A Randomised, Double-Blind, Placebo-Controlled, Dose-Response Study of the Efficacy and Safety of MEDI7352 in Subjects With Painful Diabetic Neuropathy
Phase: PHASE2
Conditions: Painful Diabetic Neuropathy
Sponsor: AstraZeneca

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 1 of 114
PROTOCOL AMENDMENT
PRODUCT NAME/NUMBER:
MEDI7352
PROTOCOL NUMBER:
D5680C00002
EUDRACT NUMBER:
2018-002523-42
DEVELOPMENT PHASE:
2
PROTOCOL TITLE:
A Randomised, Double-Blind, Placebo-Controlled,
Dose-Response Study of the Efficacy and Safety of 
MEDI7352 in Subjects with Painful Diabetic Neuropathy
PROTOCOL DATE:
Original Protocol Version 1.0, 24-Jul-2018
AMENDMENT 1 DATE:
Amended Protocol Version 2.0, 29-May-2019
AMENDMENT 2 DATE:
Amended Protocol Version 3.0, 21-Feb-2020
AMENDMENT 3 DATE:
Amended Protocol Version 4.0, 01-Oct-2020 (Not 
submitted/not implemented at sites)
AMENDMENT 4 DATE:
Amended Protocol Version 5.0, 04-Dec-2020
AMENDMENT 5 DATE:
Amended Protocol Version 5.1, 15-Mar-2021 (Specific to 
Denmark only)
AMENDMENT 6 DATE:
Amended Protocol Version 6.0, 26-Oct-2021
AMENDMENT 7 DATE:
Amended Protocol Version 7.0, 13-Apr-2022
SPONSORED BY:
AstraZeneca AB
151 85 
Sodertalje, Sweden
CONTRACT RESEARCH 
ORGANIZATION:
Premier Research
3800 Paramount Parkway, Suite 400
Morrisville, NC 27560 USA
This study will be performed in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices and applicable regulatory requirements, including the archiving of 
essential documents. Information contained in this protocol is confidential in nature, and may not 
be used, divulged, published, or otherwise disclosed to others except to the extent necessary to 
obtain approval of the institutional review board or independent ethics committee, or as required 
by law. Persons to whom this information is disclosed should be informed that it is confidential 
and may not be further disclosed without the express permission of AstraZeneca AB.
674 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 2 of 114
1
SPONSOR SIGNATURES
PROTOCOL NUMBER:
D5680C00002
PROTOCOL TITLE:
A Randomised, Double-Blind, Placebo-Controlled,
Dose-Response Study of the Efficacy and Safety of MEDI7352 in 
Subjects with Painful Diabetic Neuropathy
This Clinical Study Protocol has been subjected to an internal AstraZeneca peer review.
I agree to the terms of this Clinical Study Protocol/Amendment.
Biopharmaceuticals R&D, Neuroscience
AstraZeneca 
Aaron Klug Building
Granta Park
Cambridge CB21 6GH
United Kingdom
Tel: 
Date
(Day Month Year)
675 of 938
PPD
PPD
PPD
PPD
PPD

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 3 of 114
PROTOCOL NUMBER:
D5680C00002
PROTOCOL TITLE:
A Randomised, Double-Blind, Placebo-Controlled, 
Dose-Response Study of the Efficacy and Safety of MEDI7352 in 
Subjects with Painful Diabetic Neuropathy
This Clinical Study Protocol has been subjected to an internal AstraZeneca peer review.
I agree to the terms of this Clinical Study Protocol/Amendment.
, Clinical Development, Neuroscience
R&D Biopharmaceuticals, Neuroscience
AstraZeneca 
Aaron Klug Building
Granta Park
Cambridge CB21 6GH
United Kingdom
Tel: 
Date
(Day Month Year)
676 of 938
PPD
PPD
PPD
PPD
PPD

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 4 of 114
AMENDED PROTOCOL
The following are the amended protocol and appendices, including all revisions specified in the 
Reasons for Amendment and Summary of Amended Sections.
677 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 5 of 114
2
PROTOCOL SUMMARY
2.1
Synopsis
PRODUCT 
NAME/NUMBER
MEDI7352
PROTOCOL 
NUMBER
D5680C00002
EUDRACT 
NUMBER
2018-002523-42
DEVELOPMENT 
PHASE
2
PROTOCOL TITLE
A Randomised, Double-Blind, Placebo-Controlled, Dose-Response Study of the Efficacy 
and Safety of MEDI7352 in Subjects with Painful Diabetic Neuropathy
INDICATION
Painful Diabetic Neuropathy
OBJECTIVES
Primary: To assess the efficacy of MEDI7352 versus placebo on chronic pain in subjects 
with painful diabetic neuropathy (PDN) currently taking standard of care medication for 
their PDN pain.
Secondary:
To assess the safety and tolerability of MEDI7352 in subjects with PDN
To assess the pharmacokinetics (PK),
pharmacodynamics (PD), and 
immunogenicity of MEDI7352 in subjects with PDN 
To characterise the dose-response relationship of MEDI7352 on chronic pain in 
subjects with PDN
Exploratory: 
RATIONALE
The study is comprised of 4 stages. The first stage will assess safety of 
 in the 
PDN population. The second stage will compare an expected efficacious dose, 
, 
to placebo. The third stage will compare the highest expected efficacious dose, 
 
to placebo. The fourth stage will study 3 dose levels of MEDI7352 (
, and 
) versus placebo to enable a thorough characterisation of the efficacy 
dose-response relationship.
STUDY DESIGN
This is a randomised, double-blind, placebo-controlled study of MEDI7352 in subjects 
with moderate to severe chronic PDN persistent for 6 months or longer, not adequately 
controlled by standard of care treatments, caused by type 1 or type 2 diabetes mellitus. 
The study incorporates a screening period of up to 45 days and a 12-week double-blind 
treatment period during which MEDI7352 or placebo will be administered intravenously 
(IV) on 6 occasions, with each dose separated by 14 days. There will be a 6-week 
follow-up period. There will be 4 stages in the study: in the first stage, subjects will be 
678 of 938
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 6 of 114
randomly assigned to placebo or the lowest dose (
) until at least 10 subjects have 
been recruited. In the second stage, up to a maximum of 30 subjects will be randomly 
assigned to placebo or 
of MEDI7352; prior to commencing the second stage, 
the safety and tolerability experience following administration of multiple doses of
in the Phase 1 study of MEDI7352 will be evaluated. In stage 3 of the study,
approximately 67 subjects will be randomly assigned to placebo or 
MEDI7352 to ensure that sufficient subjects are evaluable for the pre-planned interim 
analysis. Prior to commencing the third stage, the safety and tolerability experience 
in the Phase 1 study of 
MEDI7352 will be evaluated. Administrative analyses will also be conducted during the 
third stage of the study to confirm decision making for stage 4 with respect to the exact 
sample size and dose allocation ratio. Upon enrolment of approximately 67 subjects in 
stage 3, approximately 165 eligible subjects will be randomly assigned to treatment with 
equal allocation across 3 dose levels of MEDI7352 or placebo in stage 4, to ensure that 
approximately 236 subjects are evaluable for the efficacy analysis of stages 2-4
combined.
PLANNED NUMBER 
OF SUBJECTS
Approximately 272 eligible subjects will be randomly assigned to double-blind treatment 
with one of 4 dose levels of MEDI7352 (dependent upon stage of the study) or placebo 
to ensure that approximately 236 subjects are evaluable for the efficacy analysis of stages 
2-4 combined.
STUDY ENTRY 
CRITERIA
Inclusion criteria:
General
1.
Male, or postmenopausal or surgically sterile female, 18 to 80 years of age 
(inclusive) on the day of randomisation. Post-menopausal women must have had 
months of spontaneous amenorrhea (with follicle-stimulating hormone [FSH] 
years; women >60 years do not require a FSH test) and 
must have had a negative pregnancy test result at screening. Surgically sterile women 
are defined as those who have had a hysterectomy, bilateral ovariectomy 
(oophorectomy), bilateral salpingectomy, or bilateral tubal ligation. Women who are 
surgically sterile must provide suitable medical documentation of the adequacy of 
the procedure; eg, an operative report or confirmatory ultrasound report. Men who 
are biologically capable of having children must agree and commit to use an adequate 
form of contraception (see Appendix B) for the duration of the treatment period and 
for 3 months after the last administration of study drug. A male subject is considered 
capable of having children even if his sexual partner is sterile or using contraceptives.
2.
2.
3.
Subjects must understand the nature of the study and must provide signed and dated 
written informed consent prior to the initiation of any study procedures.
4.
The subject should be willing and able to understand and participate in all scheduled 
evaluations and to complete all required tests and procedures including the use of 
subject diaries, as judged by the investigator.
5.
The subject must be considered likely to comply with the study protocol and to have 
a high probability of completing the study, as judged by the investigator.
6.
For subjects participating in the optional genetic research, a separate signed and 
dated written informed consent must be provided. If a subject declines to participate 
in the genetic research, this will have no influence on the ability of the subject to 
participate in the study.
679 of 938
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 7 of 114
Diagnostic
7.
Chronic PDN persistent for 6 months or longer, not adequately controlled by 
standard of care treatments.
8.
Pain (beginning in the feet and with relatively symmetrical onset for 6 months or 
greater) due to bilateral peripheral neuropathy caused by either type 1 or type 2 
diabetes mellitus, with bilateral decrease or absent reflexes at the ankles, or bilateral 
decrease of a sensory sign in the distal lower extremities, based on medical history 
and peripheral neurological examination. [NOTE: for sensory evaluation, the 
relevant components of the Total Neuropathy Score-Nurse (TNSn) for the lower 
limb should be undertaken, to include sensory symptom score, pin sensibility score, 
and vibration sensibility score.]
9.
4, as measured on an 11-point (0-10) NRS by 
completion of a subject diary for a minimum of 7 days prior to Day 1 (ie, Day -7 to 
Day -1). At least 5 of 7 days need to be recorded by the subject to obtain a valid 
baseline value. Pain scores from Day -7 to Day -1 will be centrally reviewed by the 
study team, and if there is significant variability in the scores during this baseline 
period of pain evaluation, it will be discussed with the investigator and the subject 
may be excluded.
Concomitant medication
10. The subject must be willing and able to discontinue all NSAID or COX-2 analgesic 
therapy from the start of the washout period until the end of follow-up. This includes 
over-the-counter (OTC) pain medications and topical analgesics that contain an 
NSAID or COX-2 inhibitor. The use of NSAIDs (eg, ibuprofen, naproxen) or COX-2
medications (eg, celecoxib) at any time during the study and through to completion 
of drug washout (5 half-lives) is prohibited and contraindicated.
11. Subjects should currently be taking medication for the treatment of PDN. Subjects 
should be taking at least one of the first-line medications (consistent with regional or 
local standard of care guidelines for PDN) belonging to either the anticonvulsant 
class (pregabalin or gabapentin) or the antidepressant class (duloxetine, venlafaxine, 
or amitriptyline), but no more than one medication from a single class. Subjects 
receiving treatment with opioids alone (as a monotherapy) should be excluded, 
unless the opioids are being prescribed as a second-line treatment for PDN because 
the first-line therapies were found to be poorly tolerated or not efficacious. For all 
drug classes, subjects should be established on a stable dosing regimen that is 
consistent with regional or local standards of accepted prescribing practice for no 
less than 3 months before the anticipated randomisation date. Subjects should be 
willing to maintain this dosing regimen for the duration of study participation until 
the last follow-up visit. Subjects must be willing to use only the protocol-specified 
rescue medications during the study.
12. If the subject is receiving permitted medications for the treatment of non-excluded 
medical conditions (eg, antihypertensive medication, cholesterol-lowering 
treatment, antidiabetic medication), the dose and dosing regimen must be stable for 
at least 28 days before randomisation and should be expected to remain stable for the 
duration of study participation until at least the last follow-up visit.
Exclusion criteria:
General
1.
Requires current treatment with another biologic therapeutic agent.
2.
Previously received any form of anti-nerve growth factor (NGF) or anti-tumor 
necrosis factor (TNF) therapy. 
A mean pain intensity score of 2: 
680 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 8 of 114
3.
Participation in another clinical study with an investigational product (IP) or device 
within 60 days or 5 half-lives prior to screening, whichever is longer.
4.
Plasma donation within 28 days of screening or any blood donation or blood loss 
>500 mL within 2 months of screening.
5.
Previous allogeneic bone marrow or stem cell transplant.
6.
Received non-leukocyte-depleted whole blood transfusion within 120 days of the 
genetic research sample collection, if participating in the optional genetic research.
7.
Poor venous access such that IV drug delivery would be difficult.
8.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and staff at the study site) and in accordance with local regulations.
Medical history
9.
Presence of other clinically significant neuropathy (eg, hereditary neuropathy, 
inflammatory neuropathy) or other clinically significant disorder (eg, nerve 
compression injury) involving abnormal peripheral sensation, with an aetiology that 
is considered to be distinct from that of PDN, and that is likely to interfere with 
assessment of peripheral nerve function, as judged by the investigator.
10. History of osteonecrosis, rapidly progressive OA, subchondral insufficiency 
fractures, neurogenic arthropathy, or analgesia-induced arthropathy. 
11. Diagnosis of clinically significant OA currently affecting a major joint in the upper 
extremity (shoulder, elbow, or wrist) or lower extremity (hip, knee, or ankle) or axial 
spine; or other degenerative disease affecting any joint in subjects for whom, in the 
opinion of the investigator, there is an identified risk of osteonecrosis, rapidly 
progressive OA, subchondral insufficiency fractures, neurogenic arthropathy, or 
analgesia-induced arthropathy.
NOTE: The diagnosis and evaluation of OA should be guided by American College 
of Rheumatology (ACR)-endorsed criteria, where applicable, and should incorporate 
radiologic investigation for the assessment of OA severity consistent with the 
relevant ACR guidance (Altman et al. 1986, Altman et al. 1990, Altman et al. 
1991)35,36,37 at the discretion of the investigator, or otherwise guided by local 
rheumatologic, orthopaedic, or radiologic expert advice. Where Kellgren and 
Lawrence grading is used for the radiographic evaluation of major joint OA, grade 
n. In subjects for whom 
there is evidence of clinically significant sensory impairment in the distal lower 
extremity (based on medical history, clinical examination, TNSn, or evidence of 
sensory nerve conduction impairment available from nerve conduction studies), 
there is an absolute requirement for bilateral feet and ankle radiographs to be 
undertaken for the evaluation of OA severity to exclude the possibility of neuropathic 
arthropathy. All radiologic investigations should be reported locally and the reports 
should be retained in the patient files as source documentation and made available in 
the event that subsequent adjudication of rheumatologic adverse events is required.
Radiologic images should also be retained and made available in the event that 
subsequent adjudication of rheumatologic adverse events is required.
12. Chronic pain condition, other than PDN, that is likely to interfere with the evaluation 
by the investigator.
13. Presence of any major psychiatric disorder according to the criteria of the Diagnostic 
and Statistical Manual of Mental Disorders, 5th Edition, if, in the opinion of the 
investigator, the psychiatric disorder or symptom is likely to confound interpretation 
study.
~2 would be considered exclusionary for trial participatio 
of the subject's PDN pain, as judged 
of drug effect, affect pain assessment, or affect the subject's ability to complete the 
681 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 9 of 114
14. Significant cardiovascular disease, including Class 3 or Class 4 (The Criteria 
Committee of the New York Heart Association (NYHA) classification standards 
1994)38 congestive heart failure (ejection fraction of <40%) or clinically significant 
stenosis or occlusion of a carotid or vertebral artery or clinically significant 
arrhythmias. 
NOTE: Validated NYHA classification standards:
Class 1: cardiac disease but no symptoms and no limitations in ordinary physical 
activity (no shortness of breath when walking, climbing stairs)
Class 2: mild symptoms (mild angina or shortness of breath) and slight limitation 
with ordinary physical activity
Class 3: marked limitation due to symptoms, even during less than ordinary 
activities such as walking 20 to 100 meters; comfortable only at rest
Class 4: severe limitations and symptoms at rest
NOTE: Subjects designated as NYHA functional Class 1 or Class 2 are not 
necessarily excluded from participation. However, such subjects should have 
left ventricular ejection fraction measured by echocardiography and 
documented at baseline.
15. Significant or chronic lung disease, including severe or unstable chronic obstructive 
pulmonary disease (COPD), or severe or unstable asthma.
16. Known or suspected systemic infection, including HIV, hepatitis B virus (HBV), 
hepatitis C virus (HCV), or tuberculosis (TB) as judged by the investigator or from 
screening testing. At screening, a QuantiFERON test will be conducted for TB
(Nyendak et al. 2009; Duarte et al. 2012; Cush et al. 2010).39,40,41
17. History or evidence of any significant autoimmune disease or disorder, including 
inflammatory bowel disease, multiple sclerosis, or systemic lupus erythematosus.
18. History of severe allergy/hypersensitivity reactions or history of hypersensitivity to 
immunisations or immunoglobulins.
19. History of cancer within 5 years of screening or between screening and 
randomisation, with the exception of non-metastatic basal cell carcinoma of the skin, 
carcinoma in situ of the cervix, or non-progressive prostate cancer.
20. Transient ischaemic attack or stroke in the last 3 years.
21. History of alcohol or recreational drug dependence according to the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition criteria, within 2 years of 
screening, with the exception of nicotine dependence, which is permitted.
NOTE: Where there is a documented or suspected history of excessive alcohol usage 
or recreational drug usage, it is expected that the impact of this with respect to risk
be evaluated at screening using the appropriate quantitative or semi-quantitative 
methodologies according to local standards of accepted medical or psychiatric 
practice. For example, use of the Fast Alcohol Screening Test (FAST) and Alcohol 
Use Disorders Identification Test (AUDIT) alcohol screening questions for the initial 
evaluation of harm and risk associated with excessive alcohol consumption.
22. Within 1 year of screening or between screening and randomisation, any of the 
following: myocardial infarction, hospitalisation for unstable angina or arrhythmia, 
or unexplained syncope.
23. Clinically important infection, including chronic, persistent, or acute infection, 
within 3 months of screening or between screening and randomisation.
• 
• 
• 
• 
682 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 10 of 114
24. Current serious or unstable clinically important illness, including avascular 
necrosis, respiratory, cardiovascular, gastrointestinal, endocrinologic (excluding 
well-controlled type 1 or type 2 diabetes), immunologic, haematologic, neurologic, 
ability to complete the study, as judged by the investigator.
Procedural contraindications
25. Any significant medical or surgical procedure or trauma within 28 days of Day 1, or 
planned to be undertaken within the timeframe of the clinical trial, that will likely 
of the study data, as judged by the investigator.
Physical and neurological examination, vital signs, ECG, laboratory values, and 
imaging
26. Clinically important abnormality in the physical and neurological examination, vital 
ability to complete the study, or the integrity of the clinical trial data, as judged by 
the investigator.
27. Poorly controlled hypertension (defined as systolic blood pressure [SBP] of 
>165 mmHg and/or diastolic blood pressure [DBP] of >95 mmHg measured in the 
clinic) or orthostatic hypotension (defined as a sustained reduction of SBP of at least 
20 mmHg and/or a DBP reduction of at least 10 mmHg within 3 minutes of standing 
from a supine position). Note: If the blood pressure (BP) measured in the clinic is
out of range, the measurements can be repeated on the same day or at another 
convenient visit.
28. Prolonged QTcF of >470 msec or family history of long QT syndrome, or shortened 
QTcF of <360 msec or family history of short QT syndrome, or any clinically 
significant abnormality in ECG rhythm, conduction, or morphology, including but 
not limited to: 
PR/PQ interval prolongation (PR/PQ >220 ms)
intermittent second or third degree atrioventricular (AV) block (AV block II 
Mobitz Type I, Wenckebach, while asleep or in deep rest is not exclusionary)
bundle branch block (BBB) or intraventricular conduction delay (IVCD) with 
QRS duration >120 ms
29. Haemoglobin A1C greater than 10.0% (>10.0%).
30. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >1.5 × 
the upper limit of normal (ULN) at screening or between screening and baseline. If 
the enzyme is >1.5 × ULN, the investigator can either exclude the subject at that time 
or decide to repeat the test once. If the repeat result is still >1.5 × ULN, the subject 
must be excluded.
31. Screening creatinine clearance of <60 mL/min as determined by the Cockcroft-Gault 
formula.
32. Clinically significant abnormal findings in coagulation or haematology laboratory 
tests, as judged by the investigator.
33. A positive pregnancy test at screening. (If the screening urine pregnancy test is more 
than 7 days before the first day of treatment, it must be repeated prior to the first 
dose.)
34. Positive drug screen for drugs of abuse (including but not limited to amphetamine, 
barbiturate, 
cannabinoids, 
cocaine, 
methadone, 
methaqualone, 
opiate, 
phencyclidine, or propoxyphene), unless there is a documented medical explanation 
or other major disease that is likely to deteriorate or affect the subject's safety or 
affect the subject's safety or ability to complete the study, or the scientific integrity 
signs, or clinical laboratory test at screening that could affect the subject's safety or 
• 
• 
• 
683 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 11 of 114
for the positive result other than drugs of abuse (eg, the subject takes opioids under 
medical supervision for pain and the prescribed opioid dosing regimen is expected 
to be stable and unchanged for the duration of the study; or where cannabinoids are 
similarly being taken for documented medical reasons). 
TEST PRODUCT
Name: MEDI7352
Dose, route, frequency: Dose levels: 
. Each 
subject will receive 6 doses, 1 dose every 2 weeks (Days 1, 14, 28, 42, 56, and 70), 
administered IV over a 60-minute period.
CONTROL
PRODUCT
Name: placebo
Dose, route, frequency: Same as MEDI7352.
PLANNED STUDY 
SITES
Approximately 40 study sites in approximately 6 countries.
CRITERIA FOR 
EVALUATION
Efficacy endpoints:
Primary efficacy endpoint: change in the weekly average of the average daily 
pain scores from the baseline week to Week 12, as measured on an 11-point 
(0-10) NRS.
Secondary efficacy endpoints:
Change in the weekly average of the average daily pain score, as measured 
on an 11-point (0-10) NRS, from baseline to Weeks 2, 4, 6, 8, and 10 of 
treatment and the week before the follow-up visit. 
Percen
the weekly average of the average daily pain score from baseline during 
Weeks 4, 8, and 12 of treatment and the week before follow-up.
Change in Galer neuropathic pain scale (NPS) from baseline to Days 28, 56, 
and 84 of treatment and the follow-up visit.  
Change in Daily Sleep Interference Scale (DSIS) from baseline to Days 28, 
56, and 84 of treatment and the follow-up visit.
,
Patient Global Impression of 
Change (PGIC) on Days 28, 56, and 84 of treatment and the follow-up visit.
Change in the 36-item Short-Form Health Survey (SF-36) from baseline to 
Day 84 of treatment.
Usage of rescue medication (yes/no) from baseline to Week 12 of treatment.
Clinical pharmacology endpoints:
Pharmacokinetic endpoints:
maximum concentration (Cmax)
time of Cmax (tmax)
area under the plasma concentration-time curve from time 0 to infinity 
(AUC0- )
area under the plasma concentration-time curve from time 0 to the time of 
the last quantifiable plasma concentration (AUC0-t)
area under the plasma concentration-time curve for the dosing interval 
(AUCtau) at steady state
684 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 12 of 114
Cmax at steady state
volume of distribution at steady state
t1/2
apparent total body clearance at steady state (CLss)
Pharmacodynamic endpoints:
free and/or total NGF measurements in 
serum/plasma
Immunogenicity (ADA) assessments
Change in the weekly average of the average daily pain scores from the baseline 
week to Week 12, as measured on an 11 point (0 to 10) NRS, versus dose
Safety endpoints:
Adverse events (AEs) and serious AEs (SAEs)
Physical and neurological examinations
Neuropathy assessments (TNSn), strength (dorsiflexion), and deep tendon reflex 
(knee and ankle) assessments
Vital signs
12-lead electrocardiograms (ECGs)
Clinical laboratory testing
(haematology, chemistry, coagulation, and 
urinalysis)
Motor and sensory nerve conduction studies
Concomitant medications and therapies
Injection site reactions and infusion reactions
STATISTICAL 
METHODS
Analysis Populations:
Screening: all subjects who provide informed consent and/or assent and provide 
randomisation and treatment status in the study. 
Safety: The safety population will include all subjects who receive at least 
1 dose of double-blind study medication.
Modified intent-to-treat (mITT): The modified intent-to-treat population will be 
used for all efficacy analyses and will include all randomised subjects who 
receive at least 1 dose of double-blind study medication and have at least 
1 post-baseline NRS assessment.
PK: The PK population will include all subjects for whom a PK sample was 
obtained and analysed.
Subject Characteristics and Disposition: Baseline subject characteristics will be listed and 
included in summaries as appropriate. Investigational product administration will be 
685 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 13 of 114
using 
descriptive statistics.
Efficacy Analyses: All efficacy variables will be summarized descriptively including 
number of observations, mean, standard deviation (SD), minimum, median, and 
maximum for continuous variables, and frequency of observations in each category and 
percentage for categorical variables. Primary and secondary endpoint efficacy data will 
data at a key analysis time-point (Weeks 4, 8, and 12) then results will also be tabulated 
-Observation-Carried-Forwar
-Observation-
Carried-
The main statistical analysis of the primary efficacy endpoint 
at Week 12 will use the multiple comparison procedure modelling (MCP-Mod) approach 
on LOCF data, which is a well-established statistical methodology for establishing both 
the existence of a dose response and modelling the underlying dose-response relationship.
In addition, changes from baseline in continuous endpoints will be compared between 
treatment groups using mixed models repeated measures including terms for pooled site, 
treatment (as a factor), time point (as a factor), the interaction between treatment and time 
point, and the baseline value of the variable undergoing analysis. Binary outcomes will 
be analysed using generalized estimating equations, with the models including the same 
terms as the mixed models repeated measures. Other non-binary categorical endpoints 
will be analysed using Cochran-Mantel-Haenszel statistics. These analyses will be 
conducted on observed cases. Further details of the longitudinal modelling will be 
included in the statistical analysis plan (SAP).
Clinical Pharmacology Analyses:
PK: Noncompartmental analysis methods will be used. The PK parameters will be 
summarized by MEDI7352 dose using descriptive statistics.
.
Safety Analyses: Safety and tolerability data will be summarised descriptively, including 
tables, listings, and graphs, as appropriate.
SAMPLE SIZE 
DETERMINATION
There is no formal sample size calculation for stage 1; 10 subjects in stage 1 is considered 
sufficient for the initial assessment of safety. The sample size for stages 2-4 combined 
was determined by a formal power calculation (see below) and the size of stage 3 was 
defined to confirm decision making for the stage 4 sample size and dose allocation ratio.
This study is powered at greater than 80% to detect a statistically significant (1-sided 
alpha = 0.025) dose-response relationship when the true Week 12 placebo-corrected
change from baseline difference at the
1.25 on the 11-point NRS scale 
(MEDI7352-placebo treatment) and the true dose-response follows a hyperbolic Emax
relationship, with the effective dose for 50% of the population (ED50) within the range 
The true SD is 2.4, which is based on other studies undertaken with pregabalin 
in PDN 
The data from stages 2, 3 and 4 are combined so that the number of subjects 
evaluable for the dose response analysis is 236. The total number of subjects 
evaluable for efficacy for the placebo, 
 and 
is equal to
81, 37, 51 and 67, respectively.
686 of 938
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 14 of 114
The dose-response hypothesis test is multiplicity adjusted in order to control the 
type 1-error.
The above calculations were performed using the following parameters:
Population SD (of change from baseline to week 12) = 2.4
Placebo effect = 1-point reduction in NRS and 450
from baseline, ie, delta = 1.25
which are all Emax models with decreasing potency/increasing ED50: 7.5, 15, 30, 
linear in dose. 
Power was assessed across 16 alternative true dose response curves, 12 Emax
having a Week 12 placebo-corrected change from baseline difference at the 
of 1.25. 
The overall withdrawal rate is anticipated to be approximately 10%. However, since the 
primary analysis will use LOCF for withdrawn subjects, and the SD estimate is taken 
from studies which also used the LOCF approach, the only additional subjects recruited 
will be to account for withdrawals in stages 2, 3 and 4 if withdrawal occurs at, or prior 
to, the Week 2 visit.
The number of subjects who will agree to participate in the genetic research is unknown. 
It is therefore not possible to establish whether sufficient data will be collected to allow 
a formal statistical evaluation or whether only descriptive statistics will be generated.
STUDY AND 
TREATMENT
DURATION
The planned sequence and maximum duration of the study periods will be as follows:
1.
Screening: 45 days
2.
Treatment: 12 weeks
3.
Follow-up: 42 days
The maximum treatment duration for each subject is approximately 12 weeks. 
The maximum study duration for each subject is approximately 25 weeks.
687 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 15 of 114
2.2
Schedule of Events
Table 2-1:
Schedule of Events
Screening
/Baseline 
(7 to 45 
Days)a
Double-blind Treatment Period (12 Weeks)
Follow-up
(or Early 
Termination)
(6 Weeks)
Study Day / Week 
Day -45 
to 
Day -1a
Day 
1
Day 14
Week 2
±3 days
Day 28
Week 4
±3 days
Day 42
Week 6
±3 days
Day 56
Week 8
±3 days
Day 70
Week 10
±3 days
Day 71
V7+24 hr
Day 77
V7+7 days
±3 days
Day 84
Week 12
±3 days
Week 18
±7 days
Clinic Visit (V) 
V1a
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Height and Weight (BMI)
X
Demographics and Medical History
X
Physical and Neurological Examination
(C=complete; T=targeted)
C
T
T
T
T
T
T
C
C
12-lead Electrocardiogram (ECG)
X
Xb
X
X
X
X
Motor and Sensory Nerve Conduction Studies
X
X
Urine Drug Screen and Urine Pregnancy Test
X a
X
X
Total Neuropathy Score-Nurse (TNSn)
X
X
X
X
X
X
X
X
X
Strength and Deep Tendon Reflexesi
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
Vital Signs c
X
X
X
X
X
X
X
X
X
X
X
Randomisation
Xe
Training and Reminders on Rating Pain and 
Entering Ratings on ePRO Systemd
X
X
X
X
X
X
X
X
Study Drug Infusion (Dosing)
X
X
X
X
X
X
Injection Site Assessment 
X
X
X
X
X
X
X
X
Daily Pain Diary (NRS) via ePRO
Xd
X
X
X
X
X
X
X
X
X
X
Daily Sleep Interference Scale (DSIS) via 
ePRO
Xd
X
X
X
X
X
X
X
X
X
X
Galer Neuropathic Pain Scale
X
X
X
X
X
Patient Global Impression of Change (PGIC)
X
X
X
X
36-item Short-Form Health Survey (SF-36)
X
X
688 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 16 of 114
Screening
/Baseline 
(7 to 45 
Days)a
Double-blind Treatment Period (12 Weeks)
Follow-up
(or Early 
Termination)
(6 Weeks)
Study Day / Week 
Day -45 
to 
Day -1a
Day 
1
Day 14
Week 2
±3 days
Day 28
Week 4
±3 days
Day 42
Week 6
±3 days
Day 56
Week 8
±3 days
Day 70
Week 10
±3 days
Day 71
V7+24 hr
Day 77
V7+7 days
±3 days
Day 84
Week 12
±3 days
Week 18
±7 days
Clinic Visit (V) 
V1a
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Blood Collection for:
Haematology, Chemistry, and Coagulation
X
X
X
X
X
X
X
X
X
Serology (HIV, hepatitis B and C, and 
tuberculosis)
X
Pharmacogenetic Sampling (Optional)
X
Haemoglobin A1c
X
Immunogenicity (ADA) Sampling
X
Xf
Xf
Xf
Xf
X
X
Pharmacokinetic Samplingh
Xf
Xf
Xf
Xf
Xf
Xh
Xh
Xh
Xh
Xg
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Rescue Medication Used
Xd
X
X
X
X
X
X
X
X
X
Concomitant Medications and Therapies
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: ADA = anti-drug antibody; BMI = body mass index; C = complete; 
 
