the additional risks caused by COVID-19 are:
!
This study is going to start enrolling only when the sponsor deems it is safe to start the 
study. In addition, the study will not start until the local confinement measures or other 


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safety restrictions linked to the COVID-19 pandemic imposed by the local authorities are 
compatible with safe conduct of the study.
!
Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.
!
Participants will be closely monitored for any signs and symptoms of COVID-19, 
including fever, dry cough, dyspnea, sore throat, and fatigue throughout the study during 
the pandemic. Once clinical signs of infection are reported by participants, the 
investigator needs to determine whether samples can be collected, and safety data can be 
recorded on site. If not, adverse events and concomitant medications will be obtained via 
phone calls. The decision to continue with dosing the participant with the study drugs in 
the event of him/her showing symptoms of COVID-19 infection will be per investigator’s 
discretion.
!
The probability of virus transmission will be controlled as much as possible by:
o
Advice for participant to adhere to local requirements for reduction of the public 
exposure while ambulatory.
o
Confirmation of COVID-19 infection by optional laboratory assessment will be 
conducted based on availability (test capacity and turnaround time) of approved tests 
and on investigator’s discretion.
o
Physical distancing and person-to-person contact restrictions will be applied during 
site visits. 
o
Where physical distancing is not possible, personal protective equipment will be used 
by study participants (surgical face mask, gloves) and staff (for example but not 
limited to masks, gloves, protectors, medical suits) if deemed appropriate by the 
investigators and site staff and guided by local requirements.
o
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing.
!
If site visits are not possible due to local restrictions, home nursing visits may be 
considered after discussion with and approval by the sponsor. Study intervention may be 
delivered direct to participant if appropriate and via sponsor approved courier service.
C 3
Restrictions Related to COVID-19
During the COVID-19 pandemic, participants are advised to adhere to local requirements for 
reduction of the public SARS-CoV-2 exposure while ambulatory. If applicable, prior to 
screening (Visit 1), potential participants should be called to confirm they are not experiencing 
any COVID-19 symptoms and signs and are asked not to attend the site in case of suspected 
infection. If appropriate, participants will be referred to the local health care system. Physical 
distancing and person-to-person contact restrictions will be applied and explained to 
participants while staying at the study site. Where physical distancing is not possible, study 


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participants will be asked to use surgical face masks and/or gloves if deemed appropriate by 
the investigator and site staff and guided by local requirements.
C 4
Data Quality Assurance Related to COVID-19
Monitoring visits at site will be limited to a minimum required as deemed appropriate during 
COVID-19 pandemic, per local regulations.
In addition, where possible, other measures for carrying out protocol related activities, such as 
but not limited to home nursing, may be employed as required.


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Appendix D
Regulatory, Ethical, and Study Oversight Considerations
D 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable ICH Good Clinical Practice (GCP) Guidelines
o
Applicable laws and regulations
!
The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure, 
and other relevant documents (eg, advertisements) must be submitted to an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
contract research organization, but the accountability remains with AstraZeneca.
!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to the sponsor of a serious adverse event (SAE) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.
!
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/ IEC, and investigators.
!
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
o
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations


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!
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
!
Prompt notification by the investigator to the sponsor of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
o
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a subject or the reliability and robustness of the data generated in the 
clinical trial.
!
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately but 
no later than 24 hours of when he or she becomes aware of it.
!
In certain regions/countries, the sponsor has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
o
The sponsor will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/ IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, the sponsor is required to enter 
details of serious breaches into the European Medicines Agency (EMA) Clinical 
Trial Information System (CTIS). It is important to note that redacted versions of 
serious breach reports will be available to the public via CTIS.
!
The investigator should have a process in place to ensure that:
o
the site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach
o
a (potential) serious breach is promptly reported to the sponsor or delegated party, 
through the contacts (e-mail address or telephone number) provided by the sponsor
D 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow 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 completion of the study.


