Clinical trial NCT04675034
Conditions: Painful Osteoarthritis of the Knee
Keywords: Osteoarthritis
Sponsor: AstraZeneca
Start date: 2020-12-02; Completion date: 2023-08-16
Enrollment: 345 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IIb randomised, double-blind, placebo-controlled, dose-response study in participants with painful osteoarthritis (OA) of the knee. The study will assess the safety and efficacy of multiple doses of MEDI7352 compared to placebo, as well as the pharmacokinetics, pharmacodynamics and immunogenicity of MEDI7352 in participants with moderate to severe chronic pain persistent for 3 months or more not adequately controlled by standard of care treatments.

Detailed description:

Arms: arm 1: Participants received 6 doses of subcutaneous (SC) MEDl7352 Dose 1 injection once every 2 weeks (Q2W) during a 12-week parallel-group treatment period. arm 2: Participants received 6 doses of SC MEDl7352 Dose 2 injection Q2W during a 12-week parallel-group treatment period. arm 3: Participants received 6 doses of SC MEDl7352 Dose 3 injection Q2W during a 12-week parallel-group treatment period. arm 4: Participants received 6 doses of SC MEDl7352 Dose 4 injection Q2W during a 12-week parallel-group treatment period. arm 5: Participants received 6 doses of SC placebo injection matched to MEDl7352 Q2W during a 12-week parallel-group treatment period.
Interventions: intervention 1: MEDI7352 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive SC injection of MEDI7352 as stated in arm description. intervention 2: Participants will receive SC injection of placebo as stated in arm description.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
1 of 253
Clinical Study Protocol – Global Amendment 3
Study Intervention
MEDI7352
Study Code
D5680C00003
Version
4.0
Date
28 June 2022 
A Randomised, Double-blind, Placebo-controlled, Dose-response 
Study of the Efficacy and Safety of MEDI7352 in Subjects with 
Painful Osteoarthritis of the Knee
Sponsor Name: AstraZeneca AB
Regulatory Agency Identifier Number(s)
EudraCT number: 2020-003797-51
This Clinical Study Protocol Amendment has been subject to a peer review according to 
AstraZeneca standard procedures. The Clinical Study Protocol is publicly registered, and the 
results are disclosed and/or published according to the AstraZeneca Global Policy on 
Bioethics and in compliance with prevailing laws and regulations.


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
2 of 253
Protocol Number: D5680C00003
Amendment Number: 3
Investigational Product: MEDI7352
Study Phase: Phase IIb
Short Title: A Study of the Efficacy and Safety of MEDI7352 in Subjects with Painful 
Osteoarthritis of the Knee


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
3 of 253
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
28-June-2022
Amendment 2
14-Oct-2021
Amendment 1
11-Mar-2021
Original Protocol (initial creation)
13-Aug-2020
Amendment 3 (28 June 2022)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
This global amendment 3 supersedes all global or country-specific protocol addendums dated 
prior to the date of this amendment as it incorporates the requirements detailed in these 
addendums.
Overall Rationale for the Amendment:
This protocol (study D5680C00003) has been amended to increase the study sample size to 
approximately 350 participants to maintain study power in light of a higher than anticipated 
rate of COVID-related withdrawals following randomisation. This amendment allows 
participants who have recovered from a previous COVID-19 infection to be enrolled sooner 
after full recovery from COVID-19 infection and allows for some participants to remain in the 
study after having had a COVID-19 infection. The amendment clarifies the interpretation of 
the prohibited concomitant medications from the start of the washout period until the Week 18 
follow-up visit. In addition, the electrocardiogram visit windows are being extended to offer 
more flexibility for procedures at the site and prevent minor protocol deviations without 
affecting the integrity of the data. Minor text edits have been made as needed to increase 
clarity or correct the interpretation of the protocol.
The Protocol Amendment Summary of Changes Table for this global amendment 3 is 
presented in Appendix M.


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
4 of 253
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE....................................3
TABLE OF CONTENTS......................................................................................................4
LIST OF FIGURES .............................................................................................................. 7
LIST OF TABLES................................................................................................................ 8
1
PROTOCOL SUMMARY................................................................................ 10
1.1
Synopsis ........................................................................................................... 10
1.2
Schema............................................................................................................. 17
1.3
Schedule of Assessments .................................................................................. 18
2
INTRODUCTION............................................................................................ 27
2.1
Study Rationale ................................................................................................ 27
2.2
Background ...................................................................................................... 27
2.2.1
Clinical Experience with anti-NGF and anti-TNF Therapeutics......................... 28
2.2.2
Clinical Experience with MEDI7352 ................................................................ 29
2.3
Benefit/Risk Assessment................................................................................... 31
2.3.1
Risk Assessment............................................................................................... 31
2.3.1.1
Potential Risks Based on Mechanisms of Action............................................... 32
2.3.1.2
Potential Risks Based on Class Effects.............................................................. 34
2.3.1.3
Considerations for Route of Administration...................................................... 34
2.3.1.4
General Risk-Mitigation Plan............................................................................ 34
2.3.2
Benefit Assessment........................................................................................... 36
2.3.3
Overall Benefit/Risk Summary ......................................................................... 37
2.3.4
Overall Benefit/Risk Conclusion....................................................................... 37
3
OBJECTIVES AND ENDPOINTS................................................................... 39
4
STUDY DESIGN ............................................................................................. 43
4.1
Overall Design.................................................................................................. 43
4.1.1
Study Conduct Mitigation During Study Disruptions due to Cases of Public 
Health Crisis..................................................................................................... 45
4.1.2
Additional Risk-Mitigation Procedures Implemented in the Context of the 
SARS‑CoV‑2/COVID‑19 Pandemic ................................................................. 46
4.2
Scientific Rationale for Study Design ............................................................... 48
4.3
Justification for Dose........................................................................................ 49
4.4
End-of-Study Definition ................................................................................... 50
5
STUDY POPULATION ................................................................................... 50
5.1
Inclusion Criteria .............................................................................................. 50
5.2
Exclusion Criteria ............................................................................................. 52
5.3
Lifestyle and Activity Considerations ............................................................... 57


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
5 of 253
5.3.1
Meals and Dietary Restrictions ......................................................................... 58
5.3.2
Tobacco Restrictions......................................................................................... 58
5.3.3
Other Restrictions ............................................................................................. 58
5.4
Screen Failures ................................................................................................. 58
5.4.1
Rescreening ...................................................................................................... 59
6
STUDY INTERVENTION............................................................................... 59
6.1
Study Intervention(s) Administered .................................................................. 59
6.1.1
Investigational Products.................................................................................... 59
6.2
Preparation/Handling/Storage/Accountability ................................................... 61
6.2.1
Preparation and Administration of Subcutaneous Injections.............................. 61
6.2.2
Handling, Labelling, and Storage...................................................................... 63
6.2.3
Accountability .................................................................................................. 63
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 64
6.3.1
Methods for Unblinding.................................................................................... 64
6.4
Study Intervention Compliance......................................................................... 65
6.5
Concomitant Therapy........................................................................................ 65
6.5.1
Permitted Concomitant Therapy........................................................................ 66
6.5.2
Prohibited Concomitant Medications ................................................................ 67
6.5.3
Rescue Medication............................................................................................ 68
6.6
Dose Modification ............................................................................................ 69
6.7
Intervention after the End of the Study.............................................................. 69
7
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL.......................................................... 69
7.1
Discontinuation of Investigational Product........................................................ 69
7.1.1
Subject-specific Criteria for Discontinuation of Investigational Product............ 70
7.1.2
Procedures for Early Discontinuation of Investigational Product....................... 72
7.1.3
Temporary Discontinuation of Investigational Product...................................... 73
7.1.4
Procedures for Handling Incorrectly Enrolled or Randomised Subjects............. 75
7.2
Subject Withdrawal from the Study .................................................................. 75
7.3
Lost to Follow-up ............................................................................................. 76
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 77
8.1
Efficacy/Pharmacodynamics Assessments ........................................................ 81
8.1.1
Daily Pain Scores.............................................................................................. 81
8.1.2
Patient Global Assessment of Osteoarthritis...................................................... 81
8.1.3
Western Ontario and McMaster Universities Osteoarthritis Index ..................... 81
8.1.4
Daily Sleep Interference Scale .......................................................................... 82
8.1.5
36-Item Short Form Health Survey Questionnaire (acute recall)........................ 82
8.1.6
European Quality of Life-5 Dimensions (EQ-5D-5L)........................................ 83
8.1.7
WPAI:OA questionnaire................................................................................... 84
8.1.8
Assessment of Healthcare Resource Utilisation................................................. 84
8.1.9
Rescue Medication............................................................................................ 85
8.2
Safety Assessments........................................................................................... 86


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
9 of 253
Appendix L
Abbreviations ........................................................................................ 166
Appendix M
Protocol Amendment History................................................................. 170


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
11 of 253
Objectives
Estimands descriptions/endpoints
!
An ‘attributable’ estimand strategy will be adopted for 
data missing or affected by any of the above 
intercurrent events: missing or affected primary 
endpoint values will be imputed, but the method of 
imputation will differ depending upon the intercurrent 
event. Specifically, data missing due to discontinuation 
due to lack of efficacy or an AE will be imputed 
assuming an unfavourable outcome. Similarly, data 
affected by prohibited or excessive rescue medication 
will be set to missing and imputed assuming an 
unfavourable outcome.
Secondary objectives
To assess the efficacy of MEDI7352 
compared to placebo on additional measures 
of efficacy in participants with painful OA 
of the knee
Key secondary endpoints:
•
Change in the WOMAC pain subscale from baseline to 
Week 12 
•
Change in the WOMAC physical function subscale from 
baseline to Week 12
•
Change in the PGA of OA from baseline to Week 12
Other secondary endpoints:
•
Change in the WOMAC pain subscale from baseline to 
Weeks 2, 4, 6, 8, 10, and 18
•
Change in the WOMAC physical function subscale from 
baseline to Weeks 2, 4, 6, 8, 10, and 18
•
Change in the WOMAC overall scores from baseline to 
Weeks 2, 4, 6, 8, 10, 12, and 18
•
Change in the WOMAC stiffness scores from baseline to 
Weeks 2, 4, 6, 8, 10, 12, and 18
•
Change in PGA of OA from baseline to Weeks 2, 4, 8, 10, 
and 18
•
Percentage of responders as measured by the OARSI 
responder index using the OMERACT-OARSI definition 
(Pham et al 2004) at Weeks 2, 4, 8, 12, and 18
•
Percentage of participants who have achieved an 
improvement of ≥2 points in PGA of OA at Weeks 2, 4, 8, 
12, and 18
•
Change in the weekly average of daily NRS pain scores from 
baseline to Weeks 2, 4, 6, 8, 10, and 18 
•
Percentage of participants who have achieved ≥30% 
and ≥50% reductions in the weekly average of daily NRS 
pain scores from baseline to Weeks 2, 4, 8, 12, and 18
•
Percentage of participants who have achieved ≥30% 
and ≥50% reductions in WOMAC pain subscale scores at 
Weeks 2, 4, 8, 12, and 18
•
Percentage of participants who have achieved ≥30% 
and ≥50% reductions in WOMAC physical function 
subscale at Weeks 2, 4, 8, 12, and 18
To assess the PK of MEDI7352 in 
participants with painful OA of the knee
•
Serum concentration of MEDI7352


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
12 of 253
Objectives
Estimands descriptions/endpoints
To assess immunogenicity of MEDI7352 in 
participants with painful OA of the knee
•
Presence of ADA to MEDI7352
•
ADA titre
Safety objectives
To assess the safety and tolerability of 
MEDI7352 compared with placebo in 
participants with painful OA of the knee
Safety and tolerability will be evaluated based on AEs, vital signs, 
and clinical laboratory assessments, including but not limited to:
•
AEs and SAEs
•
Physical examinations
•
Neurological examinations 
•
Total Neuropathy Score-nurse
•
Weight 
•
Vital signs (supine and orthostatic BP, pulse rate, 
temperature, respiratory rate)
•
Survey of Autonomic Symptoms
•
12-lead ECGs
•
Clinical laboratory testing (haematology, chemistry, 
coagulation, and urinalysis)
•
CRP (inflammatory biomarker)
•
Concomitant medications and therapies
•
Injection site reactions 
•
X-ray or/and MRI of large joints a
a
Detailed information about the joints to be evaluated by X-ray and/or MRI is found in Section 8.2.6 and 
Appendix I.
ADAs, antidrug antibodies; AE(s), adverse event(s); BP, blood pressure, CRP, C-reactive protein; 
ECGs, electrocardiograms; MRI, magnetic resonance imaging; NRS, numerical rating scale; OA, osteoarthritis; 
OMERACT-OARSI, Outcome Measures in Rheumatology-Osteoarthritis Research Society International; 
PGA, Patient’s Global Assessment; PK, pharmacokinetics; SAEs, serious adverse events; WOMAC, Western 
Ontario and McMaster Universities Osteoarthritis 
Overall Design
This is a Phase IIb, multinational, multicentre, randomised, double-blind, placebo-controlled, 
dose-response study of MEDI7352 in participants 18 to 80 years of age (inclusive) with 
moderate-to-severe chronic pain of the knee during the previous 3 months or longer, caused 
by OA, and not adequately controlled by standard-of-care treatments. The study consists of a 
screening period of up to 45 days, a 12-week treatment period, and a 24-week follow-up (FU) 
period (Table 1).
Daily pain scores (as measured on an 11-point numerical rating scale [NRS]) recorded at the 
first screening visit and from Day -7 to Day -1 (inclusive) will be used be used to determine 
eligibility. In addition, X-ray features in the target knee joint should be consistent with at least 
Grade 2 OA on the Kellgren and Lawrence grading scale of 0 to 4 as per central reader 
evaluation. 


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
14 of 253
Treatment period: 12 weeks with 6 fixed doses of IP administered at Weeks 0 (Day 1), 2, 4, 6, 
8, and 10 and an EOT visit conducted at Week 12
FU period: 24-week FU period with a final FU visit at Week 36 (± 7 days)
The maximum study duration for each participant is approximately 50 weeks. The overall 
study duration is expected to be 31 months (18 months of active screening and enrolment, 
11 months of treatment and FU, and 2 months for database lock).
Data Monitoring Committees: 
∀
Data and Safety Monitoring Board (DSMB): The DSMB will conduct periodic reviews of 
safety data from all enrolled participants throughout the clinical study. The DSMB will 
make recommendations to the sponsor, based on these data, on the future conduct of the 
clinical study and in particular on whether to continue, terminate, or modify the clinical 
study.
∀
Independent Efficacy Review Group: This group will be independent of the study team 
and will review, interpret, and make decisions on future conduct of the clinical study 
based on the proposed interim analyses for futility and efficacy and on any additional 
analyses carried out for administrative purposes.
∀
Rapidly Progressive Osteoarthritis (RPOA) Adjudication Committee (RPOA-AC): The 
role of this committee is to independently review, interpret, and adjudicate possible or 
probable joint safety events including but not limited to RPOA, subchondral insufficiency 
fracture, primary osteonecrosis, or pathological fracture cases that are experienced by the 
study participants. The RPOA-AC will review and adjudicate all treatment-emergent joint 
safety events that meet SAE or severe AE criteria or which led to joint replacement or 
other arthroplasty procedures.
Statistical Methods
An ‘attributable’ estimand strategy will be adopted for primary endpoint data missing or 
affected by any of the following 4 intercurrent events:
∀
Discontinuation due to lack of efficacy or an adverse event
∀
Discontinuation due to other reasons such as loss to FU or external circumstances
∀
Taking prohibited pain medication during the treatment period
∀
Taking excessive permitted rescue medication
Missing or affected primary endpoint values will be imputed, but the method of imputation 
will differ depending upon the intercurrent event.


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
16 of 253
will also be tabulated according to the ‘last-observation-carried-forward’ or ‘baseline-
observation-carried-forward’, as appropriate. 
The main statistical analysis of the primary efficacy endpoint at Week 12 will use a MCP-
Mod approach, which is a well-established statistical methodology for establishing both the 
existence of a dose response and modelling of the underlying dose-response relationship. Both 
the European Medicines Agency (EMA 2013) and the Food and Drug Administration (FDA) 
(FDA 2015) have recognised MCP-Mod as an efficient statistical methodology for model-
based design and analysis of Phase II dose-finding studies under model uncertainty. The 
significance level of the analysis will be at 1-sided α = 0.025. A multiple imputation approach 
will be used for missing or unevaluable data. The method of imputing missing values will be 
dependent on the reasons for missing or unevaluable data. 
Pairwise testing of prespecified MEDI7352 doses versus placebo of the primary and key 
secondary endpoints will be performed using a sequentially rejective multiple comparison 
approach (or similar) to ensure overall family-wise type 1 error across primary and key 
secondary endpoints is controlled at 1-sided α = 0.025 (Bretz et al 2009).
Clinical Pharmacology Analyses 
PK: PK of MEDI7352 will be characterised with a population PK model. MEDI7352 trough 
concentration (Ctrough) will be summarised descriptively.
Pharmacodynamics (PD) and biomarkers: PD variables (free and/or total nerve growth factor, 
CXCL13, and other relevant biomarkers) will be summarised using descriptive statistics. 
Biomarker results will be listed. The association between PD variables and efficacy endpoints 
will be evaluated. 
Immunogenicity: A summary of the number and percentage of participants who developed 
detectable antidrug antibodies (ADA) to MEDI7352 as well as ADA titres in all cohorts will 
be presented. Immunogenicity results will be listed. The effect of ADA on PK, PD, safety, and 
efficacy will be evaluated.
Analysis of pharmacogenetics data will be described in a separate analysis plan.
Safety Analyses 
Safety and tolerability data will be summarised descriptively by using tables, listings, and 
graphs, as appropriate.












Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
22 of 253
Table 1
Schedule of Activities
Double-blind treatment period
(12 weeks)
Follow-up period b
(24 weeks)
Study week
Screening/
baseline a
Wk 0 c
Wk 1
± 3 d d
Wk 2
± 3 d
Wk 4
± 3 d
Wk 6
± 3 d
Wk 8
± 3 d
Wk 10
± 3 d
Wk11
± 3 d d
Wk 11
± 3 d d
(EOT or 
ET e)
Wk 12
± 3 d
Wk 15
± 3 d
Wk 18
± 7 d
Wk 21,  
24, & 28
± 3 d
Wk 32
± 7 d
Wk 36
± 7 d
Study day
Day
-45 to -1
D 1
D 7
D 14
D 28
D 42
D 56
D 70
D 74
D 77
D 84
D 105
D 126
D 147, 
168, & 
196
D 224 Day 252
Clinic visit (V)
V1
V2
V3
V4 f
V5 f
V6
V7
V8
V9
V10
V11
Phone 
call 1
V12
Phone 
calls 2, 3,
& 4
V13
V14
Serology (HIV, 
hepatitis B, 
hepatitis C, and 
tuberculosis 
[QuantiFERON])
X
Serum pregnancy test
X a
Haemoglobin A1c
X
X
ACPA antibodies 
X
FSH test screening for 
women < 50 years
X
Immunogenicity 
(ADA) sampling
X w
X
X w
X w
X w
X w
X w
X
X
X x
X
X
PK analysis
X w
X
X w
X w
X w
X w
X w
X
X
X x
X
X
PD and exploratory 
biomarkers:
PD: free NGF
X w
X
X w
X w
X w
X w
X w
X
X
X x
X
X
PD: total NGF
X w
X
X w
X w
X w
X w
X w
X
X
X x
X
X
PD: CXCL13 
X w
X
X w
X w
X w
X w
X w
X
X
X x
X
X




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neutralises NGF, preventing its interaction with both its high- and low-affinity receptors 
(tropomyosin-related kinase A and p75 neurotrophin receptor, respectively). The TNFR2 end 
of MEDI7352 binds TNF in solution, thereby preventing its interaction with cell-surface
TNFR2 and the consequent intracellular signalling and biologic effects. MEDI7352 is thus 
designed to engage 2 biological mediators: NGF and TNF. Both mediators are considered to 
play important roles in sensitisation of the nervous system and pain pathophysiology (Pezet 
and McMahon 2006, Hefti et al 2006, Petty et al 1994, Dimitroulas et al 2017, Leung and 
Cahill 2010). 
MEDI7352 is being developed with the goal of reducing systemic and local NGF and TNFα 
concentrations related to joint inflammation to more effectively treat chronic painful 
conditions such as OA. 
Administration of MEDI7352 in nonclinical pharmacology studies using in vivo models of 
inflammatory pain in rodents produced significant analgesia at doses which are predicted by 
pharmacokinetics (PK)/pharmacodynamics (PD) modelling to sequester < 10% of circulating 
NGF. It is hypothesised that this analgesia at very low levels of NGF suppression results from 
synergy between MEDI7352 effects on NGF and TNFα binding and/or signalling pathways 
(see the current Investigator’s Brochure [IB] for maximum and average percentage of free 
NGF suppression following single intravenous [IV] doses of MEDI7352 in the Phase I study 
D5680C00001). Therefore, MEDI7352 represents a novel analgesic approach that may avoid 
unwanted effects associated with high levels of NGF suppression.
Additional information regarding nonclinical studies with MEDI7352 is provided in the 
current IB.
2.2.1
Clinical Experience with anti-NGF and anti-TNF Therapeutics
In humans, anti-NGF antibodies have demonstrated efficacy in clinical studies of OA and 
chronic lower back pain (Lane et al 2010, Katz et al 2011, Brown et al 2012, Brown et al 
2013, Kivitz et al 2013, Schnitzer et al 2015, Spierings et al 2013). This clinical efficacy 
appears to require doses of anti-NGF antibodies that are projected to sequester > 90% of 
circulating NGF (Neubert et al 2013). 
TNF receptor blockers have a well-established role for disease modification in the 
management of RA and other inflammatory joint diseases in which pain is often an important 
component of the phenotype (Croft et al 2013). While anti-TNF therapeutics do not carry a 
primary indication for the provision of analgesia, there is some evidence to suggest that a 
selected subgroup of OA patients with a marked inflammatory profile may benefit from this 
therapy (Dimitroulas et al 2017). 
There are well-known class effects of the individual anti-NGF and TNFα active moieties of 
MEDI7352, but the potential for combined effects in humans is unknown. 


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Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
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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 participant 
treated with MEDI7352), which led to the participant’s withdrawal. The pneumonia was 
considered by the investigator to be 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 participants 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 participants 
treated with MEDI7352 had TEAEs of oral herpes and urinary tract infection (5.7% each) 
compared with participants treated with placebo (0%). However, the overall incidence of 
TEAEs in the SOC of infections and infestations was similar among participants treated with 
MEDI7352 and those treated with placebo (39.6% and 36.4%, respectively).
The most common TEAEs among participants 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 participants 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 participant 
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. 
No cases of rapidly progressive OA (RPOA)or osteonecrosis were reported during the study. 
There were no discernible differences in the TEAE profiles of participants 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 participants 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). 
Phase II Study D5680C00002 (Participants with Painful Diabetic Neuropathy)
The Phase II study D5680C00002 comprises 4 successive stages, each assessing MEDI7352 
(up to 6 planned IV doses per participant) versus placebo as follows: Stage 1 assessed 
MEDI7352 5 μg/kg or placebo, Stage 2 assessed MEDI7352 150 μg/kg or placebo, Stage 3 
will assess MEDI7352 450 μg/kg or placebo, and Stage 4 will assess MEDI7352 50, 150, and 


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Version 4.0 28 June 2022
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450 μg/kg or placebo. At the time of preparation of this clinical study protocol (CSP), 
Stages 1 and 2 of the study are complete, and Stage 3 is ongoing. 
A review of blinded safety data showed that 26 of 41 treated participants (63.4%) have had at 
least one reported TEAE as of 01 June 2021. There have been no deaths or serious TEAEs. 
Three participants 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, 5 μg/kg MEDI7352 or placebo)
∀
A TEAE of infection (symptoms of sore throat, fever, nasopharyngitis, tongue burning, 
and sweating) of mild intensity (Stage 2, 150 μg/kg 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 participant’s withdrawal after 3 of 6 planned infusions 
of IP (150 μg/kg MEDI7352 or placebo). 
Headache was the most commonly reported TEAE overall: 7 of 41 participants (17.1%), 
including 3 of 10 participants (30.0%) in the completed Stage 1 (5 μg/kg MEDI7352 or 
placebo), 3 of 26 participants (11.5%) in the completed Stage 2 (150 μg/kg MEDI7352 or 
placebo) and 1 of 5 participants (20%) in the ongoing Stage 3 (MEDI7352 450 μg/kg 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 
TNSn or for parameters measured during motor and sensory nerve conduction studies.
Phase I Study D5680C00004 (Healthy Japanese and Caucasian Volunteers)
Two of the of 5 treated participants (40.0%) have had a total of 4 TEAEs as follows (one 
participant each): dyspepsia, catheter site erythema, injection site pain, and paraesthesia. All 
reported AEs were considered by the investigator to be of mild intensity. There have been no 
deaths, treatment-emergent SAEs, or withdrawals due to AEs.
A detailed description of the chemistry, pharmacology, efficacy, and safety of MEDI7352 is 
provided in the current IB.
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment
MEDI7352 is a novel, bispecific fusion protein targeting both soluble NGF and TNFα and, as 
such, the dual effect represents a novel mechanism of action. There are well-known class 


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effects of the individual anti-NGF and anti-TNFα active moieties of MEDI7352, as described 
below, but the potential for combined effects in humans is unknown. Potential risks associated 
with MEDI7352 administration are briefly summarised below. More detailed information 
about potential risks and benefits of MEDI7352 is provided in the current IB.
2.3.1.1
Potential Risks Based on Mechanisms of Action
The safety profile of MEDI7352 may include adverse reactions that are related to the expected 
pharmacological mechanisms of action, and thus may be comparable to those previously 
reported for both anti-NGF monoclonal antibodies undergoing development (eg, tanezumab, 
fulranumab, and fasinumab) and established anti-TNFα therapies (eg, etanercept, adalimumab, 
and infliximab). In addition, as with all biologics, there may be risks of immunological 
reactions including hypersensitivity reactions, injection site reactions, and the consequences of 
immunogenicity (Ingrasciotta et al 2018).
Risks Associated with the Anti-NGF Mechanism
Rapidly Progressive Osteoarthritis and other Joint Safety Events
The most common joint AE associated with anti-NGF monoclonal antibodies relates to 
clinical cases of RPOA (type 1 and type 2), which have been observed in large-scale clinical 
studies. Review of the tanezumab, fulranumab, and fasinumab programmes showed that the 
incidence of RPOA increased with increasing doses of anti-NGFs, particularly when these 
drugs were dosed concurrently with NSAIDs (FDA 2012). 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 (SIF), and pathological fracture (FDA 
2021a). There was a significantly higher incidence of events in participants treated with 
tanezumab (3.2% and 6.2% of participants treated with tanezumab 2.5 mg and 5 mg, 
respectively) compared to NSAIDs (1.5% of participants) or placebo (0% of participants) 
(FDA 2021c). In addition, a greater proportion of participants treated with tanezumab (5.5% 
and 7.8% of participants treated with tanezumab 2.5 mg and 5 mg, respectively) required total 
joint replacements when compared to those treated with NSAIDs (2.6% of participants) or 
placebo (4.5% of participants) (FDA 2021a, FDA 2021c). Overall, approximately 85% of the 
total joint replacements occurred in joints KL grade ≥ 3 at baseline (FDA 2021c); however, 
some joint safety events including total joint replacement occurred in joints KL grade 0 or 1 at 
baseline (FDA 2021a, FDA 2021c).
It was also notable in the tanezumab programme that composite joint safety events are not 
limited to arthritis joints. For participants 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%) (FDA 2021b).