; DSIS = Daily Sleep Interference Scale; ECG = electrocardiogram; ePRO = electronic patient-reported outcome system;
IP = investigational product; IWRS = interactive web response system;
NRS = numeric rating scale;
PD = pharmacodynamics; PGIC = Patient Global Impression of Change; PK = pharmacokinetics; SF-36 = 36-item Short-Form Health Survey;
T = targeted; TNSn = Total Neuropathy Score-Nurse
a
The subject must be screened within 45 days before enrolment in the study and at least 7 days before the first day of treatment to allow for 
7 days of baseline pain ratings and sleep monitoring. Screening procedures may be performed at 1 or more visits. If the screening urine 
pregnancy test is more than 7 days before the first day of treatment, it must be repeated prior to the first dose. Urine drug screen tests will be 
performed at Screening only.
b
On Day 1, 12-lead ECGs (3 replicates) will be performed pre-dose; 60 (±10) minutes after start of IP administration; and 2 and 4 hours 
(±10 minutes) after start of IP administration.
689 of 938
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 17 of 114
c
Vital signs (heart rate [HR], blood pressure [BP], respiratory rate, and body temperature):
Screening and Day 1: Supine and orthostatic.
From Day 14 onwards: Sitting and orthostatic.
e
If necessary, the randomisation transaction in IWRS can be performed on Day -1.
 
i
Strength (dorsiflexion) and deep tendon reflexes (knee and ankle) are to be scored at every visit alongside the TNSn assessments.
690 of 938
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 18 of 114
Table 2-2:
Timing of Safety Assessments and Safety Blood Sampling on Day 1
Time after Start of IP Administration
Assessment
Pre-dose
0 min
15 mins
30 mins
45 mins
60 mins
2 hours
4 hours
Administration of IP
Injection site assessments and infusion reaction assessments
X
X
X
X
X
X
12-lead ECGs (3 replicates)
X
X
X
X
Supine blood pressure, heart rate
X
X
X
X
X
X
X
Standing (orthostatic) blood pressure, heart rate
X
X
X
X
Body temperature
X
X
X
X
Respiration rate
X
X
X
X
X
Total Neuropathy Score, nurse (TNSn)
X
Targeted physical and neurological exam
X
Adverse events
Safety laboratory tests
X
Concomitant medication use
Abbreviations: BP = blood pressure; ECG = electrocardiogram; HR = heart rate; IP = investigational product, mins = minutes; RR = respiratory
rate; TNSn = Total Neuropathy Score-Nurse
Note:
60-minute orthostatic and supine vital sign assessments (blood pressure, heart rate, respiratory rate, body temperature) should be 
undertaken within 10 minutes window of completing the infusion. For all other vital signs an acceptable window for measurement is 
±5 mins of the specified time-point.
Standing blood pressure and heart rate (orthostatic vital signs) should be measured after 1 minute (>1 minute, <3 minutes) of adopting 
the standing position.
Where multiple assessments are being undertaken at the same time-point, the order of assessments should be (1) 12-lead ECG, (2) Vital 
signs (supine BP, HR, RR and temperature should be performed before standing vital signs), and (3) Blood sampling.
Safety laboratory tests taken pre-dose will include haematology, clinical chemistry, coagulation, and urinalysis.
Strength (dorsiflexion) and deep tendon reflexes (knee and ankle) are to be scored at every visit alongside the Total Neuropathy Score-
nurse (TNSn) assessments.
12-lead ECGs: 60 (±10) minutes after start of IP administration, 2 hours (±10 minutes) after start of IP administration, and 4 hours 
(±10 minutes) after start of IP administration.
• 
• 
• 
• 
• 
• 
691 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 19 of 114
3
TABLE OF CONTENTS
1 
SPONSOR SIGNATURES ......................................................................................................2 
AMENDED PROTOCOL ...............................................................................................................4 
2 
PROTOCOL SUMMARY........................................................................................................5 
2.1 
Synopsis ..........................................................................................................................5 
2.2 
Schedule of Events........................................................................................................15 
3 
TABLE OF CONTENTS .......................................................................................................19 
3.1 
LIST OF TABLES........................................................................................................23 
3.2 
LIST OF FIGURES ......................................................................................................23 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS.............................................................24 
5 
INTRODUCTION..................................................................................................................27 
5.1 
Background and Rationale............................................................................................27 
5.2 
Clinical Experience.......................................................................................................28 
5.2.1 Phase I Painful Osteoarthritis of the Knee Study..............................................29 
5.2.2 Current Phase 2 Painful Diabetic Neuropathy Study ........................................30 
5.2.3 Phase 2b Painful Osteoarthritis of the Knee Study ...........................................30 
5.2.4 Phase I Study in Healthy Volunteers.................................................................31 
5.3 
Summary of Potential Risks and Benefits.....................................................................31 
6 
OBJECTIVES.........................................................................................................................34 
6.1 
Primary Objective .........................................................................................................34 
6.2 
Secondary Objectives....................................................................................................34 
6.3 
Exploratory Objectives..................................................................................................34 
7 
STUDY DESIGN ...................................................................................................................36 
7.1 
Overall Study Design and Plan .....................................................................................36 
7.2 
Rationale and Discussion of Study Design ...................................................................39 
7.3 
Selection of Doses in the Study ....................................................................................39 
7.4 
Study Sites.....................................................................................................................39 
7.5 
Point of Contact ............................................................................................................39 
7.6 
End of Study Definition ................................................................................................39 
8 
SUBJECT POPULATION .....................................................................................................40 
8.1 
Selection of Study Population and Diagnosis ...............................................................40 
8.2 
Study Entry Criteria ......................................................................................................40 
8.2.1 Inclusion Criteria...............................................................................................40 
8.2.2 Exclusion Criteria..............................................................................................41 
8.3 
Premature Subject Withdrawal .....................................................................................45 
8.4 
Subject Replacement Criteria........................................................................................46 
9 
TREATMENTS......................................................................................................................47 
9.1 
Identification of Investigational Products .....................................................................47 
692 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 20 of 114
9.1.1 Dose, Route of Administration, and Dosing Schedule......................................48 
9.1.2 Current Treatment of Painful Diabetic Neuropathy..........................................48 
9.1.3 Rescue Medication ............................................................................................48 
9.2 
Selection of Timing of Dose for Each Subject..............................................................49 
9.3 
Dose Adjustment Criteria..............................................................................................49 
9.3.1 Safety Stopping Rules .......................................................................................49 
9.4 
Treatment Compliance..................................................................................................50 
9.5 
Method of Assigning Subjects to Treatment Groups....................................................50 
9.6 
Blinding and Unblinding Treatment Assignment .........................................................50 
9.7 
Permitted and Prohibited Therapies..............................................................................51 
9.7.1 Permitted Therapies...........................................................................................51 
9.7.2 Prohibited Therapies..........................................................................................52 
9.7.3 Restrictions........................................................................................................53 
9.8 
Treatment after End of Study........................................................................................53 
9.9 
Dispensing and Storage.................................................................................................53 
9.10 Drug Accountability......................................................................................................53 
9.11 Labelling and Packaging...............................................................................................54 
9.11.1 Labelling............................................................................................................54 
9.11.2 Packaging ..........................................................................................................54 
10 STUDY PROCEDURES........................................................................................................55 
10.1 Study Duration ..............................................................................................................55 
10.2 Study Periods and Visits ...............................................................................................55 
10.2.1 Screening and Washout.....................................................................................55 
10.2.1.1 Screening...............................................................................................55 
10.2.2 Double-blind Treatment Period (Days 1-84 [Weeks 1-12])..............................56 
10.2.2.1 Day 1 (Treatment 1)..............................................................................56 
10.2.2.2 Days 14, 28, 42, 56, and 70 (Treatments 2 to 6)...................................57 
10.2.2.3 Day 71...................................................................................................59 
10.2.2.4 Day 77...................................................................................................59 
10.2.2.5 Day 84 (End-of-treatment; Week 12) ...................................................59 
10.2.3 Follow-up (or Early Termination) Evaluation (Week 18).................................60 
10.3 Assessments ..................................................................................................................61 
10.3.1 Efficacy Variables .............................................................................................61 
10.3.1.1 Numerical Rating Scale.........................................................................61 
10.3.1.2 Galer Neuropathic Pain Scale ...............................................................61 
10.3.1.3 Daily Sleep Interference Scale..............................................................61 
10.3.1.4 Patient Global Impression of Change ...................................................62 
10.3.1.5 Short-Form Health Survey....................................................................62 
693 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 21 of 114
10.3.1.6 Rescue Medication Use.........................................................................62 
10.3.1.7 
 
10.3.2 Clinical Pharmacology ......................................................................................62 
10.3.2.1 Pharmacokinetic Analysis Methods......................................................62 
10.3.2.2 Pharmacodynamic Variables.................................................................63 
10.3.2.3 Pharmacogenetic Variables...................................................................63 
10.3.2.4 
 
10.3.2.5 Immunogenicity ....................................................................................64 
10.3.3 Safety Variables ................................................................................................64 
10.3.3.1 Clinical Laboratory Assessments..........................................................64 
10.3.3.2 Adverse Events......................................................................................67 
11 ADVERSE EVENTS..............................................................................................................68 
11.1 Definitions.....................................................................................................................68 
11.1.1 Adverse Events..................................................................................................68 
11.1.2 Adverse Drug Reaction .....................................................................................68 
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction ........................................68 
11.1.4 Serious Adverse Events.....................................................................................69 
11.1.5 Significant Adverse Events ...............................................................................69 
11.1.6 Treatment-Emergent Adverse Events ...............................................................69 
11.2 Event Assessment and Follow-up of Adverse Events ..................................................70 
11.2.1 Assessment ........................................................................................................70 
11.2.2 Evaluation..........................................................................................................71 
11.2.2.1 Severity of Adverse Events...................................................................71 
11.2.2.2 Seriousness............................................................................................71 
11.2.2.3 Action(s) Taken.....................................................................................71 
11.2.2.4 Outcome at the Time of Last Observation ............................................71 
11.2.2.5 Adverse Event Relationship to Investigational Product........................72 
11.2.3 Documentation ..................................................................................................72 
11.2.4 Treatment of Adverse Events............................................................................72 
11.2.5 Follow-up ..........................................................................................................73 
11.2.6 Reporting...........................................................................................................73 
11.2.6.1 Serious Adverse Events.........................................................................73 
11.2.6.2 Adverse Drug Reactions .......................................................................74 
11.2.6.3 Nonserious Adverse Events ..................................................................74 
11.3 Special Considerations..................................................................................................74 
11.3.1 Adverse Events of Special Interest....................................................................74 
11.3.2 Pregnancy..........................................................................................................75 
11.3.3 Overdose............................................................................................................75 
694 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 22 of 114
12 DATA SAFETY MONITORING BOARD ...........................................................................77 
13 STATISTICS ..........................................................................................................................78 
13.1 Statistical Analysis........................................................................................................78 
13.1.1 Analysis Populations .........................................................................................78 
13.1.2 Study Subjects and Demographics....................................................................78 
13.1.2.1 Disposition and Withdrawals ................................................................78 
13.1.2.2 Protocol Deviations...............................................................................78 
13.1.2.3 Demographics and Other Baseline Characteristics...............................79 
13.1.3 Exposure and Compliance.................................................................................79 
13.1.4 Efficacy Analysis ..............................................................................................79 
13.1.4.1 Efficacy Endpoints................................................................................80 
13.1.4.2 
 
13.1.5 Clinical Pharmacology Analyses.......................................................................81 
13.1.5.1 Pharmacokinetics ..................................................................................81 
13.1.5.2 Pharmacodynamics ...............................................................................81 
13.1.5.3 
 
13.1.5.4 
 
13.1.5.5 Immunogenicity ....................................................................................81 
13.1.6 Safety and Tolerability Analyses ......................................................................81 
13.1.6.1 Adverse Events......................................................................................82 
13.1.6.2 Clinical Laboratory Evaluations ...........................................................82 
13.1.6.3 Vital Signs.............................................................................................82 
13.1.6.4 Twelve-lead Electrocardiograms ..........................................................82 
13.1.6.5 Physical and Neurological Examination Findings ................................83 
13.1.6.6 Other Safety Assessments.....................................................................83 
13.1.7 Interim Analysis ................................................................................................83 
13.2 Sample Size Determination...........................................................................................83 
14 STUDY CONDUCT...............................................................................................................85 
14.1 Sponsor and Investigator Responsibilities ....................................................................85 
14.1.1 Sponsor Responsibilities ...................................................................................85 
14.1.2 Investigator Responsibilities .............................................................................85 
14.1.3 Confidentiality and Privacy...............................................................................85 
14.2 Site Initiation.................................................................................................................86 
14.3 Screen Failures..............................................................................................................86 
14.4 Study Documents ..........................................................................................................87 
14.4.1 Informed Consent..............................................................................................87 
14.4.2 Good Clinical Practice Documents ...................................................................87 
14.4.3 Case Report Forms ............................................................................................88 
695 of 938
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 23 of 114
14.4.4 Source Documents.............................................................................................88 
14.5 Data Quality Control.....................................................................................................88 
14.5.1 Monitoring Procedures......................................................................................88 
14.5.2 Data Management..............................................................................................89 
14.5.3 Quality Assurance/Audit ...................................................................................89 
14.6 Study Termination.........................................................................................................90 
14.6.1 Regular Study Termination ...............................................................................90 
14.6.2 Premature Study Termination ...........................................................................90 
14.7 Study Site Closure.........................................................................................................90 
14.7.1 Record Retention...............................................................................................91 
14.7.2 Sample Retention ..............................................................................................91 
14.8 Changes to the Protocol ................................................................................................91 
14.9 Use of Information and Publication..............................................................................92 
15 FINAL CLINICAL STUDY REPORT ..................................................................................93 
16 ETHICAL AND LEGAL CONSIDERATIONS....................................................................94 
16.1 Declaration of Helsinki and Good Clinical Practice.....................................................94 
16.2 Subject Information and Informed Consent..................................................................94 
16.3 Approval by Institutional Review Board or Independent Ethics Committee ...............95 
16.4 Finance and Insurance...................................................................................................95 
17 REFERENCES .......................................................................................................................96 
18 ATTACHMENTS.................................................................................................................100 
18.1 
............................................................................................100 
APPENDICES .............................................................................................................................101 
A. 
........................................................................................................101 
B.
Contraception Guidance..............................................................................................104 
C.
Other Study-Specific Requirements............................................................................104 
D.
Regulations and Good Clinical Practice Guidelines ...................................................105 
REASONS FOR AMENDMENT ...............................................................................................106 
SUMMARY OF AMENDED SECTIONS..................................................................................107 
3.1
LIST OF TABLES
Table 2-1:
Schedule of Events ............................................................................................15 
Table 2-2:
Timing of Safety Assessments and Safety Blood Sampling on Day 1 .............18 
Table 9-1:
Identification of Investigational Product...........................................................47 
Table 10-1:
Local Reactions to Injectable Product...............................................................67 
Table B-1:
Highly Effective Methods of Contraception ...................................................104 
3.2
LIST OF FIGURES
Figure 7-1: 
Study Design .....................................................................................................38 
Investigator's Agreement 
Hy's Law Criteria 
696 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 24 of 114
4
LIST OF ABBREVIATIONS AND DEFINITIONS
ACR
American College of Rheumatology
ADA
anti-drug antibody
ADR
adverse drug reaction
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase 
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC0-
area under the plasma concentration-time curve from time 0 to infinity 
AUC0-t
area under the plasma concentration-time curve from time 0 to the time of 
the last quantifiable plasma concentration
AUDIT
Alcohol Use Disorders Identification Test
BOCF
Baseline-Observation-Carried-Forward
BP
blood pressure
CLss
apparent total body clearance at steady state
Cmax
maximum plasma concentration
CMP
clinical monitoring plan
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CRF
case report form
CRP
C-reactive protein
CSR
clinical study report
DBP
diastolic blood pressure
DSIS
Daily Sleep Interference Scale
ECG
electrocardiogram
eCRF
electronic case report form
ED50/ED90
the effective dose for 50%/90% of the population
Emax
the maximum effect of the drug
ePRO
electronic patient-reported outcome (system)
697 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 25 of 114
FAST
Fast Alcohol Screening Test 
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HR
heart rate
IB
investigator brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
independent ethics committee
IP
investigational product
IRB
institutional review board
IV
intravenous
IWRS
interactive web response system
LOCF
Last-Observation-Carried-Forward
MAD
multiple ascending dose
MCP-Mod
multiple comparison procedure modelling
mITT
modified intent-to-treat
NCA
noncompartmental analysis
NCS
nerve conduction studies
NGF
nerve growth factor
NPS
neuropathic pain scale
NRS
numeric rating scale
NSAID
nonsteroidal anti-inflammatory drug
NYHA
New York Heart Association
OA
osteoarthritis
OTC
over-the-counter
PD
pharmacodynamic
PDN
painful diabetic neuropathy
PGIC
Patient Global Impression of Change
PK
pharmacokinetic
PRN
pro re nata (where necessary)
698 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 26 of 114
PR (PQ)
ECG interval measured from the onset of the P wave to the onset of the QRS 
complex
PT
preferred term
QRS
ECG interval measured from the onset of the QRS complex to the J point
QT
ECG interval measured from the onset of the QRS complex to the end of the 
T wave
QTc
QT interval corrected for heart rate
QTcF
RBC
red blood cell
RPOA
rapidly progressive osteoarthritis
RR
the time elapsed between 2 consecutive R waves as measured by 
electrocardiogram
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SF-36
36-item Short-Form Health Survey
SUSAR
suspected unexpected serious adverse reaction
sWFI
sterile water for injection
tmax
time of Cmax
TNF
tumor necrosis factor
TNFR2
tumor necrosis factor receptor 2
TNSn
Total Neuropathy Score-Nurse 
UADR
unexpected adverse drug reaction
ULN
upper limit of normal
699 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 27 of 114
5
INTRODUCTION
5.1
Background and Rationale
The latest estimates show that the number of people with diabetes worldwide has risen from 108 
million in 1980 to 422 million in 2014,1 making it one of the most common chronic diseases. The 
global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 
8.5% in 2014 (WHO).1 This increase in incidence parallels an increasing trend in ageing and in 
obesity. 
There is considerable morbidity and mortality associated with diabetes, not only because of the 
primary disease but also because of secondary complications. Diabetic neuropathy is the most 
common long-term complication of diabetes and is a leading cause of peripheral neuropathy (Dyck 
et al. 1993).2 The most common form is a chronic distal symmetric sensorimotor polyneuropathy
that predominantly affects the feet and legs. The prevalence of diabetic neuropathy increases with 
duration of diabetes, from 10% at diagnosis to >50% after 25 years. In a large diabetes patient 
cohort drawn from 28 community clinics in the US, 75% of the subjects had at least one 
abnormality on nerve conduction studies (NCS) (Vinik et al. 2006).3 Approximately 10% to 20% 
of patients with diabetes have peripheral neuropathic pain (painful diabetic neuropathy; PDN). 
Around 40% to 50% of those with chronic diabetic neuropathy will have PDN and the majority 
have features of chronic sensorimotor neuropathy (Veves et al. 2008; Young et al. 1993; Galer et 
al. 2000; Gordois et al. 2003).4,5,6,7 One epidemiological study reported tingling, shooting, or 
burning pain in 34% of over 15,000 diabetic patients surveyed in the community (Abbott et al. 
2011).8 Prevalence of pain was greater in patients with type 2 diabetes than for those with type 1 
diabetes (35% vs. 22%), greater in females with diabetes than in males (38% vs. 31%), and showed 
variability between ethnic groups within the study cohort. PDN is often experienced in terms of a 
burning, stabbing, pricking or aching sensation that is chronic and difficult to manage; it carries a 
substantial physical, social, and economic burden. Patients frequently experience anxiety, 
depression, and sleep disturbance. It is estimated that almost half of these patients do not receive 
any treatment for pain.
First-line treatments for PDN include tricyclic antidepressants, pregabalin, gabapentin, and 
duloxetine; other treatments include opioids, topical treatments (lidocaine and capsaicin), and 
non-pharmacological treatments including transcutaneous electrical nerve stimulation and 
acupuncture. All of these treatments have limitations, with variable efficacy and responder rates; 
many carry serious safety concerns and the potential for abuse and dependence. The number 
needed to treat for at least 50% pain relief for duloxetine (60 to 120 mg/day) is 6 (Sultan et al. 
2008)9; for gabapentin (>1200 mg/day) it is 5.8, and for pregabalin (300 to 600 mg/day) it is 5.0 
(Javed et al. 2015).10 Thus, despite the poly-pharmacy approach to PDN management, fewer than 
20% of patients can be expected to achieve meaningful pain relief with the current treatment
paradigms. There is a great medical need for new drugs for the treatment of PDN that have 
improved and more sustained symptomatic effects and better tolerability.
MEDI7352 is a bispecific fusion protein composed of a single chain variable domain fragment
(scFv) that binds nerve growth factor (NGF), linked by CH2 and CH3 domains of a human 
immunoglobulin 1 to tumor necrosis factor (TNF) receptor 2 (TNFR2). The scFv end of 
MEDI7352 effectively neutralises NGF, preventing its interaction with both its high- and 
low-affinity receptors, the tropomyosin-related kinase A receptor and the p75 neurotrophin 
receptor, respectively. The TNFR2 end of MEDI7352 binds TNF in solution, thereby preventing 
700 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 28 of 114
its interaction with cell surface TNFR2 and the consequent intracellular signalling and biologic 
effects. MEDI7352 is thus designed to engage two biological mediators, NGF and TNF, both of 
which are considered to play an important role in sensitisation of the nervous system and in pain 
pathophysiology (Pezet and McMahon 2006; Hefti et al. 2006; Petty et al. 1994; Dimitroulas et al. 
2017; Leung and Cahill 2010).11,12,13,14,15 In humans, anti-NGF antibodies demonstrate efficacy in 
clinical studies of osteoarthritis (OA) and chronic lower back pain (Lane et al. 2010; Katz et al. 
2011; Brown et al. 2012, 2013; Kivitz et al. 2013; Schnitzer et al. 2015; Spierings et al. 
2013).16,17,18,19,20,21,22 This clinical efficacy appears to require doses of anti-NGF antibodies that 
are projected to sequester almost all circulating NGF (Neubert et al. 2013).23 Such high levels of 
NGF sequestration have, however, raised concerns with regard to the safety of this therapeutic 
approach (Holmes 2012; Hochberg et al. 2012; Bannwarth and Kostine 2017).24,25,26 TNF receptor 
blockers have a well-established role for disease modification in the management of rheumatoid 
arthritis and other inflammatory joint diseases in which pain is often an important component of
the phenotype (Croft et al. 2013).27 While anti-TNF therapeutics do not carry a primary indication 
for the provision of analgesia, there is some evidence to suggest that a selected sub-group of OA 
patients with a marked inflammatory profile may benefit from this therapy (Dimitroulas et al. 
2017),14 and it is thought that TNF blockers can be at least partially efficacious in the setting of 
clinical neuropathic pain (Leung and Cahill 2010; Cohen et al. 2012).15,28
In preclinical studies, administration of MEDI7352 has been shown to produce a significant 
antihyperalgesic effect at doses that are believed to sequester <10% of circulating NGF. As such, 
it is hypothesised that the observed efficacy, which occurs at very low levels of NGF suppression, 
may result as a function of synergy with respect to the co-sequestration of NGF and TNF. Evidence 
to support such synergy is based on observations of MEDI7352-mediated analgesia being observed 
with doses at which the individual components of the protein (anti-NGF or anti-TNF), when dosed 
separately, are inactive. The observation has been made in animal models of both inflammatory 
pain and neuropathic pain. While the molecular mechanisms underpinning such efficacy remain 
to be elucidated, MEDI7352 represents a potentially novel approach to the management of chronic 
pain that may further help to avoid unwanted effects associated with high levels of NGF 
suppression.
5.2
Clinical Experience
As of 01 June 2021, it is estimated that approximately 116 subjects have been exposed to 
MEDI7352 in clinical studies. A first-in-human study of MEDI7352 evaluating safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in subjects with painful OA of the 
knee has been completed, and 3 clinical studies with MEDI7352 are ongoing:
Study D5680C00001, the completed first-in-human study 
Study D5680C00002, the present study described within this protocol
Study D5680C00003, a Phase IIb, randomised, double-blind, placebo-controlled, 
dose-response study to evaluate the efficacy, safety, tolerability, PK, immunogenicity, and 
PD of MEDI7352 in subjects with painful OA of the knee
Study D5680C00004, a Phase I, randomised, double-blind, placebo-controlled study to 
evaluate the safety, tolerability, PK, and immunogenicity of MEDI7352 in healthy 
volunteers
• 
• 
• 
• 
701 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 29 of 114
5.2.1
Phase I Painful Osteoarthritis of the Knee Study
Completed study D5680C00001
was a clinical evaluation of MEDI7352 for safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and efficacy in a first-in-human study in 
subjects with painful OA of the knee (ClinicalTrials.gov Identifier: NCT02508155). 
Single (SAD) and multiple (MAD) ascending doses were evaluated against placebo, with review 
of blinded safety data from each completed dosage cohort undertaken by a Safety Review 
Committee before further dose escalation. Study Part 1 (SAD) included a total of 53 male and 
nonfertile female subjects, aged 36 through 75 years, who received single doses of MEDI7352 or 
placebo. Overall, 39 subjects received MEDI7352 (33 intravenous [IV] and 6 subcutaneous [SC]), 
and 14 subjects received placebo (12 IV and 2 SC). The MEDI7352 IV doses studied were
 