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D 3
Informed Consent ProcessThe investigator or his/her representative will 
explain the nature of the study to the participant or his/her legally authorized 
representative and answer all questions regarding the study.
!
Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
!
Participants who are rescreened are required to sign a new ICF.
D 4
Data Protection
!
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.
!
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the ICF. 
!
The participant must be informed that his/her 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.
D 5
Dissemination of Clinical Study Data
Due to scientific reasons, results (both technical and lay summaries) for this trial will be 
disclosed to EU Clinical Trial Information System within a year from global End of Trial Date 
in all participating countries, as otherwise statistical analysis is not relevant. 
A description of this clinical study will be available on AstraZeneca Clinical Trials and 
ClinicalTrials.gov, as will the summary of the main study results when they are available. The 


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clinical study and/or summary of main study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
D 6
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy, including definition of study-critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan.
!
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan.
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).
!
Study monitors will perform ongoing source data verification as per the 
Monitoring Plan(s) to confirm that data entered into the eCRF by authorized site 
personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH 
GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period, according to the 
AstraZeneca Global retention and Disposal (GRAD) Schedule. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 


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records may be transferred to another location or party without written notification to the 
sponsor. 
D 7
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.
!
Definition of what constitutes source data can be found in source data verification plan.
D 8
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open, which will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.


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Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
D 9
Publication Policy
!
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.
!
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix E
Adverse Events Definitions and Additional Safety 
Information
E 1
Definition of Adverse Events
An adverse event (AE) is the development of any untoward medical occurrence in a patient or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
E 2
Definition of Serious Adverse Events
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital anomaly or birth defect
!
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumors reported during a study should generally be assessed as SAEs. If 
no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be used. In 
certain situations, however, medical judgment on an individual event basis should be applied 
to clarify that the malignant tumor event should be assessed and reported as a non-SAE. For 
example, if the tumor is included as medical history and progression occurs during the study, 
but the progression does not change treatment and/or prognosis of the malignant tumor, the 
AE may not fulfill the attributes for being assessed as serious, although reporting of the 
progression of the malignant tumor as an AE is valid and should occur. Also, some types of 
malignant tumors, which do not spread remotely after a routine treatment that does not require
hospitalization, may be assessed as non-serious; examples in adults include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.


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Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse
Intensity Rating Scale:
!
Mild (awareness of sign or symptom, but easily tolerated)
!
Moderate (discomfort sufficient to cause interference with normal activities)
!
Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix E 2. An AE of severe 


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intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix E 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix E 2.
E 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 


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causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
E 4
Medication Error, Drug Abuse, and Drug Misuse
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an investigational medicinal product (IMP) or AstraZeneca non-
investigational medicinal product (NIMP) that either causes harm to the participant or has the 
potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error:  
!
Occurred 
!
Was identified and intercepted before the participant received the drug 
!
Did not occur, but circumstances were recognized that could have led to an error 
Examples of events to be reported in clinical studies as medication errors: 
!
Drug name confusion 
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant 
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed eg, kept in the refrigerator when it should be at room 
temperature 
!
Wrong participant received the medication (excluding interactive response technology 
[IRT]/ randomization and trial supply management [RTSM] errors) 
!
Wrong drug administered to participant (excluding IRT/RTSM errors) 


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Examples of events that do not require reporting as medication errors in clinical studies: 
!
Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error  
!
Participant accidentally missed drug dose(s) eg, forgot to take medication 
!
Accidental overdose (will be captured as an overdose) 
!
Participant failed to return unused medication or empty packaging 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse regards a person not 
enrolled in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
!
The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)
!
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant). 