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Sensory Abnormalities and Peripheral Neuropathy
Adverse events related to sensory abnormalities have been reported by participants in clinical 
studies with tanezumab (Bélanger et al 2018, Brown et al 2012, Brown et al 2013, Brown et al 
2014, Ekman et al 2014, FDA 2021a, Gimbel et al 2014, Lane et al 2010, Katz et al 2011, 
Kivitz et al 2013, Nagashima et al 2011, Schnitzer and Marks 2015, Spierings et al 2013, Tive 
et al 2019). The most common of these AEs have been paraesthesia, hypoaesthesia 
(numbness), and burning sensation. 
In a recent pooled analysis of safety data across 9 Phase III studies of tanezumab in 
participants with moderate-to-severe OA of the knee (Tive et al 2019), AEs of abnormal 
peripheral sensation were reported in tanezumab-treated participants more frequently than in 
participants receiving placebo or active comparator. For the majority of participants receiving 
tanezumab (monotherapy or in combination with NSAIDs) and whose final neurological 
consultations indicated a new or worsening neuropathy, the diagnosis was of some form of 
mononeuropathy, predominantly carpal tunnel syndrome or radiculopathy. Few participants 
were diagnosed with polyneuropathy (Tive et al 2019). 
Additional information about this potential risk is provided in the current IB.
Autonomic Neuropathy and Sympathetic Dysfunction
According to the FDA Briefing Document for the 2021 Advisory Committee meeting for 
tanezumab (FDA 2021a), in the Phase III placebo-controlled studies with tanezumab, AEs of 
postganglionic sympathetic dysfunction (AEs of decreased sympathetic function such as 
bradycardia, orthostatic hypotension, hypohidrosis, syncope), occurred at observation-time 
adjusted rates of 20.3%, 29.1%, and 46.2% for subjects receiving placebo, tanezumab 2.5 mg, 
and tanezumab 5.0 mg, respectively; the imbalance was primarily driven by higher rates of 
bradycardia and orthostatic hypotension in the tanezumab treatment groups. In a Phase III 
active-controlled study, AEs of postganglionic sympathetic dysfunction occurred at 
observation-time adjusted rates of 37.0%, 25.7%, and 36.1% for subjects receiving NSAIDs, 
tanezumab 2.5 mg, and tanezumab 5.0 mg, respectively. Overall, the FDA concluded that 
tanezumab was not found to be associated with an increased risk of sympathetic disfunction.
Additional information about this potential risk is provided in the current IB.
Risks Associated with the Anti-TNF Mechanism
Anti-TNFα therapies have been associated with an increased risk of infection in the clinic. 
Infections, including serious infections such as tuberculosis (TB), bacterial sepsis, and 
invasive fungal infections, have been observed in participants treated with anti-TNFα 
therapies. 
Patients older than 65 years of age, patients with co-morbid conditions and/or patients taking 
concomitant immunosuppressants may be at greater risk of infection. The risks and benefits of 


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#
Exclusion of participants with active infection and clinically important infection, 
including chronic, persistent, or recurrent infections or recent acute infections within 
3 months prior to screening or between screening and randomisation
#
Screening for the identification and exclusion of participants with human 
immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), 
or TB.
#
Exclusion of participants who are receiving disease-modifying antirheumatic drugs 
(DMARDs) and other immunosuppressants 
#
Exclusion of participants with history of any underlying condition that predisposes 
participant to infections (such as splenectomy or primary or secondary 
immunodeficiency syndrome)
#
Exclusion of participants with a history of an opportunistic infection or who lived in 
areas with endemic fungal infections 
∀
Clinical safety monitoring and assessment procedures conducted at appropriate intervals 
at specified clinic visits during the clinical study, specifically including:
#
Complete physical examinations at appropriate frequencies
#
Neurological examination, including peripheral nervous system examination with 
TNSn assessment at appropriate frequencies. 
#
Follow-up (FU) required for cases of suspected occurrence or worsening of 
neuropathy by neurologist and on protocol-prespecified cases of bradycardia, 
orthostatic hypotension, syncope, anhidrosis, or hypohidrosis by a neurologist and/or 
cardiologist (Section 8.2.2)
#
Baseline evaluation of left ventricular ejection fraction (LVEF) using 
echocardiography in cases of Class 1 and Class 2 (NYHA 1994) heart failure and 
follow-up on cases of suspected new occurrence or worsening of heart failure by 
cardiologist. 
#
Monitoring for AEs (including but not limited to evidence of infection, joint safety 
events, cancer, symptoms of neuropathy, and sympathetic autonomic dysfunction), 
vital signs (including orthostatic blood pressure [BP] measurements), ECGs, and 
safety laboratory tests (haematology, clinical chemistry including C-reactive protein 
(CRP), liver function tests, coagulation tests, and urinalysis) at appropriate 
frequencies 
#
Monitoring of concomitant medication use
#
Monitoring for injection site reactions and hypersensitivity 
#
Use of appropriate imaging techniques (X-ray or magnetic resonance imaging [MRI]) 
for evaluation of protocol-prespecified major joints at relevant time points (including 
baseline and FU) and at any time point (in addition to protocol-prespecified joints), 
when clinically indicated (Section 8.2.6).


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∀
Independent expert adjudication of suspected or confirmed cases of possible or probable 
joint safety events including but not limited to RPOA, SIF, primary osteonecrosis, or 
pathological fracture cases that are experienced by the study participants (Section 8.2.7
and Section 9.6).
∀
Application of individual stopping criteria (Section 7.1.1) 
∀
Unblinded Data and Safety Monitoring Board (DSMB) to review safety data (Section 9.6)
2.3.2 Benefit Assessment 
Analgesics, ranging from paracetamol and opioids to NSAIDs and intra-articular hyaluronan, 
are prescribed for treating pain in OA, but their effect is often small (mean analgesic effect 
size from 0.15 to 0.30) and not sufficient in many patients (van der Kraan et al 2016). The use 
of opioids is constrained by poor responder rates and potential for dependence. NSAID and 
opioid use is also limited by safety concerns, including gastrointestinal bleeds and 
cardiovascular risks with NSAIDs and constipation, respiratory depression, and dependence 
with opioids.
For this reason, there is a significant medical need for drugs with improved and more 
sustained symptomatic effects and better tolerability for the treatment of chronic pain, 
including OA.
MEDI7352 has selective, high-affinity binding to both NGF and TNFα, which are mediators 
of both neuropathic and inflammatory pain signalling (Ji et al 2013, Lu et al 2014, Pezet and 
McMahon 2006). MEDI7352 is being developed with the goal of reducing systemic and local 
NGF and TNFα concentrations related to joint inflammation to more effectively treat chronic 
painful conditions such as OA.
MEDI7352 has been shown to be a highly effective analgesic in nonclinical studies, with 
significant efficacy observed at levels of sequestration of NGF that are significantly lower 
than those required for an anti-NGF antibody alone to demonstrate efficacy. Administration of 
MEDI7352 in a rodent chronic joint pain model produced significant analgesia at doses 
which, by modelling, sequester < 10% of circulating NGF. It is hypothesised that this 
analgesia at relatively low levels of NGF suppression results from synergistic engagement of 
NGF and TNF targets. 
As conventional anti-NGF approaches are thought to require almost complete sequestration of 
NGF in both nonclinical and clinical studies, MEDI7352 represents a potential analgesic 
approach that may avoid unwanted effects associated with high levels of NGF suppression.
The completed first-time-in-human (FTIH) SAD/MAD study with MEDI7352 
(D5680C00001) was conducted in participants with OA, rather than healthy participants, as 
there was the potential to observe at least some short-term efficacy signals in this population 


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Overall, no clinically important safety issues have emerged that preclude further evaluation of 
MEDI7352 in the relevant clinical study populations at exposures equivalent to those achieved 
with repeated IV doses up to 450 μg/kg. The MEDI7352 doses used in this study are 
supported by adequate safety margins, and the benefit-risk evaluation remains favourable for 
clinical development. 


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3
OBJECTIVES AND ENDPOINTS
The primary and secondary objectives and associated endpoints are detailed below.
Table 2
Primary and Secondary Objectives
Objectives
Estimands descriptions/endpoints
Primary objectives
To assess the efficacy of MEDI7352 compared to 
placebo on chronic pain in participants with 
painful OA of the knee at Week 12
•
Population: Adults with moderate-to-severe chronic 
OA pain of the knee, persistent for 3 months or 
longer, not adequately controlled by standard-of-care 
treatments
•
Primary endpoint: 
!
Change in weekly average of daily NRS pain 
scores from baseline to Week 12
•
Intercurrent events: 
!
Discontinuation due to lack of efficacy or an AE
!
Discontinuation due to other reasons such as loss 
to follow-up or external circumstances
!
Taking prohibited pain medication during the 
treatment period
!
Taking excessive permitted rescue medication
•
Summary measures: 
!
Difference in mean changes in weekly average 
daily NRS pain scores between MEDI7352 
doses and placebo
!
An ‘attributable’ estimand strategy will be 
adopted for primary endpoint data missing or 
affected by any of the above intercurrent events: 
Missing or affected primary endpoint values will 
be imputed, but the method of imputation will 
differ depending upon the intercurrent event. 
Specifically, data missing due to discontinuation 
due to lack of efficacy or an AE will be imputed 
assuming an unfavourable outcome. Similarly, 
data affected by prohibited or excessive rescue 
medication will be set to missing and imputed 
assuming an unfavourable outcome.
Secondary objectives
To assess the efficacy of MEDI7352 compared to 
placebo on additional measures of efficacy in 
participants with painful OA of the knee 
Key secondary endpoints:
•
Change in the WOMAC pain subscale from baseline 
to Week 12
•
Change in the WOMAC physical function subscale 
from baseline to Week 12
•
Change in the PGA of OA from baseline to Week 12
Other secondary endpoints:


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Table 2
Primary and Secondary Objectives
Objectives
Estimands descriptions/endpoints
•
Change in the WOMAC pain subscale from baseline 
to Weeks 2, 4, 6, 8, 10, and 18
•
Change in the WOMAC physical function subscale 
from baseline to Weeks 2, 4, 6, 8, 10, and 18
•
Change in the WOMAC overall scores from baseline 
to Weeks 2, 4, 6, 8, 10, 12, and 18
•
Change in the WOMAC stiffness scores from baseline 
to Weeks 2, 4, 6, 8, 10, 12, and 18
•
Change in PGA of OA from baseline to Weeks 2, 4, 8, 
10, and 18
•
Percentage of responders as measured by the OARSI 
responder index using the OMERACT-OARSI 
definition (Pham et al 2004) at Weeks 2, 4, 8, 12, 
and 18
•
Percentage of participants who have achieved an 
improvement of ≥2 points in PGA of OA at Weeks 2, 
4, 8, 12, and 18
•
Change in the weekly average of daily NRS pain 
scores from baseline to Weeks 2, 4, 6, 8, 10, and 18 
•
Percentage of participants who have achieved ≥30% 
and ≥50% reductions in the weekly average of daily 
NRS pain scores from baseline to Weeks 2, 4, 8, 12, 
and 18
•
Percentage of participants who have achieved ≥30% 
and ≥50%, reductions in WOMAC pain subscale 
scores at Weeks 2, 4, 8, 12, and 18.
•
Percentage of participants who have achieved ≥30% 
and ≥50% reductions in WOMAC physical function 
subscale at Weeks 2, 4, 8, 12, and 18
To assess the PK of MEDI7352 in participants 
with painful OA of the knee 
•
Serum concentration of MEDI7352
To assess immunogenicity of MEDI7352 in 
participants with painful OA of the knee 
•
Presence of ADA to MEDI7352
•
ADA titre
Safety objectives
To assess the safety and tolerability of MEDI7352 
compared with placebo in participants with painful 
OA of the knee 
Safety and tolerability will be evaluated based on AEs, 
vital signs, and clinical laboratory assessments including 
but not limited to:
•
AEs and SAEs
•
Physical examinations
•
Neurological examinations
•
Total Neuropathy Score-nurse 
•
Weight
•
Vital signs (supine and standing BP, pulse rate, 
temperature, respiratory rate) 
•
Survey of Autonomic Symptoms
•
12-lead ECGs




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4
STUDY DESIGN
4.1
Overall Design
Study D5680C00003 is a Phase IIb, multicentre, multinational, randomised, double-blind, 
placebo-controlled, dose-response study of MEDI7352 in participants 18 to 80 years of age 
(inclusive) with moderate-to-severe chronic pain of the knee during the previous 3 months or 
longer, caused by OA, and not adequately controlled by standard-of-care treatments. The 
study consists of a screening period of up to 45 days (one or more visits), a 12-week 
double-blind treatment period (10 scheduled visits), and a 24-week FU period (3 scheduled 
visits and 4 phone calls).
The participant should be randomised and IP administered within 45 days of initiating 
screening. One rescreening attempt is allowed (Section 5.4.1). Screening procedures may be 
performed at one or more visits (Table 1). Participants will start recording daily pain scores 
(using an 11-point numerical rating scale [NRS]), Daily Sleep Interference Scale (DSIS) 
scores, and rescue medication from Day -14 until the FU visit at Week 18. Participants will 
record WOMAC questionnaire responses at different time points throughout the study. NRS 
pain score recorded at the first screening visit and the daily pain scores from Day -7 to Day -1 
(inclusive) will be used to determine eligibility.
All participants should undergo a diagnostic X-ray on the shoulder, knee, and hip joints during 
the screening period (Section 8.2.6.1). The reported features in the target knee joint should be 
consistent with at least Grade 2 OA on the Kellgren and Lawrence (KL) grading scale of 
0 to 4 as per central reader evaluation. If other major joints (elbows, wrists, and ankles) 
exhibit signs or symptoms associated with OA, these should also be imaged during the 
screening period.
An MRI of the bilateral knees and the joints with a KL grade at baseline of ≥3 (per screening 
X-ray assessment) should be conducted during the screening period (exceptions are listed in 
Section 8.2.6.2). Eligibility (absence of specified joint abnormalities) will be determined by a 
central imaging reader. All participants must stop taking their disallowed current pain 
medication(s) for at least 48 hours or 5 half-lives, whichever is longer, prior to the start of the 
NRS pain score baseline period on Day -7 (Section 8 “Washout Period”). Participants who 
develop unacceptable pain at any stage of the study (including the washout period) will be 
permitted to initiate rescue analgesic therapy with paracetamol in a regimen that is aligned 
with local guidelines/label (Section 6.5.3).
After screening and confirmation of eligibility criteria, eligible participants will be 
randomised on Day 1 by using an Interactive Response Technology/Randomisation and Trial 
Supply Management (IRT/RTSM). 




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(ie, those who complete the treatment period and those who discontinue IP early) are expected 
to complete the EOT/ET visit and the 24-week FU period.
The 24-week FU period consists of 3 clinic visits (Weeks 18, 32, and 36) and 4 FU phone 
calls (Weeks 15, 21, 24, and 28). Safety X-ray imaging will be performed on the knee and hip 
joints at the Week 32 visit. The last study visit will occur at Week 36 to follow up on any new 
and clinically significant X-ray findings from the Week 32 visit. All FU assessments will be 
performed at the time points indicated in the SoA (Table 1). 
This is a placebo-controlled Phase IIb study in which approximately 350 eligible participants 
will be randomly assigned to the IPs (one of 4 dose levels of MEDI7352 or placebo).
The study incorporates 2 interim analyses: (1) a futility analysis will take place when 
approximately 25% of participants are evaluable for the primary endpoint; this analysis will 
assess the likely success of the study outcome and will enable the sponsor to make a go/no-go 
decision regarding continuation of the study; and (2) an interim analysis of efficacy data will 
take place when approximately 50% of participants are evaluable for the primary endpoint; 
this analysis will enable the sponsor to plan future project-related activities, but without 
making any changes to the current study. 
The maximum study duration for each participant is approximately 50 weeks. The overall 
study duration is expected to be 31 months (18 months of active screening and enrolment, 
11 months of treatment and FU, and 2 months for database lock). The primary database lock is 
targeted to occur 2 months after the last participant has completed the Week 36 FU visit. 
4.1.1
Study Conduct Mitigation During Study Disruptions due to Cases of 
Public Health Crisis
The guidance and risk-mitigation procedures given below will be implemented during cases of 
civil crisis, natural disaster, or public health crisis (eg, quarantines and resulting site closures, 
regional travel restrictions, and other considerations due to severe acute respiratory syndrome 
coronavirus 2 [SARS-CoV-2]/coronavirus disease 2019 [COVID-19] or similar pandemic 
infection).
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice, and minimise risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, and deemed necessary by the investigator and 
sponsor, these changes may include the following options:


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∀
Local and regional regulations and/or guidelines regarding consent/reconsent of study 
participants should be checked and followed for obtaining consent/reconsent for the 
mitigation procedures and appropriate means of carrying out visits and assessments.
∀
Appropriate means of carrying out visits or assessments may include the following:
#
Home or remote visit: Performed by a site qualified health care provider (HCP) or 
HCP provided by a third-party vendor.
#
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
Additional information regarding the options above can be found in Appendix H.
4.1.2
Additional Risk-Mitigation Procedures Implemented in the Context of 
the SARS‑CoV‑2/COVID‑19 Pandemic
Additional risk mitigation procedures are to be implemented into the current CSP in the 
context of the current SARS‑CoV‑2/COVID‑19 pandemic.
The objective of these risk mitigation procedures is to minimise the risk posed by SARS-
CoV-2 to study participants, local investigational researchers, and other staff. 
The risk-mitigation actions outlined below are guided by international and national 
recommendations with regard to COVID-19 as well as an ongoing evaluation by AstraZeneca 
of the evolving COVID-19 situation (EMA 2020, FDA 2020). 
These changes will remain implemented until the risk posed by COVID-19 has diminished 
and with all due respect to international, national, and regional public health requirements and 
guidance. 
The following criteria should be met at baseline (prior to the first IP administration) and prior 
to all subsequent dosing visits:
∀
Study participants must be willing to comply with all applicable national or regional 
public health requirements and local institutional risk mitigation procedures with respect 
to the COVID-19 pandemic.
∀
Study participants must be tested once for SARS-CoV-2 at baseline (within 72 hours prior 
to randomisation) and prior to all dosing visits (within 72 hours prior to IP 
administrations). All tests must be negative before each IP dose is administered. The 
SARS-CoV-2 test should have sufficient sensitivity and specificity for detection of 
SARS-CoV-2 and should meet the accepted local or regional public health standards for 
screening of asymptomatic participants. Treatment options should be discussed with the 
participant if the COVID-19 test is positive.
∀
Study participants must have a body temperature < 37.8°C and show no clinical signs and 
symptoms consistent with COVID-19 infection. Participants with a body temperature 


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37.8°C or above will be required to undergo further tests, including a COVID-19 test 
before they can be allowed to receive the IP.
∀
Where applicable, additional local requirements for the definition of a SARS-CoV-2 
negative test result should be satisfied. These may include but are not necessarily limited 
to the need for repeating the SARS-CoV-2 test. 
The following additional assessments will be performed prior to each dosing visit and as 
needed (per investigator’s discretion): 
∀
COVID-19 symptom screening (presence of symptoms in the last 14 days; screening 
conducted by the investigational site staff or by a questionnaire administered either in 
person or remotely, eg, by phone). Relevant symptoms include, but are not necessarily 
limited to, fever, cough, dyspnoea, sore throat, and loss of taste/smell.
∀
Body temperature will be checked prior to every dosing visit.
∀
Within 72 hours prior to each dosing visit, COVID-19 nose swab and/or throat/saliva 
swab will be performed according to local laboratory standards and protocols for sample 
acquisition.
∀
Blood sample (2 to 5 mL) for COVID-19 antibody testing may be undertaken, if required 
according to local risk mitigation procedures for COVID-19.
Participants with clinical signs and symptoms consistent with COVID-19 infection (eg, fever, 
cough, dyspnoea, sore throat, loss of taste/smell) or active COVID-19 infection confirmed by 
the appropriate laboratory test should not be considered eligible for IP administration. Also 
refer to exclusion criterion 31. 
If a study participant is diagnosed with SARS-CoV-2 active infection and/or COVID-19 
disease, IP administration should be interrupted and treatment should be provided according to 
the local area guidance; local-area quarantine guidance should also be followed. To assess if 
the participant meets permanent IP discontinuation criteria, refer to Sections 7.1.1, 7.1.2 and 
7.1.3 for criteria for temporary and permanent discontinuation of IP and procedures for 
discontinuation of IP.
For participants experiencing signs and symptoms indicating COVID-19 (SARS-CoV-2) 
infection, the investigator should attempt to determine the infectious organism and record the 
AE (refer to Section 8.3 for collection and FU of AEs/serious AEs [SAEs]). If a participant 
presents with clinical signs and symptoms consistent with COVID-19, a SARS-CoV-2 test 
should be performed where possible, and the test results should be recorded in the case report 
form as follows:
∀
If the test is positive, record ‘COVID-19 confirmed.’
∀
If the test is negative and signs and symptoms, as judged by the investigator, are not 
suspicious of COVID-19 infection, record either the signs and symptoms or the other 
diagnosis, if one has been established, as applicable AE/SAE.


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4.4
End-of-Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last FU visit.
The end of the study is defined as the date of last participant’s last visit in the study. 
5
STUDY POPULATION
Investigators should keep a record of participants who entered screening. Each participant 
should meet all of the inclusion criteria and none of the exclusion criteria for this study. 
Participants who do not meet all the eligibility criteria will not be enrolled.
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
General/Informed Consent
1
Participants must understand the nature of the study and must give signed and dated 
written informed consent prior to the initiation of any study procedures as described in 
Appendix B, which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
2
For participants participating in the optional genetic research, a separate signed and 
dated optional genetic research ICF must be provided prior to collection of samples for 
optional genetic research that supports the Genomics Initiative. If a participant declines 
to participate in the genetic research, this will have no influence on the ability of a 
participant to participate in the study.
3
The participant should be willing and able to understand and comply with all protocol-
specified restrictions and procedures and be able to use an electronic patient-reported 
outcome (ePRO) device as judged by the investigator.
4
The participant 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.
5
The participant must be willing and able to discontinue analgesic therapy for OA with 
NSAID or COX-2 inhibitors from the start of the washout period until the end of the FU 
period. This includes over-the-counter (OTC) pain medications and topical analgesics 
that contain an NSAID or COX-2 inhibitor. There are additional restrictions for 
medications use during the different periods of the clinical study; refer to Section 6.5
for permitted and prohibited medications. 


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Age/Gender/Weight
6
Study participants will be males or postmenopausal or surgically sterile females, 18 to 
80 years of age (inclusive) on the day of randomisation. 
#
Surgically sterile women are defined as those who have had a hysterectomy, bilateral 
ovariectomy (oophorectomy), or bilateral tubal ligation. Women who are surgically 
sterile must provide documentation of the procedure by an operative report or by 
ultrasound.
#
Postmenopausal women are defined as follows:
o
Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone (FSH) levels are in the 
postmenopausal range.
o
Women ≥50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment.
o
Note that women who are not surgically sterile must not have a positive serum 
pregnancy test at screening.
#
Men who are biologically capable of having children must agree and commit to use 
an adequate form of contraception (Appendix J) for the duration of the treatment 
period and for 3 months and 20 days after the last IP administration. Contraceptive 
use by men should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. A male participant is 
considered capable of having children even if his sexual partner is sterile or using 
contraceptives.
#
If the female partner of a male participant biologically capable of having children is a 
woman of child-bearing potential, the female partner should adhere to highly 
effective birth control methods (Appendix J) for the duration of the treatment period 
and 3 months and 20 days after the last IP administration.
7
Body mass index should be ≤39 kg/m2.
Diagnostic
8
One knee must be designated as the target joint. Pain in the target joint must exceed 
pain experienced in other joints and must also exceed pain experienced from any 
concurrent medical conditions. 
9
Participant should be diagnosed with OA of the target knee based on American College 
of Rheumatology-endorsed clinical and radiographic criteria for classification of 
idiopathic OA of the knee (Altman et al 1986) used in conjunction with imaging criteria 
in inclusion criterion 11.


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10 Participant has target joint pain (OA of the knee) in the moderate-to-severe range as per 
investigator’s judgement based on medical history data and has experienced pain most 
days in the 3 months prior to screening.
11 Radiological features are consistent with a diagnosis of OA in the target knee. X-ray KL 
grade must be ≥2 at target knee as evaluated by the central reader.
12 Documented history of inadequate pain relief from past or ongoing treatment according 
to the recommended dosing guidelines with acetaminophen (paracetamol) and oral 
NSAIDs/COX-2 inhibitors unless contraindicated/not tolerated, and opioids unless 
(a) opioids are contraindicated/not tolerated, (b) there is no access to opioids as per 
local standards of care, or (c) the patient is unwilling to take opioids. (Note that ongoing 
strong opioids are exclusionary.)
13 Participants must have a self-reported pain intensity score in the target joint ≥5, as 
assessed by an 11-point Numeric Rating Scale (NRS) during the week prior to the first 
screening visit.
14 A mean pain intensity score ≥5 in the target knee as measured on an 11-point NRS 
(0 to 10) by completion of a daily diary for 7 days prior to Day 1 (ie, Day -7 to Day -1, 
inclusive). At least 5 of 7 daily scores need to be recorded by the participant. 
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
General
1
Requires current treatment with another biologic therapeutic agent, DMARD, or other 
immunosuppressants
2
Previously received any form of anti-NGF; received anti-TNFs including but not 
limited to golimumab, certolizumab, infliximab, adalimumab, etanercept, or rituximab 
within 12 months prior to screening, or other biological DMARDs (including but not 
limited to abatacept, tocilizumab, and tofacitinib), or other immunosuppressants within 
6 months prior to screening (with the exception of inhaled or topical corticosteroids; for 
exclusionary intra-articular corticosteroids use, refer to exclusion criterion 36).
3
Currently receiving strong opioids for any indication
4
Administration of COVID-19 vaccine (regardless of modality or vaccine delivery 
platform, eg, vector, lipid nanoparticle) within 30 days prior to randomisation (from last 
vaccination or booster dose, whichever is required to consider vaccination complete in 
line with applicable guidance)
5
Participation in another clinical study with an IP or device within 60 days or 5 half-
lives, whichever is longer, prior to screening 
6
Plasma donation within 28 days prior to screening or any blood donation or blood 
loss > 500 mL within 2 months prior to screening 


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7
Previous allogeneic bone marrow or stem cell transplant
8
Received nonleukocyte-depleted whole blood transfusion within 120 days prior to the 
genetic research sample collection, if participating in the optional genetic research
9
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
10 Diagnosis of RA. Evaluation for diagnostic purposes should include serology for anti-
citrullinated protein antibodies (ACPA) at screening.
11 Participants with a documented history of gout should not be enrolled in this study. 
Participants with a history or diagnosis of pseudogout (calcium pyrophosphate 
dihydrate crystal deposition disease) can enrol if there has not been a flare within 
6 months prior to screening and use of NSAIDs is not required for management of this 
condition.
12 Current diagnosis of a comorbid condition known to be associated with other forms of 
arthritis or joint pathology other than OA, including but not necessarily limited to 
immunological or autoimmune diseases (eg, RA, lupus erythematosus, inflammatory 
bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis); seronegative 
spondyloarthropathies; or other diseases involving the target joint (including 
endocrinopathies, metabolic joint diseases, joint infections, Paget’s disease, or tumours)
Note: Non-OA causes of pain in the target knee such as anserine or patellar bursitis are 
exclusionary.
13 The following conditions (based on screening imaging results as per central reader 
evaluation) should be excluded: RPOA, primary osteonecrosis (including spontaneous 
osteonecrosis of the knee), SIF, avascular necrosis, osteoporotic fractures, hip 
dislocation, pathological fractures, or stress fracture or reaction. 
14 History of significant trauma (eg, intra-articular fracture) to a knee, hip, or shoulder 
within 1 year prior to screening or between screening and randomisation. 
15 Participants who, in the opinion of the investigator, are not suitable candidates for joint 
replacement surgery 
16 Presence of neuropathic pain (except for pain related to tunnel neuropathies in upper 
limbs), or chronic primary pain syndromes (per the eleventh edition of the International 
Classification of Diseases): eg, fibromyalgia. 
17 Presence of OA of other major joints (including but not limited to nontarget knee joint) 
that could interfere with assessment of pain due to OA of the target knee 
18 Presence of clinically significant neuropathy (eg, hereditary, autonomic or 
inflammatory neuropathy).
Note: entrapment/tunnel neuropathy affecting the upper limbs that is considered stable 
is not necessarily excluded; sensory neuropathy that is considered stable and 


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non-progressive for at least 6 months is not necessarily excluded.
Note: for non-exclusionary neuropathies, there is a requirement for participants to 
undergo a baseline evaluation by a neurologist and to have relevant nerve conduction 
studies conducted and documented at baseline.
19 Requires wheelchair for mobility
20 History or current diagnosis of 
#
Severe major depression
#
Psychotic disorders 
#
Somatoform disorders 
#
Bipolar disorders 
#
Suicidal attempts
#
Hospital admission for depression within 5 years prior to screening
#
Or any other of psychiatric illness according to the criteria in the Diagnostic and 
Statistical Manual of Mental Disorders (fifth edition), if, in the opinion of the 
investigator, the psychiatric disorder or symptom is likely to confound interpretation 
of drug effect, affect pain assessment, or affect the participant’s ability to complete 
the study 
21 Significant cardiovascular disease including:
#
Class 3 or Class 4 (NYHA 1994) heart failure (ejection fraction of < 40%) or 
clinically significant stenosis or occlusion of a carotid or vertebral artery
#
Acute coronary syndrome/acute myocardial infarction, unstable angina, or coronary 
intervention with percutaneous coronary intervention or coronary artery bypass 
grafting within 6 months prior to screening 
#
High-degree AV block II-III, clinically significant sinus node dysfunction not treated 
with pacemaker, heart rate of ≤45 beats per minute on screening ECG
#
Ventricular or atrial arrhythmias requiring treatment. Participants with permanent 
atrial fibrillation and optimally regulated ventricular rate who are not on medication 
with an anticoagulant are eligible.
o
NOTE: Participants designated as NYHA functional Class 1 or Class 2 are not 
necessarily excluded from participation. However, such participants should have 
LVEF measured by echocardiography and documented at baseline.
22 Significant or chronic lung disease, including severe or unstable chronic obstructive 
pulmonary disease, severe or unstable asthma, current pneumonitis, or interstitial lung 
disease 
23 Diabetes complicated with retinopathy (by history) or nephropathy. Uncomplicated, 
stable diabetes that is well controlled and actively managed is not exclusionary. 
Haemoglobin A1c levels above 8.5 are exclusionary.