Study Part 2 (MAD) included a total of 
75 male and nonfertile female subjects, aged 31 through 75 years, who received up to 4 planned 
IV doses of MEDI7352 or placebo administered 2 weeks apart. Overall, 53 subjects received 
was enrolled and randomised but not dosed due to poor venous access.
In the SAD phase, 17 of 39 subjects (43.6%) treated with MEDI7352 (across all dose levels) and 
9 of 14 subjects (64.3%) treated with placebo had at least one treatment-emergent adverse event 
(TEAE). Most TEAEs were considered by the investigator to be mild or moderate intensity and 
not related to investigational product (IP). There were no deaths, serious TEAEs, or 
discontinuations due to TEAEs.
The most common TEAEs among subjects treated with MEDI7352 in the SAD phase (across all 
dose levels) were headache (12.8%), back pain (7.7%), and epistaxis (5.1%), with no clear dose-
response relationship. Among subjects treated with placebo, the most common TEAEs were 
headache (28.6%) and oropharyngeal pain (14.3%).
In Study Part 2 (MAD), 44 of 53 subjects (83.0%) treated with MEDI7352 (across all dose levels), 
and 16 of 22 subjects (72.7%) treated with placebo had at least one TEAE. Most TEAEs were 
considered by the investigator to be of mild or moderate intensity and not related to IP. There were 
no deaths. There was 1 reported serious TEAE (pneumonia in a subject treated with MEDI7352), 
which led to the subject
severe in intensity and not related to the IP or study procedures, as it was considered a complication 
of influenza (reported simultaneously by several other family members). Four subjects were 
withdrawn from the MAD phase of the study due to non-serious TEAEs: viral upper respiratory 
tract infection; erysipelas; nasopharyngitis and pyrexia; and infusion-related reaction. A higher 
proportion of subjects treated with MEDI7352 had TEAEs of oral herpes and urinary tract 
infection (5.7% each) compared with subjects treated with placebo (0%). However, the overall 
incidence of TEAEs in the SOC of infections and infestations was similar among subjects treated 
with MEDI7352 and those treated with placebo (39.6% and 36.4%, respectively). The most 
common TEAEs among subjects treated with MEDI7352 in the MAD phase (across all dose 
levels) were nasopharyngitis (26.4%), headache (28.3%), back pain (11.3%), and arthralgia and 
oropharyngeal pain (9.4% each). Among subjects treated with placebo, the most common TEAEs 
were nasopharyngitis and headache (27.3% each). No infusion-related reactions were reported in 
the SAD phase of the study. One subject treated with MEDI7352 in the MAD phase had a 
nonserious infusion-related reaction (dyspnoea, flushing, dizziness), which led to discontinuation 
as noted above. The TEAE began within 3 minutes of the start of the second IV infusion of 
MEDI7352 (Day 15); treatment was discontinued, and the event resolved in less than 1 hour.
702 of 938
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 30 of 114
No cases of rapidly progressive OA (RPOA) or osteonecrosis were reported during the study. 
There were no discernible differences in the TEAE profiles of subjects with and without ADA in 
either study phase, suggesting that there were no apparent effects of immunogenicity on safety.No
clinically significant changes or dose-related trends for mean changes from baseline or differences 
between MEDI7352- and placebo-treated subjects in either study phase were observed for other 
safety parameters, including laboratory safety tests (haematology, coagulation, clinical chemistry 
and urinalysis), vital signs (blood pressures, temperature, and pulse rate), electrocardiogram (ECG) 
assessments, physical examinations, or neuropathy assessments (Total Neuropathy Score, nurse).
Please refer to the investigator brochure (IB) for further details.
5.2.2
Current Phase 2 Painful Diabetic Neuropathy Study
Here we present the study protocol to evaluate the analgesic efficacy of MEDI7352 further in a 
human neuropathic pain condition, by conducting a placebo-controlled trial in subjects with PDN. 
MEDI7352 or placebo will be administered to subjects as an adjunct to existing therapeutics 
prescribed for PDN. To enable efficient modelling of the dose-response relationship for 
MEDI7352 in neuropathic pain, it is planned to evaluate 4 dose levels of MEDI7352 and placebo.
As of 01 June 2021, a total of 41 subjects with PDN have received blinded study treatment (up to 
6 planned IV doses, administered every 2 weeks). It is estimated that 21 subjects have received 
MEDI7352 
) and 20 subjects have received placebo.
A review of blinded safety data showed that 26 of 41 treated subjects (63.4%) have had at least 
one reported TEAE as of 01 June 2021. There have been no deaths or serious TEAEs. 
Three subjects have discontinued IP due to nonserious adverse events (AEs) as listed below; none 
of which was considered by the investigator to be related to IP:
A TEAE of cellulitis of moderate intensity (Stage 1,
 MEDI7352 or placebo)
A TEAE of infection (symptoms of sore throat, fever, nasopharyngitis, tongue burning, 
and sweating) of mild intensity (Stage 2, 
MEDI7352 or placebo)
An AE of alanine aminotransferase (ALT) increased of mild intensity that was reported in 
Stage 2 before the treatment period began and thought to be due to excessive alcohol 
consumption, and which led to the subject
IP (
MEDI7352 or placebo). 
Headache was the most commonly reported TEAE overall: 7 of 41 subjects (17.1%), including 
3 of 10 subjects (30.0%) in the completed Stage 1 (
MEDI7352 or placebo), 3 of 26 subjects
(11.5%) in the completed Stage 2 (
MEDI7352 or placebo) and 1 of 5 subjects (20%) in 
the ongoing Stage 3 (MEDI7352 
or placebo). All TEAEs reported in each study stage 
were considered by the investigator to be of mild or moderate intensity. 
No clinically significant changes or trends for changes from baseline have been observed for other 
safety parameters, including ECG assessments; vital signs; laboratory safety tests; and Total 
Neuropathy Score-Nurse (TNSn) or for parameters measured during motor and sensory NCS.
5.2.3
Phase 2b Painful Osteoarthritis of the Knee Study
In the ongoing Phase IIb study D5680C00003, one subject had received blinded SC study 
treatment (MEDI7352 
 and 
or placebo) as of 01 June 2021. This subject had 
703 of 938
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 31 of 114
nonserious TEAEs of diarrhoea and irritability, both considered by the investigator to be of 
moderate intensity. The subject withdrew from the study (ie, consent withdrawal) after receiving 
5 of 6 planned SC injections of study treatment.
5.2.4
Phase I Study in Healthy Volunteers
In the Phase I study D5680C00004, 5 subjects had received blinded SC study treatment 
(MEDI7352 
or placebo) as of 01 June 2021. Two of the of 5 treated subjects (40.0%) have 
had a total of 4 TEAEs as follows (1 subject each): dyspepsia, catheter site erythema, injection site 
pain, and paraesthesia. All reported TEAEs were considered by the investigator to be of mild 
intensity. There have been no deaths, treatment-emergent SAEs, or withdrawals due to AEs.
5.3
Summary of Potential Risks and Benefits
The potential benefits of study participation are that subjects with PDN may experience a reduction 
in symptoms as a result of treatment with MEDI7352. No other benefits of participation are 
anticipated.
The potential risks of study participation include those associated with exposure to MEDI7352, as 
well as those related to medical procedures, including venepuncture undertaken for blood sampling 
and administration of investigational product (IP). Although no important risks have been 
identified for MEDI7352 to date in the completed Phase 1 clinical study or the 3 ongoing studies,
MEDI7352 may have risks similar to those reported with both anti-NGF and anti-TNF therapies, 
as well as those reported with therapeutic proteins in general.
Potential risks associated with MEDI7352 include:
Potential risks based on class effects and mechanisms of action
o
Risks associated with the anti-NGF mechanism
Rapidly progressive OA and other joint safety events. This risk is not 
limited to osteoarthritic joints 
Sensory abnormalities and peripheral neuropathy 
Autonomic neuropathy and sympathetic dysfunction 
o
Risks associated with the anti-TNF mechanism 
Increased risk of infection, including tuberculosis, bacterial sepsis, and 
invasive fungal infections 
Warnings and precautions for etanercept (anti-
hypersensitivity reactions; exacerbation or new onset of demyelinating 
disease; malignancies, including lymphoma, leukaemia, melanoma and 
non-melanoma skin cancer; serious haematological reactions including 
pancytopenia, or aplastic anaemia; new onset or worsening congestive heart 
failure; reactivation of hepatitis B; autoimmune conditions including 
autoimmune hepatitis, autoimmune renal disease and a lupus-like syndrome 
(ENBREL Prescribing Information, ENBREL Summary of Product 
Characteristics). 
704 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 32 of 114
General risks associated with protein therapeutics include immunological reactions: 
hypersensitivity reactions, injection site reactions, and the consequences of 
immunogenicity (eg, immune-complex disease). 
The most significant adverse effect of anti-NGF monoclonal antibodies has been infrequent 
clinical cases of RPOA (type 1 and 2) observed in large-scale clinical studies, which led the Food 
and Drug Administration (FDA) to impose a clinical hold on this mechanism in 2010. At a 2012 
Arthritis Advisory Committee meeting that reviewed results of the tanezumab, fulranumab, and 
fasinumab programs, sponsors presented data showing that these events increased with increased 
doses of anti-NGFs and particularly when the drugs were dosed concurrently with nonsteroidal 
anti-inflammatory drugs (NSAIDs).29
At the FDA Advisory Committee Meeting in 2021, safety data from 3 studies of tanezumab were 
presented using a composite joint safety event endpoint to capture events including RPOA type 1, 
RPOA type 2, osteonecrosis, subchondral insufficiency fracture, and pathological fracture.30 There 
was a significantly higher incidence of events in subjects treated with tanezumab (3.2% and 6.2% 
of subjects treated with tanezumab 2.5 mg and 5 mg, respectively) compared to NSAIDs (1.5% of 
subjects) or placebo (0% of subjects).31 In addition, a greater proportion of subjects treated with 
tanezumab (5.5% and 7.8% of subjects treated with tanezumab 2.5 mg and 5 mg, respectively) 
required total joint replacements when compared to those treated with NSAIDs (2.6% of subjects)
or placebo (4.5% of subjects). 30, 31 Overall, approximately 85% of the total joint replacements 
31 however, some joint safety events including total 
joint replacement occurred in joints KL grade 0 or 1 at baseline. 30, 31
It was also notable in the tanezumab programme that composite joint safety events are not limited 
to arthritis joints. For subjects with joints KL grade 0 or 1 enrolled in the tanezumab study 1058, 
there was a higher incidence of CJSE in the tanezumab 5 mg treatment arm (19 events, 1.9%) than 
in the NSAID arm (2 events, 0.2%).32
There have been no reports of RPOA or destructive arthropathy in the MEDI7352 clinical program
to date.
Peripheral neuropathy
both autonomic and sensory
has also been identified as a risk with 
anti-NGF antibodies (Bélanger et al. 2018; Dewanjee et al. 2018).33,34 In the MEDI7352 13-week 
good laboratory practice toxicology study undertaken in rats, axonal degeneration has been 
observed in peripheral nerves. No clear dose-response relationship has been observed for this 
unclear whether sensory nerves or motor nerves or both are affected. No functional consequences 
have been observed in neurobehavioural assessments in the animals and the effect has been 
described as non-adverse in the rodents. The underlying mechanism and potential relevance of the 
finding to humans is unknown. It is not known whether MEDI7352 might worsen a pre-existing 
neuropathy as a function of NGF inhibition. For the present clinical study, the risk will be managed 
through appropriate peripheral nervous system monitoring and will include nerve conduction 
studies (NCS).
TNF-alpha inhibitors carry labelled safety warnings and precautions regarding the risk of serious 
infections (including tuberculosis [TB], bacterial sepsis, invasive fungal infections, and other 
opportunistic infections) and malignancies (including lymphoma and other malignancies). 
Additional warnings and precautions for etanercept include exacerbation or new onset of 
• 
occurred in joints KL grade 2: 3 at baseline; 
effect, although a trend for increased 'average' severity with increasing dose was noted. It is 
705 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 33 of 114
demyelinating disease, lymphoma, pancytopenia or aplastic anaemia, new onset or worsening 
congestive heart failure, and reactivation of hepatitis B virus (HBV).
General risks of biologic therapies include infusion-related reactions (defined as a collection of 
signs and symptoms ranging from local skin reactions at the injection site, pyrexia, and an 
influenza-like syndrome, to an acute anaphylaxis, usually occurring within 2 hours of the infusion; 
hypersensitivity reactions; and development of anti-drug antibodies to MEDI7352. Antidrug 
antibodies to MEDI7352 could result in immune-complex disease (with manifestations including 
arthralgia, serum-sickness, and vasculitis), auto-immunity, or altered MEDI7352 levels or activity.
A summary of the pharmacological properties and known potential risks of MEDI7352 is provided 
in the current version of the IB. The investigator must become familiar with all sections of the 
MEDI7352 IB before the start of the study.
706 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 34 of 114
6
OBJECTIVES
6.1
Primary Objective
The primary objective is to assess the efficacy of MEDI7352 versus placebo on chronic pain in 
subjects with PDN currently taking standard of care medication for their PDN pain.
6.2
Secondary Objectives
To assess the safety and tolerability of MEDI7352 in subjects with PDN
To assess the PK, PD, and immunogenicity of MEDI7352 in subjects with PDN
To characterise the dose-response relationship of MEDI7352 on chronic pain in subjects 
with PDN
6.3
Exploratory Objectives
Objectives
Endpoints
Primary
To assess the efficacy of MEDI7352 
versus placebo on chronic pain in 
subjects with PDN currently taking 
standard of care medication for their 
PDN pain
Primary:
Change in the weekly average of the average daily pain scores 
from the baseline week to Week 12 of MEDI7352 compared to 
placebo, as measured on an 11-point (0-10) NRS.
Secondary:
Change in the weekly average of the average daily pain score, 
as measured on an 11-point (0-10) NRS, from baseline to 
Weeks 2, 4, 6, 8, and 10 of treatment and the week before the 
follow-up visit. 
Percen
reductions in the weekly average of the average daily pain score 
from baseline during Weeks 4, 8, and 12 of treatment and the 
week before follow-up.
Change in Galer Neuropathic Pain Scale (NPS) from baseline
to Days 28, 56, and 84 of treatment and the follow-up visit.  
Change in Daily Sleep Interference Scale (DSIS) from baseline 
to Days 28, 56, and 84 of treatment and the follow-up visit.
,
Patient 
707 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 35 of 114
Global Impression of Change (PGIC) on Days 28, 56, and 84 of 
treatment and the follow-up visit.
Change in the 36-item Short-Form Health Survey (SF-36) from 
baseline to Day 84 of treatment.
Change in the amount of rescue medication used (in terms of 
dosage/day) from baseline to Week 12 of treatment.
Secondary
To assess the safety and tolerability of 
MEDI7352 in subjects with PDN 
Safety and tolerability assessments: AEs and SAEs, physical 
and neurological examinations, neuropathy assessments
(TNSn), strength (dorsiflexion) and deep tendon reflex (knee 
and ankle) assessments, vital signs, 12-lead ECGs, clinical 
laboratory testing (haematology, clinical chemistry, 
coagulation, and urinalysis), motor and sensory nerve 
conduction, concomitant medication assessment, injection site 
reaction assessment, and infusion reaction assessments.
To assess the PK, PD, and 
immunogenicity of MEDI7352 in 
subjects with PDN
Primary PK parameters of MEDI7352 will include maximum 
concentration (Cmax), time of Cmax (tmax), area under the plasma 
concentration-time curve from time 0 to infinity (AUC0- ), area 
under the plasma concentration-time curve from time 0 to the 
time of the last quantifiable plasma concentration (AUC0-t), area 
under the plasma concentration-time curve for the dosing 
interval (AUCtau) at steady state, Cmax at steady state, volume of 
distribution at steady state, t1/2, and apparent total body 
clearance at steady state (CLss).
Pharmacodynamics: free and/or total NGF measurements in 
serum/plasma.
Immunogenicity (ADA) assessments.
To characterise the dose-response 
relationship of MEDI7352 on chronic 
pain in subjects with PDN
Change in the weekly average of the average daily pain scores 
from the baseline week to Week 12, as measured on an 
11-point (0-10) NRS, versus dose.
Exploratory
708 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 36 of 114
7
STUDY DESIGN
7.1
Overall Study Design and Plan
This is a randomised, double-blind, placebo-controlled study of MEDI7352 in subjects with 
moderate to severe PDN. The study incorporates a screening period of up to 45 days and a 12-week 
double-blind treatment period during which MEDI7352 or placebo will be administered IV on 
6 occasions, with each dose separated by 14 days. There will be a 6-week follow-up period.
Subjects must have chronic PDN persistent for 6 months or longer, not adequately controlled by 
standard of care treatments, caused by type 1 or type 2 diabetes mellitus. Subjects must have 
bilateral decrease or absent reflexes at the ankles, or bilateral decrease of a sensory sign in the 
distal lower extremities, based on medical history and physical or neurological examination.
NSAIDs and COX-2 inhibitors are strictly contraindicated throughout the study. If eligible subjects 
are using NSAIDs or COX-2 inhibitors at the time of screening, they must be willing to withdraw 
from them. 
Subjects will be required to report pain scores on an 11-point (0-10) numeric rating scale (NRS) 
by completion of a subject diary for a minimum of 7 days prior to Day 1 (ie, Day -7 to Day -1). If 
the diary is started prior to Day -7, then data from Day -7 to Day -1 will be used to determine 
eligibility. At least 5 of 7 days need to be recorded by the subject to obtain a valid baseline value. 
To be el
4 is required. There will be 4
stages in the study: in the first stage, subjects will be randomly assigned to placebo or the lowest 
dose (
) until at least 10 subjects have been recruited. In the second stage, up to a maximum 
of 30 subjects will be randomly assigned to
; prior to 
commencing the second stage, the safety and tolerability experience following administration of 
e 1 study of MEDI7352 will be evaluated. In stage 3 of the 
study, approximately 67 subjects will be randomly assigned to placebo or
.
The third stage will include an interim analysis to assess key assumptions of the sample size 
calculation. Upon enrolment of approximately 67 subjects in stage 3, approximately 165 eligible 
subjects will be randomly assigned to treatment with equal allocation across 3 dose levels of 
MEDI7352 or placebo to ensure approximately 236 subjects are evaluable for the efficacy analysis 
of stages 2 to 4 combined. In summary, the numbers of subjects randomised to receive treatment 
in the various stages is as follows: at least 10 subjects in stage 1, up to a maximum of 30 subjects 
in stage 2, an estimated 67 subjects in stage 3, and an estimated 165 subjects in stage 4 (ie, 272 in 
total across all study stages 1 to 4).
All treatments and assessments will be undertaken in a double-blind fashion. Treatments will be 
administered IV over a 60-minute period. Subjects will be dosed as outpatients and will participate 
in 6 independent dosing sessions, once every 2 weeks. Safety and efficacy assessments will be 
undertaken at each of the dosing sessions and during follow-up visits.
 