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Examples of drug misuse include but are not limited to: 
!
The drug is used with the intention to cause an effect in another person 
!
The drug is sold to other people for recreational purposes  
!
The drug is used to facilitate assault in another person 
!
The drug is deliberately administered by the wrong route 
!
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 
!
Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose 
!
Someone who is not enrolled in the study intentionally takes the drug 
E 5
Guide to Skin Reaction Assessment
This Appendix describes the process to be followed to appropriately identify, assess, and 
report cases of skin reactions. Skin reactions, including maculopapular rash, will be 
considered AEs of special interest in this study. To ensure that data are collected 
systematically, any skin reaction will be recorded on a special eCRF page. All skin reactions 
should be recorded and reported as AEs or SAEs.
If the rash is considered maculopapular, it will be evaluated using Common Terminology 
Criteria for Adverse Events (CTCAE) Grades 1 to 3 for rash maculopapular; if not considered 
maculopapular, severity will be captured as mild/moderate/severe, along with data element 
components generally used for CTCAE grading of other skin reactions, given that CTCAE 
grading is specific to the particular type of skin lesion. For all rashes, various aspects of the 
rash will be documented, including start/end date, morphology of lesions (maculopapular vs 
other morphologies), body surface area impacted, anatomical site(s), symptoms, effect on 
participant (including activities of daily living [ADL] impacted), concomitant medications, 
medication administered, and specific rash diagnosis, if available. 
If maculopapular rash Grade 1, 2, or 3 has developed, participant must be permanently 
discontinued from IP, and AstraZeneca medical staff should be informed. 
If the participant develops a rash or skin reaction that is not considered a maculopapular rash, 
the participant must permanently discontinue if the rash/skin reaction is considered an SAE or 
is a generalized rash/skin reaction. AstraZeneca medical staff should be informed.
At all visits, participants will be instructed to contact the investigator immediately if rash has 
developed at any time point during the study. Participants will be recommended to make an 
acceptable quality self-photo of skin affected with rash.


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Participants who develop skin reactions, including rash, will be asked to return to the clinic for 
an additional visit that will include a full physical examination and blood samples for safety, 
high-sensitivity C-reactive protein (hs-CRP), and pharmacokinetics (PK). If a participant is 
discontinued from investigational product and proceeds to the early discontinuation visit 
(EDV), exploratory biomarker sample and blood and urine samples for exploratory metabolite 
analysis will also be collected. The mandatory genetic sample per Section 8.6.1 should also be 
collected at the EDV if not previously collected from the participant. Initiation of treatment 
for maculopapular rash is suggested, in line with local standard treatment guidelines which 
could include, but not limited to, a topical steroid and/or oral antihistamine. The treatment 
should be individualized per participant and based on investigator discretion. The participant 
can be provided with a treatment for the skin rash, according to clinical management standard. 
Patients should be referred to a dermatologist if they experience a skin reaction or rash that is 
considered severe, serious, persists ≥ 7 days, continues worsening after discontinuing the 
investigational agent, or if the investigator deems it otherwise necessary. It would be 
recommended that the dermatologist determine whether the individual subject will benefit 
with additional treatment and recommended that a biopsy is performed if deemed necessary 
by the dermatologist in these scenarios.
Blood samples should be drawn prior to treatment, if possible, and without delaying treatment.
The investigator should make quality photo(s) of participant’s skin affected with rash, that 
will allow the evaluation of rash according to the guidance given in this section. Photos taken 
by the investigator and participant should avoid identifying features like the face, use adequate 
lighting, and capture both a close-up photo(s) of the affected skin and photo(s) from farther 
away to give context to the size of the affected area and the location of the skin reaction/rash. 
Face, tattoos, piercings, and other identifiers must not be seen in the photo(s) to avoid 
identification of the participant (participant can cover them when making photo, or these can 
be masked/edited afterwards by investigator).
Participant must not send any photo(s) to investigator via SMS, e-mail, or in any other way in 
order to keep the data privacy and anonymity. Investigator may take a photo of participant’s 
photo(s) showed on digital device (phone, tablet, etc). Alternatively, participant can print out 
photo(s) at the site visit and give them to the site staff for scanning. 
The Common Terminology Criteria for AEs is a descriptive terminology that can be used for 
AE reporting.
In general, CTCAE Guidelines describe the Grades of AE severity from 1 to 5:
Grade 1:
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated


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Grade 2:
Moderate; minimal, local, or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL*
Grade 3:
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.
Note: for Maculopapular rash, only 3 CTC Grades exist:
Maculo-Papular Rash
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as 
morbilliform rash, it is one of the most common cutaneous AEs, frequently affecting the upper trunk, 
spreading centripetally, and associated with pruritis.
Grade 1
Macules/papules covering < 10% Body Surface Area with or without symptoms (eg, pruritus, 
burning, tightness)
Grade 2
Macules/papules covering 10 - 30% Body Surface Area, with or without symptoms (eg, pruritus, 
burning, tightness); limiting Instrumental Activities of Daily Living*; rash covering > 30% Body 
Surface Area with or without mild symptoms
Grade 3
Macules/papules covering > 30% Body Surface Area, with moderate or severe symptoms; 
limiting Self-care Activities of Daily Living **
CTCAE v5.0 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf
To assess the Body Surface Area affected by rash, follow the algorithm described below:
Area
Number of palms
Percent area
Whole body
100
100%
Head and Neck
10
10%
Upper extremities
20
20%
Trunk
30
30%
Lower extremities
40
40%


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The participant’s palm is defined as ”1”, representing 1% of total Body Surface Area. 
Total Body Surface Area = 100% (100 palms). 


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Appendix F
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
F 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
Specific guidance on stopping criteria and dose adaptations in possible hepatocellular drug-
induced liver injury (DILI) and in possible cholestatic DILI can be found in Appendix F 8 of 
the CSP.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine aminotransferase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory. 
The investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the IMP. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious adverse events (SAEs) and AEs according to the outcome of the review and 
assessment in line with standard safety reporting processes.
F 2
Definitions
Potential Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2× ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP. 
Hy’s Law
AST or ALT ≥3× ULN together with TBL ≥2× ULN, where no other reason, other than the 


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IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
F 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥3 × ULN
!
AST ≥3 × ULN
!
TBL ≥2 × ULN 
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:
!
Notify the AstraZeneca representative.
!
Request a repeat of the test (new blood draw) by the central laboratory without delay.
!
Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result.
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:
!
Determine whether the participant meets PHL criteria (definition in Section F 2) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results).


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F 4
Follow-up
F 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the investigator will:
!
Inform the AstraZeneca representative that the participant has not met PHL criteria. 
!
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
F 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team.
!
Within 1 day of PHL criteria being met, the investigator will report the case as a SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.
!
For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition.
!
The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data.
!
Subsequent to this contact the investigator will:
o
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Complete follow-up SAE Form as required.
o
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the HL lab kit should be used.
o
Complete the 3 Liver eCRF Modules as information becomes available. 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.


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F 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.
!
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
o
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply.
o
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to IMP and seriousness criteria 
is medically important, according to CSP process for SAE reporting.


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!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
F 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention 
This section is applicable to participants who meet PHL criteria on study intervention, having 
previously met PHL criteria at a study visit prior to starting study intervention.
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participants’ condition# compared with 
the last visit where PHL criteria were met#.
!
If there is no significant change no action is required.
!
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section F 4.2. 
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.


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F 7
Laboratory Tests
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 