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24 Known or suspected systemic infection, including HIV, HBV, HCV, or TB should be 
excluded. If QuantiFERON test is positive at screening, participants will be excluded 
from the study except for the cases when the QuantiFERON test remains positive after 
the successful treatment of TB as confirmed and documented by the relevant specialist.
Other tests could be performed if deemed necessary by the investigators to exclude 
systemic infection. Note: Positive results of hepatitis B surface antigen (HBsAg) or 
antibody to hepatitis B core antigen (anti-HBc) are exclusionary.
25 Participants with a history of an opportunistic infection or who lived in areas with 
endemic fungal infections 
26 History or evidence of demyelinating disorder, including multiple sclerosis, optic 
neuritis, transverse myelitis, history or current diagnosis of epilepsy 
27 History of anaphylactic/severe hypersensitivity reactions, history of hypersensitivity to 
immunisations or immunoglobulins and/or biological therapies (eg, etanercept), or 
ongoing hypersensitivity reactions
28 Lifetime history of haematopoietic malignancies, history of other cancers within 5 years 
prior to screening except for cervical carcinoma in situ, in situ colon cancer, or 
non-invasive malignant colon polyps treated by excision at least 2 years ago with no 
evidence of recurrence. Diagnosis of any cancer between screening and randomisation.
29 Transient ischaemic attack in the last 6 months prior to screening or stroke in the last 
12 months prior to screening; transient ischaemic attack or stroke between screening 
and randomisation 
30 History of substance use disorders (SUD) including alcohol or recreational drugs 
according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders 
(fifth edition) within 2 years prior to randomisation (with the exception of tobacco 
SUD)
31 Current active infection, chronic or persistent systemic infection, or serious or severe 
localized or systemic infection within 3 months prior to screening or between screening 
and randomisation, or history of any underlying condition that predisposes participant to 
infections (such as splenectomy or primary or secondary immunodeficiency syndrome). 
Note that: 
#
Any history of severe COVID-19 infection (eg, requiring hospitalisation, intensive 
care unit care, or assisted ventilation) or any prior COVID-19 infection with 
unresolved sequelae is exclusionary. Any acute COVID-19 infection, including 
asymptomatic, mild, or moderate (lab confirmed or suspected based on clinical 
symptoms) that is not resolved 1 month prior to randomisation is exclusionary. [Note: 
a subject who has had an asymptomatic COVID-19 infection or recovered fully from 
a previous mild or moderate COVID-19 infection, without medical sequelae 
(including relevant negative testing that suggests they are no longer carrying 


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replicating SARS-COV-2 virus), and remains well for at least 1 month prior to 
randomisation may be considered for study eligibility].
32 Current serious or unstable clinically important illness, including respiratory, 
cardiovascular, gastrointestinal, endocrinologic, immunologic, haematologic, or 
neurological or other major disease that is likely to deteriorate or affect the participant’s 
safety or ability to complete the study, as judged by the investigator. Note: current 
diagnosis of cirrhosis of the liver is exclusionary.
33 Family history of long QT syndrome
34 History of intolerability or contraindications to acetaminophen (paracetamol) 
Procedural contraindications
35 History of surgery to a knee, hip, or shoulder within 1 year prior to screening or 
between screening and randomisation except for arthroscopy. 
Note: Nondiagnostic arthroscopy performed on the target knee joint within 180 days 
prior to screening; or diagnostic arthroscopy performed on the target knee joint within 
90 days prior to screening are exclusionary. Arthroscopy performed between screening 
and randomisation is exclusionary. 
36 Corticosteroid injection or intra-articular hyaluronic acid injection on target knee within 
12 weeks prior to screening, corticosteroid injection on a nontarget joint within 
12 weeks prior to screening, or intra-articular hyaluronic acid injection on nontarget 
joint within 6 weeks prior to screening. If a participant has had multiple injections 
within the year prior to screening, then the total dose of corticosteroid used should be no 
more than 180 mg of triamcinolone, methylprednisolone, or their equivalent. 
37 Intra-articular platelet-rich plasma treatment on the target joint within 6 months prior to 
screening or between screening and randomisation.
38 Received cell therapy on the target joint 
39 Any medical or surgical procedure (including minor intervention) or trauma within 
28 days prior to Day 1 
40 Any planned surgical procedure during the duration of the study
41 Contraindications to MRI
Physical examination, vital signs, ECG, laboratory values, and imaging
42 Clinically important abnormality at screening or between screening and randomisation 
in physical examination, vital signs, ECG, or clinical laboratory test that may 
compromise the participant’s safety or ability to complete the study, or the integrity of 
the clinical trial data, as judged by the investigator
43 Significant hypertension (defined as systolic BP of > 165 mmHg and/or diastolic BP 
of > 95 mmHg). If the BP results are out of range, the measurements can be repeated on 
the same day or at another convenient visit during screening. 


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44 Orthostatic hypotension (defined as a sustained reduction of systolic BP of at least 
20 mmHg and/or diastolic BP of at least 10 mmHg within 3 minutes of standing from a 
supine position, provided that supine BP is stable). If supine BP results are not stable, 
the measurements can be repeated on the same day or at a subsequent screening visit. If 
it is not possible to establish stable supine BP, then participant is not eligible for the 
study. 
45 Any clinically significant abnormality in ECG rhythm, conduction, or morphology as 
judged by the investigator. 
∀Note that a corrected QT interval by Fredericia (QTcF) interval measurement 
of◦>◦470◦milliseconds is exclusionary. 
46 Participant with > 2 × upper limit of normal (ULN) of any of the following: ALT, 
aspartate aminotransferase (AST), or alkaline phosphatase (ALP) or > 1.5 × ULN total 
bilirubin 
#
For participants with a test result > ULN for ALT, AST, ALP, or total bilirubin, a 
diagnosis or the cause of any clinically meaningful elevation must be understood and 
recorded in the source documents and electronic case report form (eCRF) 
47 Estimated creatinine clearance ≤50 ml/min at screening 
48 Clinically significant abnormal findings in coagulation or haematology laboratory tests
49 A positive pregnancy test at screening
50 Positive drug screen for drugs of abuse unless there is a documented medical 
explanation for the positive result other than drugs of abuse (eg, prescribed opioids for 
pain or benzodiazepines). A urine drug screen positive for cannabinoids is exclusionary 
unless there is a documented legitimate medical reason for the participant’s cannabinoid 
use (eg, chronic pain) and the investigator and medical monitor agree that the 
participant can abstain from use for the duration of the study.
51 Participant requires aspirin at doses greater than 325 mg/day for cardiovascular 
prophylaxis or requires treatment with vitamin K-dependent anticoagulant (eg, 
warfarin). 
5.3
Lifestyle and Activity Considerations
Participants should maintain their daily normal routine including stable doses of permitted 
medication. Participants are also permitted to continue their nonpharmacologic activities 
interventions during the clinical study. Participants participating in a regular prescribed 
physiotherapy programme should maintain this for the duration of their participation in the 
study. Participants should be cautioned against performing strenuous exercise regimens during 
the study as it may influence laboratory results and pain data. Participants may participate in 
light exercise and recreational activities during the study.


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Participants participating in a regular homeopathy or naturopathy programme should maintain 
this for the duration of their participation in the study.
Refer to Section 6.5 for guidance on permitted and prohibited medications.
5.3.1
Meals and Dietary Restrictions
Participants will be asked to avoid foods containing poppy seeds for 5 days prior to the 
screening visit.
Participants will be asked to avoid any changes in OTC products and herbals, vitamins, and 
minerals from at least 14 days prior to the first IP administration on Day 1 through to the end 
of the FU period. 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 participant 
should remain in the study or be dismissed from the study. Procedures for early 
discontinuation of IP are provided in Section 7.1.2.
5.3.2
Tobacco Restrictions
Participants who use nicotine patches may continue to use them at the same dose and at the 
same time of day and must keep their smoking habit unchanged until at least Week 18 of the 
study. Although no change in smoking habits is preferred, smokers are permitted to quit 
smoking during the study. The investigator should be consulted, and the conversation 
documented in the participant’s chart.
5.3.3
Other Restrictions
Participants must refrain from blood and plasma donation during the study and for at least 
2 months after the final FU visit. 
Fertile male participants must use appropriate contraception and must refrain from sperm 
donation from first dosing on Day 1 until at least 3 months and 20 days after the last dose of 
IP (Section 8.3.10).
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study because they do not meet the eligibility criteria for 
participation in this trial (screen failure) due to, but not limited to, the following criteria: a 
laboratory result, test result, consent withdrawal, pain severity, disallowed medication, or 
other reversible condition. 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.


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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the discretion of the investigator. Rescreening procedures are described 
below.
5.4.1
Rescreening
One rescreening attempt is permitted for each participant. 
For the participants who have undergone X-ray assessments during the screening period (and 
provided that there were no triggering events [eg, trauma] affecting the joints or any clinically 
significant changes in joint condition since the X-ray evaluation during the screening period 
based on the investigator’s assessment), then rescreening, if deemed necessary, must occur 
within 90 days from this first screening X-ray assessment. If it is not possible to assess such 
changes in clinical condition over the above-mentioned period, then the participants should 
not be rescreened. Note: There is no rescreening option beyond the above-mentioned 90 days 
for participants who have been exposed to X-rays during screening.
For the study participants who were considered screen failures before any X-ray images were 
obtained, one rescreening attempt is allowed at any time point while the study is ongoing. 
All screening procedures and assessments (except for X-ray/MRI if performed at screening) 
should be repeated for the rescreened participants. A participant should sign a new ICF if they 
are to rescreened for any reason.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to or medical device(s) utilised by a study participant 
according to the study protocol. Study intervention (or IP) in this study refers to MEDI7352 
and placebo.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
The IPs that will be used in this study are outlined in Table 3.


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6.2.2
Handling, Labelling, and Storage
AstraZeneca will provide the investigators with adequate quantities of MEDI7352 using 
designated distribution centres. Unblinded site personnel will prepare the IP for each 
participant according to the IP manual provided by AstraZeneca and the randomisation 
scheme.
The IP(s) 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(s) 
according to the dosage scheme and for ensuring proper storage of the IP(s).
The investigator (or designee) must confirm the receipt of the IP(s) with his or her signature. 
Until the IP is administered to the participant, it must be stored in a refrigerator at 2 to 8°C 
(36 to 46°F) in a secure area with restricted access. 
If the IP(s) have not been refrigerated or stored properly, the excursion should be reported 
upon discovery. The IP(s) must be quarantined until the sponsor provides specific instructions 
to the site and documentation of permission to use, return, or destroy the IP(s). Use of the 
IP(s) prior to the sponsor’s approval will be considered a protocol deviation.
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. 
The IP for each participant will be prepared according to the handling instructions provided by 
AstraZeneca and the randomisation scheme.
6.2.3
Accountability
It is the investigator’s responsibility to establish a system for handling study treatments, 
including IP(s). The investigator (or designee) must maintain adequate records showing the 
receipt, dispensing, return, or other disposition of the IP(s), including the date, quantity, batch 
or code number, and identification of participants (participant number) who received the IP(s). 
The investigator will not supply the IP(s) to any person except those named as 
subinvestigators and designated study personnel in this study. The investigator will not 
dispense the IP(s) from any study sites other than those authorised. Investigational product(s) 
may not be relabelled or reassigned for use by other participants. If any of the IP(s) are not 
dispensed, are lost, stolen, spilled, unusable, or are received in a damaged container, this 


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information must be documented and reported to the sponsor and appropriate regulatory 
agencies, as required.
Upon completion of the study, the IP(s) (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(s) according to approved procedures or to return the IP(s) to the sponsor or 
designee for destruction.
6.3
Measures to Minimise Bias: Randomisation and Blinding
All participants will be centrally assigned to randomised IP using an IRT/RTSM system. 
Before the study is initiated, the telephone number and call-in directions for the IRT and/or 
the log in information and directions for the RTSM will be provided to each site. 
The IRT/RTSM will provide the investigator(s) or appropriate study personnel with the kit 
identification number to be allocated to the participant at the IP dosing visit.
Details for this will be described in the IRT/RTSM user manual that will be provided to each 
centre.
All participants, investigators, and study personnel involved in the conduct of the study will 
be blinded to treatment assignment. The unblinded study personnel (eg, site pharmacist) will 
not participate in study procedures or data analysis prior to unblinding of the study data to all 
study-related personnel. Unblinded AstraZeneca personnel who are not otherwise involved in 
the study will prepare data for review and interim analyses.
The IP will be administered at the study visits according to the SoA (Table 1).
6.3.1
Methods for Unblinding
Study personnel will make every effort to safeguard the integrity of the study blind to 
minimise 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. The randomisation code should only be broken in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, where the knowledge of the specific blinded-study intervention will affect the 
immediate management of the participant’s condition, the investigator has the sole 
responsibility for determining if unblinding of a participant’s intervention assignment is 
warranted. Participant safety must always be the first consideration in making such a 
determination. If a participant’s intervention assignment is unblinded, AstraZeneca must be 
notified within 24 hours of breaking the blind. The investigator must document and report the 


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action to AstraZeneca, without revealing to the AstraZeneca staff which treatment was given 
to the participant.
Unblinding should be discussed in advance with the medical monitor if possible and if a 
participant’s treatment assignment is unblinded, the investigator should contact the medical 
monitor for advice. If the investigator is not able to discuss treatment unblinding in advance, 
the investigator will document and report the action to AstraZeneca (without revealing the 
treatment given to the participant) to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Randomisation codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented.
6.4
Study Intervention Compliance
Participants are dosed at the site; they will receive IP directly from the investigator or 
designee, under medical supervision. The date, and time if applicable, of IP dose administered 
in the clinic will be recorded in the source documents and in the eCRF. The dose of IP and 
study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the IP. Any deviations from the planned 
dosing procedure will be recorded in the eCRF.
6.5
Concomitant Therapy
Any medicinal product, whether prescribed or available OTC (including herbal supplements 
or vitamins), is considered a concomitant medication. Any concomitant medication that the 
participant is receiving at the time of enrolment or during the study must be recorded in the 
eCRF along with:
∀
Reason for use
∀
Dates of administration including start and end dates
∀
Dosage information including dose and frequency
The study physician should be contacted if there are any questions regarding concomitant or 
prior therapy. Prior and concomitant medication use must be recorded for 28 days prior to 
screening through to the last FU visit as indicated in the SoA (Table 1). 
Concomitant medication use may be warranted for the treatment of AEs. The use of 
concomitant medications to treat AEs should be discussed between the investigator and the 
medical monitor.


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Any therapy appropriate to the participant’s condition is permitted, with the exception of those 
listed as prohibited. Permitted concomitant medications should be maintained on a stable dose 
regimen during the study whenever possible.
6.5.1
Permitted Concomitant Therapy
The following treatments are permitted, with restrictions:
∀
Paracetamol as rescue analgesic is permitted for participants who develop unacceptable 
pain during the study including the washout period and the period between completion of 
washout and randomisation (as described in Section 6.5.3). 
∀
Medications for the treatment of non-excluded medical conditions (eg, depression, 
hypertension, and diabetes mellitus) are permitted, including antihypertensive, 
cholesterol-lowering, and antidiabetic medications; antidepressants; and 
sedative/hypnotics as judged clinically acceptable by the investigator. 
∀
Low-dose aspirin up to 325 mg/day is permitted for cerebrovascular or cardiovascular 
prophylaxis. 
∀
Short-term sedation and/or analgesia if needed to perform study procedure (eg, MRI) 
(should not be given within 48 hours prior to a study visit or during the collection of 
ePRO pain data from Day -7 to Day -1 [inclusive] for baseline NRS pain evaluation). 
∀
Limited (no more than 10 days per 8-week period) concomitant use of prescription or 
OTC NSAIDs may be allowed on an occasional basis for self-limiting conditions not 
related to osteoarthritis (eg, migraine attack), after the Week 18 FU visit. The study 
medical monitor should be contacted for approval prior to use whenever possible, and all 
doses and days of use will be recorded in the eCRF.
∀
Other medication considered necessary for the participant’s safety and well-being may be 
given at the discretion of the investigator. In such cases, the reason for the introduction of 
the new medication should be captured in the eCRF, and an AE is expected to be 
reported. 
If a new medication has to be introduced or the dose of concomitant medication needs to be 
changed during the double-blind treatment period, consultation with the medical monitor is 
advisable.
If the participant is receiving permitted medications for the treatment of non-excluded medical 
conditions, the dose must be stable for at least 28 days prior to randomisation (28 days prior to 
screening for serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants) 
and should be expected to remain stable until at least the FU visit at Week 18 of the study.
For participants who complete the treatment period, standard-of-care therapy may be given for 
their pain after the FU visit at Week 18 as deemed appropriate by the investigator and in 
alignment with local guidelines/label. However, intra-articular injections/interventions, 
NSAIDs, COX-2 inhibitors, and aspirin (in doses that exceed 325 mg/day) are prohibited until 
after the last FU visit (Visit 14).


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Participants who discontinue IP early may be given standard-of-care therapy for their pain 
after the ET visit as deemed appropriate by the investigator and in alignment with local 
guidelines/label. Additional information on the allowed and prohibited medications and other 
procedures for early discontinuation of IP is provided in Section 7.1.2.
6.5.2
Prohibited Concomitant Medications
The following treatments are prohibited during the study:
∀
The use of analgesics other than paracetamol rescue medication (including but not limited 
to opioids, topical applications of capsaicin and formulations containing local anaesthetic 
for OA pain treatment) is prohibited from the start of the washout period until the 
Week 18 FU visit. 
∀
The use of NSAIDs, COX-2 inhibitors for OA treatment, or use of aspirin (> 325 mg/day) 
at any time from the start of the washout period until after the last FU visit (Week 36) is 
prohibited. This includes OTC pain medications and topical analgesics that contain an 
NSAID or COX-2 inhibitor. For participants who discontinue IP early, NSAIDs, COX-2 
inhibitors, or aspirin use is described in Section 7.1.2.
∀
COVID-19 vaccines
#
If a study participant is being considered for enrolment into the study and also for 
COVID-19 vaccination, the participant must not be randomised until 30 days after 
the last dose of COVID-19 vaccine or ‘booster dose’ (whichever is required to 
consider vaccination complete in line with applicable guidance). Note that this is 
applicable only to COVID-19 vaccines, irrespective of their modality, which are 
currently approved by Health Authorities or otherwise approved under relevant 
regulations, eg, emergency use authorisation (FDA)/conditional marketing 
authorisation (European Medicines Agency)/temporary supply (Medicines and 
Healthcare Products Regulatory Agency). 
∀
Live viral or attenuated bacterial vaccines are disallowed from 28 days prior to the first 
IP dose, during IP administration, and for 2 months after the last IP administration.
∀
Intra-articular injections are not permitted during the study, including the screening 
period, with the exception of cases of ET when this treatment option is deemed necessary 
by the investigator. In such cases, initiation of intra-articular corticosteroid injections 
should be deferred until at least 8 weeks after the last IP administration.
∀
The following therapies are prohibited during the study starting from the screening period 
(please also refer to exclusion criteria 2, 5, 36, 51): 
#
Etanercept and medications known to interact with etanercept, specifically anakinra, 
abatacept, and sulfasalazine
#
Other DMARDs, including but not limited to golimumab, certolizumab, infliximab, 
adalimumab, rituximab, tocilizumab, and tofacitinib
#
Any other form of anti-TNF or anti-NGF therapy 


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#
Other immunosuppressants. The restrictions related to use of intra-articular 
corticosteroid injections are mentioned above.
#
Vitamin K-dependent anticoagulants (eg, warfarin)
#
Oral, IV, intramuscular, or any other parenteral steroids (Note that inhaled steroids 
for well-controlled chronic obstructive pulmonary disease or asthma or topical 
steroids for eczema are permitted). 
#
Any drug of abuse including but not limited to amphetamine, barbiturate, cannabis, 
cocaine, methadone, methaqualone, opiate, phencyclidine, or propoxyphene, with the 
following exceptions:
o
Sedative/hypnotics used as described above
o
Barbiturates as a constituent of antimigraine medication (eg, Fioricet)
o
Short-term sedation and/or analgesia if needed to perform study procedure (eg, 
MRI). (Note: These should not be given within 48 hours prior to a study visit or 
during the collection of ePRO pain data from Day -7 to Day -1 [inclusive] for 
baseline NRS pain evaluation.)
#
Muscle relaxants, anticonvulsants, anti-Parkinsonian medications, or neuroleptic 
medications, unless used for non-excluded conditions, such as restless leg syndrome, 
are prohibited.
#
Any other investigational drug or device, including other immunotherapeutics 
Participants receiving prohibited therapies will be ineligible for study enrolment or for 
continuation in the study (the latter at the discretion of the investigator and the sponsor).
Other medication considered necessary for the participant’s safety and well-being may be 
given at the discretion of the investigator. 
6.5.3 Rescue Medication 
Participants who develop unacceptable pain during the study until the Week 18 visit or ET 
visit, whichever is earlier (including during the washout period and the period between 
completion of washout and randomisation) will be permitted to initiate rescue analgesic 
therapy with paracetamol using a dosing regimen that is aligned with local standards of 
prescribing practice and as described in the patient information leaflet and approved by the 
investigator. Paracetamol will be provided by the study site in its approved packaging for use 
as a rescue medication.
Participants will be requested not to take any paracetamol rescue medication within 24 hours 
prior to a study visit. Any participant who requires rescue analgesic medication for ≥4 days in 
any 7-day period should be interviewed by the study site personnel to determine if this is due 
to lack of efficacy or other reasons. The investigator should then determine if IP 


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administration should be permanently discontinued due to lack of efficacy. Participants will be 
instructed to keep a daily record of rescue medication use in a patient diary and the following 
information needs to be captured: 
∀
Reason for use (eg, pain from the target joint, pain from other joints, non-OA pain)
∀
Dates and time of administration including start and end dates
∀
Dosage information including dose and frequency.
Rescue medication will be recorded daily from Day -14 and will continue to be recorded by 
the participant in their dairy until the Week 18 visit. Participants who discontinue IP early, 
will stop recording rescue medication after the ET visit.
Participants will bring their rescue medication (bottles/cartons/blisters) to each study visit to 
assess rescue medication compliance. Site staff should check returned paracetamol against 
what the participant has recorded in their diary. Participants should be warned to guard against 
taking other OTC medications containing paracetamol to avoid overuse.
If per investigator's judgement, the amount of rescue medication taken by the participant poses 
a risk for them to continue safely in the study, the investigator should discontinue IP. The 
participant will be asked to complete the study assessments at the ET visit and then enter the 
FU period. Procedures for early discontinuation of IP are provided in Section 7.1.2. If the 
rescue medication intake had been driven by pain in the target knee, the reason for 
discontinuation should be reported as a lack of efficacy. 
Note: If paracetamol (acetaminophen) overdose is suspected, consideration should be given to 
the measurement of paracetamol levels and immediate referral for specialist treatment.
6.6
Dose Modification
Dose adjustment is not allowed in this study. Participants will be allocated to a single dosing 
regimen at randomisation.
6.7
Intervention after the End of the Study
After the end of the study, each participant will be treated according to standard clinical 
practice and local practice, at the discretion of the investigator. 
7
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Investigational Product
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
IP. Participants will discontinue IP in the following situations:


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∀
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. Participants must be withdrawn from the study if they 
withdraw consent to participate. The participant should always be asked about the 
reason(s) and presence of any AEs.
∀
AE that, in the opinion of the investigator, contraindicates further dosing
∀
Serious noncompliance with the CSP
∀
Risk to participant as judged by the investigator or AstraZeneca
∀
If a study participant is vaccinated with a COVID-19 vaccine during the treatment period 
of the study, he/she should be discontinued from IP administration. The study participant 
will still be required to attend scheduled safety visits and to complete the follow-up 
period of the study (Refer to Section 7.1.2 for “Procedures for Early Discontinuation of 
Investigational Product”). If a study participant is vaccinated during the follow-up period, 
they should continue participation in the follow-up period of the study.
∀
Development of any of the participant-specific criteria for discontinuation (Section 7.1.1)
The sponsor reserves the right to request the withdrawal of a participant due to protocol 
deviations or other reasons. 
Participants will be asked to complete study assessments at the ET visit (ie, Week 12 
assessments) as soon as possible and then to enter the FU period. Refer to the SoA (Table 1) 
for assessments to be performed at the ET visit and FU period and to Section 7.1.2 for 
procedures for early discontinuation of IP.
7.1.1
Subject-specific Criteria for Discontinuation of Investigational Product
For any individual participant, further administration of IP will be stopped if any of the 
following scenarios occur:
#
Reports of drug-related SAE(s) or drug-related AE(s) including but not necessarily 
limited to:
o
Serious or severe drug-related injection site reactions 
o
Anaphylactic reaction, defined as an immediately life-threatening allergic 
reaction with bronchoconstriction, angioedema, and/or hypotension (FDA 2014); 
or serious hypersensitivity reactions
o
Development of moderate-to-severe sensory abnormalities (eg, paraesthesia, 
dysesthesia, burning, pins and needles) that are not resolved within a 14-day 
period
o
Development of peripheral neuropathy 
o
New onset of demyelinating disorder
o
Serious systemic infection 
o
Serious non-systemic infection if deemed necessary by the investigator


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#
Any of the following are criteria for immediate and permanent discontinuation of IP 
(Section 8.2.11.1):
o
ALT or AST > 5 × ULN for more than 2 weeks
o
ALT or AST ≥3 × ULN and coexisting total bilirubin ≥2 × ULN (Hy’s Law 
[HL]). Hy’s law is described in Section 8.3.8 and FU of HL cases is provided in 
Appendix F.
o
ALT or AST ≥3 × ULN and coexisting international normalised ratio 
(INR) > 1.5 
o
ALT or AST ≥3 × ULN and associated with symptoms (which may be either 
transient or persistent) of hepatitis or hypersensitivity. Hepatitis symptoms 
include fatigue, nausea, vomiting, right upper quadrant pain or tenderness. 
Hypersensitivity symptoms include eosinophilia (≥5%), rash, or fever without 
clear alternative cause. 
o
Any change in ALT or AST level (eg, < 3 × ULN) if there is a possibility of 
development of autoimmune hepatitis as per investigator’s judgement. 
Participant should have a consult with a hepatologist, and liver chemistry values, 
as well as additional tests, should be completed as soon as possible (Appendix 
F 7)
#
AEs suggestive of autonomous nervous system dysfunction, including but not limited 
to confirmed orthostatic hypotension (Section 8.2.3.2) or significant bradycardia 
(Section 8.2.4) or syncope that after evaluation by a cardiologist (and/or neurologist) 
are considered to be a manifestation of sympathetic autonomic dysfunction
#
Cases when sympathetic neuropathy is not confirmed but orthostatic hypotension 
remains symptomatic for more than 14 days
#
Participants who have a proven diagnosis of sympathetic autonomic neuropathy
#
Development of malignancy
#
Development of Class 3 or Class 4 (NYHA 1994) heart failure
#
Positively-adjudicated possible or probable RPOA, SIF, primary osteonecrosis 
(including spontaneous osteonecrosis of the knee), or pathological fracture.
#
Participants who plan to undergo total joint replacement (knee, hip, or shoulder) or 
other arthroplasty procedure during the study
#
Haematologic toxicity, defined as one or more of the following:*
o
Leukocyte count < 2.0 × 109/L
o
Neutrophil count < 1.0 × 109/L
o
Platelet count < 75 × 109/L
*
Note: Participants must be advised to seek immediate medical attention if 
they develop any symptoms suggestive of blood dyscrasia or infection (eg, 


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persistent fever, sore throat, bruising, bleeding, or pallor). Haematology 
testing should be performed as soon as possible to exclude blood dyscrasia.
#
Development of a lupus-like syndrome, autoimmune hepatitis, or immune-complex 
disease
#
Development of COVID-19 infection that meets moderate or severe severity AE 
criteria.
#
Treatment with anti-SARS-CoV-2 monoclonal antibodies for COVID-19 infection of 
any severity.
#
Mild or asymptomatic COVID-19 infection with symptoms that have not resolved 
within 28 days since the last IP administration or results of appropriate testing for 
COVID-19 infection (ie, antigen-based) suggesting that a participant is carrying a 
replicating virus and remains positive within 28 days since the last IP administration.
#
There are other ongoing sequelae from COVID-19 infection, or the participant
requires treatment for the manifestations of COVID-19 infection for the period 
beyond 28 days since the previous IP administration, or less than 5 half-lives have 
passed since the last COVID-19 antiviral medications administration within the
28-day period since the last IP administration. 
#
If per investigator's judgement, the amount of rescue medication taken by the 
participant poses a risk for the participant to continue safely in the study.
7.1.2
Procedures for Early Discontinuation of Investigational Product
A participant who discontinues IP early (ie, prior to receiving the last dose of IP) should 
always be asked about the reason(s) and the presence of any AEs. The reason for premature 
discontinuation of IP should be documented in the source documentation and recorded in the 
eCRF. 
Participants who discontinue IP early will be asked to complete study assessments at the ET 
visit (ie, Week 12 assessments) as soon as possible and then to enter the FU period.
Participants who discontinue IP prematurely may be given standard-of-care therapy for their 
pain after the ET visit as deemed appropriate by the investigator and in alignment with local 
guidelines/label (including paracetamol, aspirin, NSAIDs, and COX-2 inhibitors if deemed 
necessary). However, initiation of NSAIDs, COX-2 inhibitors, and aspirin (in doses that 
exceed 325 mg/day) is prohibited until after 5 half-lives following the last IP administration 
(ie, approximately 3 weeks). Note that it is recommended to postpone NSAIDs/COX-2 
inhibitors intake until 8 weeks after the last IP administration. In addition, initiation of 
corticosteroid therapy (eg, intra-articular injections) should be deferred until at least 8 weeks
after the last IP administration. 