Efficacy will be evaluated by subject assessments of daily average pain, as measured on an 
11-point (0-10) NRS; the Galer Neuropathic Pain Scale (NPS); the Daily Sleep Interference Scale 
(DSIS); the Patient Global Impression of Change (PGIC); and the 36-item Short-Form Health 
Survey (SF-36).
709 of 938
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 37 of 114
The PK, PD (free and/or total plasma/serum NGF) and immunogenicity of MEDI7352 will be 
characterized.
 
.
 
.
Safety will be assessed by evaluating adverse events (AEs), clinical laboratory test results, vital 
sign measurements, and 12-lead ECGs. Physical and neurological examinations will be 
undertaken. Additional monitoring of the peripheral nervous system will be undertaken through 
evaluation of TNSn, strength (dorsiflexion), deep tendon reflexes (knee and ankle), and NCS of 
motor and sensory nerves. Monitoring will be undertaken for injection site reactions and infusion-
related reactions. Concomitant medication use will be monitored.
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of the signing of the informed consent and/or assent through the posttreatment visits) will be 
documented.
Medical monitors will review safety data on an ongoing basis. An interim review of blinded
aggregate safety data will be undertaken following completion of follow-up for approximately 
every 30 subjects enrolled in the study (see Section 9.3.1). The interim review will be performed 
by AstraZeneca Neuroscience in conjunction with the pharmacovigilance and safety agent, MMS 
Holdings.
710 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 38 of 114
Figure 7-1:
Study Design
711 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 39 of 114
7.2
Rationale and Discussion of Study Design
A randomised, double-blind, placebo-controlled study design with multiple dose levels of 
MEDI7352 is appropriate to assess the efficacy, safety, tolerability, PK, PD, and immunogenicity 
of MEDI7352 as compared to placebo. Subjects must have chronic PDN that is not adequately 
controlled by standard of care treatments, and will receive MEDI7352 as adjunctive therapy for 
12 weeks. Placebo is included in the study to permit comparative assessment of the safety, 
tolerability, PK, PD, and immunogenicity of MEDI7352, and to further evaluate the balance of 
benefit and risk of MEDI7352. The study is comprised of 4 stages. The first stage will assess safety 
of
in the PDN population. The second stage will compare an expected efficacious dose,
, to placebo. The third stage will compare the highest expected efficacious dose, 
 to placebo and includes an interim analysis that will confirm decision making for stage 
4 with respect to exact sample size and dose allocation ratio. If there are no changes following the 
interim analysis, the fourth stage will study 3 doses of MEDI7352 (
) versus 
placebo to enable a robust characterisation of the efficacy dose-response relationship.
7.3
Selection of Doses in the Study
MEDI7352 has undergone clinical evaluation for safety, PK, PD, and efficacy in a first-in-human 
study in subjects with painful OA of the knee (ClinicalTrials.gov Identifier: NCT02508155). In 
that study, testing of single IV doses of up to
and repeat ascending IV doses of 
 and
every 2 weeks have been completed. Single SC doses of 
have 
also been evaluated. No safety or tolerability concerns were reported. A full description of the 
current clinical experience with MEDI7352 is in Section 5.2.
Based on the results of the first-in-human study, the planned dosages in this protocol are
 and
 administered every 2 weeks with a total of 6 doses per
subject. Thus, the dose range to be explored in this study encompasses an equivalent dose range 
that has been studied in the preceding Phase 1 study and the highest dose planned for the current 
study is the same as the highest dose assessed in the Phase 1 study.
7.4
Study Sites
The study will take place at approximately 40 sites in approximately 6 countries. Each site is 
anticipated to screen a sufficient number of subjects to randomise approximately 8 subjects. A
study site with a high recruitment rate may be allowed to recruit more subjects if other sites have 
slow enrolment.
7.5
Point of Contact
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of subjects, and whom to contact in case of a study-related 
injury. This information will be provided in the subject information and informed consent form
(ICF).
7.6
End of Study Definition
The clinical trial is considered completed when the last 
last study visit has occurred.
712 of 938
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 40 of 114
8
SUBJECT POPULATION
8.1
Selection of Study Population and Diagnosis
Approximately 272 eligible subjects will be randomly assigned to double-blind treatment with 1
of 4 dose levels of MEDI7352 (
and 
 dependent upon the stage of the study)
or placebo to ensure that approximately 236 subjects are eligible for the efficacy analysis of 
stages 2, 3 and 4 combined.
Subjects who do not meet all of the eligibility criteria will not be enrolled.
8.2
Study Entry Criteria
8.2.1
Inclusion Criteria
A subject will be eligible for study participation if he or she meets all of the following criteria:
General
1. Male, or postmenopausal or surgically sterile female, 18 to 80 years of age (inclusive) on the 
day of randomisation. Post-menopausal women
amenorrhea (with follicle-stimulating hormone [FSH]
years; 
women >60 years do not require a FSH test) and must have had a negative pregnancy test result 
at screening. Surgically sterile women are defined as those who have had a hysterectomy, 
bilateral ovariectomy (oophorectomy), bilateral salpingectomy, or bilateral tubal ligation. 
Women who are surgically sterile must provide suitable medical documentation of the 
adequacy of the procedure; eg, an operative report or confirmatory ultrasound report. Men who 
are biologically capable of having children must agree and commit to use an adequate form of 
contraception (see Appendix B) for the duration of the treatment period and for 3 months after 
the last administration of study drug. A male subject is considered capable of having children 
even if his sexual partner is sterile or using contraceptives.
2.
2.
3. Subjects must understand the nature of the study and must provide signed and dated written 
informed consent prior to the initiation of any study procedures.
4. The subject should be willing and able to understand and participate in all scheduled 
evaluations and to complete all required tests and procedures including the use of subject 
diaries, as judged by the investigator.
5. The subject must be considered likely to comply with the study protocol and to have a high 
probability of completing the study, as judged by the investigator.
6. For subjects participating in the optional genetic research, a separate signed and dated written 
informed consent must be provided. If a subject declines to participate in the genetic research, 
this will have no influence on the ability of the subject to participate in the study.
Diagnostic
7. Chronic PDN persistent for 6 months or longer, not adequately controlled by standard of care 
treatments.
8. Pain (beginning in the feet and with relatively symmetrical onset for 6 months or greater) due 
to bilateral peripheral neuropathy caused by either type 1 or type 2 diabetes mellitus, with
713 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 41 of 114
bilateral decrease or absent reflexes at the ankles, or bilateral decrease of a sensory sign in the 
distal lower extremities, based on medical history and peripheral neurological examination.
[NOTE: for sensory evaluation, the relevant components of the TNSn for the lower limb should 
be undertaken, to include sensory symptom score, pin sensibility score, and vibration 
sensibility score.]
9.
4, as measured on an 11-point (0 to 10) NRS by completion 
of a subject diary for a minimum of 7 days prior to Day 1 (ie, Day -7 to Day -1). At least 5 of 
7 days need to be recorded by the subject to obtain a valid baseline value. Pain scores from 
Day -7 to Day -1 will be centrally reviewed by the study team, and if there is significant 
variability in the scores during this baseline period of pain evaluation, it will be discussed with 
the investigator and the subject may be excluded.
Concomitant medication
10. The subject must be willing and able to discontinue all NSAID or COX-2 analgesic therapy 
from the start of the washout period until the end of follow-up. This includes over-the-counter 
(OTC) pain medications and topical analgesics that contain an NSAID or COX-2 inhibitor. 
The use of NSAIDs (eg, ibuprofen, naproxen) or COX-2 medications (eg, celecoxib) at any 
time during the study and through to completion of drug washout (5 half-lives) is prohibited 
and contraindicated.
11. Subjects should currently be taking medication for the treatment of PDN. Subjects should be 
taking at least one of the first-line medications (consistent with regional or local standard of 
care guidelines for PDN) belonging to either the anticonvulsant class (pregabalin or 
gabapentin) or the antidepressant class (duloxetine, venlafaxine, or amitriptyline), but no more 
than one medication from a single class. Subjects receiving treatment with opioids alone (as a 
monotherapy) should be excluded, unless the opioids are being prescribed as a second-line 
treatment for PDN because the first-line therapies were found to be poorly tolerated or not 
efficacious. For all drug classes, subjects should be established on a stable dosing regimen that 
is consistent with regional or local standards of accepted prescribing practice for no less than 
3 months before the anticipated randomisation date. Subjects should be willing to maintain this 
dosing regimen for the duration of study participation until the last follow-up visit. Subjects 
must be willing to use only the protocol-specified rescue medications during the study.
12. If the subject is receiving permitted medications for the treatment of non-excluded medical 
conditions (eg, antihypertensive medication, cholesterol-lowering treatment, antidiabetic 
medication), the dose and dosing regimen must be stable for at least 28 days before 
randomisation and should be expected to remain stable for the duration of study participation 
until at least the last follow-up visit.
8.2.2
Exclusion Criteria
A subject will be excluded from the study if he or she meets any of the following criteria:
General
1. Requires current treatment with another biologic therapeutic agent.
2. Previously received any form of anti-NGF or anti-TNF therapy. 
A mean pain intensity score of~ 
714 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 42 of 114
3. Participation in another clinical study with an IP or device within 60 days or 5 half-lives prior 
to screening, whichever is longer.
4. Plasma donation within 28 days of screening or any blood donation or blood loss >500 mL 
within 2 months of screening.
5. Previous allogeneic bone marrow or stem cell transplant.
6. Received non-leukocyte-depleted whole blood transfusion within 120 days of the genetic 
research sample collection, if participating in the optional genetic research.
7. Poor venous access such that IV drug delivery would be difficult.
8. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and 
staff at the study site) and in accordance with local regulations.
Medical history
9. Presence of other clinically significant neuropathy (eg, hereditary neuropathy, inflammatory 
neuropathy) or other clinically significant disorder (eg, nerve compression injury) involving 
abnormal peripheral sensation, with an aetiology that is considered to be distinct from that of 
PDN, and that is likely to interfere with assessment of peripheral nerve function, as judged by 
the investigator.
10. History of osteonecrosis, rapidly progressive OA, subchondral insufficiency fractures, 
neurogenic arthropathy, or analgesia-induced arthropathy. 
11. Diagnosis of clinically significant OA currently affecting a major joint in the upper extremity 
(shoulder, elbow, or wrist) or lower extremity (hip, knee, or ankle) or axial spine; or other 
degenerative disease affecting any joint in subjects for whom, in the opinion of the investigator,
there is an identified risk of osteonecrosis, rapidly progressive OA, subchondral insufficiency 
fractures, neurogenic arthropathy, or analgesia-induced arthropathy.
NOTE: The diagnosis and evaluation of OA should be guided by American College of 
Rheumatology (ACR)-endorsed criteria, where applicable, and should incorporate radiologic 
investigation for the assessment of OA severity consistent with the relevant ACR guidance 
(Altman et al. 1986, Altman et al. 1990, Altman et al. 1991)35,36,37 at the discretion of the 
investigator, or otherwise guided by local rheumatologic, orthopaedic, or radiologic expert 
advice. Where Kellgren and Lawrence grading is used for the radiographic evaluation of major 
joint OA, gra
whom there is evidence of clinically significant sensory impairment in the distal lower 
extremity (based on medical history, clinical examination, TNSn, or evidence of sensory nerve 
conduction impairment available from NCS), there is an absolute requirement for bilateral feet 
and ankle radiographs to be undertaken for the evaluation of OA severity to exclude the 
possibility of neuropathic arthropathy. All radiologic investigations should be reported locally 
and the reports should be retained in the patient files as source documentation and made 
available in the event that subsequent adjudication of rheumatologic adverse events is required.
Radiologic images should also be retained and made available in the event that subsequent 
adjudication of rheumatologic adverse events is required.
12. Chronic pain condition, other than PDN, that is likely to interfere with the evaluation of the 
the investigator.
de 2:2 would be considered exclusionary for trial participation. In subjects for 
subject's PDN pain, as judged by 
715 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 43 of 114
13. Presence of any major psychiatric disorder according to the criteria of the Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition, if, in the opinion of the investigator, the 
psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect pain 
14. Significant cardiovascular disease, including Class 3 or Class 4 (The Criteria Committee of the 
New York Heart Association (NYHA) classification standards 1994)38 congestive heart failure 
(ejection fraction of <40%) or clinically significant stenosis or occlusion of a carotid or 
vertebral artery or clinically significant arrhythmias. 
NOTE: Validated NYHA classification standards:
Class 1: cardiac disease but no symptoms and no limitations in ordinary physical activity 
(no shortness of breath when walking, climbing stairs)
Class 2: mild symptoms (mild angina or shortness of breath) and slight limitation with 
ordinary physical activity
Class 3: marked limitation due to symptoms, even during less than ordinary activities such 
as walking 20 to 100 meters; comfortable only at rest
Class 4: severe limitations and symptoms at rest
NOTE: Subjects designated as NYHA functional Class 1 or Class 2 are not necessarily 
excluded from participation. However, such subjects should have left ventricular ejection 
fraction measured by echocardiography and documented at baseline
15. Significant or chronic lung disease, including severe or unstable chronic obstructive pulmonary 
disease (COPD), or severe or unstable asthma.
16. Known or suspected systemic infection, including HIV, HBV, hepatitis C virus (HCV), or TB 
as judged by the investigator or from screening testing. At screening, a QuantiFERON test will
be conducted for TB (Nyendak et al. 2009; Duarte et al. 2012; Cush et al. 2010).39,40,41
17. History or evidence of any significant autoimmune disease or disorder, including inflammatory 
bowel disease, multiple sclerosis, or systemic lupus erythematosus.
18. History of severe allergy/hypersensitivity reactions or history of hypersensitivity to 
immunisations or immunoglobulins.
19. History of cancer within 5 years of screening or between screening and randomisation, with 
the exception of non-metastatic basal cell carcinoma of the skin, carcinoma in situ of the cervix, 
or non-progressive prostate cancer.
20. Transient ischaemic attack or stroke in the last 3 years.
21. History of alcohol or recreational drug dependence according to the Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition criteria, within 2 years of screening, with the 
exception of nicotine dependence, which is permitted.
NOTE: Where there is a documented or suspected history of excessive alcohol usage or 
recreational drug usage, it is expected that the impact of this with respect to risk be evaluated 
at screening using the appropriate quantitative or semi-quantitative methodologies according 
to local standards of accepted medical or psychiatric practice. For example, use of the Fast 
Alcohol Screening Test (FAST) and Alcohol Use Disorders Identification Test (AUDIT)
assessment, or affect the subject's ability to complete the study . 
• 
• 
• 
• 
716 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 44 of 114
alcohol screening questions for the initial evaluation of harm and risk associated with excessive 
alcohol consumption.  
22. Within 1 year of screening or between screening and randomisation, any of the following: 
myocardial infarction, hospitalisation for unstable angina or arrhythmia, or unexplained 
syncope.
23. Clinically important infection, including chronic, persistent, or acute infection, within 
3 months of screening or between screening and randomisation.
24. Current serious or unstable clinically important illness, including avascular necrosis, 
respiratory, cardiovascular, gastrointestinal, endocrinologic (excluding well-controlled type 1 
or type 2 diabetes), immunologic, haematologic, neurologic, or other major disease that is 
the investigator.
Procedural contraindications
25. Any significant medical or surgical procedure or trauma within 28 days of Day 1, or planned 
safety or ability to complete the study, or the scientific integrity of the study data, as judged by 
the investigator.
Physical and neurological examination, vital signs, ECG, laboratory values, and imaging
26. Clinically important abnormality in the physical and neurological examination, vital signs, or 
o complete 
the study, or the integrity of the clinical trial data, as judged by the investigator.
27. Poorly controlled hypertension (defined as systolic blood pressure [SBP] of >165 mmHg 
and/or diastolic blood pressure [DBP] of >95 mmHg measured in the clinic) or orthostatic 
hypotension (defined as a sustained reduction of SBP of at least 20 mmHg and/or a DBP 
reduction of at least 10 mmHg within 3 minutes of standing from a supine position). Note: If 
the blood pressure (BP) measured in the clinic is out of range, the measurements can be 
repeated on the same day or at another convenient visit.
28. Prolonged QTcF of >470 msec or family history of long QT syndrome, or shortened QTcF of 
<360 msec or family history of short QT syndrome, or any clinically significant abnormality 
in ECG rhythm, conduction, or morphology, including but not limited to: 
PR/PQ interval prolongation (PR/PQ >220 ms)
intermittent second or third degree atrioventricular (AV) block (AV block II Mobitz 
Type I, Wenckebach, while asleep or in deep rest is not exclusionary)
bundle branch block (BBB) or intraventricular conduction delay (IVCD) with QRS 
duration >120 ms
29. Haemoglobin A1C greater than 10.0% (>10.0%).
30. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >1.5 × the upper 
limit of normal (ULN) at screening or between screening and baseline. If the enzyme is 
>1.5 × ULN, the investigator can either exclude the subject at that time or decide to repeat the 
test once. If the repeat result is still >1.5 × ULN, the subject must be excluded.
likely to deteriorate or affect the subject's safety or ability to complete the study, as judged by 
to be undertaken within the timeframe of the clinical trial, that will likely affect the subject's 
clinical laboratory test at screening that could affect the subject's safety or ability t 
• 
• 
• 
717 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 45 of 114
31. Screening creatinine clearance of <60 mL/min as determined by the Cockcroft-Gault formula.
32. Clinically significant abnormal findings in coagulation or haematology laboratory tests, as 
judged by the investigator.
33. A positive pregnancy test at screening. (If the screening urine pregnancy test is more than 
7 days before the first day of treatment, it must be repeated prior to the first dose.)
34. Positive drug screen for drugs of abuse (including but not limited to amphetamine, barbiturate, 
cannabinoids, cocaine, methadone, methaqualone, opiate, phencyclidine, or propoxyphene), 
unless there is a documented medical explanation for the positive result other than drugs of 
abuse (eg, the subject takes opioids under medical supervision for pain and the prescribed 
opioid dosing regimen is expected to be stable and unchanged for the duration of the study; or 
where cannabinoids are similarly being taken for documented medical reasons).
8.3
Premature Subject Withdrawal
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. Subjects must be withdrawn from the study if they 
withdraw consent to participate. Investigators must attempt to contact subjects who fail to attend 
scheduled visits by telephone or other means to exclude the possibility of an AE being the cause 
of withdrawal. Should this be the cause, the AE must be documented, reported, and followed as 
described in Section 11.2.
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or
other reasons.
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the case report form (CRF) or 
electronic case report form (eCRF). Whenever possible and reasonable, the evaluations that were 
to be conducted at the completion of the study should be performed at the time of premature 
discontinuation.
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study.
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
ddress or local 
medical record or study file. 
's opinion, to protect the subject's best interest . 
• 
• 
necessary, a certified letter to the participant's last known mailing a 
equivalent methods). These contact attempts should be documented in the participant's 
718 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 46 of 114
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
8.4
Subject Replacement Criteria
Withdrawn subjects may be replaced if withdrawal occurs at, or prior to, the Week 2 visit.
• 
719 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 47 of 114
9
TREATMENTS
9.1
Identification of Investigational Products
The products that will be used in this study are outlined in Table 9-1.
Table 9-1:
Identification of Investigational Product
Product 
Strength and dosage form 
Manufacturer/Supplier 
MEDI7352 
Solvent for reconstitution of 
MEDI7352 
Diluent for reconstituted 
MEDI7352 and placebo 
IV bag protectant 
720 of 938
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 48 of 114
9.1.1
Dose, Route of Administration, and Dosing Schedule
Once randomized, subjects will be dosed with either MEDI7352 or placebo on Day 1, Day 14, 
Day 28, Day 42, Day 56, and Day 70. MEDI7352 or placebo will be administered IV over a
60-minute period.
MEDI7352 or placebo should be administered by the investigator or site personnel prepared to 
manage infusion reactions and anaphylaxis. The infusion rate may be slowed or interrupted if the 
subject develops an infusion reaction. [NOTE: If the infusion is slowed or interrupted, the total 
infusion time should not exceed 4 hours at room temperature.] Investigators/site personnel should 
be aware of the risk of hypersensitivity reactions, which may present as infusion reactions, and 
monitor subjects closely. In the event of a serious reaction, MEDI7352 or placebo administration 
must be discontinued immediately and the appropriate medical therapy administered.
Subjects will be dosed as outpatients but should remain under clinical supervision and should be 
monitored for no less than 4 hours after completion of each infusion. Should clinical features of 
acute hypersensitivity occur, an extended period of monitoring in an appropriate environment may 
be relevant, based on clinical judgement. This may include, but is not necessarily limited to, 
monitoring vital signs and observing for any untoward reactions. Consultation with the appropriate 
local clinical services may be warranted (eg, high dependency or intensive therapy unit).
Subjects should be made aware of the potential risks of acute hypersensitivity and infusion-related 
reactions, the signs and symptoms of such reactions, and the importance of immediately seeking 
medical attention should they occur.
9.1.2
Current Treatment of Painful Diabetic Neuropathy
Subjects should currently be taking medication for the treatment of PDN. Subjects should be taking 
at least one of the first-line medications (consistent with regional or local standard of care 
guidelines for PDN) belonging to either the anticonvulsant class (pregabalin or gabapentin) or the 
antidepressant class (duloxetine, venlafaxine, or amitriptyline), but no more than one medication 
from a single class. Subjects receiving treatment with opioids alone (as a monotherapy) should be 
excluded, unless the opioids are being prescribed as a second-line treatment for PDN because the 
first-line therapies were found to be poorly tolerated or not efficacious. For all drug classes, 
subjects should be established on a stable dosing regimen that is consistent with regional or local 
standards of accepted prescribing practice for no less than 3 months before the anticipated 
randomisation date. Subjects should be willing to maintain this stable dosing regimen for the 
duration of study participation until the last follow-up visit.  
9.1.3
Rescue Medication
Subjects who develop unacceptable pain during any stage of the study (including during the 
washout period prior to randomisation) will be permitted to initiate rescue analgesic therapy with 
paracetamol up to a maximum dose of two 500 mg tablets (ie, 1 g per dose) up to 4 times daily 
(ie, 4 g per 24-hour period).
investigator
consultation with the medical monitor.
Subjects may use sedative/hypnotics (eg, benzodiazepines) on a pro re nata (PRN; where 
necessary) basis, but these should not be taken more than 3 times a week or within 24 hours of a 
If paracetamol does not relieve the subject's pain, they may receive stronger analgesics as rescue 
medication (including tramadol and other 'weak' opiates) at the 
's discretion and in 
721 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 49 of 114
clinic visit and such use will be considered a protocol deviation. Prohibited therapies are listed in 
Section 9.7.2. Other restrictions are listed in Section 9.7.3.
As a guideline, rescue medication should not generally be given for more than 3 consecutive days. 
All rescue medication use must be captured in the CRF and subjects will be required to record 
reasons for use. 
The study site will not supply rescue medication. 
The date and time of rescue medication administration as well as the name and dosage regimen of 
the rescue medication must be recorded.
9.2
Selection of Timing of Dose for Each Subject
The 2-weekly dose interval has been chosen based on PK, PD (NGF suppression) and efficacy 
considerations. In the first-in-human study in subjects with OA, the dosing schedule was 2-weekly,
and preliminary (blinded) data indicated that the effect of MEDI7352 on OA pain was detectable 
for 2 weeks.
9.3
Dose Adjustment Criteria
Dose adjustment is not allowed in this study. Subjects will be allocated to a single dosing regimen 
at randomisation.
9.3.1
Safety Stopping Rules
Safety will be monitored by the study-appointed medical monitors from Premier Research and 
AstraZeneca throughout the study in accordance with the Medical Monitoring Plan. In addition, 
an Interim Safety Review of blinded aggregate safety data will be undertaken following 
completion of follow-up visits for approximately every 30 subjects enrolled in the study and no 
less frequently than every 3 months. The interim review will be performed by AstraZeneca 
Neuroscience in conjunction with the pharmacovigilance and safety agent, MMS Holdings in
accordance with the Safety Management Plan.
Based on the interim safety reviews of aggregate safety data, the study may be stopped if the risks 
are found to outweigh the potential benefits.
For any individual subject, further administration of IP will be stopped if any of the following 
scenarios occur with a reasonable possibility of a causal relationship to administration of 
MEDI7352:
Reports of drug-related serious AE (SAE[s]) or drug-related severe AE(s) including (but
not necessarily limited to):
o
Infusion reactions and injection site reactions
o
Worsening of existing cutaneous sensory abnormalities or development of new 
cutaneous sensation AEs (eg, paraesthesia, dysesthesia, burning, pins and needles) 
that are considered serious or severe and drug-related
o
Positively adjudicated destructive arthropathy
o
Serious systemic infection
• 
722 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 50 of 114
o
Anaphylactic reaction, defined as an immediately life-threatening allergic reaction 
with bronchoconstriction, angioedema, and/or hypotension (refer to FDA Guidance 
for Industry, Immunogenicity assessment for therapeutic protein products, 2014).42
o
3 ×
2 × ULN, 
in the absence of a significant increase in alkaline phosphatase (ALP) and in the 
absence of an alternative diagnosis that could explain the increase in bilirubin
o
Severe autonomic AEs, including but not limited to symptomatic orthostatic 
hypotension and orthostatic intolerance, that are considered drug-related
o
Renal toxicity,
1.5 × ULN
o
Haematologic toxicity, defined as one or more of the following:
Leukocyte count <2.0 × 109/L
Neutrophil count <1.0 × 109/L
Platelet count <75 × 109/L
9.4
Treatment Compliance
All subjects will receive the IP infusion at the study site under the surveillance of appropriate study 
9.5
Method of Assigning Subjects to Treatment Groups
The randomisation schedule will be computer generated using a permuted block algorithm
appropriate to the treatment groups included in each stage and will randomly allocate IP to 
randomisation numbers. The randomisation numbers will be assigned sequentially through a 
central interactive web response system (IWRS) as subjects are entered into the study. The 
randomisation schedule will not be stratified and study center will not be a blocking factor in the 
randomisation schedule.
The randomisation schedule will be prepared by Premier Research before the start of the study.
No one involved in the study performance will have access to the randomisation schedule before 
official unblinding of treatment assignment. No subject will be randomised into this study more 
than once.
9.6
Blinding and Unblinding Treatment Assignment
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a specified 
unblinded statistician and programmer from Premier Research who will have access to the 
randomization code, unblinded site monitors and clinical manager from Premier Research, and the 
unblinded pharmacist at each study site. The unblinded study personnel will not participate in 
study procedures or data analysis prior to unblinding of the study data to all study-related 
personnel. Unblinded personnel who are not otherwise involved in the study will prepare data for 
review and interim analysis.
Study personnel will make every effort to safeguard the integrity of the study blind to minimize 
bias in the conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
Fulfilling Hy's Law, defined as AST or ALT:::: 
defined as serum creatinine :::=: 
personnel. Infusion details will be recorded in the subject's eCRF. 
subject's treatment assignment. 
ULN and bilirubin :::: 
723 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 51 of 114
Unblinding should be discussed in advance with the medical monitor if possible. For emergency 
unblinding, study personnel will use the IWRS. Only authorized users will have access to the 
unblinding function in the IWRS, and the IWRS will reveal the treatment information for the 
selected subject only. If the investigator is not able to discuss treatment unblinding in advance, 
then he/she must notify the medical monitor as soon as possible about the unblinding incident 
The IWRS will also send a blinded 
notification to the clinical team alerting them that a break blind occurred.
The investigator or designee must record the date and reason for treatment unblinding on the 
appropriate CRF for that subject. In all cases that are not emergencies, the investigator must discuss 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
remaining subjects in the study. Thus, the overall study blind will not be compromised. If a 
tment assignment is unblinded, he/she will be asked to withdraw from the study. The 
investigator will make this decision after consultation with the medical monitor.
Overall unblinding will take place at the end of the study only after database lock has been 
achieved.
9.7
Permitted and Prohibited Therapies
All concomitant medications used (including OTC medications and herbal supplements) will be 
recorded in the source document and on the appropriate eCRF.
9.7.1
Permitted Therapies
As detailed in Section 9.1.2, subjects should continue to take their prescribed medication for the 
treatment of PDN.
The following medications are permitted during the study, with restrictions:
Subjects who develop unacceptable pain due to PDN or other conditions (eg, headache, 
muscular pain, etc.) during any stage of the study (including during the washout period 
prior to randomisation) will be permitted to initiate rescue/analgesic therapy with 
paracetamol up to a maximum dose of two 500 mg tablets (ie, 1 g per dose) up to 4 times 
daily (ie, 4 g per 24-hour period).
As a guideline, rescue medication should not generally be given for more than 
3 consecutive days. All rescue medication use must be captured in the CRF and subjects 
will be required to record reasons for use. Subjects will be requested not to take any rescue 
therapy within 24 hours of a clinic visit.
PDN pain, they may receive stronger 
analgesics as rescue medicat
investigator
medical monitor.
Subjects may use sedative/hypnotics (eg, benzodiazepines) on a PRN basis, but these 
should not be taken more than 3 times a week or within 24 hours of a clinic visit.
Low dose aspirin for cardiovascular prophylaxis.
without revealing the subject's treatment assignment. 
the event with the medical monitor prior to unblinding the subject's treatment assignment. 
that subject's treatment assignment without unblinding the treatment assignments for the 
subject's trea 
• 
• 
• 
If paracetamol does not relieve the subject's 
• 
• 
ion (including tramadol and other 'weak' opiates) at the 
's discretion and in consultation with the 
724 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 52 of 114
If the subject is receiving permitted medications for the treatment of non-excluded medical 
conditions (eg, antihypertensive medication, cholesterol-lowering treatment, antidiabetic 
medication), the dose and dosing regimen must be stable for at least 28 days before 
randomisation and should be expected to remain stable for the duration of study 
participation until at least the last follow-up visit.
Other medicat
-being may be 
given at the discretion of the investigator (eg, a regular prescribed treatment regimen for 
glycaemic control in the management of diabetes; antihypertensive medication). 
9.7.2
Prohibited Therapies
The following therapies are prohibited during the study:
NSAIDs or analgesic doses of aspirin (325 mg/day or higher). The subject must be willing 
and able to discontinue all NSAID or COX-2 analgesic therapy from the start of the 
washout period until the end of follow-up. This includes OTC pain medications and topical 
analgesics that contain an NSAID or COX-2 inhibitor. The use of NSAIDs (eg, ibuprofen, 
naproxen) or COX-2 medications (eg, celecoxib) at any time during the study and through 
to completion of drug washout (5 half-lives) is prohibited and contraindicated.
Any other investigational drug or device, including other immunotherapeutics and live 
viral or attenuated bacterial vaccines.
Any drug of abuse including but not limited to: amphetamine, barbiturate, cannabinoids,
cocaine, methadone, methaqualone, opiate, phencyclidine, or propoxyphene, unless there 
is a documented medical explanation other than drugs of abuse (eg, the subject takes 
opioids under medical supervision for pain and the prescribed opioid dosing regimen is 
expected to be stable and unchanged for the duration of the study; or where cannabinoids 
are similarly being taken for documented medical reasons); or sedative/hypnotics used as 
described above.
Muscle relaxants, anticonvulsants, anti-Parkinsonian medications, or neuroleptic 
medications, unless used for non-excluded conditions such as Restless Leg Syndrome or 
as an adjuvant for pain on a regular schedule.
Oral, IV, intramuscular, or any other parenteral
steroids
(inhaled steroids for 
well-controlled COPD or asthma, or topical steroids for eczema, are permitted).
Treatment with another biologic therapeutic agent.
The following therapies are prohibited both before and during the study:
Previously received any form of anti-NGF or anti-TNF therapy. 
Participation in another clinical study with an IP or device within 60 days or 5 half-lives 
prior to screening, whichever is longer.
Any significant medical or surgical procedure or trauma within 28 days of Day 1, or 
planned to be undertaken within the timeframe of the clinical trial, that will likely affect 
the subject s safety or ability to complete the study, or the scientific integrity of the study 
data, as judged by the investigator.
• 
• 
ion considered necessary for the subject's safety and well 
• 
• 
• 
• 
• 
• 
• 
• 
• 
725 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 53 of 114
Subjects receiving excluded therapies will be ineligible for study enrolment or for continuation in 
the study, at the discretion of the investigator.
9.7.3
Restrictions
Subjects will be asked to avoid foods containing poppy seeds for 5 days prior to the 
screening visit.
Subjects will be asked to avoid any changes in OTC products and herbals, vitamins, and 
minerals from at least 14 days before first dosing on Day 1 through to the end of follow-up. 
If needed, a nasal spray for nasal congestion may be used occasionally. If a change in 
concomitant medication is needed, the investigator must decide if the subject should remain 
in the study or be dismissed from the study.
Subjects who use nicotine patches or other nicotine formulations may continue to use them 
at the same dose regimen.
Subjects must refrain from blood and plasma donation during the study and up to 2 months 
after the final follow-up visit.
Male subjects must use appropriate contraception (see Appendix B) and must refrain from 
sperm donation from first dosing on Day 1 until at least 3 months after the last dose.
Discharge from the clinical unit after administration of study drug may be delayed for 
safety reasons at the discretion of the investigator.
9.8
Treatment after End of Study
After the end of the study, each subject will be treated according to standard clinical practice.
9.9
Dispensing and Storage
AstraZeneca will provide the investigators with adequate quantities of MEDI7352 using 
designated distribution centers. Pharmacy personnel will prepare all the IPs for each subject 
according to handling instructions provided by AstraZeneca and the randomisation scheme.
The IP supplied by AstraZeneca is to be used exclusively in the clinical study according to the 
instructions of this protocol. The investigator is responsible for dispensing the IP according to the 
dosage scheme and for ensuring proper storage of the IP.
The investigator (or designee) must confirm the receipt of the IP with his or her signature. A copy 
of this receipt must be kept by the investigator and another copy will be stored at AstraZeneca
and/or Premier Research. 
 