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F 8
Recommended Stopping Criteria
Table F9
Recommended Stopping Criteria and Dose Adaptations for Possible 
Hepatocellular DILI in Phase II-III NASH Clinical Trials in Participants 
with Normal or Elevated Baseline ALT (> 1.5 × ULN)a
Treatment 
Emergent ALT 
Elevations
TBL Values at Time of 
Treatment Emergent 
ALT Elevation
Presence of 
Liver-related 
Symptomsb
Action
NASH Participants with Near Normal ALT at Baselinec
≥3 × ULN but 
< 5 × ULN
< 2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin < 2 ×
baseline AND INR ≤ 1.5
Absent
Repeat ALT, AST, ALP, TBL in 2-3 days.
Follow-up for symptoms.
Present
Repeat ALT, AST, ALP, TBL in 2-3 days.
Follow-up for symptoms.
Initiate evaluation for other etiologies of 
abnormal liver tests.
TBL ≥2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin ≥2 ×
baseline or INR > 1.5
Irrespective of 
symptoms
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
≥5 × ULN but 
< 8 × ULN
< 2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin < 2 ×
baseline AND INR ≤1.5
Absent
Repeat ALT, AST, ALP, TBL in 2-3 days.
Follow-up for symptoms.
Initiate evaluation for other etiologies of 
abnormal liver tests.
Present
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
TBL ≥2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin ≥2 ×
baseline or INR > 1.5
Irrespective of 
symptoms
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
≥8 × ULN
Irrespective of TBL
Irrespective of 
symptoms
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
NASH Participants with Elevated ALT at Baselinec
≥2 × baseline but 
< 3 × baseline 
AND (<  300 U/L)
< 2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin < 2 ×
baseline AND INR ≤1.5
Absent
Repeat ALT, AST, ALP, TBL in 2-3 days.
Follow-up for symptoms.
Present
Repeat ALT, AST, ALP, TBL in 2-3 days.
Follow-up for symptoms.


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Table F9
Recommended Stopping Criteria and Dose Adaptations for Possible 
Hepatocellular DILI in Phase II-III NASH Clinical Trials in Participants 
with Normal or Elevated Baseline ALT (> 1.5 × ULN)a
Treatment 
Emergent ALT 
Elevations
TBL Values at Time of 
Treatment Emergent 
ALT Elevation
Presence of 
Liver-related 
Symptomsb
Action
Initiate evaluation for other etiologies of 
abnormal liver tests.
TBL ≥2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin ≥2 ×
baseline or INR > 1.5
Irrespective of 
symptoms
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
(≥3 × baseline but 
< 5 × baseline 
AND < 500 U/L)
or
(≥300 U/L AND 
< 500 U/L AND 
< 5 × baseline)
< 2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin < 2 ×
baseline AND INR ≤1.5
Absent
Repeat ALT, AST, ALP, TBL in 2-3 days.
Follow-up for symptoms.
Initiate evaluation for other etiologies of 
abnormal liver tests.
Present
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
TBL ≥2 × ULN
Participants with 
Gilbert’s syndrome: 
direct bilirubin ≥2 ×
baseline or INR > 1.5
Irrespective of 
symptoms
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
≥5 × baseline 
or ≤500 U/L
Irrespective of TBL
Irrespective of 
symptoms
Interrupt study drug. Initiate close monitoring 
and workup for competing etiologies. Study drug 
can be restarted only if another etiology is 
identified, and liver enzymes return to baseline.
a
Adapted from: (Regev et al 2019)
b
Liver-related symptoms include: severe fatigue, nausea, vomiting, right upper quadrant pain
c
Baseline ALT is derived from an average of 2 pretreatment ALT measurements at least 2 weeks apart. 
Elevated baseline is defined as ALT ≥1.5 × ULN. If on treatment a participant has 2 or more consecutive 
ALT values, at least 2 weeks apart, each less than 50% of the baseline ALT with any 2 consecutive values 
being within 40% of each other (with percentage calculated based on the larger value as the denominator), 
then a new baseline should be set to be the minimum of the latest consecutive pair of values that are 
“stable” (ie, within 40% of each other).
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-
induced liver injury; INR, international normalized ratio; NASH, non-alcoholic steatohepatitis; TBL, total 
bilirubin; ULN, upper limit of normal