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Refer to the SoA (Table 1) for assessments to be performed at the ET visit and FU period. All 
participants prematurely discontinued from IP are expected to complete the ET visit and the 
24-week FU period, which consists of 3 FU clinic visits and 4 phone calls at the times 
indicated below:
∀
ET visit: Week 12 assessments to be performed as soon as possible after the last IP 
administration. The following assessments/procedures will not be performed beyond the 
ET visit:
#
Daily NRS pain score 
#
DSIS
#
Rescue medication recording
#
WOMAC
#
PGA
#
Blood collection for PK, ADA, and PD biomarkers
∀
FU phone call 1: To be conducted 5 weeks after the last IP administration
∀
FU visit 1: Week 18 assessments to be performed 8 weeks after the last IP administration
∀
FU phone call 2: To be conducted 11 weeks after the last IP administration
∀
FU phone call 3: To be conducted 14 weeks after the after the last IP administration
∀
FU phone call 4: To be conducted 18 weeks after the last IP administration
∀
FU visit 2: Week 32 assessments to be performed 22 weeks after the last IP 
administration 
∀
FU visit 3: Week 36 assessments to be performed 26 weeks after the last IP 
administration
7.1.3
Temporary Discontinuation of Investigational Product
Withholding IP administration temporarily may be considered in the following cases:
∀
Development of sensory abnormalities (eg, paraesthesia, dysesthesia, burning, pins and 
needles) to confirm their resolution within 14 days prior to the next IP administration
∀
AE suggestive of new occurrence or worsening of peripheral neuropathy 
∀
Participants who have the following sympathetic function AEs (any seriousness or 
severity): 
#
Meet the prespecified criteria for bradycardia (Section 8.2.4)
#
Meet the prespecified criteria for confirmed orthostatic hypotension (Section 8.2.3.2)
#
Have syncope 
#
Report anhidrosis or hypohidrosis
∀
Cases where additional evaluation or adjudication is needed to exclude possible or 
probable RPOA, SIF, primary osteonecrosis (including spontaneous osteonecrosis of the 
knee), or pathological fracture.


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∀
Cases of signs/symptoms suggestive of worsening or new occurrence of heart failure
∀
When follow-up on cases of abnormal liver function is needed before the decision on 
permanent IP discontinuation is made (eg, identification of potential HL (PHL) cases 
needed or further evaluation in order to exclude HL required, or ALT or AST ≥5 × ULN 
for less than 2 weeks)
∀
A positive test for SARS-CoV-2 at any time point during participation in the study.
∀
Symptoms or signs consistent with COVID-19 infection (eg, fever, cough, dyspnoea), 
confirmed by an appropriate laboratory test.
Participants who meet criteria for bradycardia, orthostatic hypotension, who have had a 
syncope, or report anhidrosis or hypohidrosis should be evaluated by a cardiologist or 
neurologist as soon as possible. 
Participants with AEs suggestive of new occurrence or worsening of peripheral neuropathy as 
per investigator’s neurological assessment should be evaluated by a neurologist as soon as 
possible.
Participants with clinical signs/symptoms suggestive of worsening or new occurrence of heart 
failure should be evaluated by a cardiologist as soon as possible. Echocardiography should be 
performed if clinically indicated. The participant should not be dosed with the subsequent 
dose of IP until (if applicable) the absence of sensory abnormalities, sympathetic dysfunction, 
new occurrence or worsening of peripheral neuropathy or Class 3 or Class 4 (NYHA 1994) 
heart failure have been confirmed, or RPOA, SIF, primary osteonecrosis, or pathological 
fracture have been excluded.
Please refer to the Appendix F for guidance on follow-up procedures for PHL and HL cases 
and Section 8.2.11.1 for management of other cases of abnormal liver function.
Administration of IP can be resumed if deemed appropriate by the investigator in participants 
with fully resolved asymptomatic or mild COVID-19 infection (confirmed by negative 
SARS-CoV-2 testing (ie, antigen-based), suggesting that the participant is no longer carrying 
replicating virus) provided that it is completely resolved without sequalae within 28 days since 
the previous IP administration and participants do not require ongoing treatment for 
COVID-19 infection as well as do not have ongoing adverse drug reactions associated with 
treatment of COVID-19 infection as assessed by the investigator. Additionally, more than 
5 half-lives of COVID-19 antiviral medications should elapse before IP administration is
resumed. Participants who were treated with anti-SARS-CoV-2 monoclonal antibodies are not 
eligible for further IP administration. For participants treated with COVID-19 antiviral 
medications, the investigator should contact the medical monitor and agree if and when 
further IP administration is appropriate.


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If more than 28 days have elapsed since the last IP administration, IP should be permanently 
discontinued. The participants will be asked to complete the ET visit as soon as possible and 
then enter the FU period. Refer to the SoA (Table 1) for assessments to be performed at the 
ET visit and FU period and to Section 7.1.2 for procedures for early discontinuation of IP.
If less than 28 days have elapsed since the last IP administration and once the above 
mentioned events have been evaluated/adjudicated as not meeting individual discontinuation 
criteria (and the participant does not meet any other IP discontinuation criteria), IP should be 
administrated as soon as possible. The participant should be brought back to the study 
schedule as soon as feasible using the allowed visit windows (provided the interval between 
subsequent IP administrations is not shorter than 8 days).
7.1.4
Procedures for Handling Incorrectly Enrolled or Randomised Subjects
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive IP. Participants who are enrolled but subsequently found not to meet all 
the eligibility criteria must not be randomised and must be withdrawn (screen failed) from the 
study. A participant may be rescreened once and then be screen failed if he/she still does not 
meet the eligibility criteria (Section 5.4.1).
Where a participant does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on IP, the investigator should inform the sponsor’s study physician or 
designee immediately.
7.2
Subject Withdrawal from the Study
∀
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.
∀
A participant who considers withdrawing from the study must be informed by the 
investigator about modified FU options (eg, telephone contact, a contact with a relative or 
treating physician, or information from medical records).
∀
At the time of withdrawal from the study, if possible, an ET visit should be conducted as 
described in the SoA (Table 1). Participants who have received at least one dose of IP are 
expected to complete study assessments at the ET visit as soon as possible and then to 
enter the FU period (Section 7.1.2).
∀
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
∀
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.


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Investigators must attempt to contact participants 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 8.3.
7.3
Lost to Follow-up
A participant will be considered lost to FU if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
To prevent a participant being lost to FU, it is recommended that the study sites maintain up-
to-date contact details for participants, including next of kin or other emergency contacts (if 
allowed by national regulation). 
The investigator should educate the participant on the importance of maintaining contact with 
the investigator/study site throughout the study.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
∀
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
∀
Before a participant is deemed lost to FU, the investigator or designee must make every 
effort to regain contact with the participant or next of kin/emergency contact by repeated 
telephone calls, emails and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods. These contact attempts should be 
documented in the participant’s medical record.
∀
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to FU. The participant will be 
classified as lost to FU only if he/she has failed to return for the required study visits and 
his/her vital status remains unknown at the end of the study (ie, Week 36) despite all the 
above listed efforts. For the primary analysis purposes, a participant will be classified as 
lost to FU if he/she has failed to return for the required study visits and his/her vital status 
remains unknown at the time of primary database lock (ie, after the Week 36 visit).
∀
Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants randomised, including those who did not receive IP. 
Public sources may be searched for vital status information. If vital status is determined as 
deceased, this will be documented, and the participant will not be considered lost to FU. 
AstraZeneca personnel will not be involved in any attempts to collect vital status 
information.
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix B.


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In general, patient-reported instruments should be completed by the participant upon arrival at 
the study site, and vital signs (including orthostatic BP) should be collected prior to any blood 
draws and IP administration, where applicable.
*Additional risk mitigation procedures in the context of the current SARS‑CoV‑2/COVID-19 
pandemic are provided in Section 4.1.2.
Screening 
The participant should be randomised, and IP administered within 45 days of initiating
screening. A clinic visit should be scheduled approximately 14 days prior to the first dose of 
IP for participants to receive ePRO training and get an ambulatory blood pressure monitoring 
(ABPM) device (Table 1).
Screening procedures may be performed at one or more visits (Table 1). NRS pain score at the 
first screening visit and the daily pain scores from Day -7 to Day -1 (inclusive) will be used to 
determine eligibility. 
Participants must have a self-reported pain intensity score in the target joint ≥5 (as assessed 
by an 11-point NRS) during the week prior to the first screening visit. All participants should 
undergo a diagnostic X-ray on the shoulder, knee, and hip joints during the screening period 
(Section 8.2.6.1). The reported features in the target knee joint should be consistent with at 
least Grade 2 OA on the KL grading scale of 0 to 4 as per central reader evaluation. If other 
major joints (elbows, wrists, and ankles) exhibit signs or symptoms associated with OA, these 
should also be imaged during the screening period (refer to American College of 
Rheumatology for the classification and reporting of OA [Altman et al 1986]).
A bilateral MRI of the knees and other joints with a KL grade at baseline of ≥3 (per screening 
X-ray assessment) should be conducted during the screening period (exceptions are listed in 
Section 8.2.6.2). Eligibility (absence of specified joint abnormalities) will be determined by a 
central imaging reader. 
The central reader must confirm that the target knee meets the required KL grade criteria and 
that none of the specified joint abnormalities are present before participant randomisation can 
occur.
All screening assessments will be completed, and the results reviewed prior to the start of the
NRS pain score baseline period on Day -7. Refer to the study site manual for more 
information on screening procedures. 
Note: Serum pregnancy tests will be performed at screening only. 
Screening procedures and their timing are summarised in the SoA (Table 1). 


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The 24-week FU period consists of 3 clinic visits (at Weeks 18, 32, and 36) and 4 phone calls 
(at Weeks 15, 21, 24, and 28). Safety X-ray imaging will be performed on the knee and hip 
joints at the Week 32 visit. Any potentially clinically significant findings detected on the 
X-ray assessment performed at the Week 32 visit will be further assessed and adjudicated (if 
needed) by the final FU visit at Week 36. 
The full list of procedures and timing of assessments to be performed during the FU visits are 
provided in the SoA (Table 1). 
All participants who receive IP during the study are expected to complete the FU period.
8.1
Efficacy/Pharmacodynamics Assessments
8.1.1
Daily Pain Scores
Average daily pain scores in the target joint will be recorded using an NRS. The NRS is an 
11-point Likert scale used to assess pain, where participants are asked to describe their 
average pain in the target knee by identifying a number from 0 = “no pain” to 10 = “most 
severe pain imaginable over the previous 24 hours.” Participants will be instructed to assess 
their average daily pain at approximately the same time every morning, and to record their 
response in a patient diary. The daily NRS pain scores recorded at the first screening visit and 
from Day -7 to Day -1 (inclusive) will be used to determine eligibility. The daily NRS pain 
scores from Day -7 to Day -1 (inclusive) will also be used to determine the baseline NRS pain. 
Participants will record daily pain scores from Day -14 until the Week 18 visit; participants 
who discontinue IP early, however, will stop recording daily NRS pain after the ET visit 
(Table 1). 
8.1.2
Patient Global Assessment of Osteoarthritis
The PGA of OA is a 5-point Likert scale used to assess symptoms and activity impairment 
due to OA of the knee. Participants are asked to identify a number from 1 = very good 
(asymptomatic and no limitation to normal activities) to 5 = very poor (very severe symptoms 
which are intolerable and inability to carry out all normal activities) based on the question 
“Considering all the ways that OA of the knee affects you, how are you feeling today?” 
Participants will record their responses at the times indicated in the SoA (Table 1). On dosing 
days, the PGA of OA will be completed prior to IP administration. Participants who complete 
the treatment period will have their last PGA of OA at the Week 18 visit; participants who 
discontinue IP early will have their last PGA of OA assessment at the ET visit (Table 1).
8.1.3
Western Ontario and McMaster Universities Osteoarthritis Index 
The WOMAC multiscale index is used to assess pain, stiffness, and joint functionality in the 
past 48 hours in participants with OA of the knee or hip. Participants will record their 
WOMAC questionnaire responses at the times indicated in the SoA (Table 1). Participants 


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who complete the treatment period will have their last WOMAC at the Week 18 visit; 
participants who discontinue IP early will have their last WOMAC assessment at the ET visit.
The WOMAC questionnaire will be completed for the target knee. On dosing days, the 
WOMAC questionnaire will be completed prior to IP administration.
The WOMAC pain subscale consists of 5 questions assessing the participant’s pain due to OA 
in the target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC 
pain subscale score is calculated as the mean score from all 5 questions, where higher scores 
represent higher pain.
The WOMAC physical function subscale consists of 17 questions assessing the participant’s 
difficulty in performing activities of daily living due to OA in the target knee. Each question is 
scored on an NRS scale from 0 to 10, and the WOMAC physical function subscale score is 
calculated as the mean score from all 17 questions, where higher scores represent worse 
function.
The WOMAC stiffness function subscale consists of 2 questions assessing stiffness due to OA 
in the target knee. Stiffness is defined as a sensation of decreased ease of movement in the 
target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC stiffness 
function subscale score is calculated as the mean score from the 2 questions, where higher 
scores represent higher stiffness.
8.1.4
Daily Sleep Interference Scale
Participants will assess how their pain interferes with their sleep using the DSIS. The DSIS is 
an 11-point Likert scale, with 0 = pain did not interfere with sleep and 10 = pain completely 
interfered with sleep. The DSIS is completed by participants via a patient diary once a day 
(upon awakening) to accurately capture variability in sleep interference due to pain on a daily 
basis, thus minimising recall bias. Participants will record DSIS from Day -14 until the 
Week 18 visit as indicated in the SoA (Table 1); participants who discontinue IP early, 
however, will stop recording DSIS after the ET visit. 
8.1.5
36-Item Short Form Health Survey Questionnaire (acute recall) 
The 36-Item Short Form Health Survey Questionnaire version 2 (SF-36v2) is a 36-item, self-
report survey of functional health and well-being, with a 1- to 4-week recall period (Maruish 
2011). Responses to 35 of the 36 items are used to compute an 8-domain profile of functional 
health and well-being scores. The remaining item, referred to as the ‘health transition’ item, 
asks participants to rate how their current state of health compared to their state of health 
one year ago, and is not used to calculate domain scores. The 8-domain profile consists of the 
following subscales: physical functioning (PF), role limitations due to physical health (RP), 
bodily pain (BP), General Health Perceptions (GH), Vitality (VT), Social Functioning (SF), 


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role limitations due to emotional problems (RE), and mental health (MH). Psychometrically-
based physical and mental health component summary scores (PCS and MCS, respectively) 
are computed from subscale scores to give a broader metric of physical and mental health-
related quality of life.
Two types of thresholds have been developed for interpretation of SF-36v2 scores. The first 
type is suitable for comparing group mean scores and is generally referred to as the minimally 
clinically important difference. The second type is suitable for interpreting change at the 
individual level and is referred to as the responder threshold or responder definition (Table 5)
(Maruish 2011). 
Table 5
Threshold values for the SF-36v2 scale and summary measures
SF-36v2 score
Threshold
PCS
MCS
PF
RP
BP
GH
VT
SF
RE
MH
Group difference
2
3
3
3
3
2
2
3
4
3
Individual change
3.4
4.6
4.3
3.4
6.2
7.2
6.2
6.9
4.5
6.2
BP, bodily pain; GH, general health perceptions; MCS, mental health summary; MH, mental health; 
PCS, physical component summary; PF, physical functioning; RE, emotional problems; RP, role limitations due 
to physical health; SF, social functioning; VT vitality
The participant will complete the SF-36v2 on the ePRO device as specified in Table 1. Any 
within-window assessment that has not been completed prior to the scheduled visit will be 
completed at the site prior to other study procedures.
8.1.6
European Quality of Life-5 Dimensions (EQ-5D-5L)
The EQ-5D-5L™ questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 response options (no 
problems, slight problems, moderate problems, severe problems, and extreme problems) that 
reflect increasing levels of difficulty. The questionnaire score is translated into an index value 
or utility score. The EQ-5D-5L is a self-administered questionnaire.
The participant will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual
analogue scale, where the participant will be asked to rate current health status on a scale of 
0 to 100, with 0 being the worst imaginable health state. Participants will record their 
responses at the study site at the times indicated in the SoA (Table 1). 


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8.1.7
WPAI:OA questionnaire
The WPAI:OA is a self-administered tool comprised of 6 questions that measure absenteeism, 
presenteeism, work productivity, and activity impairment due to OA of knee. This tool 
captures data from the past 7 days. Each subscale score is expressed as a percentage 
impairment from 0 to 100, where higher numbers indicate greater impairment and less 
productivity. 
The participant will complete the WPAI:OA at the times indicated in the SoA (Table 1). Any 
within-window assessment that has not been completed prior to the site visit will be 
completed at the site prior to other study procedures.
8.1.8
Assessment of Healthcare Resource Utilisation
The utilisation of healthcare resources (eg, doctor office visits, hospitalisations, surgeries, or 
other procedures) used by participants prior to entering the study (ie, 3 months prior to 
baseline) and during the study will be assessed at the times indicated in the SoA (Table 1).
Healthcare resource utilisation data associated with medical encounters will be collected by 
the investigator and study-site personnel for all participants throughout the study. Protocol-
mandated procedures, tests, and encounters are excluded. After the baseline assessment, the 
question should be asked by recalling the period between visits. 
The data collected may be used to conduct exploratory economic analyses and will include:
∀
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)
∀
Duration of hospitalisation (total days or length of stay, including duration by wards 
(eg, intensive care unit)
∀
Number and type of diagnostic and therapeutic tests and procedures
∀
Outpatient medical encounters and interventions (including physician or emergency room 
visits, tests and procedures, and medications).
The following HCRU resources should be collected:
∀
Services:
#
Primary care physician visits
#
Neurologist visits
#
Rheumatologist visits
#
General practitioner or nurse practitioner
#
Pain specialist visits
#
Orthopaedists


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#
Physical therapists
#
Chiropractors
#
Alternative medicine or therapy (concomitant medications)
#
Podiatrist
#
Nutritionist/Dietician
#
Radiologist
#
Home Healthcare services
#
Other
∀
Emergency department visits
∀
Hospitalisation for knee OA
∀
Aid/devices:
#
Wheelchair 
#
Walking
#
Device or utensils to help with dressing, bathing, or eating
∀
A question on how OA has interfered with work activities can also be asked:
#
Did you quit your job because of OA?
#
How long before you quit your job because of your OA?
8.1.9
Rescue Medication
Rescue medication will be recorded daily from Day -14 and will continue to be recorded by 
the participant in their diary until the Week 18 visit as indicated in the SoA (Table 1). 
Participants who discontinue IP early, will stop recording rescue medication after the ET visit.
The dosage strength of the paracetamol tablets and the number of tables taken in a 24-hour 
period should be recorded by the participant. 
The participant will be asked in the diary a question similar to the following: “Have you used 
any paracetamol in the last 24 hours?” The participants will respond: Yes or No 
If yes, record the following:
∀
Reason for use (eg, pain from the target joint, pain from other joints, non-OA pain)
∀
Dates and time of administration including start and end dates
∀
Dosage information including dose and frequency.
Rescue medication use (number of days, cumulative consumption) from baseline to Weeks 4, 
8, 12, and 18 (Note: Week 18 only for participants who completed the treatment period) will 
be compared between participants taking MEDI7352 or placebo.


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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Physical Examinations
A physical examination will be performed and include assessments of the following: general 
appearance, skin, head and neck, examination of the oral cavity for any lesions, lymph nodes, 
thyroid, abdomen (bowel sounds, liver, and spleen palpation), back (including costovertebral 
angle tenderness), musculoskeletal/extremities, cardiovascular, and respiratory systems. 
If clinical signs/symptoms suggestive of worsening or new occurrence of heart failure are 
noted, a consultation with a cardiologist should be obtained as soon as possible. 
Echocardiography should be performed if clinically indicated. Participants designated as 
NYHA functional Class 1 or Class 2 should have LVEF measured by echocardiography and 
documented at baseline. 
The participant should not be dosed with the subsequent dose of IP until the absence of 
Class 3 or Class 4 (NYHA 1994) heart failure has been confirmed (refer to the Section 7.1.3).
Height and weight will be measured at screening and weight at the Week 12 visit. Weight 
should also be measured when change is suspected or fluid retention occurs.
8.2.2
Neurological Examinations
The neurological examination should be performed by a neurologist or an appropriately 
experienced physician and will include assessment of mental status, cranial nerves, motor 
examination (muscle strength and tone), upper and lower extremity deep tendon reflexes, 
plantar responses, sensory system examination, coordination, and gait. Also information about 
presence of anhidrosis or hypohidrosis should be collected during the examination. 
Ideally, the neurological examination should be performed by the same examiner at each 
clinic visit. 
A neurologic evaluation should be performed by a consulting neurologist if any of the 
following occurs:
∀
An AE suggestive of new occurrence or worsening of peripheral neuropathy 
∀
AE of new occurrence or worsening of abnormal sensation such as allodynia, burning 
sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, or sensory loss 
∀
A new or worse clinically significant abnormality on the neurological exam (in addition 
to the guidance above) 
∀
A neurological AE considered medically important by the investigator 


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If the participant experiences any of the events above, a neurological examination by a 
consulting neurologist should be obtained as soon as possible (including a nerve conduction 
velocity test if deemed necessary by the neurologist) after these signs and symptoms are 
identified. 
For participants with clinical manifestations consistent with worsening of pre-existing 
neuropathy, follow-up nerve conduction studies should be performed and documented at the 
time points deemed appropriate by the neurologist, but at least once during participation in the 
study. The results should be recorded in the appropriate eCRF. Adverse events should be 
reported where applicable as described in Section 8.3 and Appendix C.
The participant should not be dosed with the subsequent dose of IP until the absence of the 
neurological condition that meets prespecified criteria for IP discontinuation has been 
confirmed. Refer to Section 7.1.1 for prespecified criteria for discontinuation of IP and 
Section 7.1.3 for temporary discontinuation of IP.
Cases of anhidrosis or hypohidrosis should be further evaluated by a neurologist (or another 
relevant specialist trained in the assessment of autonomic nervous function, eg, cardiologist) 
to exclude presence of sympathetic autonomic neuropathy as soon as possible.
The participant should not be dosed with the subsequent dose of IP until the absence of 
autonomic neuropathy has been confirmed. 
If sympathetic autonomic neuropathy is not confirmed and the participant does not meet other 
individual IP discontinuation criteria, the participant can continue in the study as planned 
provided no more than 28 days passed since last IP administration (Section 7.1.3).
8.2.3
Vital Signs
8.2.3.1
Blood Pressure and Pulse Rate
At each clinic visit, BP and pulse rate should be taken using a standard sphygmomanometer 
after the participant has rested in a supine position for at least 5 minutes (10 minutes when 
supine BP and pulse rate measurements are followed by orthostatic BP evaluation). 
On all dosing days, BP and pulse rate are to be assessed prior to any blood draw and IP 
administration and repeated 5 ± 5 minutes after completion of IP administration. Additional 
measurements of supine BP and pulse rate will be taken on Day 1 at the following time points: 
30 ± 5 minutes, 60 ± 10 minutes, 2 hours ± 10 minutes, and 4 hours ± 10 minutes after the 
start of IP administration.


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8.2.3.2
Orthostatic Blood Pressure Measurements and Follow-up of Confirmed 
Orthostatic Hypotension 
Orthostatic BP measurements will be obtained at all clinic visits using a standard 
sphygmomanometer and taken after scheduled supine measurements (1 and 3 minutes after 
the participant stands) and prior to any required blood draw or IP administration (and prior to 
randomisation on Day 1). 
To minimise chances of orthostatic hypotension related to volume depletion, participants 
should be well hydrated when they come to the clinic for study visits. Investigators should 
advise that participants drink 8 to 16 ounces (240 to 480 mL) of water prior to reporting for 
the study visit. 
Supine BP measures will be collected after participants have been lying down for at least 
10 minutes. To ensure that a stable supine BP is obtained, at least 2 systolic and 2 diastolic BP 
measurements will be obtained. If the replicate measurements differ by no more than 
10 mmHg and 5 mmHg, respectively, the supine BP will be considered stable. The mean 
value of each replicate (mean systolic and mean diastolic value) will represent the baseline BP 
for that visit. After stable BP is achieved, the participant will stand and a BP measurement 
will be taken at 1 and 3 minutes after the participant stands. If the BP measurements do not 
meet the criteria for orthostatic hypotension, no additional measurement is needed (refer to 
exclusion criterion 43 for screening visit and Visit 2 assessments and Table 6 for the 
assessments after Visit 2). If BP measurements taken at the screening visit or Visit 2 meet 
exclusion criterion 43, then the participant is not eligible for participation in the study. After 
Visit 2 (Day 1), if the initial BP measurement meets any of the criteria shown in Table 6, 
investigators will repeat the supine and standing measurements up to 2 additional times.
Table 6
Orthostatic Blood Pressure Criteria and Management
Mean supine systolic BP
Decrease in BP indicative of  
orthostatic hypotension 
Actions for both criteria
≤150 mmHg
≥20 mmHg systolic or 
≥10 mmHg diastolic
Repeats the BP measurements (supine and 
standing) up to 2 additional times. 
•
If either the 1 minute or 3 minute 
standing BP meets the orthostatic 
(postural) hypotension criteria, then the 
sequence is considered indicative of 
orthostatic hypotension. 
•
If 2 of 2 or 2 of 3 sequences are 
positive, then orthostatic hypotension is 
confirmed and an AE of orthostatic 
hypotension will be reported.
> 150 mmHg
≥30 mmHg systolic or 
≥15 mmHg diastolic
AE, adverse event; BP, blood pressure
Blood pressure changes meeting the prespecified criteria and confirmed as described above 
will be designated as a confirmed orthostatic hypotension episode. The event should be 


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reported as an AE whether or not the participant had accompanying symptoms. If a confirmed 
case of orthostatic hypotension occurs, the participant should be evaluated as soon as possible 
by a neurologist or cardiologist in order to determine the presence of sympathetic autonomic 
neuropathy. The participant should not receive further administration of IP until absence of 
sympathetic neuropathy is confirmed. 
∀
If sympathetic neuropathy is confirmed, administration of IP will be permanently 
discontinued, and the participant will be asked to complete the assessments at the ET visit 
(Week 12 assessments) and then to enter the FU period (Section 7.1.2). 
∀
If sympathetic neuropathy is not confirmed and orthostatic hypotension is not 
symptomatic, the participant can continue in the study as planned provided no more than 
28 days passed since last IP administration (Section 7.1.3).
∀
If sympathetic neuropathy is not confirmed but orthostatic hypotension remains 
symptomatic for more than 14 days, administration of IP will be permanently 
discontinued, and the participant will be asked to complete the assessments at the ET visit 
(Week 12 assessments) and then to enter the  FU period (Section 7.1.2). 
Refer to the SoA (Table 1) for assessments to be performed at the ET visit and the FU period 
and Section 7.1.2 for procedures for early discontinuation of IP. 
8.2.3.3
Blood Pressure Measured by an Ambulatory Blood Pressure Monitoring 
Device
Participants will be given training at their local study site about how to set up and apply the 
ABPM device. In brief, an appropriate size cuff encircling 80% to 100% of the arm will be 
selected and the device will be fitted to the nondominant arm of the participant, with the 
bladder placed over the artery, and an initial test reading performed. The participants will be 
advised that for the first reading the device will inflate to a pressure of 180 mm Hg, and 
thereafter the device will adapt to inflate to a pressure just above the last recorded BP. The 
participant will be advised to undergo normal daily activities while wearing the cuff, and 
he/she will be advised to avoid any strenuous form of activity, bathing, or showering while 
wearing the cuff. The participant will be advised to remain still during a measurement with the 
arm relaxed at heart level. The participant will also be given advice on how to wear the device 
during the day and at night while sleeping, and what to expect in terms of frequency of 
readings during the day (every 15 minutes) and overnight (every 30 minutes). During ABPM, 
systolic BP, diastolic BP, pulse pressure, pulse rate, and mean arterial pressure readings will 
be recorded over a period of 24 hours. 
Participants will wear the ABPM device for a period of 24 hours at 2 separate times during the 
study: one time during the screening period and one time during the double-blind treatment 
period (between Weeks 8 and 12) (Table 1). Participants will receive the ABPM device at the 
study site, and training will be provided. The participant will wear the monitor/cuff for 
approximately 24 hours (including overnight at home) and will remove the device at home at 


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the end of the 24-hour period. Participants will return the device to the clinic at their next 
scheduled study visit after completing the 24-hour ABPM measurement.
8.2.3.4
Body Temperature
Body temperature will be measured in degrees Celsius using an automated thermometer at the 
visits and times indicated in the SoA (Table 1).
Body temperature will be taken at all clinic visits. On all dosing days, vital signs (including 
body temperature) are to be assessed prior to any blood draw and IP administration (and prior 
to randomisation on Day 1) and repeated 5 ± 5 minutes after completion of IP administration. 
On Day 1, body temperature will also be assessed at the following time points: 
30 ± 5 minutes, 60 ± 10 minutes, 2 hours ± 10 minutes, and 4 hours ± 10 minutes after the 
start of IP administration.
8.2.3.5
Respiratory Rate
Respiratory rate will be measured in breaths per minute by observation at the visits and times 
indicated in the SoA (Table 1). 
Respiratory rate will be measured at all clinic visits. On all dosing days, vital signs (including 
respiratory rate) are to be assessed prior to any blood draw and IP administration (and prior to 
randomisation on Day 1) and repeated 5 ± 5 minutes after completion of IP administration. On 
Day 1, respiratory rate will also be assessed at the following time points: 30 ± 5 minutes, 
60 ± 10 minutes, 2 hours ± 10 minutes, and 4 hours ± 10 minutes after the start of IP 
administration.
8.2.4
Electrocardiograms
At the visits and time points specified in the SoA (Table 1), a 10-second, 12-lead safety ECG 
will be obtained after 10 minutes of supine rest, using the study site’s own ECG machines. 
On Day 1, ECG recording will be performed 30 to 120 minutes prior to IP administration (and 
prior to randomisation) and 4 hours ± 30 minutes after IP administration. On all other dosing 
days, ECG recording will be performed at 30 to 120 minutes prior to IP administration; 
thereafter, ECGs will be recorded at Week 12 and Week 32. ECG recording should be 
performed prior to any blood draw.
The investigator will judge the overall interpretation as normal or abnormal clinically 
nonsignificant or abnormal clinically significant, and this evaluation will be reported in the 
eCRF. Clinically significant findings should also be documented on the AE page of the CRF if 
applicable. The PI may add extra 12-lead resting ECG safety assessments, if needed. These 
assessments should be entered as an unscheduled assessment.