9.10 Drug Accountability
The investigator (or designee) must maintain adequate records showing the receipt, dispensing, 
return, or other disposition of the IPs, including the date, quantity, batch or code number, and 
identification of subjects (subject number) who received the IPs. The investigator will not supply 
the IP to any person except those named as sub-investigators, designated study personnel, and 
subjects in this study. The investigator will not dispense the IPs from any study sites other than 
those authorized. Investigational product(s) may not be relabelled or reassigned for use by other 
726 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 54 of 114
subjects. If any of the IPs are not dispensed, are lost, stolen, spilled, unusable, or are received in a 
damaged container, this information must be documented and reported to the sponsor and 
appropriate regulatory agencies, as required.
Upon completion of the study, the IPs (partly used, unused, and empty packaging) must be left in 
the original packaging until the study site has been instructed in writing to either destroy the IP 
according to approved procedures or to return the IP to the sponsor or designee for destruction.
9.11 Labelling and Packaging
9.11.1 Labelling
Each vial of IP will have a label affixed that meets the applicable regulatory requirements and may 
include the following: IP name/study drug, dosage form, directions for use including route of 
administration, protocol number, regulatory statements if required, storage conditions, expiry date,
and sponsor identification. Each IP kit will have a unique number that is printed on all labels within 
the kit (ie, the outer carton label and the label of each container within the carton). Each carton 
and vial will be labelled with the same unique sequence number range.
Final labelling will comply with the regulatory requirements of each country where the study will 
be conducted.
9.11.2 Packaging
 
727 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 55 of 114
10
STUDY PROCEDURES
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy.
For the timing of assessments and procedures throughout the study, refer to the Schedule of Events 
(Table 2-1). Throughout the study, every reasonable effort should be made by study personnel to 
follow the timing of assessments and procedures in the Schedule of Events for each subject. If a
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible.
10.1 Study Duration
The planned sequence and maximum duration of the study periods will be as follows:
1. Screening: 45 days
2. Treatment: 12 weeks
3. Follow-up: 42 days
The maximum treatment duration for each subject is approximately 12 weeks. 
The maximum study duration for each subject is approximately 25 weeks.
10.2 Study Periods and Visits
The study consists of a total of 11 visits: 1 (or more) screening visit(s), 6 treatment visits, 2 visits 
solely for blood draws, an end-of-treatment visit, and a follow-up visit.
10.2.1 Screening and Washout
10.2.1.1 Screening
The subject must be screened within 45 days before enrolment in the study and at least 7 days 
before the first day of treatment to allow for 7 days of baseline pain ratings. Screening procedures 
may be performed at 1 or more visits. The following procedures will be performed at screening:
1. Obtain written informed consent.
2. Assess inclusion/exclusion criteria.
3. Collect demographic information.
4. Record medical history, including current therapies (eg, prescription and non-prescription
medications).
5. Perform a complete physical and neurological examination (excluding the genitourinary 
examination, unless warranted), including weight and height.
6. Measure vital signs in supine position (HR, BP [in supine position after a 5-minute rest], 
respiratory rate, and temperature). To assess orthostasis, repeat the measurement of BP and 
pulse 1 minute (>1 minute, <3 minutes) after the subject stands.
7. Perform 3 replicates of 12-lead ECGs (with printouts) after the subject has been resting in the 
supine position for at least 10 minutes.
8. Perform motor and sensory NCS.
728 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 56 of 114
9. Perform TNSn, strength (dorsiflexion), and deep tendon reflex (knee and ankle) assessments.
10. Collect blood sample for the following:
serology (HIV, hepatitis B and C, and TB [QuantiFERON] testing)
chemistry, haematology, and coagulation
hemoglobin A1c
immunogenicity (ADA) testing
pharmacogenetic testing (optional)
11. Collect urine sample for the following:
urinalysis
urine drug screen
urine pregnancy test (for women who are not surgically sterile) (If the screening urine 
pregnancy test is more than 7 days before the first day of treatment, it must be repeated 
prior to the first dose)
12. Perform Galer NPS.
13. Perform SF-36.
14. Train the subject on rating their daily pain and DSIS, and entering these data into the electronic 
patient-reported outcome (ePRO) system. To determine eligibility, pain scores from Days -7
to -1 are required.
15.
Procedures for rescreening subjects who initially fail to meet study entry criteria are described in 
Section 14.3.
10.2.2 Double-blind Treatment Period (Days 1-84 [Weeks 1-12])
The treatment period consists of 6 treatment visits every 2 weeks (from Day 1 to Day 70), 2 blood 
draw visits on Days 71 and 77, and an end-of-treatment visit on Day 84 (2 weeks after the last 
dose).
10.2.2.1 Day 1 (Treatment 1)
The timing of safety assessments and safety blood sampling on Day 1 is presented in Table 2-2.
The following procedures will be performed on Day 1 before treatment with the IP:
1. Record AEs and concomitant medications and therapies.
2. Perform a targeted physical and neurological examination. 
3. Perform TNSn, strength (dorsiflexion), and deep tendon reflex (knee and ankle) assessments.
729 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 57 of 114
4. Perform 3 replicates of 12-lead ECGs (with printouts) after the subject has been resting in the 
supine position for at least 10 minutes.
5. Measure supine vital signs (HR, BP [supine after a 5-minute rest], respiratory rate, and 
temperature). To assess orthostasis, repeat the measurement of BP and pulse 1 minute 
(>1 minute, <3 minutes) after the subject stands.
6. Confirm that all inclusion/exclusion criteria are satisfied.
7. Assign a randomisation number via IWRS. If necessary, the randomisation transaction in 
IWRS can be performed on Day -1. [Note: Subjects who have been randomised in the IWRS,
but who do not receive a subsequent dose and do not continue study participation, will be 
classified as Early Terminated Subjects].
The following procedures will be performed on Day 1 after randomisation:
8. Collect pre-dose blood samples for the following:
chemistry, haematology, and coagulation
PK 
9. Collect urine sample for urinalysis.
10. Administer the IP infusion.
11. Repeat 3 replicates of ECGs (with printouts) at 60 (±10) minutes after the start of IP 
administration, and 2 and 4 hours (±10 minutes) after the start of IP administration. Subjects 
must rest in the supine position for 10 minutes prior to each ECG recording session.
12. Vital signs measurements. Assess supine blood pressure and heart rate at 15 mins, 30 mins, 
45 mins, 60 mins (within 10 minutes of infusion end), 2 hours, and 4 hours after start of 
infusion. Orthostatic vital signs (standing heart rate and BP) should be measured at 60 mins 
(within 10 minutes of infusion end), 2h and 4h after start of infusion. These orthostatic 
measurements should be taken after the supine measurements and after the subject has 
adopted the standing position for 1 minute (>1 minute, <3 minutes). Assess body temperature
at 60 mins, 2h and 4h after start of infusion. Assess respiratory rate at 15 mins, 60 mins, 
2 hours, and 4 hours after start of infusion. [Note: unless where stated, an acceptable window 
for measurement of vital signs is ± 5 minutes in relation to the specified time-point].
13. Assess the IV injection site for local reactions at 15 mins, 30 mins, 45 mins, 60 mins, 2 hours, 
and 4 hours after start of infusion.
14. Assess and record any AEs occurring during the visit.
15. Remind the subject to continue entering their daily pain and DSIS into the ePRO system and 
rescue medication into the paper diary.
10.2.2.2 Days 14, 28, 42, 56, and 70 (Treatments 2 to 6)
The following procedures will be performed on Days 14, 28, 42, 56, and 70:
730 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 58 of 114
1. Perform Galer Neuropathic Pain Scale (NPS) (Days 28 and 56 only).
2. Perform PGIC (Days 28 and 56 only).
3. Perform a targeted physical and neurological examination. 
4. Perform TNSn, strength (dorsiflexion), and deep tendon reflex (knee and ankle) assessments.
5. Perform 3 replicates of 12-lead ECGs (with printouts) after the subject has been resting in the 
supine position for at least 10 minutes (Days 28 and 56 only).
6. Measure pre-dose sitting vital signs (HR, BP [sitting after a 5-minute rest], respiratory rate, 
and temperature). To assess orthostasis, repeat the measurement of BP and pulse 1 minute 
(>1 minute, <3 minutes) after the subject stands.
7. Collect pre-dose blood samples for the following:
chemistry, haematology, and coagulation
immunogenicity (ADA) testing (Days 14, 28, 56, and 70 only)
PK 
8. Collect urine sample for the following:
urinalysis
9. Administer the IP infusion.
11. Five (5) minutes (± 5 minutes) after completion of the infusion, repeat sitting vital signs (HR, 
BP [sitting after a 5-minute rest], respiratory rate, and temperature). Orthostatic vital signs
(standing heart rate and BP) should be measured at 5 minutes (± 5 mins) after completion of 
the infusion. These orthostatic measurements should be taken after the sitting measurements 
and after the subject has adopted the standing position for 1 minute (>1 minute, <3 minutes).
12. Assess the IV injection site for local reactions.
13. Approximately 8 hours (± 15 mins) after the start of the infusion, collect a blood sample for
the following (Day 70 only):
PK
14. Record AEs and concomitant/rescue medications and therapies.
731 of 938
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 59 of 114
15. Remind the subject to continue entering their daily pain and DSIS into the ePRO system and 
rescue medication into the paper diary.
16. Schedule the subject to return to the clinic for the next visit (on Day 70, schedule the subject 
to return to the clinic for the 24-hour blood sample).
10.2.2.3 Day 71
1. Measure sitting vital signs (HR, BP [sitting after a 5-minute rest], respiratory rate, and 
temperature). To assess orthostasis, repeat the measurement of blood pressure and pulse 
1 minute (>1 minute, <3 minutes) after the subject stands.
2. Approximately 24 hours (± 4 hours) after the start of the Day 70 infusion, collect a blood
sample for the following:
PK
3. Record AEs and concomitant/rescue medications and therapies.
4. Schedule the subject to return to the clinic for the Day 77 blood sample at approximately the 
same time of day as the Day 70 infusion.
10.2.2.4 Day 77
1. Measure sitting vital signs (HR, BP [sitting after a 5-minute rest], respiratory rate, and 
temperature). To assess orthostasis, repeat the measurement of blood pressure and pulse 
1 minute (>1 minute, <3 minutes) after the subject stands.
2. At approximately the same time of day (± 4 hours) as the Day 70 infusion, collect a blood 
sample for the following:
PK
3. Record AEs and concomitant/rescue medications and therapies.
4. Schedule the subject to return to the clinic for the Day 84 visit.
10.2.2.5 Day 84 (End-of-treatment; Week 12)
The following procedures will be performed at the end-of-treatment visit on Day 84 (2 weeks after 
the last dose):
1. Perform Galer NPS.
2. Perform PGIC.
3. Perform SF-36.
4. Perform a complete physical and neurological examination (excluding the genitourinary 
examination, unless warranted).
732 of 938
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 60 of 114
5. Perform TNSn, strength (dorsiflexion), and deep tendon reflex (knee and ankle) assessments.
6. Perform 3 replicates of 12-lead ECGs (with printouts) after the subject has been resting in the 
supine position for at least 10 minutes.
7. Measure sitting vital signs (HR, BP [sitting after a 5-minute rest], respiratory rate, and 
temperature). To assess orthostasis, repeat the measurement of blood pressure and pulse 
1 minute (>1 minute, <3 minutes) after the subject stands.
8. Collect blood samples for the following:
chemistry, haematology, and coagulation
immunogenicity (ADA) testing
PK
9. Collect urine sample for the following:
urinalysis
urine pregnancy test (for women who are not surgically sterile)
10. Assess the IV injection site for local reactions.
11. Record AEs and concomitant/rescue medications and therapies.
12. Remind the subject to continue entering their daily pain and DSIS into the ePRO system and 
rescue medication into the paper diary.
13. Schedule the subject to return to the clinic for the Week 18 visit.
10.2.3 Follow-up (or Early Termination) Evaluation (Week 18)
At 6 weeks after the last visit (8 weeks after the last administration of the IP) or upon early 
termination of the study, the following procedures will be performed:
1. Perform Galer NPS.
2. Perform PGIC.
3. Perform a complete physical and neurological examination (excluding the genitourinary 
examination, unless warranted).
4. Perform TNSn, strength (dorsiflexion), and deep tendon reflex (knee and ankle) assessments.
5. Perform 3 replicates of 12-lead ECGs (with printouts) after the subject has been resting in the 
supine position for at least 10 minutes.
6. Perform motor and sensory NCS.
7. Collect blood samples for the following:
chemistry, haematology, and coagulation
733 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 61 of 114
immunogenicity (ADA) testing
PK and 
(only if this is an Early Termination Visit)
8. Collect urine sample for the following:
urinalysis
urine pregnancy test (for women who are not surgically sterile)
9. Measure sitting vital signs (HR, BP [sitting after a 5-minute rest], respiratory rate, and 
temperature). To assess orthostasis, repeat the measurement of BP and pulse 1 (>1 minute, 
<3 minutes) minute after the subject stands.
10. Assess the IV injection site for local reactions.
11. Record AEs and concomitant medications and therapies.
10.3 Assessments
10.3.1 Efficacy Variables
Efficacy will be assessed by daily average pain, as measured on an 11-point (0-10) NRS; the Galer 
NPS the DSIS; the PGIC; and the SF-36.
 
The time points for each assessment are listed in Schedule of Events 
(Table 2-1).
10.3.1.1 Numerical Rating Scale
Subjects will assess their perceived average neuropathic pain over the previous 24 hours using an 
11-point NRS, with 0 representing no pain and 10 representing the worst pain imaginable. Subjects 
will be instructed to assess their average daily pain at approximately the same time every morning,
and to record their response in a subject diary (ePRO).
10.3.1.2 Galer Neuropathic Pain Scale
Subjects will assess their neuropathic pain using the Galer NPS. The NPS includes 2 descriptors 
of pain, including intensity and unpleasantness, and 8 descriptors that assess specific qualities of 
neuropathic pain: sharp, hot, dull, cold, sensitive, itchy, deep, and surface pain. Each of these 
10 dimensions has a 0 to 10 NRS in which 0 is equal to no pain and 10 equals the most intense 
pain.
10.3.1.3 Daily Sleep Interference Scale
Subjects will assess how their neuropathic pain interferes with their sleep using the DSIS. The 
DSIS is an 11-point Likert scale, with 0 indicating that pain did not interfere with sleep and 10 
indicating that pain completely interfered with sleep. The DSIS is completed by subjects once a 
day (upon awakening) to accurately capture variability in sleep interference due to pain on a daily 
basis, thus minimizing recall bias.
734 of 938
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 62 of 114
10.3.1.4 Patient Global Impression of Change
Subjects will rate their overall improvement in health status using the PGIC. The PGIC consists 
of a 7-point scale where 1 =
=
. Subjects will be 
Very Much Improved
1
Much Improved
2
Minimally Improved
3
No Change
4
Minimally Worse
5
Much Worse
6
Very Much Worse
7
10.3.1.5 Short-Form Health Survey
-36.
The SF-36 assesses 8 health concepts: 1) limitations in physical activities because of health 
problems; 2) limitations in social activities because of physical or emotional problems; 
3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general 
mental health (psychological distress and well-being); 6) limitations in usual role activities because 
of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The 
items use Likert-type scales with either 5 or 6 points, or 2 or 3 points.
10.3.1.6 Rescue Medication Use
Subjects will record all rescue medications they take for neuropathic pain in a paper diary.
10.3.1.7
10.3.2 Clinical Pharmacology
Samples will be collected at the time points specified in the Schedule of Events (Table 2-1).
10.3.2.1 Pharmacokinetic Analysis Methods 
The PK characterization of drug concentrations for each dose to be profiled will use 
noncompartmental analysis (NCA). Standard PK parameters assessed will include measures of the 
extent of absorption using estimates of the area-under-the-curve (AUC) and rate-of-absorption 
using the Cmax and Tmax. The following PK parameters will be determined:
735 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 63 of 114
Maximum plasma concentration (Cmax)
Time to maximum plasma concentration (Tmax)
Apparent first order terminal elimination half-life (t½) 
Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable plasma concentration (AUC0-t)
Area under the plasma concentration-time curve from time 0 to infinity (AUC 0- )
AUCtau at steady state
Cmax at steady state
Volume of distribution at steady state
Apparent total body clearance at steady state (CLss)
Actual sampling times will be used for all PK parameter estimation.
Additional details of the parameters and their calculation and evaluation will be included in the 
SAP.
10.3.2.2 Pharmacodynamic Variables
Plasma or serum samples will be collected for exploration of free and/or total NGF.
10.3.2.3 Pharmacogenetic Variables
Pharmacogenetic analysis is optional. If a subject declines to participate in the genetic research, 
this will have no influence on the ability of the subject to participate in the study. 
 