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Table F10
Stopping Criteria for Possible Cholestatic DILI
Criteria
Action
!
ALP ≥ 2 ULN and DBL ≥ 2 ULN (if subject 
has Gilbert’s syndrome) or
!
ALP ≥ 2 ULN and TBL ≥ 2 ULN 
!
ALP ≥ 2 ULN and TBL/DBL ≥ 2 ULN and 
INR > 1.5 
!
ALP ≥ 2 ULN and TBL/DBL ≥ 2 ULN and 
symptoms of clinical hepatitis
Interrupt study drug. Initiate close monitoring and 
workup for competing etiologies. Study drug can be 
restarted only if another etiology is identified, and
laboratory and clinical symptoms have resolved.
Liver-related symptoms include: severe fatigue, nausea, vomiting, right upper quadrant pain


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Figure F2
Recommended Stopping Criteria and Dose Adaptations for Possible Hepatocellular DILI in Participants with 
Normal/Near Normal ALT at Baseline
a
Liver-related symptoms include: severe fatigue, nausea, vomiting, right upper quadrant pain
Baseline ALT is derived from an average of 2 pretreatment ALT measurements at least 2 weeks apart. Elevated baseline is defined as ALT > 1.5 × ULN. If on 
treatment a participant has 2 or more consecutive ALT values, at least 2 weeks apart, each less than 50% of the baseline ALT with any 2 consecutive values 
being within 40% of each other (with percentage calculated based on the larger value as the denominator), then a new baseline should be set to be the minimum 
of the latest consecutive pair of values that are “stable” (ie, within 40% of each other).
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; INR, international normalized 
ratio; TBL, total bilirubin; ULN, upper limit of normal


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Figure F3
Recommended Stopping Criteria and Dose Adaptations for Possible Hepatocellular DILI in Participants with 
Elevated ALT at Baseline
a
Liver-related symptoms include: severe fatigue, nausea, vomiting, right upper quadrant pain
Baseline ALT is derived from an average of 2 pretreatment ALT measurements at least 2 weeks apart. Elevated baseline is defined as ALT > 1.5 × ULN. If on 
treatment a participant has 2 or more consecutive ALT values, at least 2 weeks apart, each less than 50% of the baseline ALT with any 2 consecutive values 
being within 40% of each other (with percentage calculated based on the larger value as the denominator), then a new baseline should be set to be the minimum 
of the latest consecutive pair of values that are “stable” (ie, within 40% of each other).
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; INR, international normalized 
ratio; TBL, total bilirubin; ULN, upper limit of normal


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Appendix G
Handling of Human Biological Samples
G 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Biobank Team 
during the entire sample life cycle.
G 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.
!
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures that the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and that the action documented, and the study site is notified.


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G 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B, or Exempt.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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Appendix H
Abbreviations
Abbreviation or special 
term
Explanation
ADL
activities of daily living
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase/transaminase
AST
aspartate aminotransferase/transaminase
AUDIT
Alcohol Use Disorder Identification Test
AV
atrioventricular
BMI
body-mass index
BP
blood pressure
bpm
beats per minute
COVID-19
coronavirus disease 2019
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CYP3A4
Cytochrome P450 3A4
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DRC
Data Review Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
EDC
electronic data capture
EDV
early discontinuation visit
FAS
full analysis set
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
CCI
CCI
CCI
CCI
CCI
CCI


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Abbreviation or special 
term
Explanation
HbA1c
hemoglobin A1c
HFpEF
heart failure with preserved ejection fraction
HIV
human immunodeficiency virus
Hs-CRP
high-sensitivity C-reactive protein
IATA
International Airline Transportation Associations
IB
Investigator’s Brochure
ICF
informed consent form
IEC
independent ethics committee
IMP
investigational medicinal product
IP
investigational product
IRB
Institutional Review Board
IRT
interactive response technology
MAD
Multiple Ascending Dose
MCMC
Markov chain Monte Carlo
MELD
model for end-stage liver disease
MI
multiple imputation
MPO
myeloperoxidase
MPOi
myeloperoxidase inhibitor
NAFLD
non-alcoholic fatty liver disease
NAS
non-alcoholic fatty liver disease activity score
NASH
non-alcoholic steatohepatitis
NFS
non-alcoholic fatty liver disease fibrosis score
NIMP
non-investigational medicinal product
PHL
potential Hy’s Law
PK
pharmacokinetic(s)
Pro-C3
released N-terminal propeptide of type III collagen
PROC
The PROC step consists of a group of SAS statements that call and execute a 
procedure
RTSM
randomization and trial supply management
SAE
serious adverse event 
CCI
CCI
CCI
CCI