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Cardiovascular findings that are considered to be potential indicators of sympathetic nervous 
system dysfunction should be evaluated by a cardiologist or neurologist as soon as possible. 
Such findings include but are not necessarily limited to significant bradycardia (defined as 
pulse rate of ≤45 beats per minute on an ECG). (Note that this value is exclusionary at 
screening.)
8.2.5
Survey of Autonomic Symptoms (SAS)
The SAS is a validated, easily administered instrument to measure autonomic symptoms and 
has been proposed as a valuable tool in assessing autonomic neuropathies in clinical trials 
(Zilliox et al 2011). 
The SAS scale evaluates the presence of symptoms and the degree of severity. The SAS 
consists of 11 questions in women and 12 questions in men. Each question has a Yes or No 
answer to symptoms occurring 6 months prior to IP administration. Questions answered with 
“Yes” are further rated from 1 to 5 by asking the participant how much each symptom is 
bothering him or her. Each answer is scored on a scale from 1 to 5 where 1 = not at all and 
5 = a lot, and a total symptom impact score is determined.
The questions in the questionnaire assess the following domains: orthostatic, sudomotor 
symptoms, vasomotor, gastrointestinal, urinary, and sexual dysfunction.
Participants will complete the SAS at the times indicated in the SoA (Table 1).
8.2.6
Imaging
8.2.6.1
Radiographic (X-ray) Assessment
A diagnostic X-ray should be performed for all participants during the screening period on the 
shoulder, knee, and hip joints. The reported features in the target knee joint should be 
consistent with at least Grade 2 OA on the KL grading scale of 0 to 4 as per central reader 
evaluation. 
Central radiology readers will review the X-ray images for assessment of eligibility criteria 
including the KL grade and exclusionary joint conditions as described in the exclusion criteria 
(see exclusion criteria 10, 12, 13, and 17). Participants must not start IP until the X-ray data is 
reviewed, and eligibility criteria are confirmed.
If other major joints (elbows, wrists, and ankles) exhibit signs or symptoms associated with 
OA, these should also be imaged via X-ray during the screening period (Also refer to 
American College of Rheumatology for the classification and reporting of OA [Altman et al 
1986]). 
At the Week 32 visit, safety X-ray imaging will be performed on the knee and hip joints. Any 
potentially clinically significant findings detected on X-ray performed at Week 32 will be 


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further assessed and adjudicated (if needed) by the final FU visit (Week 36). Any AEs or AEs 
of special interest (AESIs) related to X-ray findings reported will be followed as long as 
deemed medically necessary (ie, until resolution, stabilisation, the event is otherwise 
explained, or the participant is lost to FU).
In addition, an unscheduled X-ray should be done “for cause” for any joints except for hip 
joints with a KL grade at baseline of ≥3 (for which an MRI as a first step of the assessment is 
required) to follow up on any worsening of symptoms (including pain) considered clinically 
significant by the investigator. Note that X-ray for hip joints with KL grade at screening ≥3 
might be performed as well if deemed necessary by the investigators or RPOA-AC.
After study Day 1, central radiologists will review radiographic images taken “for cause”, eg, 
to follow up on any newly occurring symptoms or worsening of symptoms (including pain) 
considered clinically significant by the investigator or due to joint-related AEs warranting 
further evaluation by the RPOA-AC. The adjudication committee will review cases of 
suspected joint safety events (including but not limited to RPOA, SIF, primary osteonecrosis 
(including spontaneous osteonecrosis of the knee), or pathological fracture cases) to determine 
whether or not they meet accepted diagnostic criteria.
For assessment of joint safety events, see Section 8.2.7. 
Certified X-ray technologists performing X-ray of the knees or other major joints will be 
trained in the appropriate radiographic protocols for the study. All X-ray technologists will be 
approved by AstraZeneca or its representative before they can perform any X-ray deemed 
necessary for the study. 
Details of the image acquisition will be described in the Procedure Manuals for X-ray and 
MRI Image Acquisition.
8.2.6.2
Magnetic Resonance Imaging 
MRI of the bilateral knee joints must be done during the screening period (Table 1) except for 
the cases when a study participant has undergone a total joint replacement and has an artificial 
nontarget joint or when a knee joint is no longer present due to leg amputation. In that case 
only acquire MRI images of the opposite (target) knee. An MRI should also be performed 
during the screening period for the joints with a KL grade at baseline of ≥3 as per screening 
X-ray assessment.
Eligibility (absence of specified joint abnormalities) will be determined by a central imaging 
reader. 
In addition, unscheduled MRIs should be done “for cause” in the knee joints or the joints with 
a KL grade at baseline of ≥3 to follow up on any newly occurring symptoms or worsening of 


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symptoms considered clinically significant by the investigator (except for the cases when a 
study participant has undergone a total joint replacement and has an artificial joint). 
An MRI may also be performed for imaging of any other joints at any other point during the 
study if clarification of X-ray findings is deemed necessary as per the central 
reader/RPOA-AC (eg, to confirm/exclude diagnosis of a SIF or possible osteonecrosis). 
Details of the image acquisition will be described in the Procedure Manuals for X-ray and 
MRI Image Acquisition.
8.2.7
Follow-up of Clinically Significant Findings in Major Joints
Any participant who based on the investigator’s assessment has clinically significant findings 
related to major joints should undergo the following assessments as soon as possible:
∀
X-ray should be done for any joints except for hip joints with KL grade at screening ≥3 
(for which an MRI as a first step of the assessment is required*).
∀
MRI of knee joints or the joints with a KL grade at baseline of ≥3 (which required MRI 
at baseline)
*Note: X-ray for hip joints with KL grade at screening ≥3 might be performed as well if 
deemed necessary by the investigators or RPOA-AC.
X-ray images (and MRI if performed) will be sent to the central reader for review and 
assessment. The RPOA-AC will review cases of suspected joint safety events (including but 
not limited to RPOA, SIF, primary osteonecrosis (including spontaneous osteonecrosis of the 
knee), or pathological fracture cases) to determine whether or not they meet accepted 
diagnostic criteria. The RPOA-AC will also review all joint safety events that meet SAE or 
severe AE criteria.
Participants should not be administered with the subsequent dose of IP until RPOA, SIF, 
primary osteonecrosis (including spontaneous osteonecrosis of the knee), or pathological 
fracture cases are excluded based on central reader assessment and, if required, adjudicated by 
the RPOA-AC (Section 7.1.3).
Participants who prematurely discontinue IP due to positively-adjudicated possible or 
probable RPOA, SIF, primary osteonecrosis (including spontaneous osteonecrosis of the 
knee), or pathological fracture cases will be asked to complete the study assessments at the ET 
visit (Table 1) and then to enter the FU period. Any AEs or AESIs related to joint safety 
events will be followed as long as deemed medically necessary (ie, until resolution, 
stabilisation, the event is otherwise explained, or the participant is lost to FU). Procedures for
early discontinuation of IP are provided in Section 7.1.2.


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For additional information regarding the RPOA-AC refer to Section 9.6 and Appendix B 5.
8.2.8
Total Neuropathy Scores-Nurse 
The TNSn, a semiquantitative clinical assessment of peripheral nervous system function, will 
be administered at the times indicated in the SoA (Table 1). The TNSn provides for an 
assessment of sensory symptoms, 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. Each 
domain of the TNSn is scored from 0 to 4 with a total score ranging from 0 to 20. Details on 
administration of the assessment and scoring will be described in the study site manual.
8.2.9
Injection Site Reactions 
Investigators should evaluate injection site reactions that occur during or immediately 
following IP administration per the FDA Guidance for Industry, Immunogenicity Assessment 
for Therapeutic Protein Products (FDA 2014) and FDA Guidance for Industry, Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (FDA 2007). See Section 2.3 for potential risks related to injection site 
reactions. 
Investigators should evaluate injection site reactions using the toxicity grading scale 
summarised in Table 7.
Table 7
Local Reaction to Injectable Product
Local Reaction
Mild
Moderate
Severe a
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/redness b
2.5 to 5 cm
5.1 to 10 cm
> 10 cm
Induration/swelling c
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
a
In addition, the reactions in which ulceration or severe necrosis occurs should be considered as severe as 
per CTCAE v5.
b
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable.
c
Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement.
CTCAE, common terminology criteria for adverse events
Source: FDA 2007


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Injection site reactions will be monitored at the study visits indicated in the SoA (Table 1). On 
Day 1, injection site reactions will be monitored at approximately 5, 15, 30, 45, and 
60 minutes and 2 and 4 hours after completion of IP administration. On other dosing days, 
injection site reactions will be monitored per standard process of AE collection (participants 
will be instructed to report any changes occurred at the injection site).
8.2.10
Procedures for Subjects Undergoing Joint Replacement
Participants who have undergone or plan to undergo total joint replacement or other 
arthroplasty procedures during the study should discontinue IP. It is recommended to have at 
least 3 weeks between IP administration and joint replacement surgery. Participants will be 
asked to complete study assessments at the ET visit as soon as possible and then to enter the 
FU period. Refer to the SoA (Table 1) for assessments to be performed at the ET visit and FU 
period and to Section 7.1.2 for procedures for early discontinuation of IP. 
All available information including but not limited to prior orthopaedic consultations, imaging 
studies of the affected joint, preoperative assessments, and results of histopathological 
examination will be collected. Wherever possible, the surgeon’s assessment of procedural 
difficulty (uneventful; minor complications (including but not limited to impaired wound 
healing); or major complications (taking into consideration the participant’s  medical history 
and physical condition prior to surgery) should be collected as well.
The RPOA-AC will review and adjudicate all joint safety events that led to joint replacement 
or other arthroplasty procedures. 
AEs that led to joint replacement surgery should be followed up by the investigator for as long 
as medically indicated but no less than up to the end of the FU period or 4 months since joint 
replacement surgery (whichever is longer). Data on additional or corrective procedures (for 
example a revision or implant replacement) that were necessary after total joint replacement 
and their outcomes should be collected wherever possible as well. 
AstraZeneca retains the right to request additional information for any participant who had 
undergone joint replacement at the end of the study if deemed necessary.
8.2.11
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
serology, drug screening, pregnancy tests, and urinalysis will be taken at the visits indicated in 
the SoA (Table 1). 
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
site as source data for laboratory variables. 


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For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection, and results (values, units and reference ranges) will 
be recorded in the eCRF.
Blood and urine samples for haematology, serum chemistry, coagulation, urinalysis, and 
serology will be sent to a central laboratory for analysis. Urine drug screens will be conducted 
at the study sites. Serum pregnancy test will be conducted at the central laboratory; urine 
pregnancy test will be conducted at study sites.
Samples for laboratory tests will include the following:
∀
Haematology: haemoglobin, haematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count 
(or estimate), white blood cell count, and white blood cell differential
∀
Serum chemistry: albumin, total and direct bilirubin, total protein, calcium, ALP, ALT, 
AST, gamma glutamyl transferase, blood urea nitrogen, creatinine*, glucose, sodium, 
potassium, chloride, bicarbonate, calcium, phosphorus, lactate dehydrogenase, uric acid, 
CRP, cholesterol, triglycerides, creatine phosphokinase. Procedures for following up on 
abnormal liver function tests are described in Section 8.2.11.1.
*Note: Serum chemistry reports should include calculation of creatinine clearance using 
the Cockcroft-Gault equation.
∀
Coagulation panel: prothrombin time, activated partial thromboplastin time, fibrinogen
∀
Urinalysis: pH, specific gravity, blood, leukocytes, glucose, protein, ketones, bilirubin 
∀
Urine drug screen: including but not limited to amphetamine, barbiturate, cannabinoids, 
cocaine, methadone, methaqualone, opiate, phencyclidine, and propoxyphene. A general 
urine drug screen will be performed at screening and a urine screen for opiates only will 
be performed at the Week 2 visit.
∀
Urine pregnancy test
∀
Serology: HIV, hepatitis B, and hepatitis C screen, TB (QuantiFERON), and ACPA 
(screening only)
∀
Endocrinology: FSH (Female < 50 years of age only and at screening only, to confirm 
menopausal state), β-HCG beta human chorionic gonadotropin (female participants, not 
surgically sterile only, at screening only).
∀
Other: haemoglobin A1c
Clinical laboratory tests (haematology, chemistry, or coagulation) could be repeated at the 
discretion of the investigator during screening if clinically indicated.


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Instructions for sample collection, processing, storage, and shipment are provided in the study 
site manual.
8.2.11.1
Guidance for Evaluation of Abnormal Liver Function Tests
Evaluation of abnormal liver function tests (including evaluation of potential drug-induced 
liver injury) should be initiated according to the approach outlined in Table 8. 


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Table 8
Required Investigations and Management of Cases of Abnormal Liver Function 
Laboratory value
Immediate action
Follow-up
AST or 
ALT a
Total 
bilirubin
Symptom of 
hepatitis or 
hypersensitivity b
Consultation 
required
Actions
Tests
Evaluation
≥3 × ULN
≥2 × ULN c
NA
Hepatology 
consultation d
Case must be 
discussed with the 
medical monitor 
ASAP
Immediate and permanent 
discontinuation of IP
Essential: Must have liver 
chemistry values and 
additional testing 
completed ASAP 
(Appendix F 7) or follow-
up events of PHL or HL, if 
applicable as per 
Appendix F)
Monitoring of liver 
chemistry values at least 
twice per week until values 
normalise, stabilise, or 
return to within baseline
level e
≥3 × ULN
NA
Yes
≥5 × ULN
< 2 × ULN f
No
Case must be 
discussed with the 
medical monitor 
ASAP
Immediate IP discontinuation 
required. 
Permanent IP discontinuation 
required if follow-up tests 
reveal AST or ALT ≥3 × ULN 
and INR > 1.5, or ALT or 
AST > 5 × ULN for more than 
2 weeks
Essential: Must have liver 
chemistry values and 
additional testing 
completed ASAP 
(Appendix F 7)
Hepatology consultation d; 
Monitoring of liver 
chemistry values at least 
twice per week until 
values normalise, 
stabilise, or return to 
within baseline level e
≥3 × ULN 
(and ≥2 ×
baseline) and 
< 5 × ULN
< 2 × ULN f
No
Discussion with 
medical monitor 
required
Temporal IP discontinuation 
needed for the period required 
for obtaining repeated liver 
function tests and INR. 
Permanent discontinuation of 
IP required if follow-up tests 
reveal AST or ALT ≥ 3 × ULN 
and INR > 1.5 or as deemed 
necessary by the investigator
Measure ALT, AST, 
ALP, GGT, and bilirubin 
(total and direct), INR, 
albumin in 48-72 hours. 
Other tests might be 
performed as medically 
indicated (at the 
discretion of the 
investigator)
If tests reveal AST or 
ALT ≥3 × ULN and 
INR > 1.5, then 
hepatology consultation 
and monitoring of liver 
chemistry values required 
at least twice per week 
until values normalise, 
stabilise, or return to 
within baseline level


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a
Note that IP should be permanently discontinued if there is a possibility of development of autoimmune hepatitis as per investigator’s judgement 
irrespective of ALT or AST level (eg, < 3 × ULN). Participant should have a consult with a hepatologist and liver chemistry values, as well as additional 
tests, should be completed as soon as possible (Appendix F 7).
b
Hepatitis symptoms include fatigue, nausea, vomiting, right upper quadrant pain or tenderness. Hypersensitivity symptoms include eosinophilia (≥5%), 
rash, or fever without clear alternative cause.
c
If the participant also has ≥2 × ULN of ALP, the possibility of an indication of biliary obstruction should be discussed with medical monitor.
d
Hepatologist or another appropriate specialist referral 
e
Unless an alternative monitoring schedule is agreed with by the investigator and medical monitor. Determination of stability of the liver enzyme profile is at 
the discretion of investigator in consultation with the hepatologist (as applicable) and medical monitor, as needed.
f
All bilirubin values since the start of IP exposure should be checked to exclude PHL criteria (Appendix F 2). If the PHL criteria are met, IP should be 
immediately discontinued, and the case needs to be reported and followed-up as per guidance in Appendix F. 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; ASAP, as soon as possible; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; 
HL, Hy’s law; INR, international normalised ratio; IP, investigational product; NA, not applicable; PHL, potential Hy’s law; ULN, upper limit of normal 


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The criteria below make provision for the continuation of IP treatment at the discretion of the 
investigator. 
∀
Participants with ALT or AST ≥3 × ULN (and ≥2 × baseline) and < 5 × ULN, total 
bilirubin < 2 × ULN and INR ≤1.5 with no symptoms of hepatitis or hypersensitivity 
(Table 8).
When IP is discontinued, all concomitant medications and herbal supplements that are not 
medically necessary should be discontinued. The investigator should also consider dose 
reduction for medically necessary concomitant medication and consider changing any 
medically required concomitant medications know to be hepatotoxic to a suitable alternative.
The following additional information should be collected: 
New or updated information:  
∀
Concomitant medications including rescue medication (paracetamol), dosages and days
∀
Participant’s medical history: 
#
History of liver disease
#
Adverse reactions to drugs
#
Allergies
#
Recent travel 
∀
The appearance or worsening clinical symptoms of hepatitis and hypersensitivity
∀
Recent clinically significant hypotension with compromised cardiopulmonary function
∀
Results of liver imaging or liver biopsy, if done
∀
Any pathology reports
See Appendix F for further instructions on actions required in cases of increases in liver 
biochemistry and evaluation of HL. 
8.2.11.2
Pregnancy
Serum pregnancy testing for β-human chorionic gonadotropin is applicable for female 
participants not surgically sterile and will be performed at screening as indicated in the SoA 
(Table 1). Urine pregnancy tests will be conducted at all dosing visits prior to IP 
administration as indicated in the SoA (Table 1).
Female participants who are not surgically sterile must not have a positive pregnancy test at 
screening as specified in inclusion criterion 6. A woman who is found to be pregnant at the 
screening visit will be excluded from the study and be considered a screen failure.
Urine pregnancy testing will be conducted prior to each IP administration on every woman 
who is not surgically sterile. 


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Women should be instructed to contact the investigator or study staff immediately if 
pregnancy occurs or is suspected. 
Procedures to be implemented if a woman becomes pregnant during the study and pregnancy 
reporting requirements are found in Section 8.3.10.
8.2.11.3
Urine Drug Screen
The urine drug test will be performed at the time points shown in Table 1. The drug screening 
includes but may not limited to amphetamine, barbiturate, cannabinoids, cocaine, methadone, 
methaqualone, opiate, phencyclidine, and propoxyphene.
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE, SAE, and an AESI can be found in Appendix C.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs 
refer to Section 8.3.2.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from Visit 1 (including AEs related to washout period at 
screening), throughout the study, and including the FU period (last contact with participant).
Serious AEs will be recorded from the time the participant signs the ICF and throughout the 
study. All SAEs and AESIs will be recorded and reported to AstraZeneca or designee within 
24 hours of awareness, as indicated in Appendix C. The investigator will submit any updated 
SAE data to AstraZeneca within 24 hours of it being available.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
AstraZeneca.


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The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix C.
8.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the participant is lost to FU.
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. AstraZeneca retains the right to request 
additional information for any participant with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary.
8.3.3
Adverse Event Data Collection 
'The following variables will be collected for each AE:
∀
AE (verbatim)
∀
Date and time when the AE started and stopped
∀
Severity of the AE 
∀
Whether the AE is serious or not
∀
Investigator causality rating against the IP(s) (yes or no)
∀
Action taken with regard to IP(s)
∀
AE caused participant’s withdrawal from study (yes or no)
∀
Outcome
In addition, the following variables will be collected for SAEs:
∀
Date AE met criteria for SAE
∀
Date investigator became aware of SAE
∀
AE is serious due to 
∀
Date of hospitalisation
∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Autopsy performed
∀
Causality assessment in relation to study procedure(s)
∀
Causality assessment to other medication


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8.3.4 Causality Collection
The investigator should assess causal relationship between IP and each AE, and answer ‘yes’ 
or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event 
may have been caused by the IP?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix C.
8.3.5
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 2.3.1 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 8.3.1 through Section 8.3.4:
∀
Positively-adjudicated possible or probable RPOA, SIF, primary osteonecrosis, or 
pathological fracture 
∀
Infections that meet SAE or severe AE criteria*
∀
Anaphylactic reactions; serious or severe hypersensitivity reactions; or injection site 
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 8.3.9).
*Note: A serious infection is any infection that meets the SAE criteria in CSP Appendix C 2
“Definition of Serious Adverse Event.” 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.


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8.3.6 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: ‘Have you had any health problems since the 
previous visit/since you were last asked?’, or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately.
8.3.7 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR). 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the IP, or are considered to be clinically relevant as 
judged by the investigator (which may include, but not be limited to, consideration as to 
whether treatment or non-planned visits were required or other action was taken with the IP, 
eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
should use the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.8 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total 
bilirubin ≥2 × ULN may need to be reported as SAEs. Refer to Appendix F for further 
instruction on cases of increases in liver biochemistry and evaluation of HL.


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8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the IP or to the 
study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representative within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it by completing the appropriate forms in the 
electronic data capture (EDC) system and submitting electronically to the safety team. Any 
follow-up information received must also be updated within the system and resubmitted 
within 24 hours of being made aware. SAE reporting via paper forms will only serve as 
backup if the EDC system were to be temporarily unavailable for any unforeseen reasons. In 
such cases, the electronic SAE form can be completed within the EDC system when it 
becomes available. This will ensure safety events are still reported within 24 hours of any site 
staff being made aware. The paper SAE report forms are available in the investigator site files 
and must be completed by the principal investigator by signing and dating the SAE Report 
Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the AstraZeneca representative.
∀
Email: drugsafety@mmsholdings.com
∀
Fax number: +1 734 468 0850
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
FU will be undertaken immediately. Investigators or other site personnel will inform the 
AstraZeneca representative of any FU information on a previously reported SAE within one 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
The reference document for definition of expectedness/listedness is the IB for MEDI7352.
For further guidance on the definition of an SAE, see Appendix C.
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca or 
representative except for any pregnancy that is discovered before the study participant has 
received any IP.


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Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs.
A woman who becomes pregnant during IP treatment or within 30 days of discontinuing the 
IP will be immediately withdrawn from study participation. The investigator must report the 
pregnancy to AstraZeneca or representative as if it were an SAE (within 24 hours of learning 
of the pregnancy) by completing the appropriate forms in the EDC system and submitting 
electronically to the safety team. Pregnancy reporting via paper forms will only serve as 
backup if the EDC system were to be temporarily unavailable for any unforeseen reasons, as 
described in Section 8.3.9. The paper pregnancy notification and outcome forms are available 
in the investigator site files.
All pregnancies and their subsequent outcome (spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital abnormality) should be reported to AstraZeneca 
or representative via the EDC system. If paper pregnancy notification and outcome forms are 
used as backup, these must be completed by the principal investigator and sent via the same 
fax number and/or email address as for SAE reporting.
∀
Email: drugsafety@mmsholdings.com
∀
Fax number: +1 734 468 0850
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 FU information must be reported to AstraZeneca or representative (MMS) by 
submitting a pregnancy notification and outcome EDC report form. 
8.3.10.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. 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 be considered a screen failure. 
Should a pregnancy still occur, the IP should be discontinued immediately and the pregnancy 
reported to AstraZeneca or its representative via the EDC system. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the participant 
was discontinued from the study.


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If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
must inform the appropriate AstraZeneca representatives within one day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for SAEs (Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.3.10.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 3 months and 20 days following the last dose.
Pregnancy in a participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose of IP until 3 months 
and 20 days after the last dose of IP should, if possible, be followed up and documented in the 
pregnancy EDC report form. The site will update the information within the EDC system and 
submit to AstraZeneca or representative (MMS). Consent from the partner must be obtained 
before the pregnancy report form is completed. 
8.3.11
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel must inform the appropriate AstraZeneca representatives within one day, ie, 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or FU fatal/life-
threatening) or 5 (other serious initial and FU) calendar days if there is an SAE associated 
with the medication error (Section 8.3.9) and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix C 5. 
8.3.12
Management of investigational product-related toxicities
As with any biologic therapeutic agent, allergic reactions to dose administration are possible. 
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions, must be immediately 
available when IP is administered and study site personnel must be trained to recognise and 
treat anaphylaxis (Lieberman et al 2010). Details on anaphylaxis management are provided in 
Appendix G.


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Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both and at least one of the following: a) respiratory compromise or b) 
reduced BP or symptoms of end-organ dysfunction; or
2
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced BP or associated symptoms, 
and/or persistent gastrointestinal symptoms; or
3
Reduced BP after exposure
Further details on the clinical criteria for defining anaphylaxis and immune complex disease 
are provided in Appendix G 2.
Participants will have had a preassessment (ie, vital signs and lung function) prior to IP 
administration. Participants should be observed for a minimum of one hour after each IP 
administration for the appearance of any acute drug reactions.
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local laboratory at the discretion of the investigator.
8.4
Overdose
The maximal dose of IP should not be exceeded during the study. The investigator must report 
any overdose to an AstraZeneca representative within 24 hours of learning of the overdose by 
completing the appropriate forms in the EDC system and submitting electronically to the 
safety team. Drug overdose reporting via paper forms will only serve as backup if the EDC 
system were to be temporarily unavailable for any unforeseen reasons, as described for SAE 
reporting (Section 8.3.9). The paper forms are available in the investigator site files and must 
be completed by the principal investigator.
In case of a known or suspected overdose, symptomatic treatment as well as monitoring of 
vital functions should be performed based on the judgement of the investigator. If the 
overdose does not result in an AE, it should be reported to the designated individuals who 
receive SAE notification. The information contained therein should include study site 
identification, reporter identification, participant identification, IP, dose, action taken (eg, 
supportive measures or therapy), and any comments.
∀
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the overdose eCRF module. Symptomatic
treatment as well as monitoring of vital functions should be performed based on the 
judgement of the investigator. 