 
10.3.2.4
736 of 938
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 64 of 114
standard operating procedures and analytical requirements. 
10.3.2.5 Immunogenicity
Blood samples will be collected for assessment of ADA levels.
10.3.3 Safety Variables
Safety assessments will include the evaluation of AEs, clinical laboratory tests, vital signs, 12-lead 
ECGs, physical and neurological examination findings, neuropathy assessments (TNSn), strength 
(dorsiflexion), and deep tendon reflex (knee and ankle) assessments, motor and sensory nerve
conduction, concomitant medications, injection site reactions, and infusion reactions.
10.3.3.1 Clinical Laboratory Assessments
10.3.3.1.1 Clinical Laboratory Tests to be Performed 
Samples for laboratory tests will be collected at the time points specified in the Schedule of Events 
(Table 2-1) and will include the following:
Haematology:
hemoglobin, haematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential
Serum Chemistry:
albumin, total bilirubin, total protein, calcium, ALP, ALT, AST, blood 
urea nitrogen, creatinine*, glucose, sodium, potassium, chloride, 
bicarbonate, lactate dehydrogenase, uric acid, C-reactive protein (CRP)
*serum chemistry reports should include calculation of creatinine 
clearance using the Cockcroft-Gault equation for estimation of GFR 
(eGFR)
Coagulation Panel:
prothrombin time, partial thromboplastin time, fibrinogen
Urinalysis:
pH, specific gravity, blood urine, glucose, protein, ketones
Pregnancy Test 
[urine]:
for women who are not surgically sterile
Urine Drug Screen:
including but not limited to amphetamine, barbiturate, cannabinoids, 
cocaine, 
methadone, 
methaqualone, 
opiate, 
phencyclidine,
and 
propoxyphene
Serology:
HIV, hepatitis B and C, and tuberculosis (QuantiFERON)
Blood and urine samples for haematology, serum chemistry, urinalysis, and serology will be sent 
to a central laboratory for analysis. Urine drug screens and pregnancy tests will be conducted at 
the study sites.
737 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 65 of 114
10.3.3.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities.
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of infectious samples are outlined in the study manual. The investigator is responsible for ensuring 
that all study samples that are to be transported to another location are packed and shipped 
appropriately according to the applicable regulations.
10.3.3.1.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for the clinical laboratory assessments in this study will be provided 
by the responsible laboratory and submitted to AstraZeneca prior to the beginning of the study.
They will be regarded as the reference ranges on which decisions will be made.
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate CRF/eCRF.
All clinical laboratory values that
pathological changes during or after termination of treatment must be reported as AEs and 
followed, as described in Section 11.2.5.
All measurements described in this section are recognized standard methods.
10.3.3.1.4 Clinical Examinations 
10.3.3.1.5 Vital Signs 
Vital signs (HR, BP, respiratory rate, and temperature) will be measured after the subject has been 
in a supine position for 5 minutes at screening and Day 1 and in a sitting position for 5 minutes at 
all other visits. To assess orthostasis, BP and pulse will be measured again 1 minute (>1 minute, 
<3 minutes) after the subject stands.
Vital signs will be assessed as follows:
Screening: Measure respiratory rate, temperature, and HR and BP after a 5-minute rest in 
supine position. To assess orthostasis, repeat BP and HR 1 minute after the subject stands. 
Day 1 pre-dose: Measure respiratory rate, temperature, and HR and BP after a 5-minute 
rest in supine position. To assess orthostasis, repeat BP and HR 1 minute after the subject 
stands.
Day 1 post-dose: Supine and orthostatic BP and HR at 15 mins, 30 mins, 45 mins, 
60 mins, 2 hours, and 4 hours after start of infusion. Temperature and supine and 
orthostatic BP and HR at 60 mins, 2 hours, and 4 hours after start of infusion. Respiratory 
rate at 15 mins, 60 mins, 2 hours, and 4 hours after start of infusion. The 60-minute 
assessments should be performed within 10 minutes of the end of the infusion. [Note: An
acceptable window for these vital sign assessments is ± 5 mins in relation to the specified 
time.]
m the investigator's opm10n show clinically relevant or 
• 
• 
• 
738 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 66 of 114
Days 14, 28, 42, 56, and 70 pre-dose: Measure respiratory rate, temperature, and HR and 
BP after a 5-minute rest in sitting position. To assess orthostasis, repeat BP and HR 
1 minute after the subject stands.
Days 14, 28, 42, 56, and 70 post-dose: 5 minutes after completion of infusion, measure
respiratory rate, temperature, and HR and BP after a 5-minute rest in sitting position. After 
measuring sitting vital signs, assess orthostatic BP and HR 1 minute after the subject 
stands.
Days 71, 77, and Week 18 or early termination: Measure respiratory rate, temperature, and 
HR and BP after a 5-minute rest in sitting position. To assess orthostasis, repeat BP and 
HR 1 minute after the subject stands. 
10.3.3.1.6 Twelve-lead Electrocardiogram 
All subjects will undergo ECGs as indicated in the schedule of assessments. Where applicable, 
digital ECGs will be collected using the ECG equipment delivered by the central ECG laboratory 
(ECG lab) and will be transferred to and analys
operating procedures. Further details are provided in the ECG Manual.
Paper printouts of the 12-lead ECGs will be reviewed in real time by the principal investigator, or 
delegate, for safety monitoring. The results of the evaluation will be reported in the eCRF as 
normal or abnormal (if abnormal, the ECG is also to be reported as not clinically significant or 
clinically significant). The details of any ECG abnormalities should be described and captured in 
the eCRF (irrespective of whether they are considered not clinically significant or clinically 
significant).
10.3.3.1.7 Physical and Neurological Examination 
A complete physical and neurological examination (excluding the genitourinary examination,
unless warranted) will be performed at Screening, Week 12, and Week 18/Early Termination, as 
indicated in the schedule of assessments.
A targeted physical and neurological examination based on symptoms and previous findings will 
be performed at all other visits.
Height and weight will be measured at Screening.
10.3.3.1.8 Total Neuropathy Scores--Nurse  
The TNSn, a semi-quantitative clinical assessment of peripheral nervous system function, will be 
administered at Screening, Day 1, Week 2, Week 4, Week 6, Week 8, Week 10, Week 12 and 
Week 18/Early Termination. The TNSn provides for an assessment of motor symptoms, autonomic 
symptoms, pin sensibility, vibration sensibility, and deep tendon reflexes. Strength (dorsiflexion) 
and deep tendon reflexes (knee and ankle) are to be scored at every visit alongside the TNSn 
assessments.
10.3.3.1.9 Motor and Sensory Nerve Conduction Studies 
Motor and sensory NCS will be undertaken in relevant lower and upper limb nerves (sural,
peroneal, and median/ulnar nerves). Relevant endpoints including peak latency, amplitude, 
conduction velocity and duration of nerve action potentials will be captured using standard 
antidromic or orthodromic determination according to protocol and will be recorded at baseline 
and at the follow-up visit.
• 
• 
• 
ed by the ECG lab according to the lab's standard 
739 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 67 of 114
10.3.3.1.10 Injection Site or Infusion Reactions 
Investigators should evaluate infusion reactions that occur during or immediately following 
infusion per the FDA Guidance for Industry, Immunogenicity Assessment for Therapeutic Protein 
Products (2014) and FDA Guidance for Industry, Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007).42,43 See Section 5.3
for discussion of potential infusion reactions.
Investigators should evaluate injection site reactions using the toxicity grading scale summarized 
in Table 10-1.
Table 10-1:
Local Reactions to Injectable Product
Local Reaction 
Mild 
Moderate 
Severe 
Pain 
Does not interfere 
with activity 
Repeated use of non-narcotic 
pain reliever >24 hours or 
interferes with activity 
Any use of narcotic pain 
reliever or prevents daily 
activity 
Tenderness 
Mild discomfort to touch 
Discomfort with movement 
Significant 
discomfort at rest 
Erythema/rednessa
2.5 to 5 cm 
5.1 to 10 cm 
>10 cm 
Induration/swellingb
2.5 to 5 cm and does not 
interfere with activity 
5.1 to 10 cm or interferes 
with activity 
>10 cm or prevents daily 
activity 
Source: FDA 200743
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable.
b Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement.
10.3.3.2 Adverse Events
The definitions and management of AEs, and any special considerations for AEs, are provided in 
Section 11.
740 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 68 of 114
11
ADVERSE EVENTS
11.1 Definitions
11.1.1 Adverse Events
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavourable and unintended sign (including an
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product.
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.)
Events that occur in subjects treated with placebo, or during treatment-free periods of the study,
are also considered AEs.
11.1.2 Adverse Drug Reaction
All noxious and unintended responses to an IP related to any dose should be considered adverse 
drug reactions (ADRs).
n investigational 
n
IP and an AE is at least a reasonable possibility, ie, the relationship cannot be ruled out. All AEs 
judged by either the reporting investigator or the sponsor as having a reasonable causal relationship 
to an IP qualify as ADRs.
All AEs
ADRs. If a relationship to IP is not provided, then the AE must be treated as if it were
.
11.1.3 Unexpected Adverse Event/Adverse Drug Reaction
An expected AE or ADR is one for which the nature or severity is consistent with the known AE 
profile of the product. For a pre-approval test product, the known information is contained in the 
IB. For a marketed product, the known information is contained in the current package insert for 
the product.
An unexpected AE or unexpected adverse drug reaction (UADR) is one for which the nature or 
Brochure for an unapproved IP or package insert/summary of product characteristics for an 
approved product). For example, hepatic necrosis would be unexpected (greater severity) if the IB 
only listed elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (greater specificity) if the IB only listed cerebral vascular 
accidents.
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be (a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of fulminant
hepatitis (fulminant hepatitis would be unexpected.)
The phrase "responses to a 
product" means that a causal relationship between a 
for which the judgment of relationship to IP is "possible" or higher will be considered 
"possible" 
severity of which is not consistent with the applicable product information (eg, Investigator's 
741 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 69 of 114
11.1.4 Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
results in death
is life-threatening
-
the patient was at risk of death at the time of the event; it does not refer to an event that
hypothetically might have caused death if it were more severe.
requires inpatient hospitalization or prolongation of existing hospitalization
NOTE: Outpatient treatment in an emergency room is not in itself a serious AE, although the 
reasons for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness or 
disease existed before the subject was enrolled in the study, provided that it did not deteriorate 
in an unexpected way during the study.
results in persistent or significant disability/incapacity
is a congenital anomaly
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP during 
pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has received an
IP is not considered an SAE unless it is suspected that the IP(s) interacted with a contraceptive 
method and led to the pregnancy. 
is an important medical event
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above. Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, 
development of drug dependency, or drug abuse. The occurrence of malignant tumors is also 
to be considered serious.
11.1.5 Significant Adverse Events
Other significant AEs are defined as marked haematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy.
11.1.6 Treatment-Emergent Adverse Events
An AE is defined as treatment-emergent if the first onset or worsening is after the first 
administration of IP and not more than 30 days after the last administration of IP.
• 
• 
NOTE: The term "life threatening" in the definition of "serious" refers to an event in which 
• 
• 
• 
• 
742 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 70 of 114
11.2 Event Assessment and Follow-up of Adverse Events
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study 
monitor.
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate eCRF. Information to be collected includes event description, time of onset, 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution.
Any medical condition that is present at the time that the participant is screened will be considered 
at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.
The site staff will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for nonserious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs 
since the last visit. Events will be followed for outcome information until resolution or 
stabilization.
11.2.1 Assessment
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as
nce your last visit?
Any clinically relevant observations made during the visit will also be considered AEs.
clinician's assessment of severity, relationship to study product (assessed only by those with the 
as baseline and not reported as an AE. However, if the study participant's condition deteriorates 
• 
"How are you feeling?" 
• 
"Have you experienced any issues si 
" 
• 
"Have you taken any new medications since your last visit?" 
743 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 71 of 114
11.2.2 Evaluation
11.2.2.1 Severity of Adverse Events
The clinical severity of an AE will be classified as:
Mild
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living.
Moderate
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject.
Severe
Interrupts usual activities of daily living, or significantly affects clinical status,
or may require intensive therapeutic intervention.
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.4.
11.2.2.2 Seriousness
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.4.
11.2.2.3 Action(s) Taken
Action(s) taken may consist of:
Dose increased
An indication that a medication schedule was modified by addition; either 
by changing the frequency, strength, or amount.
Dose not changed
An indication that a medication schedule was maintained.
Dose reduced
An indication that a medication schedule was modified by subtraction, 
either by changing the frequency, strength, or amount.
Drug interrupted
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication.
Drug withdrawn
An indication that a medication schedule was modified through 
termination of a prescribed regimen of medication.
Not applicable
Determination of a value is not relevant in the current context.
Unknown
Not known, not observed, not recorded, or refused.
11.2.2.4 Outcome at the Time of Last Observation
The outcome at the time of last observation will be classified as:
Recovered/resolved
Recovered/resolved with sequelae
Recovering/resolving
Not recovered/not resolved
• 
• 
• 
• 
744 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 72 of 114
Fatal*
Unknown
*Only select fatal as an outcome when the AE results in death. If more than one AE is judged to 
be 
d for each such 
death should be reported as SAEs.]
11.2.2.5 Adverse Event Relationship to Investigational Product
relationship to the IP. The categories for 
he relationship are as follows:
Related
A reasonable possibility exists of a relationship between the AE and IP.
Not related
No reasonable possibility exists of a relationship between the AE and IP.
11.2.3 Documentation
All AEs that occur within the period of observation for the study must be documented in the CRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.)
AE name or term
When the AE first occurred (start date and time)
Severity of the AE
Seriousness (hospitalization, death, etc.)
Actions taken
Outcome
Investigator opinion regarding the AE relationship to the IP(s)
11.2.4 Treatment of Adverse Events
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the decision about whether the 
subject may continue in the study will be made by the sponsor after consultation with the 
investigator and/or medical monitor.
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the
study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate.
For double-blinded studies, it is not necessary to unblind a 
circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 9.6 for a
description of the unblinding procedures.
• 
• 
possibly related to the subject's death, the outcome of death should be indicate 
AE. [ Although "fatal" is usually an event outcome, events such as sudden death or unexplained 
The investigator must make an assessment of each AE's 
classifying the investigator's opinion oft 
• 
• 
• 
When the AE stopped (stop date and time or an indication of "ongoing") 
• 
• 
• 
• 
• 
subject's involvement m the 
subject's treatment assignment in most 
745 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 73 of 114
11.2.5 Follow-up
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (ie, concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. All findings relevant to the final 
and recorded on the eCRF.
11.2.6 Reporting
11.2.6.1 Serious Adverse Events
The investigator or designee must report all SAEs promptly to MMS Holdings Inc. (MMS) within 
24 hours of first becoming aware of the event by completing, signing and dating the Serious 
Adverse Event Report Form, verifying the accuracy of the information recorded in the form with 
the source documents and eCRF, and sending the SAE form to MMS by one of the following 
methods:
Email: drugsafety@mmsholdings.com
Fax number: +1 734 468 0850
This written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if
available:
Protocol number
Reporter (study site and investigator)
Suspect IP
year of birth
Date of first dose of IP
Date of last dose of IP, if applicable
Adverse event term
Date of occurrence of the event
A brief description of the event, outcome to date, and any actions taken
The seriousness criteria that were met
Concomitant medication at onset of the event
outcome of an AE must be reported in the subject's medical record 
• 
• 
• 
• 
Subject's study number 
• 
Subject's 
• 
Subject's gender 
• 
• 
• 
• 
• 
• 
• 
746 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 74 of 114
Relevant medical history information
Relevant laboratory test findings
IP
ility that the IP
Whether and when the investigator was unblinded as to the subject
Any missing or additional relevant follow-up information concerning the SAE should be sent to 
the sponsor/sponsor representative via the same contact details above as soon as possible on a
follow-up SAE Report Form, together with the following minimal information (initial report, AE,
date of occurrence, subject identification (ID), study ID, IP, and site number); this will allow the 
follow-up information to be linked to the initial SAE report.
Specific information may be requested by the MMS Pharmacovigilance Department using a 
follow-up request form or via email communication.
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his or her health authorities, institutional review board 
(IRB)/independent ethics committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. Each investigator is obligated to learn about the reporting 
requirements for investigators in his/her country. 
11.2.6.2 Adverse Drug Reactions
All ADRs should be reported by the investigator in the eCRF.
Suspected serious ADRs must be reported to the sponsor immediately, regardless of the time 
elapsed since the end of the observation period.
11.2.6.3 Nonserious Adverse Events
Nonserious AEs will be recorded in the eCRF and reported by Premier Research to the sponsor
according to the Safety Management Plan.
11.3 Special Considerations
11.3.1 Adverse Events of Special Interest
An AESI is a treatment-emergent AE of scientific and medical interest specific to understanding 
of the effects of the IP and may require close monitoring and collection of additional information
by the investigator. An AESI may be serious or nonserious. The rapid reporting of AESIs allows 
ongoing surveillance of these events in order to characterise and understand them in association 
with the use of MEDI7352.
Refer to Section 5.3 for a summary of potential risks and the IB for a detailed discussion of 
potential risks.
The following AESIs have been identified specifically for this MEDI7352 protocol and are to be 
reported as described in Section 11.2.6.1.
• 
• 
• 
Investigator's opinion of the relationship to 
caused the SAE? Yes or No?") 
• 
("Is there a reasonable possib 
's treatment assignment 
747 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 75 of 114
Positively-adjudicated possible or probable RPOA, subchondral insufficiency fractures,
primary osteonecrosis, or pathological fracture 
Infections that meet SAE or severe AE criteria*
Anaphylactic reactions or infusion-related reactions that lead to permanent discontinuation 
of administration of IP
Adverse events of special interest irrespective of their severity and seriousness should be reported 
immediately using the same procedure as for SAE reporting (Section 11.2.6.1).
*Note: A serious infection is any infection that meets the SAE criteria in Section 11.1.4. Serious
infection AEs should be reported as SAEs. A severe infection is any infection that does not meet 
SAE criteria but is incapacitating, with inability to perform normal activities. Non-serious severe 
infections are reported as AEs. It is expected that microorganism culture results and all diagnostic 
or therapeutic procedure results performed on a study participant experiencing a serious or severe 
infection will be provided as an SAE/AESI update.
11.3.2 Pregnancy
All women who participate in the study must be postmenopausal or surgically sterile. Women 
should be instructed to contact the investigator or study staff immediately if pregnancy occurs or 
is suspected.
Pregnancy testing will be conducted prior to administration of the IP on every woman who is not 
surgically sterile. A woman who is found to be pregnant at the screening visit will be excluded 
from the study and considered to be a screening failure.
Men who are biologically capable of having children must agree and commit to use an adequate
form of contraception (see Appendix B) for the duration of the treatment period and for 3 months 
after the last administration of study drug. A male subject is considered capable of having children 
even if his sexual partner is sterile or using contraceptives.
A woman who becomes pregnant during IP treatment or within 30 days of discontinuing the IP 
will be immediately discontinued from study participation. The investigator must report the 
pregnancy as if it were an SAE within 24 hours of learning of the pregnancy, to MMS 
Pharmacovigilance using the Pregnancy Notification and Outcome Form via the same fax number 
and/or email address as for SAE reporting.
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy. The investigator is also responsible for following the pregnancy until delivery or 
termination. The follow-up information must be reported to MMS Pharmacovigilance using a new 
Pregnancy Notification and Outcome Form. The event meets the SAE criterion only if it results in 
a spontaneous abortion or a congenital anomaly.
11.3.3 Overdose
The maximal dose of IP should not be exceeded during the study. The investigator must report any 
overdose to MMS PV within 24 hours of learning of the overdose using the Overdose Report Form 
provided by MMS PV. In case of known or suspected overdose, symptomatic treatment as well as 
monitoring of vital functions should be performed based on the judgment of the investigator. If the 
overdose does not result in an AE, it should be reported in written form to the designated 
individuals who receive SAE notification. The information contained therein should include study 
• 
• 
• 
748 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 76 of 114
site identification, reporter identification, subject identification, IP, dose, action taken (eg, 
supportive measures or therapy), and any comments.
749 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 77 of 114
12
DATA SAFETY MONITORING BOARD
A data safety monitoring board will not be used in this study. 
750 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 78 of 114
13
STATISTICS
13.1 Statistical Analysis
This section presents a summary of the planned statistical analyses. A statistical analysis plan 
(SAP) that describes the details of the analyses to be conducted will be finalized prior to database 
lock for the interim analysis.
Unless otherwise indicated, all formal testing of statistical significance will be one-sided, and a 
difference resulting in a 1-sided
25 will be considered statistically significant. For 
estimation purposes, 2-sided 90% and 95% confidence intervals will be presented.
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of subjects in each category.
13.1.1 Analysis Populations
The following 4 analysis populations are planned for this study: 
Screening: all subjects who provide informed consent and/or assent and provide 
randomisation and treatment status in the study. 
Safety: The safety population will include all subjects who receive at least 1 dose of 
double-blind study medication.
Modified intent-to-treat (mITT): The modified intent-to-treat population will be used for 
all efficacy analyses and will include all randomised subjects who receive at least 1 dose 
of double-blind study medication and have at least 1 post-baseline NRS assessment.
PK: The PK population will include all subjects for whom a PK sample was obtained and 
analysed.
Inclusion in the analysis populations will be determined prior to database lock.
If a subject is randomised incorrectly or is administered the incorrect IP, analyses of the mITT 
population will be based on the IWRS-assigned treatment whereas all other analyses will be based 
on the actual treatment.
13.1.2 Study Subjects and Demographics
13.1.2.1 Disposition and Withdrawals
The numbers of subjects randomised, completing, and withdrawing, along with reasons for 
withdrawal, will be tabulated overall and by treatment group. The number of subjects in each 
analysis population will be reported.
13.1.2.2 Protocol Deviations
Subjects who violate any inclusion and/or exclusion criteria or who have major protocol deviations 
during the study (such as incorrect treatment assignment or use of prohibited medications) will be 
summarised and listed.
P value of S0.0 
• 
demographic and/or baseline screenmg assessments, regardless of the subject's 
• 
• 
• 
751 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 79 of 114
13.1.2.3 Demographics and Other Baseline Characteristics
These analyses will be conducted for all analysis populations. 
Demographic variables will be collected for any eventual analysis of differences in response to the 
IP, in accordance with local regulatory requirements. Baseline subject characteristics including
medical history, physical and neurological examination findings, and other baseline disease history
will be listed and included in summaries as appropriate.
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary Anatomical Therapeutic Chemical classes and preferred terms (PTs).
13.1.3 Exposure and Compliance
Investigational product administr
and number of infusions received. Descriptive statistics for these quantities, including the mean, 
median, SD, minimum, maximum, and quartiles, will be provided by treatment group. In addition,
any incomplete infusions will be listed. 
13.1.4 Efficacy Analysis
All efficacy variables will be summarized descriptively including number of observations, mean, 
SD, minimum, median, and maximum for continuous variables, and frequency of observations in 
each category and percentage for categorical variables. 
Primary and secondary endpoint e
approach. In addition, if there is missing data at a key analysis time-point (Weeks 4, 8, and 12) 
then resul
-Observation-Carried-
-Observation-Carried-
For example, if an endpoint is missing from a 
post-randomisation visit then the last non-missing post-baseline endpoint recorded prior to the visit 
will replace the missing value. For endpoints with separate scales, if an individual scale item is 
missing then the item will be carried forward from the previous visits rather than the total score. 
For post-baseline diary data, if a subject has at least 4 out of 7 days diary data prior to the visit,
then this will be taken as a valid observed weekly average score. However, if a subject has 3 or 
fewer days of diary data, this will be counted as a missing weekly score, and the LOCF approach 
will carry forward the last 7 non-missing entries of the diary data prior to the visit in order to 
calculate the weekly mean score at endpoint score.
The main statistical analysis of the primary efficacy endpoint at Week 12 will use the multiple 
comparison procedure modelling (MCP-Mod) approach on LOCF data, which is a well-established 
statistical methodology for establishing both the existence of a dose response and modelling the 
underlying dose-response relationship. Both EMA (2014)44 and FDA (2015)45 have recognized 
MCP-Mod as an efficient statistical methodology for model-based design and analysis of Phase 2
dose finding studies under model uncertainty. 
There are two steps to MCP-Mod:
1.
protecting the type I error and, if the dose-response relationship is statistically significant, 
then
2.
el parameters, 
such as ED50 (the effective dose for 50% of the population) in the case of Emax relationship.
ation will be summarized in terms of each subject's total dose 
fficacy data will be tabulated according to the 'Observed Cases' 
ts will also be tabulated according to 'Last 
Forward' (LOCF) and 
'Baseline 
Forward' (BOCF). 
The 'MCP' step is a rigorous method to establish presence of a dose response while 
The 'MOD' step estimates the dose response function and associated mod 
752 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 80 of 114
The MCP test will use linear contrasts corresponding to the five candidate models described in 
Section 13.2. The underlying model will be an analysis of covariance (ANCOVA) with dependent 
Week
o-medication type. The random error is assumed to be normally and independently 
distributed with constant variance.
If the MCP test is statistically significant, then the MOD step will select the most appropriate 
model from hyperbolic Emax, sigmoidal Emax, or l
maxlin
Kirby et al. (2011).46 From this model (including the same covariates as the ANCOVA model), 
various estimates will be derived (together with confidence intervals) of parameters of interest 
such as ED50, ED90, dose to achieve selected target effects, and model estimates of the treatment 
effect at doses studied.
In addition to the analysis of all stages combined, a supplementary analysis using an adaptive 
MCP-MOD method will be conducted where stages 2+3 and stage 4 will be analysed separately 
and the results combined using an inverse-normal p-value combination function, with weights 
related to the original planned sample sizes. Further details of the analysis will be included in the 
SAP.
To complement the MCP-MOD outputs, estimates and confidence intervals of each pairwise 
comparison versus placebo from the ANCOVA model described in the MCP step will be produced.
In addition, changes from baseline in continuous endpoints will be compared between treatment 
groups using mixed models repeated measures including terms for pooled site, treatment (as a 
factor), time point (as a factor), the interaction between treatment and time point, and the baseline 
value of the variable undergoing analysis. Binary outcomes will be analysed using generalized 
estimating equations, with the models including the same terms as the mixed models repeated 
measures. 
Other 
non-binary 
categorical 
endpoints 
will 
be 
analysed 
using 
Cochran-Mantel-Haenszel statistics. These analyses will be conducted on observed cases. Further 
details of the longitudinal modelling will be included in the SAP.
13.1.4.1 Efficacy Endpoints
The primary efficacy endpoint is the change in the weekly average of the average daily pain scores 
from the baseline week to Week 12, as measured on an 11-point (0-10) NRS.
The secondary endpoints are the following:
Change in the weekly average of the average daily pain score, as measured on an 11-point 
(0-10) NRS, from baseline to Weeks 2, 4, 6, 8, and 10 of treatment and the week before 
the follow-up visit. 
average of the average daily pain score from baseline during Weeks 4, 8, and 12 of 
treatment and the week before follow-up.
Change in Galer NPS from baseline to Days 28, 56, and 84 of treatment and the follow-up
visit.  
Change in DSIS from baseline to Days 28, 56, and 84 of treatment and the follow-up visit.
variable 'change from baseline to 
score' and c 
• 
12', and independent variables will include dose, 'baseline 
inear using the 'E 
'approach as described by 
• 
Percentage of subjects who have achieved 2:30% and 2:50% reductions in the weekly 
• 
• 
753 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 81 of 114
Proportion of subjects who have improved , much improved , or very much improved
relative to baseline on the PGIC on Days 28, 56, and 84 of treatment and the follow-up
visit.
Change in the SF-36 from baseline to Day 84 of treatment.
Usage of rescue medication (yes/no) from baseline to Week 12 of treatment.
13.1.4.2
13.1.5 Clinical Pharmacology Analyses
13.1.5.1 Pharmacokinetics
For noncompartmental analysis, plasma concentrations will be listed and summarized at each time 
point using descriptive statistics; graphical representations will also be provided. The PK 
parameters will be summarized by dose using descriptive statistics including geometric mean, 
geometric SD, arithmetic coefficients of variation, and geometric coefficients of variation. The 
potential relationships between PK and efficacy and safety parameters may be explored 
graphically. Statistical analyses of PK parameters will be outlined in the SAP. Subjects receiving 
placebo will not be included in the summary and analysis of PK parameters.
13.1.5.2 Pharmacodynamics
The PD variables (free and/or total NGF) will be summarized using descriptive statistics. The 
association between PD variables and efficacy endpoints will be explored. Further details will be 
included in the SAP.
13.1.5.3
13.1.5.4
13.1.5.5 Immunogenicity
Immunogenicity results will be listed and the effects of ADAs on PK and PD will be explored.
13.1.6 Safety and Tolerability Analyses
Safety and tolerability data will be summarised descriptively, including tables, listings, and graphs, 
as appropriate. Unless otherwise stated, descriptive summary statistics for continuous variables 
will include number of observations, mean (ie, arithmetic mean), SD, minimum, median, and 
754 of 938
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 82 of 114
maximum. Descriptive summary statistics for categorical data will include frequencies and 
percentages. 
13.1.6.1 Adverse Events
All AEs will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
(MedDRA).
Treatment-emergent AEs are defined as:
AEs with onset at the time of or following the start of treatment with IP through the
Follow-up Visit or Early Termination Visit, whichever occurs first, or
AEs starting prior to the start of treatment but increasing in severity or relationship at the 
time of, or following, the start of treatment with IP through the Follow-up Visit or Early 
Termination Visit, whichever occurs first.
The number and percentage of subjects with AEs will be displayed for each treatment group by 
system organ class and preferred term (PT). Summaries of AEs by severity and relationship to IP 
will also be provided. Serious adverse events and AEs resulting in discontinuation of IP will be 
summarized separately in a similar manner. Subject listings of AEs, SAEs, and AEs causing 
discontinuation of IP will be produced.
13.1.6.2 Clinical Laboratory Evaluations
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point.
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges, or other specific ranges of interest, will be tabulated showing change from baseline 
(shift tables) for each clinical laboratory analyte by treatment group and by study visit. 
Laboratory values that are outside the normal range will also be flagged in the data listings and 
presented with the corresponding normal ranges. Any out-of-range values that are identified by 
the investigator as being clinically significant will also be shown in a data listing.
13.1.6.3 Vital Signs
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for SBP, DBP, HR, respiratory rate, and temperature.
13.1.6.4 Twelve-lead Electrocardiograms
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point. Abnormal results will be grouped as
clinically significant and not clinically significant. A description of ECGs evaluated as abnormal
will be provided.
If applicable (digital ECGs), descriptive summaries will be provided for measures provided by the 
ECG core laboratory from the digital ECGs for PR, QRS, QT, RR intervals and for the calculated 
variables QTcF and HR for each treatment group and time point.
• 
• 
755 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 83 of 114
13.1.6.5 Physical and Neurological Examination Findings
Physical and neurological examination findings will be listed.
13.1.6.6 Other Safety Assessments
Findings from other safety assessments (TNSn, strength (dorsiflexion), deep tendon reflexes (knee 
and ankle), motor and sensory NCS, and injection site reactions) will be listed and may be 
summarized if warranted.
13.1.7 Interim Analysis
Interim analyses are planned after approximately 60 subjects have completed at least 2 weeks of 
randomised treatment across placebo and
in stage 3. Unblinded personnel who are not 
otherwise involved in the study will prepare the data for review by an Interim Analysis Review 
Committee.
The members of the Interim Analysis Review Committee are independent of the day-to-day study 
activities. The study team will remain blinded to the results of the interim analysis for the duration 
of the study. Firewalls will be put in place to ensure that information is not inadvertently 
disseminated to the blinded members of the study team.
The primary aim of the analysis is to validate the key assumptions of the original sample size 
calculation, which could result in a recommendation to adjust the sample size (overall and/or to 
individual dose groups) or the treatment allocation ratio in stage 4. Further details of the sample 
size adjustment methodology will be included in an Interim Analysis SAP.
In addition, administrative analyses of efficacy data are planned to enable the sponsor to plan 
future project-related activities, but without making any changes to the design of the current study.
13.2 Sample Size Determination
756 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 84 of 114
757 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 85 of 114
14
STUDY CONDUCT
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management.
14.1 Sponsor and Investigator Responsibilities
14.1.1 Sponsor Responsibilities
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 16). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.7), and/or to discontinue the study 
(Section 14.6.2).
AstraZeneca agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol.
14.1.2 Investigator Responsibilities
18.1), the investigator indicates that he or she 
has read the protocol carefully, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol.
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the April 1996 International 
Conference on Harmonisation (ICH) Guidance for Industry E6 Good Clinical Practice (GCP), the
Integrated Addendum to ICH E6 (R2) of November 2016, and in agreement with the 2013 version 
of the Declaration of Helsinki. While delegation of certain aspects of the study to sub-investigators
and study coordinators is appropriate, the investigator will remain personally accountable for 
overseeing the study closely and for ensuring compliance with the protocol and all applicable 
regulations and guidelines. The investigator is responsible for maintaining a list of all persons that 
are/have been delegated study-related responsibilities (eg, sub-investigators
and study 
coordinators) and their specific study-related duties.
Investigators should ensure that all persons who are delegated study-related responsibilities are 
adequately qualified and informed about the protocol, the IP(s), and their specific duties within the 
context of the study. Investigators are responsible for providing AstraZeneca with documentation 
of the qualifications, GCP training, and research experience for themselves and their staff as 
required by the sponsor and the relevant governing authorities.
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals.
14.1.3 Confidentiality and Privacy
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor and their interventions. This confidentiality is extended to cover testing 
of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
By signing the Investigator's Agreement (Section 
758 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 86 of 114
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
regulatory agencies, or pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. 
The clinical study site will permit access to such records.
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, institutional policies, or sponsor 
requirements.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored by Premier Research
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by clinical sites and by Premier Research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived.
14.2 Site Initiation
Study personnel may not screen or enrol subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until:
1. The study site has received the appropriate regulatory authority and IRB/IEC approval for 
the protocol and the appropriate ICF.
2. All GCP documents have been submitted to and approved by the sponsor or its designee.
3. The study site has a Clinical Trial Agreement in place.
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting.
14.3 Screen Failures
Subjects who do not meet the criteria for participation in this trial (screen failure) because of a 
laboratory result, disallowed medication, or other reversible condition may be rescreened at the 
discretion of the investigator.
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in 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.
The study participant's contact information will be securely stored at each clinical site for internal 
. This will not include the participant's 
759 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 87 of 114
14.4 Study Documents
All documentation and material provided by AstraZeneca for this study are to be retained in a 
secure location and treated as confidential material.
14.4.1 Informed Consent
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.
IRB-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
poses, 
procedures, and potential risks of the study and of their rights as research participants. Participants 
will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must 
be informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for 
their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study.
14.4.2 Good Clinical Practice Documents
The GCP documents are listed below.
Curricula vitae of all investigators and sub-investigators
Name and address of the laboratories
List of laboratory reference ranges, and if available, a quality certificate
Form Signature Log/Delegation of Study-related Duties
Any other relevant GCP documents
The GCP documents must be received from the investigator and reviewed and approved by 
AstraZeneca or its designee before the study site can initiate the study and before AstraZeneca will 
GCP documents must be 
retained at the study site in a secure location. Additional documents, including a copy of the 
protocol and applicable amendment(s), the IB, eCRF completion guidelines, copies of regulatory 
references, copies of IRB/IEC correspondence, and IP accountability records should also be 
GCP
Informed consent is a process that is initiated prior to the individual's agreeing to participate in the 
study and continues throughout the individual's study participation. Consent forms will be 
explanation will be provided in terms suited to the participant's comprehension of the pur 
• 
Signed original protocol (ie, Investigator's Agreement) 
• 
• 
• 
• 
• 
authorize shipment of IP to the study site. Copies of the investigator's 
retained as part of the investigator's 
documents. It is the investigator's responsibility to 
760 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 88 of 114
ensure that copies of all required GCP documents are organized, current, and available for 
inspection.
14.4.3 Case Report Forms
s Agreement (Section 18.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF.