Clinical Study Protocol - 2.0
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CONFIDENTIAL AND PROPRIETARY
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Abbreviation or special 
term
Explanation
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
ULN
upper limit of normal
CCI
CCI


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11
REFERENCES
Alkhouri et al 2012
Alkhouri N, Morris-Stiff G, Campbell C, Lopez R, Tamimi TAR, Yerian L, et al. Neutrophil to 
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nonalcoholic fatty liver disease. Liver Int. 2012;32(2):297-302.
Angulo 2007
Angulo P. GI epidemiology: Non-alcoholic fatty liver disease. Aliment Pharmacol Ther 
2007;25(8):883-9.
Angulo et al 2015
Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et 
al. Liver fibrosis, but no other histologic features, associates with long-term outcomes of 
patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149(2):389-97.e10.
Bellentani et al 2010
Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver 
disease. Dig Dis. 2010;28(1):155-61.
Bellentani 2017
Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int. 2017;37 Suppl 
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Cholankeril et al 2017
Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non-alcoholic 
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Dulai et al 2017
Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality 
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Hepatology. 2017;65(5):1557-65. 
Estes et al 2018
Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic 
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Inker et al 2021
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Marra et al 2013
Marra F, Lotersztajn S. Pathophysiology of NASH: perspectives for a targeted treatment. Curr 
Pharm Des. 2013;19(29):5250-69.
Mishra and Younossi 2012
Mishra A, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver 
disease. J Clin Exp Hepatol. 2012;2(2):135-44.
Nalbantoglu and Brunt 2014
Nalbantoglu ILK, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J 
Gastroenterol. 2014;20(27):9026-37. 
Neuschwander-Tetri 2017
Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017;15(1):45.
Nicholls and Hazen 2005
Nicholls SJ and Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb 
Vasc Biol. 2005;25(6):1102-11.
Pais et al 2016
Pais R, Barritt AS, Calmus Y, Scatton O, Runge T, Lebray P, et al. NAFLD and liver 
transplantation: Current burden and expected challenges. J Hepatol. 2016;65(6):1245-57.
Pulli et al 2015
Pulli B, Ali M, Iwamoto Y, Zeller MWG, Schob S, Linnoila JJ, et al. Myeloperoxidase-
hepatocyte-stellate cell cross talk promotes hepatocyte injury and fibrosis in experimental 
nonalcoholic steatohepatitis. Antioxid Redox Signal. 2015;23(16):1255-69.
Pulli et al 2017
Pulli B, Wojtkiewicz G, Iwamoto Y, Ali M, Zeller MW, Bure L, et al. Molecular MR imaging 
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Regev A, Palmer M, Avigan MI, Dimick-Santos L, Treem WR, Marcinak JF, et al. Consensus: 
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induced liver injury during clinical trials in patients with nonalcoholic steatohepatitis. Aliment 
Pharmacol Ther. 2019;49(6):702-13.
Rensen et al 2009
Rensen SS, Slaats Y, Nijhuis J, Jans A, Bieghs V, Driessen A, et al. Increased hepatic 
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Rensen SS, Bieghs V, Xanthoulea S, Arfianti E, Bakker JA, Shiri-Sverdlov R, et al. 
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lipoprotein receptor-deficient mice. PLoS One. 2012;7(12):e52411.
Wong et al 2014
Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing 
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Younossi et al 2016
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of 
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outcomes. Hepatology. 2016;64(1):73-84.

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