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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
114 of 253
See Appendix E for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found in 
Appendix E and in the study site manual provided to the sites.
For storage and destruction of genetic samples see Appendix E. 
The results of the analyses will be reported separately from the CSR in a scientific report or 
publication.
8.8
Medical Resource Utilisation and Health Economics
Healthcare Resource Utilisation will be assessed as an exploratory efficacy endpoint. 
Additional information can be found in Section 8.1.8. 
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
Formal statistical testing is designed to preserve the overall family-wise type-error at 1-sided 
α = 0.025.
Multiple Comparison Procedure-Modelling Statistical Tests
The multiple comparison stage of the Multiple Comparison Procedure-Modelling (MCP-Mod) 
analysis will test for the primary endpoint ‘Change in the weekly average of daily NRS pain 
scores from baseline to Week 12’ the global null hypothesis of no dose-response effect, ie, the 
linear contrasts of group means corresponding to each of the 6 prespecified candidate dose-
response models are all identically zero. 
The analysis will be performed at the 1-sided type-1 error of α = 0.025. The minimum of the 
multiplicity adjusted p-values corresponding to each candidate model will be used as the basis 
for concluding statistical significance. 
Pairwise statistical tests 
For primary and key secondary endpoints, pairwise analyses will test for each dose versus 
placebo the null hypothesis of no treatment effect, ie, MEDI7352 dose – placebo = 0.
Pairwise testing of prespecified MEDI7352 doses versus placebo of the primary and key 
secondary endpoints will be performed using a sequentially rejective multiple comparison 
approach to ensure overall family-wise type 1 error across primary and key secondary 
endpoints is controlled at 1-sided α = 0.025 (Bretz et al 2009).
The testing process will commence with the primary endpoint and testing of the key 
secondary endpoints will only be considered if statistical significance is demonstrated for the 
primary endpoint.


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
116 of 253
Table 9
Populations for Analysis
Population/Analysis set
Description
Full analysis set
This set will be used for all efficacy analyses, and it is defined according to 
the intent-to-treat principle as including all randomised participants.
PK set
This set includes all participants who received at least one dose of double-
blind IP per the protocol for whom any postbaseline PK data are available 
and who do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses.
Safety set
This set will include all participants who receive at least one dose of double-
blind IP
IP, investigational product; PK, pharmacokinetics
9.4
Statistical Analyses
The SAP will be finalised before the first interim analysis and will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints.
9.4.1
General Considerations
Formal statistical analysis will be undertaken for the primary and key secondary efficacy 
endpoints, with the aim of maintaining overall family-wise type-1 error at 5% level (2-sided) 
or, equivalently, at 2.5% level (1-sided). The analysis of any remaining endpoints (including 
other efficacy, safety, and those in Section 9.4.4) will be for estimation purposes.
Generally, for each endpoint, baseline is defined as the latest assessment prior to the first dose 
of randomised treatment. For the primary endpoint (change in weekly average of daily NRS 
pain scores), the baseline is defined as the mean of daily NRS pain scores recorded during the 
7-day period immediately prior to randomisation, ie, Day -7 to Day -1, inclusive. Details of 
‘analysis visit windows’ used for statistical reporting will be included in the SAP. 
9.4.2
Efficacy 
All efficacy variables will be summarised 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 efficacy data will be tabulated according to the ‘observed cases’ approach. In 
addition, if there is missing or unevaluable data at a key analysis time-point (Weeks 4, 8, 
and 12) then results will also be tabulated according to single imputation ‘last-observation-
carried forward’ (LOCF) or ‘baseline-observation-carried-forward’ (BOCF), depending upon 
the intercurrent event leading to missing or unevaluable data. The presentation of single 


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
117 of 253
imputed data is intended as an approximation to the approach taken for the formal analyses 
and also to allow historical comparison.
9.4.2.1
Primary Endpoint
An ‘attributable 4’ estimand strategy will be adopted for primary endpoint data missing or 
affected by any of the following 4 intercurrent events:
∀
Discontinuation due to lack of efficacy, or an AE
∀
Discontinuation due to other reasons such as loss to FU or external circumstances
∀
Taking prohibited pain medication during the treatment period that may confound the 
effect of initially randomised treatment on the primary endpoint
∀
Taking excessive permitted rescue medication that may confound the effect of initially 
randomised treatment on the primary endpoint
The rationale for choosing the attributable estimand (Darken et al 2020) is because if a 
participant does not receive treatment for the duration of the study (due to an AE or lack of 
efficacy), or switches to a prohibited therapy, or uses excessive rescue medication, he/she is 
considered to be a treatment failure and so handled with a composite estimand strategy, while 
a hypothetical estimand strategy is used for intercurrent events not considered to be related to 
randomised treatment such as discontinuation due to ‘other reasons’.
Note that it is expected that participants would be switched to alternative treatments following 
discontinuation of randomised treatment or withdrawal, which would confound any 
assessment of efficacy attributable to randomised treatment; therefore, retrieved dropout 
information will not be collected.  
Primary endpoint data missing due to discontinuation due to lack of efficacy or an AE will be 
imputed assuming an unfavourable outcome. Data affected by prohibited or excessive rescue 
medication will be set to missing and imputed assuming an unfavourable outcome. For these 
intercurrent events, a return-to-baseline multiple imputation approach will be used which 
assumes that any treatment effects observed prior to the intercurrent event are washed out, 
such that the mean effect at the end of the study among such participants is the same as that at 
baseline. This seems reasonable where participants enter the study with a chronic level of 
moderate-to-severe pain and the treatment effect is expected to be reversible. 
Primary endpoint data missing due to other reasons will be imputed using a “missing-at-
random” multiple imputation approach. 
Further details of the multiple imputation models and number of imputations will be included 
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The main statistical analysis of the primary efficacy endpoint at Week 12 will use the MCP-
Mod approach, which is a well-established statistical methodology for establishing both the 
existence of a dose response and modelling the underlying dose-response relationship (EMA 
2013, FDA 2015). 
There are 2 steps to MCP-Mod:
∀
The ‘MCP’ step is a rigorous method to establish presence of a dose response while 
protecting the type 1 error and, if the dose-response relationship is statistically significant, 
then 
∀
The ‘Mod’ step estimates the dose response function and associated model parameters, 
such as ED50 in the case of Emax relationship.
The MCP test will use linear contrasts corresponding to the 6 candidate models described in 
Section 9.2. The underlying model will be an analysis of covariance (ANCOVA) with 
dependent variable ‘change from baseline to Week 12’, and independent variables will include 
dose, ‘baseline score’ and KL grade. 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 
dose-response model (including the same covariates as the ANCOVA model) from which 
various estimates will be derived (together with confidence intervals) of parameters of interest 
such as ED50, 90% of the Emax (ED90), dose to achieve selected target effects, and model 
estimates of the treatment effect at doses studied. 
Pairwise testing will be performed using the multiple comparison approach described in 
Section 9.1 based upon the same ANCOVA model as used for the MCP-Mod analyses. 
For each analysis, the testing and estimation will be based upon Rubin’s method of 
combination of the repeated analyses of complete multiply-imputed datasets.
9.4.2.2
Secondary Endpoint(s)
The same analysis approach as for the primary endpoints will be applied to the analysis of the 
key secondary endpoints WOMAC pain, WOMAC physical function, and PGA of OA.
Other continuous secondary endpoints will be analysed by single BOCF/LOCF imputation 
approaches, where LOCF is used for intercurrent event discontinuation due to other reasons 
and BOCF for other intercurrent events.
For binary (responder-type) secondary endpoints, a logistic regression analysis will be 
performed with the same covariates as for the respective continuous endpoint. A mixed 
BOCF/LOCF imputation will be used for missing or unevaluable data. In this analysis, LOCF 


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The incidence of cases of joint replacement surgery will be listed by the number of 
participants per treatment group and by differences between MEDI7352 and placebo. 
Participant listings of AESIs and also AEs, SAEs, and AEs causing discontinuation of IP will 
be generated.
Full details of AE analyses will be provided in the SAP.
9.4.3.2
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 participants with clinical laboratory values categorised 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 be 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.
Elevation in liver parameters for assessment of HL will be collected and reported 
appropriately if potential cases have been identified during the course of the study.
A frequency table for urinalysis will present the number of participants reporting at least one 
treatment emergent increase in baseline category. A shift table for urinalysis will present the 
baseline assessment against the maximum on-treatment category. 
9.4.3.3
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
(n, mean, SD, minimum, Q1, median, Q3, and maximum) will be presented for systolic BP, 
diastolic BP, pulse rate, orthostatic BP changes, respiratory rate, and temperature.
For each scheduled postbaseline visit, descriptive statistics for all vital sign parameters will be 
presented for observed values and change from baseline.
In addition, the incidence of orthostatic hypotension and mean changes in postural BP will be 
summarised.
9.4.3.4
12-Lead Electrocardiogram
Results of the safety ECGs, including normal/abnormal and specific findings will be listed for 
each participant.


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recommendations to the sponsor, based on these data, on the future conduct of the clinical 
study and in particular on whether to continue, terminate, or modify the clinical study.
∀
Independent Efficacy Review Group: This group will be independent of the study team 
and will review, interpret, and adjudicate on the proposed interim analyses for futility and 
efficacy and on any additional analyses carried out for administrative purposes.
∀
RPOA-AC: The role of this committee is to independently review, interpret, and 
adjudicate possible or probable joint safety events including but not limited to RPOA, 
SIF, primary osteonecrosis, or pathological fracture cases that are experienced by the 
study participants. The RPOA-AC will review and adjudicate all treatment-emergent joint 
safety events that meet SAE or severe AE criteria or which led to joint replacement or 
other arthroplasty procedures.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 


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Appendix A
Clinical Study Protocol Signatures












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Appendix B
Regulatory, Ethical, and Study Oversight Considerations
B 1
Regulatory and Ethical Considerations
∀
This study will be conducted in accordance with the protocol and with the following:
#
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines
#
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines
#
Applicable laws and regulations
∀
The protocol, protocol amendments, informed consent form (ICF), Investigator’s
Brochure (IB), and other relevant documents (eg, advertisements) must be submitted to an 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.
∀
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
∀
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.
∀
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/ IEC, European Regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations.
Regulatory Reporting Requirements for Serious Adverse Events 
∀
Prompt notification by the investigator to the sponsor of a serious adverse event (SAE) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of an IP under clinical investigation are met.
∀
AstraZeneca has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of an investigational product (IP) under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.
∀
For all studies except those utilising medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
∀
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.


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B 2
Financial Disclosure
Investigators and subinvestigators will provide AstraZeneca with sufficient, accurate financial 
information as requested to allow AstraZeneca to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for one year after completion of the study. Study completion is defined as the date when 
the last participant completes protocol-defined activities.
B 3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorised representative and answer all questions regarding the study.
Participants must be informed that their participation is voluntary, and they are free to refuse 
to participate and may withdraw their consent at any time and for any reason during the study. 
Participants or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study centre.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorised person obtaining the informed consent must also sign the ICF.
Participants must be consented/reconsented to the most current version of the ICF(s) during 
their participation in the study.
A copy of the ICF(s) must be provided to the participant or the participant’s legally authorised 
representative.
A participant who is rescreened is required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or their future use and may withdraw their consent at any 
time and for any reason during the retention period. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorised designee will explain 
the objectives of the exploratory research to each participant. Participants will be told that they 


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are free to refuse to participate and may withdraw their consent at any time and for any reason 
during the storage period. The participant will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will indicate this in the ICF. If a participant withdraws 
consent to the use of donated biological samples, the samples will be disposed of/destroyed, 
and the action documented. If samples have been analysed already at the time of the request,
AstraZeneca will not be obliged to destroy the results of this research.
All participants will be asked to donate a sample for the Genomics Initiative (see Section 8.7
and Appendix E for additional information regarding informed consent). For inclusion in this 
genetic research, participants must fulfil all of the inclusion criteria described in the main 
body of the clinical study protocol (CSP) and must provide informed consent for the 
Genomics Initiative sampling and analyses. If a participant declines participation in any 
voluntary exploratory genetic research component of the study, there will be no penalty or loss 
of benefit to the participant and he/she will not be excluded from other aspects of the study.
B 4
Data Protection
Participants will be assigned a unique identifier by AstraZeneca. Any participant records or 
datasets that are transferred to AstraZeneca will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the participant in the informed consent 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
B 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be appointed and will report 
to AstraZeneca. The DSMB will be responsible for safeguarding the interests of the 
participants in the study by assessing the safety of the IP during the study. The DSMB will 
have access to the individual treatment codes and be able to merge these with the collected 
study data while the study is ongoing if necessary. 


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The DSMB will make recommendations to the sponsor, based on these data, on the future 
conduct of the trial and in particular on whether to continue, terminate, or modify the study. 
To do so, the DSMB may make their recommendations on the basis of access to unblinded 
data at both the participant and treatment group level. Along with a recommendation, the 
committee will provide sufficient contextual information such that the sponsor can determine 
whether and how to implement the recommendation. 
A DSMB charter will be prepared to detail committee membership and precise roles, 
responsibilities, and procedures to ensure maintenance of the blinding and integrity of the 
study in the review of accumulating data and interactions with AstraZeneca. The DSMB will 
ensure that the study meets high standards of ethics and patient safety.
Independent Efficacy Review Group 
The role of the Independent Efficacy Review Group is to independently review, interpret and 
adjudicate on the proposed interim analyses for futility and efficacy and on any additional 
analyses carried out for administrative purposes. The group will make recommendations to the 
study team, based on these analyses, on the future conduct of the trial and in particular on 
whether to continue, terminate or modify the study. To do so, the group will make their 
recommendations on the basis of access to unblinded data at both the participant and treatment 
group level. Along with a recommendation, the group will provide sufficient contextual 
information such that the study team can determine whether and how to implement the 
recommendation. 
The Independent Efficacy Review Group will consist of sponsor personnel who are 
independent of the study team.
The membership, responsibilities, and procedures applicable to the Independent Efficacy 
Review Group will be detailed in its charter.
Rapidly Progressive Osteoarthritis Adjudication Committee 
The role of the Rapidly Progressive Osteoarthritis Adjudication Committee (RPOA-AC) is to 
independently review, interpret, and adjudicate possible or probable joint safety events 
including but not limited to RPOA, SIF, primary osteonecrosis, or pathological fracture cases 
that are experienced by the study participants. The RPOA-AC will review and adjudicate all 
joint safety events that meet SAE or severe AE criteria or AEs that led to joint replacement or 
other arthroplasty procedures to determine whether or not they meet accepted diagnostic 
criteria. Joint safety events will be identified preliminarily by the investigators, and also by 
AstraZeneca/sponsor personnel or during the RPOA-AC process as specified in the 
committee’s charter. The RPOA-AC member/s will not have access to individual treatment 
codes for any participant and will remain blinded to treatment throughout the study duration.


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Causality assessments will also be made by the RPOA-AC in a blinded fashion. The 
committee will not possess governance authority, but its adjudication and opinion will be 
considered in relation to prespecified stopping criteria in the protocols 
The objectives for performing the adjudication of cases from study D5680C0003 are to: 
∀
Gain the adjudicators’ agreement on the definition of possible or probable RPOA (type 1 
and type 2), SIF, primary osteonecrosis, or pathological fracture cases.  
∀
Agree on a diagnosis for cases based on available X-ray, magnetic resonance imaging, 
and clinical data
∀
Receive a collective opinion on the attribution [causality] of the diagnosis of cases based 
on blinded treatment.
The RPOA-AC should comprise no less than 3 physicians from various specialities who have 
expertise in the diagnosis and treatment of RPOA and in the medical aspects of clinical trials 
in osteoarthritis. The Investigator’s Manual or other investigator material will specify the 
information to be collected for potential RPOA events.
The precise responsibilities and procedures applicable for RPOA-AC will be detailed in its 
charter.
B 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com, http://www.clinicaltrials.gov, and 
https://www.clinicaltrialsregister.eu as will the summary of the main study results when they 
are available. The clinical study and/or summary of main study results may also be available 
on other websites according to the regulations of the countries in which the main study is 
conducted.
B 7
Data Quality Assurance
∀
All participant data relating to the study will be recorded in the electronic case report 
form (eCRF) unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by electronically signing the eCRF.
∀
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
∀
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
∀
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
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noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the monitoring plan. 
∀
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
∀
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organisations).
∀
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
∀
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
B 8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Definition of what constitutes source data can be found in monitoring plan.
B 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:


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∀
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
∀
Inadequate recruitment of participants by the investigator
∀
Discontinuation of further IP development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should ensure appropriate participant treatment and/or follow-up.
B 10
Publication Policy
The results of this study may be published or presented at scientific meetings. Publications 
developed and managed by the investigator will be shared with the sponsor for review and 
approval before submission. This allows the sponsor to review the publication for accuracy 
and to ensure any proprietary information is protected. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee
of Medical Journal Editors authorship requirements.


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


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Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, 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 participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability, or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
Examples of important medical events that require judgement to determine if they are to be 
considered an SAE:
∀
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic bronchospasm
∀
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
∀
Development of drug dependency or drug abuse
Intensity Rating Scale:
∀
Mild (awareness of sign or symptom, but easily tolerated)
∀
Moderate (discomfort sufficient to cause interference with normal activities)
∀
Severe (incapacitating, with inability to perform normal activities)


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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix C 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE unless it meets the criteria 
shown in Appendix C 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be an SAE when it satisfies the criteria 
shown in Appendix C 2.
C 3
Definition of Adverse Events of Special Interest 
An AE of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring and collecting 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. Adverse events of special interest are 
described in Section 8.3.5.
C 4
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.
∀
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
∀
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
∀
Dechallenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
∀
No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
∀
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
∀
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
∀
Is this a recognised feature of overdose of the drug?
∀
Is there a known mechanism?


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Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest 
a causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
C 5
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca IP that either causes harm to the participant or has 
the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error;
∀
Occurred
∀
Was identified and intercepted before the participant received the drug
∀
Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
∀
Drug name confusion
∀
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the participant
∀
Drug not administered as indicated, eg, wrong route or wrong site of administration
∀
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 
∀
Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature 
∀
Wrong participant received the medication (excluding Interactive Response 
Technology/Randomisation and Trial Supply Management [IRT/RTSM] errors)
∀
Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:


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∀
Errors related to or resulting from IRT/RTSM errors - including those which lead to one 
of the above listed events that would otherwise have been a medication error 
∀
Participant accidentally missed drug dose(s), eg, forgot to take medication
∀
Accidental overdose (will be captured as an overdose)
∀
Participant failed to return unused medication or empty packaging
∀
Errors related to background and rescue medication, or standard-of-care medication in 
open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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


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


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Appendix E
Optional Genomics Initiative Sample
E 1
Use/Analysis of DNA
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; mechanism 
of action of the drug; disease aetiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) allow, a blood sample will be collected for DNA analysis from 
consenting participants.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. This genetic research may lead to a better understanding and diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments, or medications. Therefore, where local regulations and IRB/IEC allow, a blood
sample will be collected for DNA analysis from consenting participants.
This optional genetic research may consist of the analysis of the structure of the participant´s 
DNA, ie, the entire genome. 
The results of genetic analyses may be reported in a separate study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
E 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
All participants will be asked to participate in this genetic research. Participation is voluntary, 
and if a participant declines to participate, there will be no penalty or loss of benefit. The 
participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the clinical study protocol (CSP) and provide informed consent 
for the Genomics Initiative sampling and analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:


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∀
Previous allogeneic bone marrow transplant
∀
Non–leukocyte-depleted whole blood transfusion in 120 days of genetic sample 
collection
∀
No Genomics Initiative samples to be collected from healthy volunteers and paediatric 
participants.
Withdrawal of Consent for Genetic Research
Participants may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.2 of the main 
CSP.
Collection of Samples for Genetic Research
A 6 mL K2 ethylenediaminetetraacetic acid blood sample will be collected for the Genomics 
Initiative sample. 
The blood sample for this genetic research will be obtained from the participants at Visit 1 
specified in the schedule of assessments (Table 1). Although DNA is stable, early sample 
collection is preferred to avoid introducing bias through excluding participants who may 
withdraw due to an adverse event (AE). If for any reason the sample is not drawn at Visit 1, it 
may be taken at any visit until the last study visit. Only one sample should be collected per 
participant for genetics during the study.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum of 
15 years, from the date of last participant last visit, after which they will be destroyed. DNA is 
a finite resource that is used up during analyses. Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the sample either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).
The link between the participant enrolment/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 


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


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Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of participants 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. A statistical 
analysis plan may be prepared where appropriate.


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


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
F 3
Identification of Potential Hy’s Law Cases
To identify cases of PHL it is important to perform a comprehensive review of laboratory data 
for any participant who meets any of the following identification criteria in isolation or in 
combination:
∀
ALT ≥3 × ULN
∀
AST ≥3 × ULN
∀
TBL ≥2 × ULN
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met; where this is the case the investigator will:
∀
Notify the AstraZeneca representative.
∀
Request a repeat of the test (new blood draw) by the central laboratory without delay.
∀
Complete the appropriate unscheduled laboratory electronic case report form (eCRF) 
module(s) with the original local laboratory test result.
When the identification criteria are met from central or local laboratory results, the 
investigator will without delay:
∀
Determine whether the participant meets PHL criteria (see Appendix F 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and local 
laboratory results).
Local Laboratories Being Used:
The investigator will, without delay, review each new laboratory report, and if the 
identification criteria are met, the investigator will:
∀
Notify the AstraZeneca representative. 
∀
Determine whether the participant meets PHL criteria (see Appendix F 2 for definition) 
by reviewing laboratory reports from all previous visits.
∀
Promptly enter the laboratory data into the laboratory eCRF.


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F 4
Follow-up
F 4.1
Potential Hy’s Law Criteria not Met
If the participant does not meet PHL criteria, the investigator will:
∀
Inform the AstraZeneca representative that the participant has not met PHL criteria. 
∀
Perform follow-up of subsequent laboratory results according to the guidance provided in 
the clinical study protocol (CSP).
F 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria, the investigator will:
∀
Notify the AstraZeneca representative who will then inform the central study team. 
∀
Within one day of PHL criteria being met, the investigator will report the case as an SAE 
of PHL; serious criteria ‘important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.
∀
For participants that met PHL criteria prior to starting IP, the investigator is not required 
to submit a PHL SAE unless there is a significant change# in the participant’s condition.
∀
The study physician contacts the investigator to provide guidance, discuss, and agree on 
an approach for the study participant’s follow-up (including any further laboratory 
testing) and the continuous review of data.
∀
Subsequent to this contact the investigator will:
#
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. 
#
Complete follow-up SAE form as required.
#
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study physician. This includes deciding which tests available in 
the HL lab kit should be used. 
#
Complete the 3 liver eCRF modules as information becomes available. 
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty.
F 5
Review and Assessment of Potential Hy’s Law Cases


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


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following the CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
F 6
Actions Required for Repeat Episodes of Potential Hy’s Law 
This section is applicable when a participant meets PHL criteria on IP and has already met 
PHL criteria at a previous on-IP visit. 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Did the participant meet PHL criteria prior to starting IP and at their first on-IP visit?
If No: follow the process described in Appendix F 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met
∀
If there is no significant change no action is required
∀
If there is a significant change# follow the process described in Appendix F 4.2 for 
reporting PHL as an SAE
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty.
F 7
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests that are 
recommended when using a central laboratory.
Some of the tests may also be considered for use with local laboratories that have the 
respective testing capabilities. Any test results need to be recorded in the CRF.


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Table F10
Lab Kit for Central Laboratories for Investigations and Management of 
Cases of Abnormal Liver Function (including Hy’s Law cases)
Description
Test
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin) c
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin c
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive.
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive. 
c
CD-transferrin and transferrin are not available in China. 
F 8
References
Aithal et al, 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 
2011 Jun;89(6):806-15.


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FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix G
Anaphylaxis: Definition, Signs, Symptoms, and Management
G 1
Introduction
As with any biologic therapeutic agent, allergic reactions to dose administration are possible. 
The World Health Organisation has categorised anaphylaxis into 2 subgroups, which are 
clinically indistinguishable: immunologic (immunoglobulin E [IgE]-mediated and non-IgE-
mediated [eg, immunoglobulin G and immune complex-mediated]) and nonimmunologic 
(Johansson et al 2004). The clinical criteria for defining anaphylaxis for this study are listed in 
Section G 2 of this Appendix. A guide to the signs and symptoms and management of acute 
anaphylaxis is provided in Section G 3 of this Appendix. Appropriate drugs, such as 
epinephrine, antihistamines, corticosteroids, etc, and medical equipment to treat anaphylactic 
reactions must be immediately available at study sites, and study personnel should be trained 
to recognise and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample for serum tryptase should be collected as 
soon as possible after the event, at 90 ± 30 minutes after the event, and at discharge; analysis 
for serum tryptase will be performed at a local laboratory. Other blood or urine testing 
relevant to the diagnosis of anaphylaxis may be obtained at a local lab at the discretion of the 
investigator.
G 2
Clinical Criteria for Defining Anaphylaxis and Immune Complex 
Disease
Anaphylaxis
In adults, anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips-tongue-
uvula) and at least one of the following:
o
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia).
o
Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that participant (minutes to several hours):
o
Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, 
swollen lips-tongue-uvula).
o
Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).


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o
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, and 
incontinence).
o
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3
Reduced BP after exposure to known allergen for that participant (minutes to several 
hours). For adults, this corresponds to a systolic BP of less than 90 mm Hg or a greater 
than 30% decrease from that participant’s baseline. 
Immune Complex Disease
Immune complex disease or hypersensitivity type III is evoked by the deposition of antigen-
antibody or antigen antibody-complement complexes on cell surfaces, with subsequent 
involvement of breakdown products of complement, platelets, and polymorphonuclear 
leukocytes, and development of vasculitis; serum sickness, and nephritis are common.
G 3
Signs and Symptoms and Management of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multisystem allergic reaction in which some or 
all of the following signs and symptoms occur: 
∀
Diffuse erythema
∀
Pruritus
∀
Urticaria and/or angioedema
∀
Bronchospasm
∀
Laryngeal oedema
∀
Hypotension
∀
Cardiac arrhythmias
∀
Feeling of impending doom
∀
Unconsciousness
∀
Shock
Other earlier or concomitant signs and symptoms can include:
∀
Itchy nose, eyes, pharynx, genitalia, palms, and soles
∀
Rhinorrhoea
∀
Change in voice
∀
Metallic taste
∀
Nausea, vomiting, diarrhoea, abdominal cramps, and bloating
∀
Light-headedness
∀
Headache
∀
Uterine cramps
∀
Generalised warmth


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G 4
Management of Acute Anaphylaxis
G 4.1
Immediate Intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation.
2
Administer epinephrine intramuscularly every 5 to 15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock, and unconsciousness.
G 4.2
Possibly Appropriate, Subsequent Measures Depending on Response to 
Epinephrine
(a) Place participant in recumbent position and elevate lower extremities
(b) Establish and maintain airway
(c) Administer oxygen
(d) Establish venous access
(e) Normal saline IV for fluid replacement
G 4.3
Specific Measures to Consider After Epinephrine Injections, Where 
Appropriate
(a) Consider epinephrine infusion 
(b) Consider H1 and H2 antihistamines
(c) Consider nebulised β2 agonist (eg, albuterol [salbutamol]) for bronchospasm resistant 
to epinephrine
(d) Consider systemic corticosteroids
(e) Consider vasopressor (eg, dopamine)
(f) Consider glucagon for participant taking β-blocker
(g) Consider atropine for symptomatic bradycardia
(h) Consider transportation to an emergency department or an intensive care facility
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary
Adapted from Kemp et al 2008.


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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions, and considerations if site personnel or study 
participants become infected with severe acute respiratory syndrome coronavirus 2 or similar 
pandemic infection) during which participants may not wish to or may be unable to visit the 
study site for study visits. These changes should only be implemented if allowable by 
local/regional guidelines and following notification from the sponsor. Instructions on how to 
perform these procedures will be provided at the time of implementation.  
H 1
Reconsent of Study Subjects During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Consent/reconsent should be obtained for the alternative 
means of carrying out visits and assessments and should be obtained prior to performing the 
procedures described in Sections H 2 to H 4. Local and regional regulations and/or guidelines 
regarding reconsent of study participants should be checked and followed. Reconsent may be 
verbal if allowed by local and regional guidelines (Note: In the case of verbal reconsent, the 
informed consent form should be signed at the participant’s next contact with the study site). 
Visiting the study sites for the sole purpose of obtaining reconsent should be avoided. 
H 2
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified healthcare provider (HCP) from the study site or third-party vendor (TPV) service 
will visit the participant’s home or other remote location as per local standard operating 
procedures, as applicable. Supplies will be provided for a safe and efficient visit. The qualified 
HCP will be expected to collect information per the clinical study protocol. If applicable, 
assessments will be performed according to a revised schedule of assessments (SoA). 
H 3
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events and concomitant medications to be reported 


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and documented. If applicable, safety procedures and blood sample collection will be 
performed according to a revised SoA.
H 4
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site or TPV service or by the participants themselves (eg, numerical 
rating scale daily pain score, daily sleep interference score, rescue medicine) via appropriate 
means.