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately.
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee.
The eCRFs must be signed by the investigator or a sub-investigator. These signatures serve to 
attest that the information contained in the eCRF is accurate and true.
14.4.4 Source Documents
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to,
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records.
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site
14.5 Data Quality Control
AstraZeneca and its designees will perform quality control checks on this clinical study.
14.5.1 Monitoring Procedures
AstraZeneca and/or its designee will conduct site visits to monitor the study and ensure compliance 
with the protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associates (CRAs) will visit the investigator and study site at periodic intervals and maintain 
periodic communication. The investigator agrees to allow the CRAs and other authorized 
personnel access. The CRAs will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigator and staff. While on site, the CRAs will review
regulatory documents, directly comparing entries in the EDC system with the source 
documents
consenting procedures
AE procedures
storage and accountability of IP and study materials
By signing the Investigator' 
and should be retained with each subject's source data . 
• 
• 
• 
• 
761 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 89 of 114
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in the study manual. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations.
By signing the 
18.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow AstraZeneca or its designee
auditors or inspectors from regulatory agencies to 
review records, and to assist the inspectors in their duties, if requested.
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations. All deviations must be addressed in study source documents, reported to the sponsor. 
Protocol deviations must be sent to the reviewing IRB per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. 
14.5.2 Data Management
AstraZeneca or its designee will be responsible for activities associated with the data management 
of this study. The standard procedures for handling and processing records will be followed per 
standard operating procedures. A comprehensive data management 
plan will be developed, including a data management overview, description of database contents,
annotated CRF, pre-entry review list, self-evident correction conventions, query contacts, and 
consistency checks.
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the study manual.
14.5.3 Quality Assurance/Audit
This study will be subject to audit by AstraZeneca or its designee. Audits may be performed to
check compliance with GCP guidelines, and can include:
site audits
Trial Master File audits
database audits
document audits (eg, protocol and/or clinical study report [CSR])
AstraZeneca or its designee may conduct additional audits on a selection of study sites, requiring 
access to subject notes, study documentation, and facilities or laboratories used for the study.
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
Investigator's Agreement (Section 
GCP and Premier Research's 
• 
• 
• 
• 
's 
762 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 90 of 114
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential.
If a regulatory authority informs the investigator that it intends to conduct an inspection, the
investigator shall notify AstraZeneca immediately.
14.6 Study Termination
The study may be terminated at AstraZeneca
discretion at any time and for any reason.
14.6.1 Regular Study Termination
The end of this study is defined as the date of the last visit of the last subject (last subject out or
last subject last visit) participating in the study. Within 90 days of the end of the clinical study,
AstraZeneca or designee will notify the IECs and regulatory authorities of the regular termination 
of the study as required according to national laws and regulations.
14.6.2 Premature Study Termination
The study may be temporarily suspended or terminated prematurely if there is sufficient reasonable 
cause at any time by AstraZeneca, IECs, regulatory authorities, respective steering committees, or 
the coordinating investigator. A decision to prematurely terminate the study is binding to all 
investigators of all study sites.
Within 15 days of premature termination of a clinical study, AstraZeneca or its designee will notify 
the IECs and regulatory authorities about the premature termination as required according to 
national laws and regulations. AstraZeneca or its designee must clearly explain the reasons for 
premature termination.
Circumstances that may warrant termination or suspension include, but are not limited to:
Determination of unexpected, significant, or unacceptable risk to participants
Demonstration of efficacy that would warrant stopping   
Insufficient compliance to protocol requirements
Data that are not sufficiently complete and/or evaluable
Determination that the primary endpoint has been met
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Early Termination Visit.
14.7 Study Site Closure
At the end of the study, all study sites will be closed. AstraZeneca may terminate participation of 
a study site at any time. Examples of conditions that may require premature termination of a study 
site include, but are not limited to, the following:
Noncompliance with the protocol and/or applicable regulations and guidelines
's 
• 
• 
• 
• 
• 
subjects' 
• 
763 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 91 of 114
Inadequate subject enrolment
14.7.1 Record Retention
After completing the study, AstraZeneca will receive the original CRFs or at least a legible copy 
and retain the documents for at least 5 years after the completion of the study.
One copy will remain with the investigator. The investigator shall arrange for the retention of the 
subject identification codes, subject files and other source data until at least 5 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or until at least 2 years have elapsed since 
the formal discontinuation of the clinical development of the product. These documents need to be 
retained for a longer period of time if required by applicable regulatory authorities or by agreement 
with the sponsor.
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the 
Copies of these study records (and all study-related documents, including source data) shall be 
kept by the investigator for the maximum period of time permitted by the hospital, institution, or 
private practice.
14.7.2 Sample Retention
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed and the decision has been made that 
none of the samples needs to be reanalysed. In addition, identifiable samples can be destroyed at 
any time at the request of the subject.
-identified biological samples 
may be stored with the same goal as the sharing of data. These samples could be used to research 
the causes of PDN, its complications and other conditions for which individuals with PDN are at 
increased risk, and to improve treatment. A code-link will allow linking the biological specimens 
with the phenotypic data from each participant, maintaining the blinding of the identity of the 
participant.
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed. 
14.8 Changes to the Protocol
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of AstraZeneca. The protocol amendment must be signed by the 
investigator and approved by the regulatory authorities and IRB or IEC, if applicable, before it 
may be implemented. Protocol amendments will be filed with the appropriate regulatory agency(s) 
having jurisdiction over the conduct of the study as applicable in accordance with local 
requirements.
• 
investigator's notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor's expense. 
With the participant's approval and as approved by local IRBs, de 
764 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 92 of 114
14.9 Use of Information and Publication
All information concerning MEDI7352, AstraZeneca operations, patent applications, formula, 
manufacturing processes, basic scientific data, and formulation information supplied by 
AstraZeneca or its designee to the investigator and not previously published, is considered 
confidential and remains the sole property of AstraZeneca. Case report forms also remain the 
property of AstraZeneca. The investigator agrees to use this information for purposes of study 
execution through finalization and will not use it for other purposes without the written consent of 
the sponsor.
The information developed in this study will be used by AstraZeneca in connection with the 
continued development of MEDI7352 and thus may be disclosed as required to other clinical 
investigators or government regulatory agencies.
The information generated by this study is the property of AstraZeneca. Publication or other public 
presentation of MEDI7352 data resulting from this study requires prior review and written 
approval of AstraZeneca. Publication policies will be specified in a separate document.
765 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 93 of 114
15
FINAL CLINICAL STUDY REPORT
AstraZeneca will retain ownership of the data.
The final CSR will be written within 1 year of completion of the clinical part of the study. This 
report will include a summary of the study results based on a statistical evaluation and clinical
assessment of the protocol-defined endpoints.
The final CSR may be submitted to the regulatory authorities.
766 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 94 of 114
16
ETHICAL AND LEGAL CONSIDERATIONS
16.1 Declaration of Helsinki and Good Clinical Practice
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry E6 
GCP (including archiving of essential study documents), the Integrated Addendum to ICH E6 (R2) 
of November 2016, the 2013 version of the Declaration of Helsinki, the applicable regulations of 
the countries in which the study is conducted, and with the Commission Directives 2001/20/EC 
and 2005/28/EC.
See Appendix D for regulation and guidelines.
16.2 Subject Information and Informed Consent
A properly constituted, valid IRB or IEC must review and approve the protocol, the i
ICF, and related subject information and recruitment materials before the start of the study.
It is the responsibility of the investigator to ensure that written informed consent and/or assent is 
obtained from the subject before any activity or procedure is undertaken that is not part of routine 
care.
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed consent prior to enrolment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent and/or assent as described 
in the Declaration of Helsinki and will also comply with local regulations. 
Each subject should be made aware by the investigator of the nature of the study (objectives,
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 
deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if necessary, legal representatives 
must be given ample opportunity to inquire about details of the study. 
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms that the consent is based on information 
that has been understood. The form will also be signed by the investigator obtaining the consent 
ICF must be kept on file by 
the investigator for possible inspection by regulatory authorities, AstraZeneca and/or 
designee. Collection of informed consent and/or assent has to be documented on the eCRF.
Furthermore, the subject will be informed that if he or she wishes to drop-out or withdraw at any 
time during the study, this will not have any negative consequences. Subjects may be withdrawn 
by the investigator if any change related to safety or ethics precludes further participation in the 
study. Subjects will be asked to agree to a final assessment in the event of an early termination of 
the study.
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and that such data will not be revealed to any unauthorized third party. Data will be 
nvestigator' s 
and annotated with the study subject number. Each subject's signed 
the sponsor's 
767 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 95 of 114
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate.
16.3 Approval by Institutional Review Board or Independent Ethics Committee
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor
representative before 
shipment of investigational drug supplies, and will include the date of t
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject s condition.
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by
representative before 
implementation. 
16.4 Finance and Insurance
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor.
's 
he committee's approval 
and the chairperson's signature. 
the sponsor's 
768 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 96 of 114
17
REFERENCES
1. World Health Organization, 2017. Diabetes: key facts. http://www.who.int/news-
room/fact-sheets/detail/diabetes. Updated 15 November 2017. Accessed 02 July 2018. 
2. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types 
of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the 
Rochester Diabetic Neuropathy Study. Neurology. 1993 Apr;43(4):817-824.
3. Vinik AI, Kong X, Megerian JT, Gozani SN. Diabetic nerve conduction abnormalities in 
the primary care setting. Diabetes Technol Ther. 2006;8(6):654-662.
4. Veves A, Backonja M, Malik RA. Painful diabetic neuropathy: epidemiology, natural 
history, early diagnosis, and treatment options. Pain Med. 2008;9(6):660-674.
5. Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicenter study of 
the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic 
population. Diabetologia. 1993;36(2):150-154.
6. Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain 
description, and quality of life. Diabetes Res Clin Pract. 2000;47(2):123-128.
7. Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic 
peripheral neuropathy in the US. Diabetes Care. 2003;26(6):1790-1795.
8. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and 
characteristics of painful diabetic neuropathy in a large community-based diabetic 
population in the U.K. Diabetes Care. 2011;34(10):2220-2224. doi: 10.2337/dc11-1108.
9. Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and 
fibromyalgia pain: systematic review of randomised trials. BMC Neurol. 2008;8:29. doi: 
10.1186/1471-2377-8-29.
10. Javed S, Petropoulos IN, Alam U, Malik RA. Treatment of painful diabetic neuropathy. 
Ther Adv Chronic Dis. 2015;6(1):15-28. doi: 10.1177/2040622314552071.
11. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev 
Neurosci. 2006;29:507-538.
12. Hefti FF, Rosenthal A, Walicke PA, et al. Novel class of pain drugs based on antagonism 
of NGF. Trends Pharmacol Sci. 2006;2:85-91. doi: 10.1016/j.tips.2005.12.001.
13. Petty BG, Cornblath DR, Adornato BT, et al. The effect of systemically administered 
recombinant human nerve growth factor in healthy human subjects. Ann Neurol.
1994;36:244-246. doi: 10.1002/ana.410360221
14. Dimitroulas T, Lambe T, Klocke R, Kitas GD, Duarte RV. Biologic drugs as analgesics 
for the management of osteoarthritis. Semin Arthritis Rheum. 2017;46(6):687-691. 
doi: 10.1016/j.semarthrit.2016.12.001.
15. Leung L, Cahill CM. TNF-alpha and neuropathic pain - a review. J Neuroinflammation.
2010;7:27. doi: 10.1186/1742-2094-7-27.
16. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from 
osteoarthritis 
of 
the 
knee. 
New 
Engl 
J 
Med. 
2010;363:1521-1531. 
doi: 
10.1056/NEJMoa0901510.
769 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 97 of 114
17. Katz N, Borenstein DG, Birbara C, et al. Efficacy and safety of tanezumab in the treatment 
of chronic low back pain. Pain. 2011;152:2248-2458. doi: 10.1016/j.pain.2011.05.003.
18. Brown MT, Murphy FT, Radin DM, Davignon I, Smith MD, West CR. Tanezumab reduces 
osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase 
III trial. J Pain. 2012;13:790-798. doi: 10.1016/j.jpain.2012.05.006.
19. Brown MT, Murphy FT, Radin DM, Davignon I, Smith MD, West CR. Tanezumab reduces 
osteoarthritic hip pain: results of a randomized, double-blind, placebo-controlled phase III 
trial. Arthritis Rheum. 2013;65:1795-1803. doi: 10.1002/art.37950.
20. Kivitz AJ, Gimbel JS, Bramson C, et al. Efficacy and safety of tanezumab versus naproxen 
in the treatment of chronic low back pain. Pain. 2013;154:1009-1021. doi: 
10.1016/j.pain.2013.03.006.
21. Schnitzer TJ, Ekman EF, Spierings ELH, et al. Efficacy and safety of tanezumab 
monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of 
knee or hip osteoarthritis pain. Ann Rheum Dis. 2015;74(6):1202-1211. doi: 
10.1136/annrheumdis-2013-204905.
22. Spierings EL, Fidelholz J, Wolfram G, Smith MD, Brown MT, West CR. A phase III 
placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain 
of the hip or knee. Pain. 2013;154:1603-1612. doi: 10.1016/j.pain.2013.04.035.
23. Neubert H, Muirhead D, Kabir M, Grace C, Cleton A, Arends R. Sequential protein and 
peptide immunoaffinity capture for mass spectrometry-based quantification of total 
human-nerve growth factor. Anal Chem. 2013;85:1719-1726. doi: 10.1021/ac303031q.
24. Holmes D. Anti-NGF painkillers back on track? 
Nat Rev Drug Discov.
2012;30:11(5):337-338. doi: 10.1038/nrd3732.
25. Hochberg MC, Abramson SB, Hungerford DS, et al. Adjudication of reported serious 
adverse joint events in the tanezumab clinical development program. Arth Rheum.
2012;64:S113.
26. Bannwarth B, Kostine M. Nerve growth factor antagonists: is the future of monoclonal 
antibodies becoming clearer? Drugs. 2017;77(13):1377-1387. doi: 10.1007/s40265-017-
0781-6.
27. Croft M, Benedict CA, Ware CF. Clinical targeting of the TNF and TNFR superfamilies. 
Nat Rev Drug Discov. 2013;12:147-168. doi: 10.1038/nrd3930.
28. Cohen SP, White RL, Kurihara C, et al. Epidural steroids, etanercept, or saline in subacute 
sciatica: a multicenter, randomized trial. Ann Intern Med. 2012;156(8):551-559. doi: 
10.7326/0003-4819-156-8-201204170-00002.
29. Food and Drug Administration Center for Drug Evaluation and Research. Summary 
Minutes 
of 
the 
Arthritis 
Advisory 
Committee 
Meeting 
March 
12, 
2012. 
https://wayback.archive-
it.org/7993/20170404145629/https://www.fda.gov/downloads/AdvisoryCommittees/Com
mitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM307879.pdf. Updated 
22 May 2012. Accessed 02 July 2018.
770 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 98 of 114
30. Tanezumab. FDA Briefing Information for the Joint Meeting of Arthritis Advisory 
Committee and Drug Safety and Risk Management Advisory Committee, March 24 25, 
2021. 
[cited 
09 
September 
2021]. 
Available 
from: 
https://www.fda.gov/media/146867/download.
31. Tanezumab. Monoclonal antibody against nerve growth factor. Pfizer Inc. presentation at 
FDA Advisory Committee Meeting, March 24, 2021. [cited 09 September 2021]. Available 
from: https://www.fda.gov/media/146926/download.
32. Tanezumab: FDA Efficacy and Safety Review. Presentation at FDA Advisory Committee 
Meeting, 
March 
24, 
2021. 
[cited 
09 
September 
2021]. 
Available 
from: 
https://www.fda.gov/media/146924/download.
33. Bélanger P, West CR, Brown MT. Development of pain therapies targeting nerve growth 
factor signal transduction and the strategies used to resolve safety issues. J Toxicol Sci.
2018;43(1):1-10.
34. Dewanjee S, Das S, Das AK, et al. Molecular mechanism of diabetic neuropathy and its 
pharmacotherapeutic targets. Eur J Pharmacol. 2018 Jun 29. pii:S0014-2999(18)30366-2. 
doi: 10.1016/j.ejphar.2018.06.034.
35. Altman R, Asch E, Bloch D, et al. Development of criteria for the classification and 
reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and 
Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis 
Rheum. 1986;29(8):1039-1049.
36. Altman R, Alarcón G, Appelrouth D, et al. The American College of Rheumatology criteria 
for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum.
1990;33(11):1601-1610.
37. Altman R, Alarcón G, Appelrouth D, et al. The American College of Rheumatology criteria 
for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum.
1991;34(5):505-514.
38. New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the 
Heart and Great Vessels/The Criteria Committee of the New York Heart Association 
Classification. 9th ed. Boston: Little, Brown & Co.; 1994.
39. Nyendak MR, Lewinsohn DA, Lewinsohn DM. New diagnostic methods for tuberculosis. 
Curr Opin Infect Dis. 2009;22(2):174-182.
40. Duarte R, Campainha S, Cotter J, et al. Position paper on tuberculosis screening in patients 
with immune mediated inflammatory diseases who are candidates for biological therapy. 
Acta Reumatol Port. 2012;37:253-259.
41. Cush JJ, Winthrop K, Dao, K, et al. Screening for Mycobacterium Tuberculosis infection:
questions and answers for clinical practice. Drug Saf Q. 2010;1(2):1-4.
42. U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein 
Products.
http://www.fda.gov/downloads/drugs/guidances/ucm338856.pdf.
Updated 
August 2014. Accessed 03 July 2018. 
771 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 99 of 114
43. U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Biologics Evaluation and Research. Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials.
http://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. Updated September 
2007. Accessed 03 July 2018.
44. European Medicines Agency. Qualification Opinion of MCP-Mod as an efficient statistical 
methodology for model-based design and analysis of Phase II dose finding studies under 
model uncertainty. EMA/CHMP/SAWP/757052/2013 (adopted by CHMP in 2014). 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_g
uideline/2014/02/WC500161027.pdf. Updated 23 January 2014. Accessed 03 July 2018. 
45. Request for Qualification of MCP-Mod as an efficient statistical methodology for model-
based design and analysis of Phase II dose finding studies under model uncertainty. FDA 
qualification, 2015. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProces
s/UCM508702.pdf. Accessed 03 July 2018. 
46. Kirby S, Brain P, Jones B. Fitting E(max) models to clinical trial dose-response data.
Pharma Stat. 2011;10(2):143-149. doi: 10.1002/pst.432.
47. Satoh J, Yagihashi S, Baba M, Suzuki M, Arakawa A, Yoshiyama T. Efficacy and safety 
evaluation of pregabalin treatment over 52 weeks in patients with diabetic neuropathic pain 
extended after a double-blind placebo-controlled trial. 
J Diabetes Investig.
2011;2(6):457-463. doi: 10.1111/j.2040-1124.2011.00122.x.
48. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of painful 
diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63(11):2104-2110.
49. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of 
painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain.
2004;110(3):628-638.
50. T lle T, Freynhagen R, Versavel M, Trostmann U, Young JP Jr. Pregabalin for relief of 
neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. 
Eur J Pain. 2008;12(2):203-213.
51. Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding studies combining 
multiple comparisons and modelling procedures. J Biopharm Stat. 2006;16(5):639-656. 
doi: 10.1080/10543400600860428.
52. Thomas N, Sweeney K, Somayaji V. Meta-analysis of clinical dose response in a large 
drug 
development 
portfolio.
Stat 
Biopharm
Res. 
2014;6(4):302-317.
doi:
10.1080/19466315.2014.924876.
6 
772 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 100 of 114
18
ATTACHMENTS
18.1
PROTOCOL NUMBER:
D5680C00002
PROTOCOL TITLE:
A Randomised, Double-Blind, Placebo-Controlled,
Dose-Response Study of the Efficacy and Safety of MEDI7352 
in Subjects with Painful Diabetic Neuropathy
AMENDED PROTOCOL:
13-Apr-2022
IP
and has discussed these data with the study monitor. Having considered fully all the available 
information, the undersigned considers that it is ethically justifiable to give the IP to selected 
subjects in his/her care, according to the amended study protocol.
He or she agrees to use the study material, including IP, only as specified in the protocol. He or 
she understands that changes cannot be made to the protocol without prior written approval of 
AstraZeneca.
He or she understands that any deviation from the protocol may lead to early termination of the 
study.
He or she agrees to report to AstraZeneca within time any clinical AE or abnormal laboratory 
value that is serious, whether or not considered related to the administration of IP.
He or she agrees to comply with AstraZeneca and regulatory requirements for the monitoring and 
auditing of this study.
In addition, he or she agrees that the study will be carried out in accordance with the revised 
Declaration of Helsinki (2013) and the local laws and regulations relevant to the use of new 
therapeutic agents.
I, the undersigned, have carefully read this amended protocol and agree that it contains all the 
necessary information required to conduct the study.
Principal Investigator:
Printed Name:
Signature:
Date:
Investigator's Agreement 
The undersigned acknowledges possession of and has read the Investigator's Brochure on the 
Investigator's name and address (stamp) 
773 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 101 of 114
APPENDICES
A.
B.
Contraception Guidance
C.
Other Study-Specific Requirements
D.
Regulations and Good Clinical Practice Guidelines
A.
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a subject meets potential 
The investigator participates, together with AstraZeneca Neuroscience Innovative Medicines 
(NS iMed) clinical project representatives, in review and assessment of cases meeting PHL criteria 
is no alternative 
explanation for the elevations in liver biochemistry other than drug-induced liver injury (DILI) 
caused by the investigational medicinal product (IMP). 
The investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
adverse events (AEs) and serious adverse events (SAEs) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
DEFINITIONS 
× ULN at any point during the study irrespective of an increase 
in alkaline phosphatase (ALP). The elevations do not have to occur at the same time or within a 
specified time frame. 
×
× ULN, where no other reason, other than the IMP, can be 
found to explain the combination of increases
eg, elevated ALP indicating cholestasis, viral 
hepatitis, or another drug. The elevations do not have to occur at the same time or within a specified 
time frame.
In order to identify cases of PHL, it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:
× ULN 
× ULN 
× ULN
Hy's Law Criteria 
Hy's Law Criteria 
Hy's Law (PHL) criteria at any point during the study. 
to agree whether Hy's Law (HL) criteria are met. HL criteria are met if there 
Potential Hy's Law (PHL) 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2 3 x upper limit of normal 
(ULN) and total bilirubin (TBL) 2 2 
Hy's Law (HL) 
AST or ALT 2 3 
ULN and TBL 2 2 
IDENTIFICATION OF POTENTIAL HY'S LAW CASES 
• 
ALT2 3 
• 
AST2 3 
• 
TBL22 
Hy’s Law Criteria
774 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 102 of 114
When a subject meets any of the identification criteria, in isolation or in combination, the central 
laboratory will immediately send an alert to the investigator (also sent to NS iMED medical 
monitoring and drug safety representatives). 
The investigator will also remain vigilant for any local laboratory reports in which the 
identification criteria are met. Where this is the case, the investigator will: 
Request a repeat of the test (new blood draw) by the central laboratory 
Complete the appropriate unscheduled laboratory CRF 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 subject meets PHL criteria by reviewing laboratory reports from all 
previous visits (including both central and local laboratory results)
FOLLOW-UP 
If the subject does not meet PHL criteria, the investigator will: 
Inform the NS IMED representatives (medical monitoring and patient safety physicians) that 
the subject has not met PHL criteria. 
Perform follow-up on subsequent laboratory results according to the guidance provided in the 
Clinical Study Protocol.
If the subject does meet PHL criteria, the investigator will: 
Notify the NS IMED representatives (medical monitoring and patient safety physicians), who 
will then inform the central study team 
The medical monitor will contact the investigator, to provide guidance, discuss, and agree on an 
-up and the continuous review of data. Subsequent to this 
contact, the investigator will:
Monitor the subject until liver biochemistry parameters and appropriate clinical symptoms and 
signs return to normal or baseline levels, or as long as medically indicated
Investigate the etiology of the event and perform diagnostic investigations, as discussed with 
the study physician 
Complete the three liver CRF modules as information becomes available 
If at any time (in consultation with the study physician) the PHL case meets serious criteria, 
report it as an SAE using standard reporting procedures
• 
• 
• 
Potential Hy's Law Criteria Not Met 
• 
• 
Potential Hy's Law Criteria Met 
• 
approach for the study subjects' follow 
• 
• 
• 
• 
775 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 103 of 114
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the medical 
monitor will contact 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. The
NS IMED physician and the NS IMED representative 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. 
If 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, a 
determination of whether the AE meets the criteria for a SAE: 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF. 
If the alternative explanation is an AE/SAE, record the AE/SAE in the CRF accordingly 
and follow the NS IMED standard reporting processes. 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL elevations 
other than the IMP: 
er criteria for 
seriousness apply. 
should be assigned.
If there is an unavoidable delay of over 3 weeks 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:
causality assessment as described above. 
Continue follow-up and review according to the agreed-on plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met. Update the SAE report according to the outcome of the 
review.
REFERENCES
FDA Guidance for Industry (issued July 2009), Drug-Induced Liver Injury: Premarketing 
Clinical Evaluation:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM174090.pdf
REVIEW AND ASSESSMENT OF POTENTIAL HY'S LAW CASES 
• 
• 
• 
Report an SAE (report term, "Hy's Law") according to NS IMED standard processes. 
• 
The "medically important" criterion for seriousness should be used if no oth 
• 
As there is no alternative explanation for the HL case, a causality assessment of "related" 
• 
Report an SAE (report term "Potential Hy's Law") applying criteria for seriousness and 
• 
776 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 104 of 114
B. Contraception Guidance
For females:
Females without childbearing potential will be included in this study. Females without 
childbearing potential are defined as those who are surgically sterile (ie, women who have had a 
hysterectomy, bilateral ovariectomy (oophorectomy), bilateral salpingectomy, or bilateral tubal 
ligation) or those who are postmenopausal (defined as 12 months or more with no menses without 
an alternative medical cause).
For males:
Non-sterilized males who are sexually active with a female partner of childbearing potential must 
use condom and spermicide for the duration of the treatment period and for 3 months after the last 
administration of study drug. As male condom and spermicide are not considered to constitute a 
highly effective contraception method it is strongly recommended that female partners of a male 
study subjects also use a highly effective method of contraception throughout the study, including 
the protocol-specified follow-up period. A highly effective method of contraception is defined as 
one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. 
The acceptable methods of contraception are described in Table B-1.
Table B-1:
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Intrauterine hormone-releasing system (UIS) a
Bilateral tubal occlusion
Vasectomized partner b
Sexual abstinence c
Combined (estrogen and progestogen containing 
hormonal contraception)
Oral (combined pill)
Injectable
Transdermal (patch)
Progestogen-only hormonal contraception associated 
with inhibition of ovulation d
Injectable
Implantable
Intravaginal
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy documentation of surgical success (absence of sperm inejaculate).
c
Sexual abstinence is considered a highly effective method only if defined asrefraining from heterosexual
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primarymode of
action (eg, minipill), is not accepted as a highly effective method).
C. Other Study-Specific Requirements
All scales and details of blood volumes for assessments will be provided in a study-specific 
manual.
0 
0 
0 
0 
0 
0 
777 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 105 of 114
D. Regulations and Good Clinical Practice Guidelines
1. Regulations
European Directive 2001/20/EC and related guidance documents
European Directive 2005/28/EC and related guidance documents>
2. Good Clinical Practice Guidelines
ICH GCP guidelines can be found at the following URL:
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf
• 
• 
778 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 106 of 114
REASONS FOR AMENDMENT
1. Broadened ECG language to allow paper ECGs as an alternative to digital ECGs.
2. Clarifi
eCRF as normal, abnormal and clinically significant, or abnormal and not clinically 
significant.
4. Clarified the details relating to the interim analysis after completion of stage 3.
5. Provided additional details of vital signs capture, particularly with regard to the use of a 
supine or sitting position.
6. Corrected typographical errors, capitalizations, and abbreviation definitions.
779 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 107 of 114
SUMMARY OF AMENDED SECTIONS
The changes being made in this version of the protocol are considered to be substantial.
Section 2.1 
Synopsis
The synopsis was revised to incorporate the changes to the protocol that are described in this 
amendment.
Section 2.2
Schedule of Events
The Schedule of Events was revised to incorporate the changes to the protocol that are described 
in this amendment.
Section 4
LIST OF ABBREVIATIONS AND DEFINITIONS
The List of Abbreviations was revised to incorporate definitions for terms in the protocol that were 
not previously defined. 
Section 5.2.4
Phase I Painful Osteoarthritis of the Knee Study
Text formerly read:
In the ongoing Phase I study D5680C00004, 5 subjects had received 
blinded SC study treatment (MEDI7352 150 mg or placebo) as of 
01 June 2021. Two of the of 5 treated subjects (40.0%) have had a 
total of 4 TEAEs as follows (1 subject each): dyspepsia, catheter site 
erythema, injection site pain, and paraesthesia. 
Now reads:
In the Phase I study D5680C00004, 5 subjects had received blinded 
SC study treatment (MEDI7352 150 mg or placebo) as of 01 June 
2021. Two of the of 5 treated subjects (40.0%) have had a total of 4 
TEAEs as follows (1 subject each): dyspepsia, catheter site 
erythema, injection site pain, and paraesthesia. 
Section 6.3
Exploratory Objectives
Text formerly read:
Objectives
Endpoints
Secondary
To assess the safety and tolerability of 
MEDI7352 in subjects with PDN
Safety and tolerability assessments: AEs and SAEs, physical 
and neurological examinations, neuropathy assessments
(TNSn), strength (dorsiflexion) and deep tendon reflex (knee 
and ankle) assessments, vital signs, 12-lead digital ECGs (with 
printouts), clinical laboratory testing (haematology, clinical 
chemistry, coagulation, and urinalysis), motor and sensory 
nerve conduction, concomitant medication assessment, 
injection site reaction assessment, and infusion reaction 
assessments.
• 
• 
780 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 108 of 114
Now reads:
Objectives
Endpoints
Secondary
To assess the safety and tolerability of 
MEDI7352 in subjects with PDN
Safety and tolerability assessments: AEs and SAEs, physical 
and neurological examinations, neuropathy assessments
(TNSn), strength (dorsiflexion) and deep tendon reflex (knee 
and ankle) assessments, vital signs, 12-lead ECGs, clinical 
laboratory testing (haematology, clinical chemistry, 
coagulation, and urinalysis), motor and sensory nerve 
conduction, concomitant medication assessment, injection site 
reaction assessment, and infusion reaction assessments.
Section 7.1
Overall Study Design and Plan
Text formerly read:
In stage 3 of the study, approximately 67 subjects will be randomly 
2. The third stage will 
include an interim analysis to assess key assumptions of the sample 
size calculation. In stage 4 of the study, if there are no changes 
made following the interim analysis, eligible subjects will be 
randomly assigned to treatment with equal allocation across 3 dose 
levels of MEDI7352 or placebo to ensure approximately 236 
subjects are evaluable for the efficacy analysis of stages 2 to 4 
combined.
Now reads:
In stage 3 of the study, approximately 67 subjects will be randomly 
assigned to plac
include an interim analysis to assess key assumptions of the sample 
size calculation. Upon enrolment of approximately 67 subjects in 
stage 3, approximately 165 eligible subjects will be randomly 
assigned to treatment with equal allocation across 3 dose levels of 
MEDI7352 or placebo to ensure approximately 236 subjects are 
evaluable for the efficacy analysis of stages 2 to 4 combined.
Section 7.2
Rationale and Discussion of Study Design
Text formerly read:
The third stage will compare the highest expected efficacious dose,
, to placebo and an interim analysis that will enable
decision making for stage 4 with respect to sample size re-
estimation and dose allocation ratio.
Now reads:
The third stage will compare the highest expected efficacious dose, 
, to placebo and includes an interim analysis that will 
confirm decision making for stage 4 with respect to exact sample 
size and dose allocation ratio.
Section 7.3
Selection of Doses in the Study
Text formerly read:
MEDI7352 is currently undergoing clinical evaluation for safety, 
PK, PD, and efficacy in a first-in-human study in subjects with 
painful 
OA 
of 
the 
knee 
(ClinicalTrials.gov 
Identifier: 
781 of 938
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 109 of 114
NCT02508155). In that study, testing of single IV doses of up to 
 and repeat ascending IV doses of 
, and
every 2 weeks have been completed. The final cohort 
comprising repeat IV doses of 
 is ongoing. Single SC 
doses of 
 have also been evaluated. To date, no safety or 
tolerability concerns have been reported. A full description of the 
current clinical experience with MEDI7352 is in Section 5.2.
Now reads:
MEDI7352 has undergone clinical evaluation for safety, PK, PD, 
and efficacy in a first-in-human study in subjects with painful OA 
of the knee (ClinicalTrials.gov Identifier: NCT02508155). In that 
study, testing of single IV doses of up to 
and repeat 
ascending IV doses of 
and 
every 2 weeks 
have been completed. Single SC doses of 
have also been 
evaluated. No safety or tolerability concerns were reported. A full 
description of the current clinical experience with MEDI7352 is in 
Section 5.2.
Section 10.1
Study Duration
Deleted:
The overall study duration is expected to be 40 months (35 
months of active screening and enrolment and 5 months of 
follow-up), but this may be extended depending on the 
requirements and recommendations of international and 
national public health authorities in relation to the coronavirus 
disease 2019 (COVID-19) pandemic.
Section 10.2.1.1
Screening
Added:
11. Collect urine sample for the following:
urinalysis
urine drug screen
urine pregnancy test (for women who are not surgically 
sterile) (If the screening urine pregnancy test is more than 7 
days before the first day of treatment, it must be repeated 
prior to the first dose.)
Section 10.2.2.1
Day 1 (Treatment 1)
Text formerly read:
4. Perform 3 replicates of 12-lead dECGs (with printouts) after the
subject has been resting in the supine position for at least
10 minutes.
782 of 938
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 110 of 114
Now reads:
4. Perform 3 replicates of 12-lead ECGs (with printouts) after the 
subject has been resting in the supine position for at least 
10 minutes.
Text formerly read:
11. Repeat 3 replicates of dECGs (with printouts) at 60 (±10) 
minutes after the start of IP administration, and 2 and 4 hours (±10 
minutes) after the start of IP administration. Subjects must rest in 
the supine position for 10 minutes prior to each ECG recording 
session.
Now reads:
11. Repeat 3 replicates of ECGs (with printouts) at 60 (±10) minutes 
after the start of IP administration, and 2 and 4 hours (±10 minutes) 
after the start of IP administration. Subjects must rest in the supine 
position for 10 minutes prior to each ECG recording session.
Section 10.2.2.2
Days 14, 28, 42, 56, and 70 (Treatments 2 to 6)
Text formerly read:
5. Perform 3 replicates of 12-lead dECGs (with printouts) after the 
subject has been resting in the supine position for at least 10 minutes
(Days 28 and 56 only).
Now reads:
5. Perform 3 replicates of 12-lead ECGs (with printouts) after the 
subject has been resting in the supine position for at least 10 minutes
(Days 28 and 56 only).
Added:
8. Collect urine sample for the following:
urinalysis
Section 10.2.2.5
Day 84 (End-of-Treatment; Week 12)
Text formerly read:
6. Perform 3 replicates of 12-lead dECGs (with printouts) after the 
subject has been resting in the supine position for at least 
10 minutes.
Now reads:
6. Perform 3 replicates of 12-lead ECGs (with printouts) after the 
subject has been resting in the supine position for at least 
10 minutes.
Added:
9. Collect urine sample for the following:
urinalysis
urine pregnancy test (for women who are not surgically 
sterile)
783 of 938
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 111 of 114
from all subjects who had a baseline sample collected at 
the screening visit.
Section 10.2.3
Follow-up (or Early Termination) Evaluation (Week 18)
Added:
8. Collect urine sample for the following:
urinalysis
urine pregnancy test (for women who are not surgically 
sterile)
Section 10.3.2.4
Text formerly read:
Now reads:
Section 10.3.3.1.5
Vital Signs
Added:
Vital signs will be assessed as follows:
Screening: Measure respiratory rate, temperature, and HR 
and BP after a 5-minute rest in supine position. To assess 
orthostasis, repeat BP and HR 1 minute after the subject 
stands. 
Day 1 pre-dose: Measure respiratory rate, temperature, and 
HR and BP after a 5-minute rest in supine position. To assess 
orthostasis, repeat BP and HR 1 minute after the subject 
stands.
Day 1 post-dose: Supine and orthostatic BP and HR at 15 
mins, 30 mins, 45 mins, 60 mins, 2 hours, and 4 hours after 
start of infusion. Temperature and supine and orthostatic BP 
784 of 938
CCI
CCI
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 112 of 114
and HR at 60 mins, 2 hours, and 4 hours after start of infusion. 
Respiratory rate at 15 mins, 60 mins, 2 hours, and 4 hours 
after start of infusion. The 60-minute assessments should be 
performed within 10 minutes of the end of the infusion. [Note: 
An acceptable window for these vital sign assessments is ± 5 
mins in relation to the specified time].
Days 14, 28, 42, 56, and 70 pre-dose: Measure respiratory rate, 
temperature, and HR and BP after a 5-minute rest in sitting
position. To assess orthostasis, repeat BP and HR 1 minute 
after the subject stands.
Days 14, 28, 42, 56, and 70 post-dose: 5 minutes after 
completion of infusion, measure respiratory rate, temperature, 
and HR and BP after a 5-minute rest in sitting position. After 
measuring sitting vital signs, assess orthostatic BP and HR 1 
minute after the subject stands.
Days 71, 77, and Week 18 or early termination: Measure
respiratory rate, temperature, and HR and BP after a 
5-minute rest in sitting position. To assess orthostasis, repeat 
BP and HR 1 minute after the subject stands. 
Section 10.3.3.1.6
Twelve-lead Electrocardiogram
Text formerly read:
The digital ECGs will be collected using the ECG equipment 
delivered by the central ECG laboratory (ECG lab) and will be 
standard operating procedures. Further details are provided in the 
ECG Manual.
Paper printouts of the digital ECGs will be reviewed in real time by 
the principal investigator, or delegate, for safety monitoring. The 
following variables will be reported by the ECG Core 
laboratory: RR, PR/PQ, QRS, and QT intervals. Derived 
parameters (QTcF, HR, and others, as applicable) will be 
calculated by the statistician or designee.
Now reads:
All subjects will undergo ECGs as indicated in the schedule of 
assessments. Where applicable, digital ECGs will be collected 
using the ECG equipment delivered by the central ECG laboratory 
(ECG lab) and will be transferred to and analysed by the ECG lab 
are provided in the ECG Manual.
Paper printouts of the 12-lead ECGs will be reviewed in real time 
by the principal investigator, or delegate, for safety monitoring. The 
results of the evaluation will be reported in the eCRF as normal
or abnormal (if abnormal, the ECG is also to be reported as not 
clinically significant or clinically significant). The details of any 
ECG abnormalities should be described and captured in the 
eCRF (irrespective of whether they are considered not clinically 
significant or clinically significant).
• 
• 
• 
transferred to and analysed by the ECG lab according to the lab's 
according to the lab's standard operating procedures. Further details 
785 of 938