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Appendix I
Summary of Imaging Assessments
Imaging assessments to be performed during the study are shown in Table I11, and the timing 
of these assessments are described in Table I12. 
Table I11
Imaging Assessments to be Performed During the Study
Joints/indications
X-ray (plain radiographs)
MRI
Knee (both) a
E and S
E and S
Hip (both) a
E and S
For joints with KL grade 3 or more
Shoulders (both)
E and S
When further clarification of 
imaging findings needed
Other joints:
Any major joint with KL 
grade 3 or more
E and S
As clinically indicated (CS 
worsening of OA symptoms 
or newly occurred CS 
symptoms)
S (all joints except for hip joints
with KL grade ≥3 b)
S (knees and/or major joints with 
KL grade ≥3)
Other indications:
When the central readers or 
RPOA-AC need to further clarify 
imaging finding
S
S
At screening for other major joints 
(elbows, wrists, and ankles) 
exhibiting signs or symptoms 
associated with OA
E and S
N/A
a
Scheduled X-ray at Week 32 is required for hips and knees only.
b
Note that X-ray for hip joints with a KL grade at screening ≥3 might be also performed if deemed 
necessary by the investigators or RPOA-AC.
CS, clinically significant; E, eligibility; KL, Kellgren and Lawrence; MRI, magnetic resonance imaging; 
OA, osteoarthritis; S, safety; RPOA-AC, Rapidly Progressive Osteoarthritis Adjudication Committee


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Table I12
Schedule of Assessments - Imaging
Imaging
Knee
Hip
Shoulder
Other joints
Other time points
X-ray
At screening 
and at 
Week 32 (or 
FU clinic 
Visit 2 for 
participants 
who 
discontinued 
IP early) and 
as clinically 
indicated 
during the 
study
At screening 
and at 
Week 32 (or 
FU clinic 
Visit 2 for 
participants 
who 
discontinued 
IP early) and 
as clinically 
indicated 
during the 
study a
At screening 
and as 
clinically 
indicated 
during the 
study
At screening for other 
major joints (elbows, 
wrists, and ankles) 
exhibiting signs or 
symptoms associated 
with OA at screening; 
for any joints as 
clinically indicated 
during the study
At any time point 
during the study when 
deemed necessary by 
the investigator or 
central reader or 
RPOA-AC
MRI
Both knee 
joints at 
screening and 
as clinically 
indicated 
during the 
study
Joints with 
KL grade 3 or 
more at 
screening and
as clinically 
indicated 
during the 
study 
As clinically 
indicated 
during the 
study
At screening and as 
clinically indicated for 
joints with KL 
grade ≥3 during the 
study
When deemed 
necessary by central 
radiology readers or 
RPOA-AC
a
Note that imaging via MRI should be the first step in case of joint safety events in hip joint with KL grade 3 
or more.
FU, follow-up; IP, investigational product; KL, Kellgren and Lawrence grade, MRI, magnetic resonance 
imaging; N/A, not applicable; OA, osteoarthritis; RPOA-AC, Rapidly Progressive Osteoarthritis Adjudication 
Committee


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Appendix J
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:
Nonsterilised 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 3 months and 
20 days after the last administration of investigational product (IP). As male condom and 
spermicide are not considered to constitute a highly effective contraception method, female 
partners of male study participants must also use a highly effective method of contraception 
for the duration of the treatment period and for 3 months and 20 days after the last 
administration of IP. 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 J13.
Table J13
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
Intrauterine device
Combined (oestrogen and progestogen containing 
hormonal contraception)
Intrauterine hormone-releasing system (UIS)
a
∀
Oral (combined pill)
Bilateral tubal occlusion
∀
Injectable
Vasectomised partner
b
∀
Transdermal (patch)
Sexual abstinence
c
Progestogen-only hormonal contraception associated 
with inhibition of ovulation
d
∀
Injectable
∀
Implantable
∀
Intravaginal
a
This is also considered a hormonal method.
b
With appropriate postvasectomy documentation of surgical success (absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during 3 months and 20 days after the last IP administration and if it is the preferred and usual 
lifestyle of the participant.
d
Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action 
(eg, minipill), is not accepted as a highly effective method).
IUS, intrauterine system


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Appendix K
Half-lives of Nonsteroidal Anti-inflammatory Drugs and 
Other Analgesics
Table K14
Half-lives of NSAIDs and Other Analgesics
Analgesic
Half-life (hours)
Minimum washout 
period
Azapropazone
15.0
4 days
Bromfenac
1.3-3.1
2 days
Capsaicin (cream, ointments, patches)
2.0
2 days
Carprofen
12.0
3 days
Celecoxib
11.0
3 days
Codeine
3.5
2 days
Diclofenac
1.1
2 days
Diclofenac gels
1.9
2 days
Diclofenac/misoprostol
2.4-9.0
2 days
Diflusinal
13.0
3 days
Dipyrone
2.0-5.0
2 days
Etodolac
6.0
2 days 
Fenbufen
11.0
3 days
Fenoprofen
2.5
2 days
Flufenamic acid
1.4
2 days
Flurbiprofen
3.8
2 days
Ibuprofen
2.1
2 days
Indomethacin
4.6
2 days
Ketoprofen
1.8
2 days
Ketorolac
4.0-9.0
2 days
Lidocaine patch or EMLA (lidocaine/prilocaine)
2.0
2 days
Meclofenamate
2.0-4.0
2 days
Mefenamic acid
2.0
2 days
Meloxicam
16.0-20.0
5 days
Meperidine
3.7
2 days
Mexiletine
6.0-17.0
4 days
Nabumetone
26.0
6 days
Naproxen
14.0
3 days
Oxaprofen
40.0-50.0
11 days
Oxaprozin
58.0
13 days
Phenylbutazone
68.0
15 days


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
165 of 253
Table K14
Half-lives of NSAIDs and Other Analgesics
Analgesic
Half-life (hours)
Minimum washout 
period
Piroxicam
57.0
12 days
Pirprofen
3.8
2 days
Salicylates
2.0-15.0
4 days
Sulindac
14.0
3 days
Suprofen
2.5
2 days
Tenoxicam
60.0
13 days
Tiaprofenic acid
3.0
2 days
Tolmetin
1.0
2 days
Tramadol
5.9
2 days


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
170 of 253
Appendix M Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is presented 
on the following pages.


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
172 of 253
Section and Name
Text in CSP version 3.0
Amended or New Wording in CSP version 4.0, 
Amendment 3
(Deletions struckthrough, additions underlined)
Brief Rationale
Substantial/ 
non-
substantial
1.3 Schedule of 
Assessments 
(Table 1, footnote 
o)
On Day 1, ECG recording will be performed 30 to 
60 minutes prior to IP administration (and prior to 
randomisation) and 4 hours ± 10 minutes after IP 
administration; 30 to 60 minutes prior to IP 
administration at Weeks 2, 4, 8, and 10; and 
thereafter at Week 12 and Week 32. ECG should be 
performed prior to any blood draw (Section 8.2.4).
On Day 1, ECG recording will be performed 30 to 
120 60 minutes prior to IP administration (and prior 
to randomisation) and 4 hours ± 30 10 minutes after 
IP administration; 30 to 120 60 minutes prior to IP 
administration at Weeks 2, 4, 8, and 10; and 
thereafter at Week 12 and Week 32. ECG should be 
performed prior to any blood draw (Section 8.2.4).
To offer more flexibility for 
procedures at the site 
without affecting the 
integrity of the data.
Non-
substantial
4.1 Overall Design
This is a placebo-controlled Phase IIb study in 
which approximately 300 eligible participants will 
be randomly assigned to the IPs (one of 4 dose 
levels of MEDI7352 or placebo) to ensure that 
approximately 255 participants complete the 
treatment period.
This is a placebo-controlled Phase IIb study in which 
approximately 350 300 eligible participants will be 
randomly assigned to the IPs (one of 4 dose levels of 
MEDI7352 or placebo) to ensure that approximately 
255 participants complete the treatment period.
To increase the study 
sample size. 
Substantial
4.1.2 Additional 
Risk-Mitigation 
Procedures 
Implemented in the 
Context of the 
SARS‑CoV‑2/CO
VID‑19 Pandemic
The following criteria should be met at baseline 
(prior to the first IP administration) and prior to all 
subsequent dosing visits:
. . . . 
∀
Study participants must have a body 
temperature < 37.8°C and show no clinical 
signs and symptoms consistent with COVID-
19 infection or an acute viral respiratory 
illness.
. . . . 
Participants with clinical signs and symptoms 
consistent with COVID-19 infection or an acute 
viral respiratory illness (eg, fever, cough, dyspnoea, 
sore throat, loss of taste/smell) or active COVID 19 
infection confirmed by the appropriate laboratory 
test should not be considered eligible for IP 
administration. Also refer to exclusion criterion 30.
The following criteria should be met at baseline 
(prior to the first IP administration) and prior to all 
subsequent dosing visits:
. . . . 
∀
Study participants must have a body 
temperature < 37.8°C and show no clinical 
signs and symptoms consistent with COVID-
19 infection or an acute viral respiratory 
illness.
. . . . 
Participants with clinical signs and symptoms 
consistent with COVID-19 infection or an acute viral 
respiratory illness (eg, fever, cough, dyspnoea, sore 
throat, loss of taste/smell) or active COVID-19 
infection confirmed by the appropriate laboratory 
test should not be considered eligible for IP 
administration. Also refer to exclusion criterion 31
30.
To expand eligibility while 
continuing to minimise the 
risk posed by SARS-CoV-2 
to research participants, 
local investigational 
researchers, and other staff.
Substantial
4.1.2 Additional 
Risk-Mitigation 
If a study participant is diagnosed with SARS-
CoV-2 active infection and/or COVID 19 disease, 
If a study participant is diagnosed with SARS-CoV-
2 active infection and/or COVID 19 disease, IP 
To resume IP 
administration in some 
Substantial


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
173 of 253
Section and Name
Text in CSP version 3.0
Amended or New Wording in CSP version 4.0, 
Amendment 3
(Deletions struckthrough, additions underlined)
Brief Rationale
Substantial/ 
non-
substantial
Procedures 
Implemented in the 
Context of the 
SARS‑CoV‑2/CO
VID‑19 Pandemic
IP administration should be permanently 
discontinued, and treatment should be provided 
according to the local area guidance; local-area 
quarantine guidance should also be followed (Refer 
to Section 7.1.1 and Section 7.1.2 for criteria for 
discontinuation of IP and procedures for 
discontinuation of IP, respectively).
administration should be permanently discontinued
interrupted and treatment should be provided 
according to the local area guidance; local-area 
quarantine guidance should also be followed. To 
assess if the participant meets permanent IP 
discontinuation criteria, refer to Sections 7.1.1, and 
Section 7.1.2, and 7.1.3 for criteria for 
discontinuation of IP and procedures for temporary 
and permanent discontinuation of IP, respectively).
cases of resolved 
asymptomatic/mild 
COVID-19 infection.
5.2 Exclusion 
Criteria (no 31)
Note that: 
•
Any history of severe COVID-19 infection 
(eg, requiring hospitalisation, intensive care 
unit care, or assisted ventilation) or any prior
COVID-19 infection with unresolved 
sequelae is exclusionary. Any acute SARS-
COV-2/COVID-19 infection, including 
asymptomatic, mild, or moderate (lab 
confirmed or suspected based on clinical 
symptoms) within the last 3 months prior to 
screening or between screening and 
randomisation is exclusionary.
Note that: 
•
Any history of severe COVID-19 infection 
(eg, requiring hospitalisation, intensive care 
unit care, or assisted ventilation) or any prior 
COVID-19 infection with unresolved sequelae 
is exclusionary. Any acute SARS-COV-
2/COVID-19 infection, including 
asymptomatic, mild, or moderate (lab 
confirmed or suspected based on clinical 
symptoms) within the last 3 months that is not 
resolved 1 month prior to screening or between 
screening and randomisation is exclusionary.
[Note: a subject who has had an asymptomatic 
COVID-19 infection or recovered fully from a 
previous mild or moderate COVID-19 
infection, without medical sequelae (including 
relevant negative testing that suggests they are 
no longer carrying replicating SARS-COV-2 
virus), and remains well for at least 1 month 
prior to randomisation may be considered for 
study eligibility].
To expand eligibility while 
continuing to minimise the 
risk posed by SARS-CoV-2 
to research participants, 
local investigational 
researchers, and other staff.
Substantial
6.5.2 Prohibited 
Concomitant 
Medications
The following treatments are prohibited during the 
study:
•
The use of analgesics other than rescue 
medication (paracetamol) including but not 
limited to opioids, topical applications of 
capsaicin, and formulations containing local 
The following treatments are prohibited during the 
study:
•
The use of analgesics other than paracetamol
rescue medication (paracetamol) (including but 
not limited to opioids, topical applications of 
capsaicin, and formulations containing local 
Clarification to exclude 
potential ambiguity in the 
interpretation of the 
prohibited concomitant 
medications from the start 
of the washout period until 
Non-
substantial


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
174 of 253
Section and Name
Text in CSP version 3.0
Amended or New Wording in CSP version 4.0, 
Amendment 3
(Deletions struckthrough, additions underlined)
Brief Rationale
Substantial/ 
non-
substantial
anaesthetic for OA pain treatment is 
prohibited from the start of the washout 
period until the Week 18 FU visit.
anaesthetic for OA pain treatment) is 
prohibited from the start of the washout period 
until the Week 18 FU visit.
the Week 18 FU visit. Non-
substantial.
7.1.1 Subject-
specific Criteria 
for 
Discontinuation of 
Investigational 
Product
For any individual participant, further
administration of IP will be stopped if any of the 
following scenarios occur:
Reports of drug-related SAE(s) or drug-related AE 
(s) including but not necessarily limited to:
•
Serious or severe drug-related injection site 
reactions 
•
Anaphylactic reaction, defined as an 
immediately life-threatening allergic reaction 
with bronchoconstriction, angioedema, and/or 
hypotension (FDA 2014); or serious 
hypersensitivity reactions
•
Development of moderate-to-severe sensory 
abnormalities (eg, paraesthesia, dysesthesia, 
burning, pins and needles) that are not 
resolved within a 14 day period
•
Development of peripheral neuropathy 
•
New onset of demyelinating disorder
•
Serious systemic infection 
•
Serious non-systemic infection if deemed 
necessary by the investigator
For any individual participant, further administration 
of IP will be stopped if any of the following 
scenarios occur:
•
Reports of drug-related SAE(s) or drug-related 
AE (s) including but not necessarily limited to:
!
Serious or severe drug-related injection 
site reactions 
!
Anaphylactic reaction, defined as an 
immediately life-threatening allergic 
reaction with bronchoconstriction, 
angioedema, and/or hypotension (FDA 
2014); or serious hypersensitivity 
reactions
!
Development of moderate-to-severe 
sensory abnormalities (eg, paraesthesia, 
dysesthesia, burning, pins and needles) 
that are not resolved within a 14 day 
period
!
Development of peripheral neuropathy 
!
New onset of demyelinating disorder
!
Serious systemic infection 
!
Serious non-systemic infection if 
deemed necessary by the investigator
Bullet formatting corrected 
in this section. 
Non-
substantial
7.1.1 Subject-
specific Criteria 
for 
Discontinuation of 
Investigational 
Product
For any individual participant, further 
administration of IP will be stopped if any of the 
following scenarios occur:
. . . . 
•
A positive test for SARS-CoV-2 at any time 
point
For any individual participant, further administration 
of IP will be stopped if any of the following 
scenarios occur:
. . . .
•
A positive test for SARS-CoV-2 at any time 
point
As COVID-19 continues to 
occur in a wide-spread 
manner at the population 
level and participants with a 
recent mild or 
asymptomatic infection do 
not represent a population 
Substantial


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
175 of 253
Section and Name
Text in CSP version 3.0
Amended or New Wording in CSP version 4.0, 
Amendment 3
(Deletions struckthrough, additions underlined)
Brief Rationale
Substantial/ 
non-
substantial
•
Symptoms or signs consistent with COVID-
19 infection or an acute viral illness (eg, 
fever, cough, dyspnoea), confirmed by the 
appropriate laboratory test
•
Symptoms or signs consistent with COVID-19 
infection or an acute viral illness (eg, fever, 
cough, dyspnoea), confirmed by the 
appropriate laboratory test
•
Development of COVID-19 infection that 
meets moderate or severe severity AE criteria.
•
Treatment with anti-SARS-CoV-2 monoclonal 
antibodies for COVID-19 infection of any 
severity. 
•
Mild or asymptomatic COVID-19 infection 
with symptoms that have not resolved within 
28 days since the last IP administration or 
results of appropriate testing for COVID-19 
infection (ie, antigen-based) suggesting that a 
participant is carrying a replicating virus and 
remains positive within 28 days since the last 
IP administration. 
•
There are other ongoing sequelae from 
COVID-19 infection, or the participant 
requires treatment for the manifestations of 
COVID-19 infection for the period beyond 28 
days since the previous IP administration, or 
less than 5 half-lives have passed since the last 
COVID-19 antiviral medications 
administration within the 28 day period since 
the last IP administration
at high risk for inadequate 
antibody responses when 
treated with TNF inhibition, 
it is reasonable to allow 
participants with recent 
mild (or asymptomatic) 
COVID-19 infection to 
continue dosing, provided 
that 1) they have 
demonstrated negative 
testing (ie antigen-based) 
that suggests they are no 
longer carrying replicating 
virus, 2) symptoms have 
resolved and no ongoing 
treatments are required, 3) 
there are no other ongoing 
sequelae from infection, 4) 
and no more than 28 days 
have elapsed since the 
previous IP administration
7.1.3 Temporary 
Discontinuation of 
Investigational 
Product
Withholding IP administration temporarily may be 
considered in the following cases
. . . . 
Withholding IP administration temporarily may be 
considered in the following cases
. . . . 
•
A positive test for SARS-CoV-2 at any time 
point during participation in the study. 
•
Symptoms or signs consistent with COVID-19 
infection (eg, fever, cough, dyspnoea), 
confirmed by an appropriate laboratory test.
. . . . . 
To add certain COVID-19 
scenarios to the temporary 
discontinuation  of IP 
criteria and to describe to 
outline the conditions when 
IP administration could be 
resumed in case of resolved 
asymptomatic or mild 
COVID-19 infection. 
Substantial


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
176 of 253
Section and Name
Text in CSP version 3.0
Amended or New Wording in CSP version 4.0, 
Amendment 3
(Deletions struckthrough, additions underlined)
Brief Rationale
Substantial/ 
non-
substantial
Administration of IP can be resumed if deemed 
appropriate by the investigator in participants with 
fully resolved asymptomatic or mild COVID-19 
infection (confirmed by negative SARS-CoV-2 
testing (ie, antigen-based), that suggests that the 
participant is no longer carrying replicating virus) 
provided that it is completely resolved without 
sequalae within 28 days since the previous IP 
administration and participants do not require 
ongoing treatment for COVID-19 infection as well 
as do not have ongoing adverse drug reactions 
associated with treatment of COVID-19 infection as 
assessed by the investigator. Additionally, more than 
5 half-lives of COVID-19 antiviral medications 
should elapse before IP administration is resumed. 
Participants who were treated with anti-SARS-CoV-
2 monoclonal antibodies are not eligible for further 
IP administration. For participants treated with 
COVID-19 antiviral medications, the investigator 
should contact the medical monitor and agree if and 
when further IP administration is appropriate.
8 Study 
Assessments 
(Double-blind 
Treatment Period)
The following procedures will be performed on 
Day 1 prior to randomisation:
. . . . 
•
ECG (30 to 60 minutes prior to IP 
administration and prior to any blood draw)
. . . .
The following procedures will be performed on 
Day 1 after randomisation and administration of IP:
•
ECG will be performed 4 hours ± 10 minutes 
after IP administration.
The following procedures will be performed on Day 
1 prior to randomisation:
. . . .
•
ECG (30 to 60 120 minutes prior to IP 
administration and prior to any blood draw)
. . . .
The following procedures will be performed on Day 
1 after randomisation and administration of IP:
•
ECG will be performed 4 hours ± 10
30 minutes after IP administration.
To offer more flexibility for 
procedures at the site 
without affecting the 
integrity of the data.
Non-
substantial
8.2.4
Electrocardiogram
s
On Day 1, ECG recording will be performed 30 to 
60 minutes prior to IP administration (and prior to 
randomisation) and 4 hours ± 10 minutes after IP 
administration. On all other dosing days, ECG 
recording will be performed at 30 to 60 minutes 
On Day 1, ECG recording will be performed 30 to 
120 60 minutes prior to IP administration (and prior 
to randomisation) and 4 hours ± 30 10 minutes after 
IP administration. On all other dosing days, ECG 
recording will be performed at 30 to 120 60 minutes 
To offer more flexibility for 
procedures at the site 
without affecting the 
integrity of the data.
Non-
substantial


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
178 of 253
Amendment 2 (14 October 2021)
This amendment was considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union. 
The Protocol Amendment Summary of Changes Table for the Amendment 2 is presented on 
the following pages.


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
179 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
1.1 Synopsis 
(Overall Design)
The study consists of a screening period of up to 
45 days, a 12-week treatment period, and a 
20-week follow up (FU) period (Table 1).
The study consists of a screening period of up to 45 
days, a 12-week treatment period, and a 24 20-week 
follow up (FU) period (Table 1).
To follow participants 
for longer after the last 
IP administration to 
monitor joint-related 
AEs.
Substantial
1.1 Synopsis 
(Overall Design)
After the end-of-treatment (EOT) visit at 
Week 12, participants will enter the FU period, 
which comprises 3 clinic visits (Weeks 18, 28, 
and 32) and 3 FU phone calls (Weeks 15, 21, and 
24). 
After the end-of-treatment (EOT) visit at Week 12, 
participants will enter the FU period, which comprises 
3 clinic visits (Weeks 18, 28, and 32, and 36) and 3 4
FU phone calls (Weeks 15, 21, and 24, and 28). 
Number and time points 
of visits updated due to 
change in the duration 
of the FU period
Substantial 
(consequential)
1.1 Synopsis 
(Interim Analysis)
4.1 Overall Design
9.5 Interim 
Analyses
The study incorporates 2 interim analyses: (1) a 
futility analysis will take place when 
approximately 25% of participants are evaluable 
for the primary endpoint; this analysis will assess 
the likely success of the study outcome and will 
enable the sponsor to make a go/no go decision 
regarding continuation of the study; and (2) an 
administrative analysis of efficacy data will take 
place when approximately 50% of participants 
are evaluable for the primary endpoint; this 
analysis will enable the sponsor to plan future 
project-related activities, but without making any 
changes to the current study.
The study incorporates 2 interim analyses: (1) a 
futility analysis will take place when approximately 
25% of participants are evaluable for the primary 
endpoint; this analysis will assess the likely success of 
the study outcome and will enable the sponsor to 
make a go/no go decision regarding continuation of 
the study; and (2) an interim administrative analysis 
of efficacy data will take place when approximately 
50% of participants are evaluable for the primary 
endpoint; this analysis will enable the sponsor to plan 
future project-related activities, but without making 
any changes to the current study.
Clarification that both 
analyses are interim
Non-
substantial
1.1 Synopsis 
(Intervention 
Groups and 
Duration)
FU period: 20 week FU period with a final FU 
visit at Week 32 (± 7 days)
The maximum study duration for each 
participant is approximately 44 weeks. The 
overall study duration is expected to be 24 
months (12 months of active screening and 
enrolment, 10 months of treatment and FU, and 
2 months for database lock).
FU period: 24 20 week FU period with a final FU 
visit at Week 36 32 (± 7 days)
The maximum study duration for each participant is 
approximately 50 44 weeks. The overall study 
duration is expected to be 31 24 months (18
12 months of active screening and enrolment, 11
10 months of treatment and FU, and 2 months for 
database lock).
Time points of visits 
updated due to change 
in the duration of the 
FU period
Substantial 
(consequential)


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
185 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
During the ongoing MAD phase of the study, 
there has been one reported serious TEAE 
(pneumonia), which led to the participant’s 
withdrawal from the study. The pneumonia event 
was considered by the investigator to be 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).
In addition, 4 participants were withdrawn from 
the MAD phase of the study due to non-serious 
TEAEs: viral upper respiratory infection (one 
participant), erysipelas left leg (one participant), 
fever and common cold (one participant), and 
infusion-related reaction, ie, dyspnoea, flushing, 
dizziness (one participant). The viral upper 
respiratory infection was considered not related 
to IP by the investigator; all other TEAEs were 
considered related to IP by the investigator.
In the SAD phase of the study, the most 
commonly reported TEAEs (≥5% of 
participants) were headache (9 of 
53 participants) and back pain 
(3 of 53 participants). 
In the MAD phase of the study, the most 
commonly reported TEAEs (≥5% of 
participants) were nasopharyngitis 
(20 of 71 participants), headache 
(18 of 71 participants), back pain 
(8 of 71 participants), oropharyngeal pain 
(6 of 71 participants), and nausea, pain in 
extremity, cough, and rhinorrhoea 
(4 of 71 participants each).
doses of MEDI7352 ranging from 1 to 450 μg/kg 
every 2 weeks (Q2W) (up to 4 planned doses).
No clinically relevant safety or tolerability concerns 
were have been raised during the dose escalation in 
the SAD phase or in the MAD phases of the study
cohorts evaluated to date. 
In the SAD phase, 17 of 39 participants (43.6%) 
treated with MEDI7352 (across all dose levels) and 9 
of 14 participants (64.3%) treated with placebo had at 
least one treatment emergent adverse event (TEAE). 
Most TEAEs were considered by the investigator to 
be of 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 participants 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 participants treated with placebo, 
the most common TEAEs were headache (28.6%) and 
oropharyngeal pain (14.3%). 
In the MAD phase, 44 of 53 participants (83.0%) 
treated with MEDI7352 (across all dose levels) and 
16 of 22 participants (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 
participant treated with MEDI7352), which led to the 
participant’s withdrawal. The pneumonia was 
considered by the investigator to be 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). 


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underlined)
Brief Rationale
Substantial/ 
Non-substantial
Most TEAEs were considered by the investigator 
to be of mild intensity. Four participants had 
TEAEs that were considered by the investigator 
to be of severe intensity: one participant with a 
non-serious TEAE of influenza, one participant 
with a non-serious TEAE of abdominal pain, one 
participant with non-serious TEAEs of pain in 
right knee and back pain, and one participant 
with a serious TEAE of pneumonia. The event of 
pneumonia led to the participant’s withdrawal 
from the study, as described above. All TEAEs 
were considered not related to IP by the 
investigator.
No clinically significant changes or dose-related 
trends have been observed for any other safety 
parameters in either study phase, including 
laboratory safety tests, vital signs, 
electrocardiogram (ECG) assessments, physical 
examinations, or neuropathy assessments (Total 
Neuropathy Score-nurse [TNSn]). There have 
been no reports of rapidly progressive OA 
(RPOA) or osteonecrosis.
Phase II Study D5680C00002 (Participants 
with Painful Diabetic Neuropathy)
The Phase II study D5680C00002 comprises 3 
successive stages, each assessing MEDI7352 (up 
to 6 planned IV doses per participant) versus 
placebo as follows: Stage 1 assessed MEDI7352 
5 μg/kg or placebo, Stage 2 is assessing 
MEDI7352 150 μg/kg or placebo, and Stage 3 
will assess MEDI7352 10, 50, 150, and 
450 μg/kg or placebo. At the time of preparation 
of this clinical study protocol (CSP), Stage 1 of 
the study is complete, and Stage 2 is ongoing. A 
Four participants 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 participants treated 
with MEDI7352 had TEAEs of oral herpes and 
urinary tract infection (5.7% each) compared with 
participants treated with placebo (0%). However, the 
overall incidence of TEAEs in the SOC of infections 
and infestations was similar among participants 
treated with MEDI7352 and those treated with 
placebo (39.6% and 36.4%, respectively).
The most common TEAEs among participants 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 participants 
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 participant 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. 
No cases of rapidly progressive OA (RPOA)or 
osteonecrosis were reported during the study. 
There were no discernible differences in the TEAE 
profiles of participants with and without ADA in 
either study phase, suggesting that there were no 
apparent effects of immunogenicity on safety.