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 113 of 114
Section 13.1.6.4
Twelve-lead Electrocardiogram
Text formerly read:
The number and percentage of subjects with normal and abnormal 
ECG findings will be summarized for each treatment group at each 
time point. Abnormal results will be grouped as clinically significant 
and not clinically significant.
If warranted, a comparison of QT results will be presented and 
descriptive summaries (mean, SD, median, minimum, and 
maximum) will be presented for ECG measures of PR interval, 
QRS interval, QT interval, QTc interval (both correction 
methods), and HR for each treatment group at each time point.
Now reads:
The number and percentage of subjects with normal and abnormal 
ECG findings will be summarized for each treatment group at each 
time point. Abnormal results will be grouped as clinically significant 
and not clinically significant. A description of ECGs evaluated as 
abnormal will be provided.
If applicable (digital ECGs), descriptive summaries will be 
provided for measures provided by the ECG core laboratory 
from the digital ECGs for PR, QRS, QT, RR intervals and for 
the calculated variables QTcF and HR for each treatment group 
and time point.
Section 13.2
Sample Size Determination
Text formerly read:
786 of 938
CCI

AstraZeneca AB
Confidential
D5680C00002
13-Apr-2022
Final Amended Protocol Version 7.0
AD-MW-07.06 08-Dec-2017
Page 114 of 114
Now reads:
General
Minor typographical, abbreviation, and capitalization corrections were made throughout the 
protocol as necessary.
787 of 938
CCI