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(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
total of 33 participants with PDN have received 
blinded IP (up to 6 planned IV doses, 
administered Q2W). It is estimated that 
17 participants have received MEDI7352 
(5 μg/kg or 150 μg/kg) and 16 participants have 
received placebo.
A review of blinded safety data shows that 20 of 
33 treated participants have had at least one 
reported TEAE as of 23 April 2020. There have 
been no deaths or serious TEAEs. 
One participant in Stage 1 discontinued after 5 of 
6 planned infusions of IP due to a non-serious 
TEAE of cellulitis that was considered by the 
investigator to be of moderate intensity and not 
related to IP.
The following TEAEs have been reported for ≥3 
of treated participants overall: headache 
(6 participants) and nasopharyngitis 
(4 participants). 
Headache was the most commonly reported 
TEAE in each stage: 3 of 10 participants (30.0%) 
in Stage 1 (5 μg/kg MEDI7352 or placebo) and 
3 of 23 participants (13.0%) in Stage 2 
(150 μg/kg MEDI7352 or placebo).
Most TEAEs reported in each study stage were 
considered by the investigator to be of mild 
intensity, and none were considered to be severe. 
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 TNSn or for parameters measured during 
motor and sensory nerve conduction studies.
No clinically significant changes or dose-related 
trends for mean changes from baseline or differences 
between MEDI7352- and placebo-treated participants 
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).
A review of blinded safety data shows that 81 of 
124 treated participants have had at least one reported 
treatment-emergent adverse event (TEAE). There 
have been no deaths during the study. No serious 
TEAEs or investigational product (IP) 
discontinuations due to TEAEs were reported during 
the SAD phase of the study.  
During the ongoing MAD phase of the study, there 
has been one reported serious TEAE (pneumonia), 
which led to the participant’s withdrawal from the 
study. The pneumonia event was considered by the 
investigator to be 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).
In addition, 4 participants were withdrawn from the 
MAD phase of the study due to non-serious TEAEs: 
viral upper respiratory infection (one participant), 
erysipelas left leg (one participant), fever and 
common cold (one participant), and infusion related 
reaction, ie, dyspnoea, flushing, dizziness (one 
participant). The viral upper respiratory infection was 
considered not related to IP by the investigator; all 


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(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
A detailed description of the chemistry, 
pharmacology, efficacy, and safety of 
MEDI7352 is provided in the current IB.
other TEAEs were considered related to IP by the 
investigator.
In the SAD phase of the study, the most commonly 
reported TEAEs (≥5% of participants) were headache 
(9 of 53 participants) and back pain 
(3 of 53 participants). 
In the MAD phase of the study, the most commonly 
reported TEAEs (≥5% of participants) were 
nasopharyngitis (20 of 71 participants), headache 
(18 of 71 participants), back pain 
(8 of 71 participants), oropharyngeal pain 
(6 of 71 participants), and nausea, pain in extremity, 
cough, and rhinorrhoea (4 of 71 participants each).
Most TEAEs were considered by the investigator to 
be of mild intensity. Four participants had TEAEs that 
were considered by the investigator to be of severe 
intensity: one participant with a non-serious TEAE of 
influenza, one participant with a non-serious TEAE of 
abdominal pain, one participant with non serious 
TEAEs of pain in right knee and back pain, and one 
participant with a serious TEAE of pneumonia. The 
event of pneumonia led to the participant’s 
withdrawal from the study, as described above. All 
TEAEs were considered not related to IP by the 
investigator.
No clinically significant changes or dose related 
trends have been observed for any other safety 
parameters in either study phase, including laboratory 
safety tests, vital signs, electrocardiogram (ECG) 
assessments, physical examinations, or neuropathy 
assessments (Total Neuropathy Score nurse [TNSn]). 
There have been no reports of rapidly progressive OA 
(RPOA) or osteonecrosis.


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Phase II Study D5680C00002 (Participants with 
Painful Diabetic Neuropathy)
The Phase II study D5680C00002 comprises 4
3 successive stages, each assessing MEDI7352 (up to 
6 planned IV doses per participant) versus placebo as 
follows: Stage 1 assessed MEDI7352 5 μg/kg or 
placebo, Stage 2 assessed is assessing MEDI7352 
150 μg/kg or placebo, Stage 3 will assess MEDI7352 
450 μg/kg or placebo, and Stage 4 3 will assess 
MEDI7352 10, 50, 150, and 450 μg/kg or placebo. At 
the time of preparation of this clinical study protocol 
(CSP), Stages Stage 1 and 2 of the study are is
complete, and Stage 3 2 is ongoing. A total of 
33 participants with PDN have received blinded IP 
(up to 6 planned IV doses, administered Q2W). It is 
estimated that 17 participants have received 
MEDI7352 (5 μg/kg or 150 μg/kg) and 
16 participants have received placebo.
A review of blinded safety data showed shows that 26
20 of 41 33 treated participants (63.4%) have had at 
least one reported TEAE as of 01 June 2021
23 April 2020. There have been no deaths or serious 
TEAEs. 
Three participants 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, 5 μg/kg MEDI7352 or placebo)
•
A TEAE of infection (symptoms of sore throat, 
fever, nasopharyngitis, tongue burning, and 
sweating) of mild intensity (Stage 2, 150 μg/kg 
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 participant’s 


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underlined)
Brief Rationale
Substantial/ 
Non-substantial
withdrawal after 3 of 6 planned infusions of IP 
(150 μg/kg MEDI7352 or placebo). 
Headache was the most commonly reported TEAE 
overall: 7 of 41 participants (17.1%), including 3 of 
10 participants (30.0%) in the completed Stage 1 (5 
μg/kg MEDI7352 or placebo), 3 of 26 participants 
(11.5%) in the completed Stage 2 (150 μg/kg 
MEDI7352 or placebo) and 1 of 5 participants (20%) 
in the ongoing Stage 3 (MEDI7352 450 μg/kg or 
placebo). All TEAEs reported in each study stage 
were considered by the investigator to be of mild or 
moderate intensity.
One participant in Stage 1 discontinued after 5 of 
6 planned infusions of IP due to a non serious TEAE 
of cellulitis that was considered by the investigator to 
be of moderate intensity and not related to IP.
The following TEAEs have been reported for ≥3 of 
treated participants overall: headache (6 participants) 
and nasopharyngitis (4 participants). 
Headache was the most commonly reported TEAE in 
each stage: 3 of 10 participants (30.0%) in Stage 1 
(5 μg/kg MEDI7352 or placebo) and 3 of 
23 participants (13.0%) in Stage 2 (150 μg/kg 
MEDI7352 or placebo).
Most TEAEs reported in each study stage were 
considered by the investigator to be of mild intensity, 
and none were considered to be severe. 
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 TNSn or for parameters 
measured during motor and sensory nerve conduction 
studies.


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underlined)
Brief Rationale
Substantial/ 
Non-substantial
Phase I Study D5680C00004 (Healthy Japanese 
and Caucasian Volunteers)
Two of the of 5 treated participants (40.0%) have had 
a total of 4 TEAEs as follows (one participant each): 
dyspepsia, catheter site erythema, injection site pain, 
and paraesthesia. All reported AEs were considered 
by the investigator to be of mild intensity. There have 
been no deaths, treatment-emergent SAEs, or 
withdrawals due to AEs.
A detailed description of the chemistry, 
pharmacology, efficacy, and safety of MEDI7352 is 
provided in the current IB.
2.3.1.1 Potential 
Risks Based on 
Mechanisms of 
Action
The safety profile of MEDI7352 may include 
adverse reactions that are related to the expected 
pharmacological mechanisms of action, and thus 
may be comparable to those previously reported 
for both anti-NGF monoclonal antibodies 
undergoing development (eg, tanezumab, 
fulranumab, and fasinumab) and established anti-
TNFα therapies (eg, etanercept). 
The safety profile of MEDI7352 may include adverse 
reactions that are related to the expected 
pharmacological mechanisms of action, and thus may 
be comparable to those previously reported for both 
anti-NGF monoclonal antibodies undergoing 
development (eg, tanezumab, fulranumab, and 
fasinumab) and established anti-TNFα therapies (eg, 
etanercept, adalimumab, and infliximab). 
Updated to align with 
most recent version of 
the IB
Non-
substantial
2.3.1.1 Potential 
Risks Based on 
Mechanisms of 
Action
Rapidly Progressive Osteoarthritis and other 
Joint Safety Events
A dose-related increase in the incidence of 
RPOA was confirmed in later studies of 
tanezumab in participants with moderate-to-
severe OA (Berenbaum et al 2019, Schnitzer et 
al 2019). Emerging Phase III data are consistent 
with joint safety events occurring more 
frequently with tanezumab than with placebo 
(Berenbaum et al 2019) or with NSAIDs 
(Hochberg et al 2019). Data from a Phase IIb/III 
study of fasinumab revealed a dose- and time-
related increase in arthropathies, with a reported 
Rapidly Progressive Osteoarthritis and other Joint 
Safety Events
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, SIF, and pathological 
fracture (FDA 2021a). There was a significantly 
higher incidence of events in participants treated with 
tanezumab (3.2% and 6.2% of participants treated 
with tanezumab 2.5 mg and 5 mg, respectively) 
compared to NSAIDs (1.5% of participants) or 
placebo (0% of participants) (FDA 2021c). In 
Updated to align with 
most recent version of 
the IB
Non-
substantial


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Initial Wording under Amendment 1
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Brief Rationale
Substantial/ 
Non-substantial
5% incidence of RPOA in the fasinumab group 
(with joint space narrowing [RPOA 1] in 14 
participants and with bony changes [RPOA-2] in 
2 participants) compared to none in the placebo 
group. Subchondral insufficiency fracture 
occurred in 1.8% of participants in the combined 
fasinumab group and 1.2% in the placebo group. 
Most arthropathies (16 of 25) were discovered by 
a scheduled radiologic assessment (Dakin et al 
2019). Given the dose-relatedness of anti-NGF 
to the incidence of RPOA, including destructive 
changes in the joints, it is thought that the risk of 
those events is likely related to the level of NGF 
sequestration.
Additional information about this potential risk 
is provided in the current IB.
addition, a greater proportion of participants treated 
with tanezumab (5.5% and 7.8% of participants 
treated with tanezumab 2.5 mg and 5 mg, 
respectively) required total joint replacements when 
compared to those treated with NSAIDs (2.6% of 
participants) or placebo (4.5% of participants) (FDA 
2021a, FDA 2021c). Overall, approximately 85% of 
the total joint replacements occurred in joints KL 
grade ≥3 at baseline (FDA 2021c); however, some 
joint safety events including total joint replacement 
occurred in joints KL grade 0 or 1 at baseline (FDA 
2021a, FDA 2021c).
It was also notable in the tanezumab programme that 
composite joint safety events are not limited to 
arthritis joints. For participants 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%) (FDA 2021b). A dose-related 
increase in the incidence of RPOA was confirmed in 
later studies of tanezumab in participants with 
moderate to severe OA (Berenbaum et al 2019, 
Schnitzer et al 2019). Emerging Phase III data are 
consistent with joint safety events occurring more 
frequently with tanezumab than with placebo 
(Berenbaum et al 2019) or with NSAIDs (Hochberg et 
al 2019). Data from a Phase IIb/III study of fasinumab 
revealed a dose- and time-related increase in 
arthropathies, with a reported 5% incidence of RPOA 
in the fasinumab group (with joint space narrowing 
[RPOA 1] in 14 participants and with bony changes 
[RPOA-2] in 2 participants) compared to none in the 
placebo group. Subchondral insufficiency fracture 
occurred in 1.8% of participants in the combined 


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Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
fasinumab group and 1.2% in the placebo group. Most 
arthropathies (16 of 25) were discovered by a 
scheduled radiologic assessment (Dakin et al 2019). 
Given the dose-relatedness of anti-NGF to the 
incidence of RPOA, including destructive changes in 
the joints, it is thought that the risk of those events is 
likely related to the level of NGF sequestration.
Additional information about this potential risk is 
provided in the current IB.
2.3.1.1 Potential 
Risks Based on 
Mechanisms of 
Action
Autonomic Neuropathy and Sympathetic 
Dysfunction
In the pooled analysis of safety data across 
tanezumab Phase III clinical studies (Tive et al 
2019), AEs of postganglionic sympathetic 
dysfunction (AEs of decreased sympathetic 
function such as bradycardia, orthostatic 
hypotension, nausea, diarrhoea, or vomiting), 
occurred at similar rates in participants receiving 
placebo (4.3%), tanezumab (4.8%), or 
tanezumab plus NSAID (5.2%) in the overall 
population.
Autonomic Neuropathy and Sympathetic Dysfunction
According to the FDA Briefing Document for the 
2021 Advisory Committee meeting for tanezumab 
(FDA 2021a), in the Phase III placebo-controlled 
studies with tanezumab, AEs of postganglionic 
sympathetic dysfunction (AEs of decreased 
sympathetic function such as bradycardia, orthostatic 
hypotension, hypohidrosis, syncope), occurred at 
observation-time adjusted rates of 20.3%, 29.1%, and 
46.2% for subjects receiving placebo, tanezumab 2.5 
mg, and tanezumab 5.0 mg, respectively; the 
imbalance was primarily driven by higher rates of 
bradycardia and orthostatic hypotension in the 
tanezumab treatment groups. In a Phase III active-
controlled study, AEs of postganglionic sympathetic 
dysfunction occurred at observation-time adjusted 
rates of 37.0%, 25.7%, and 36.1% for subjects 
receiving NSAIDs, tanezumab 2.5 mg, and tanezumab 
5.0 mg, respectively. Overall, the FDA concluded that 
tanezumab was not found to be associated with an 
increased risk of sympathetic disfunction.
In the pooled analysis of safety data across tanezumab 
Phase III clinical studies (Tive et al 2019), AEs of 
postganglionic sympathetic dysfunction (AEs of 
decreased sympathetic function such as bradycardia, 
Updated to align with 
most recent version of 
the IB. 
Non-
substantial


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Brief Rationale
Substantial/ 
Non-substantial
orthostatic hypotension, nausea, diarrhoea, or 
vomiting), occurred at similar rates in participants 
receiving placebo (4.3%), tanezumab (4.8%), or 
tanezumab plus NSAID (5.2%) in the overall 
population.
2.3.1.1 Potential 
Risks Based on 
Mechanisms of 
Action
Additional warnings and precautions for 
etanercept include hypersensitivity reactions, 
exacerbation or new onset of demyelinating 
disease, malignancies, serious haematological 
reactions, new onset or worsening congestive 
heart failure, reactivation of hepatitis B, 
autoimmune hepatitis, autoimmune renal disease, 
and a lupus-like syndrome.
Patients older than 65 years of age, patients with co-
morbid conditions and/or patients taking concomitant 
immunosuppressants may be at greater risk of 
infection. The risks and benefits of treatment should 
be considered prior to initiating therapy in patients 
with underlying conditions that may predispose to 
infection, such as advanced or poorly controlled 
diabetes. Additional warnings and precautions for 
etanercept include 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.
Updated to align with 
most recent version of 
the IB. 
Non-
substantial
2.3.1.4 General 
Risk-Mitigation 
Plan
•
Implementation of appropriate 
inclusion/exclusion criteria, baseline 
evaluations, and restrictions applied during 
the conduct of the clinical studies, 
specifically:
#
… 
#
Exclusion of study participants with 
a history of RPOA, osteonecrosis, 
subchondral insufficiency fracture 
(SIF), avascular necrosis, and other 
significant arthropathies 
•
Implementation of appropriate 
inclusion/exclusion criteria, baseline 
evaluations, and restrictions applied during the 
conduct of the clinical studies, specifically:
#
… 
#
Exclusion of study participants with a 
history of RPOA, osteonecrosis, 
subchondral insufficiency fracture (SIF), 
avascular necrosis, and other significant 
arthropathies 
#
Exclusion of study participants with 
preexisting clinically significant sensory 
or motor neuropathy
The risk-mitigation 
strategy is amended in
line with the 
reassessment of 
important potential risks 
of the IP and to make 
the eligibility criteria 
more relevant for the 
population with 
common comorbidities 
who are representative 
of an OA population 
requiring chronic pain 
relief  
Substantial


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Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
#
Exclusion of study participants with 
preexisting clinically significant 
sensory or motor neuropathy
#
…
#
Exclusion of participants with a 
history of any malignancy, active 
liver disease, and psoriasis
•
Clinical safety monitoring and assessment 
procedures conducted at appropriate 
intervals at specified clinic visits during 
the clinical study, specifically including:
#
…
#
Follow-up (FU) required for cases of 
suspected neuropathy by neurologist 
and on protocol-prespecified cases of 
bradycardia, orthostatic hypotension, 
syncope, anhidrosis, or hypohidrosis 
by a neurologist and/or cardiologist 
(Section 8.2.2)
#
…
#
Exclusion of participants with a history of 
any malignancy, active liver disease, and 
psoriasis
•
Clinical safety monitoring and assessment 
procedures conducted at appropriate intervals at 
specified clinic visits during the clinical study, 
specifically including:
#
…
#
Follow-up (FU) required for cases of 
suspected occurrence or worsening of 
neuropathy by neurologist and on 
protocol-prespecified cases of 
bradycardia, orthostatic hypotension, 
syncope, anhidrosis, or hypohidrosis by a 
neurologist and/or cardiologist (Section 
8.2.2)
2.3.2 Benefit 
Assessment
It is hypothesised that this analgesia at relatively 
low levels of NGF suppression results from 
synergistic engagement of NGF and TNF targets 
(see the current IB for maximum and average 
percentage of free NGF suppression following 
single IV doses of MEDI7352 in the Phase I 
study D5680C00001) . It may also be 
hypothesised that higher doses of MEDI7352 
will be associated with increased TNFα 
suppression and could provide additional 
efficacy when compared to anti-NGF treatment 
alone.
It is hypothesised that this analgesia at relatively low 
levels of NGF suppression results from synergistic 
engagement of NGF and TNF targets (see the current
IB for maximum and average percentage of free NGF 
suppression following single IV doses of MEDI7352 
in the Phase I study D5680C00001) . It may also be 
hypothesised that higher doses of MEDI7352 will be 
associated with increased TNFα suppression and 
could provide additional efficacy when compared to 
anti-NGF treatment alone.
Updated to align with 
most recent version of 
the IB
Non-
substantial


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
197 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
moderate in intensity and unrelated to IP. There 
have been no clinically significant changes or 
trends for changes from baseline in safety 
parameters, including safety laboratory tests, 
vital signs, ECG assessments, physical 
examinations, or assessments of peripheral 
neurology. There have been no reports of 
destructive arthropathy. To date, a relatively 
small number of participants have been exposed 
to MEDI7352 across the ongoing Phase I and 
Phase II studies, so a full evaluation of 
risk/benefit is limited at present. Overall, no 
clinically important safety issues have emerged 
that preclude further evaluation of MEDI7352 in 
the relevant clinical study populations at 
repeated IV doses up to 450 μg/kg, and the 
benefit-risk evaluation remains favourable.
unrelated to IP. There have been no clinically 
significant changes or trends for changes from 
baseline in safety parameters, including safety 
laboratory tests, vital signs, ECG assessments, 
physical examinations, or assessments of peripheral 
neurology. There have been no reports of RPOA or
destructive arthropathy. To date, a relatively small 
number of participants have been exposed to 
MEDI7352 across the ongoing Phase I and Phase II 
studies, so a full evaluation of risk/benefit is limited at 
present. Overall, no clinically important safety issues 
have emerged that preclude further evaluation of 
MEDI7352 in the relevant clinical study populations 
at repeated IV doses up to 450 μg/kg, and the benefit
risk evaluation remains favourable.
2.3.4 Overall 
Benefit/Risk 
Conclusion
Based on available information regarding the 
risks of MEDI7352 and the precautions included 
in the clinical studies for participants with OA, 
the risks are considered acceptable in relation to 
the potential long-term analgesic benefits for 
patients with painful OA.
Based on available information regarding the risks of 
MEDI7352 and the precautions included in the 
clinical studies to protect for participants with OA, the 
risks are considered acceptable in relation to the 
potential long-term analgesic benefits for patients 
with painful OA.
Overall, no clinically important safety issues have 
emerged that preclude further evaluation of 
MEDI7352 in the relevant clinical study populations 
at exposures equivalent to those achieved with 
repeated IV doses up to 450 μg/kg. The MEDI7352 
doses used in this study are supported by adequate 
safety margins, and the benefit-risk evaluation 
remains favourable for clinical development.
Updated to align with 
most recent version of 
the IB
Non-
substantial


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
200 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
conditions after the 
Week 18 visit.
5.1 Inclusion 
Criteria
14
A mean pain intensity score ≥ 5 in the 
target knee as measured on an 11 point NRS (0 
to 10) by completion of a daily diary for 7 days 
prior to Day 1 (ie, Day  7 to Day  1, inclusive). 
At least 5 of 7 daily scores need to be recorded 
by the participant to obtain a valid baseline 
value.
14
A mean pain intensity score ≥ 5 in the target 
knee as measured on an 11 point NRS (0 to 10) by 
completion of a daily diary for 7 days prior to Day 1 
(ie, Day  7 to Day  1, inclusive). At least 5 of 7 daily 
scores need to be recorded by the participant to obtain 
a valid baseline value.
The “At least 5 of 7 
daily scores” criterion 
was specified as a 
confirmation of 
participant diary 
compliance. Therefore 
this phrase has been 
removed so as to align 
with the planned 
statistical analysis of 
this endpoint.  
Non-
substantial
5.2 Exclusion 
Criteria
2
Previously  received any form of 
anti-NGF, anti-TNF, or other biological 
DMARDs (including but not limited to 
golimumab, certolizumab, infliximab, 
adalimumab, etanercept, rituximab, abatacept, 
tocilizumab, and tofacitinib) within 12 months 
prior to screening or received other 
immunosuppressants within 6 months prior to 
screening (with the exception of inhaled or 
topical corticosteroids; for exclusionary intra-
articular corticosteroids use, refer to exclusion 
criterion 37).
2
Previously  received any form of anti-NGF; 
received , anti-TNFs including but not limited to 
golimumab, certolizumab, infliximab, adalimumab, 
etanercept, or rituximab within 12 months prior to 
screening, or other biological DMARDs (including 
but not limited to golimumab, certolizumab, 
infliximab, adalimumab, etanercept, rituximab,
abatacept, tocilizumab, and tofacitinib), or within 12 
months prior to screening or received other 
immunosuppressants within 6 months prior to 
screening (with the exception of inhaled or topical 
corticosteroids; for exclusionary intra-articular 
corticosteroids use, refer to exclusion criterion 36 37).
Previous use of 
biological DMARDs 
modified to ease this 
particular eligibility 
criterion as the change 
is not considered to 
pose a safety risk to 
study participants.
Substantial
5.2 Exclusion 
Criteria
10
Diagnosis of RA. Evaluation for 
diagnostic purposes should include serology for 
anti-citrullinated protein antibodies (ACPA) at 
screening, and ACPA levels should be normal 
(for reference lab)
10
Diagnosis of RA. Evaluation for diagnostic 
purposes should include serology for anti-citrullinated 
protein antibodies (ACPA) at screening
Exclusion can be 
deferred to the 
investigator’s 
judgement if ACPA 
level in the particular 
case is exclusionary
Substantial


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
201 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
5.2 Exclusion 
Criteria
12
Current diagnosis of a comorbid 
condition known to be associated with other 
forms of arthritis or joint pathology other than 
OA, including but not necessarily limited to 
immunological or autoimmune diseases (eg, RA, 
lupus erythematosus, inflammatory bowel 
disease, Crohn's disease, ulcerative colitis, 
ankylosing spondylitis ); psoriasis; seronegative 
spondyloarthropathies; or other diseases 
involving the target joint (including 
endocrinopathies, metabolic joint diseases, joint 
infections, Paget’s disease, or tumours)
12
Current diagnosis of a comorbid condition 
known to be associated with other forms of arthritis or 
joint pathology other than OA, including but not 
necessarily limited to immunological or autoimmune 
diseases (eg, RA, lupus erythematosus, inflammatory 
bowel disease, Crohn's disease, ulcerative colitis, 
ankylosing spondylitis ); psoriasis; seronegative 
spondyloarthropathies; or other diseases involving the 
target joint (including endocrinopathies, metabolic 
joint diseases, joint infections, Paget’s disease, or 
tumours)
Participants with 
psoriasis that is not 
associated with 
comorbid arthropathy, 
that could affect 
efficacy or safety 
assessment in the study 
population, can be 
included.
Substantial
5.2 Exclusion 
Criteria
13
The following  conditions (including 
screening imaging results suggestive of these 
conditions as per central reader evaluation) 
should be excluded: RPOA, primary 
osteonecrosis (including spontaneous 
osteonecrosis of the knee), SIF, avascular 
necrosis, osteoporotic fractures, atrophic OA, hip 
dislocation, congenital hip dysplasia with 
degenerative joint disease, excessive 
malalignment of the knee (anatomical axis angle 
greater than 10 degrees), pathological fractures, 
stress fracture or reaction, vertical tear of the 
posterior meniscal root, or large or extensive 
subchondral cysts.
13
The following  conditions (based on
including screening imaging results suggestive of 
these conditions as per central reader evaluation) 
should be excluded: RPOA, primary osteonecrosis 
(including spontaneous osteonecrosis of the knee), 
SIF, avascular necrosis, osteoporotic fractures, 
atrophic OA, hip dislocation, congenital hip dysplasia 
with degenerative joint disease, excessive 
malalignment of the knee (anatomical axis angle 
greater than 10 degrees), pathological fractures, or
stress fracture or reaction, vertical tear of the posterior 
meniscal root, or large or extensive subchondral cysts.
Given the relatively 
short dosing period in 
this study and that the 
excluded imaging 
findings are common in 
an OA population, it is 
considered reasonable 
to include a broader OA 
population to study risk 
factors of RPOA and 
MEDI7352 safety. The 
conditions being 
removed are not 
considered as identified 
risk factors of RPOA 
based on the available 
data from clinical 
development 
programmes for 
anti-NGFs.  
Substantial
5.2 Exclusion 
Criteria
14
History  of significant trauma (eg, 
intra-articular fracture) or surgery (excluding 
injection therapies and arthroscopy) to a knee, 
hip, or shoulder within the previous year. Refer 
14
History  of significant trauma (eg, 
intra-articular fracture) or surgery (excluding injection 
therapies and arthroscopy) to a knee, hip, or shoulder 
within 1 the previous year prior to screening or 
Surgery is moved to the 
procedures-related 
exclusion criteria.
Substantial


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Non-substantial
to exclusion criterion 34 for nondiagnostic 
arthroscopy.  
between screening and randomisation. Refer to 
exclusion criterion 34 for nondiagnostic arthroscopy.  
Added clarification that 
condition is still 
exclusionary if it occurs 
between screening and 
randomisation
5.2 Exclusion 
Criteria
16
Presence of neuropathic pain, complex 
regional pain syndrome, or the following chronic 
primary pain syndromes (per the eleventh edition 
of the International Classification of Diseases): 
fibromyalgia or chronic widespread pain.
16
Presence of neuropathic pain (except for 
pain related to tunnel neuropathies in upper limbs), 
complex regional pain syndrome, or the following
chronic primary pain syndromes (per the eleventh 
edition of the International Classification of 
Diseases): eg, fibromyalgia or chronic widespread 
pain.
Exception for tunnel 
neuropathies in upper 
limbs added to align 
with the modified 
exclusion criterion 18.
Substantial
5.2 Exclusion 
Criteria
18
Presence of clinically significant 
neuropathy (eg, hereditary neuropathy, diabetic 
neuropathy, inflammatory neuropathy, nerve 
compression injury, carpal tunnel syndrome) or 
other clinically significant disorder associated 
with sensory abnormalities
18
Presence of clinically significant 
neuropathy (eg, hereditary neuropathy, autonomic or
diabetic neuropathy, inflammatory neuropathy., nerve 
compression injury, carpal tunnel syndrome) or other 
clinically significant disorder associated with sensory 
abnormalities
Note: entrapment/tunnel neuropathy affecting the 
upper limbs that is considered stable is not necessarily 
excluded; sensory neuropathy that is considered stable 
and non-progressive for at least 6 months is not 
necessarily excluded.
Note: for non-exclusionary neuropathies, there is a 
requirement for participants to undergo a baseline 
evaluation by a neurologist and to have relevant nerve 
conduction studies conducted and documented at 
baseline.
Make the eligibility 
criteria more relevant 
for the older population 
with OA who require 
pain relief with 
comorbidities such as 
tunnel and sensory 
neuropathies 
Substantial
5.2 Exclusion 
Criteria
19
Requires walker or wheelchair for 
mobility
19
Requires wheelchair for mobility  
Participants using 
walkers will be allowed 
to take part in the study 
Substantial
5.2 Exclusion 
Criteria
22
Significant or chronic lung disease, 
including severe or unstable chronic obstructive 
pulmonary disease, severe or unstable asthma, 
22
Significant or chronic lung disease, 
including severe or unstable chronic obstructive 
pulmonary disease, severe or unstable asthma, current 
pneumonitis, or interstitial lung disease
To allow inclusion of 
participants with past 
history of pneumonitis 
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Substantial/ 
Non-substantial
current or past history of pneumonitis, or 
interstitial lung disease
or interstitial lung 
disease who have been 
cured and whose 
condition is not ongoing 
5.2 Exclusion 
Criteria
23
Diabetes complicated with retinopathy 
(by history), neuropathy (by history or physical 
examination), or nephropathy. Uncomplicated, 
stable diabetes that is well controlled and 
actively managed is not exclusionary.
23
Diabetes complicated with retinopathy (by 
history), neuropathy (by history or physical 
examination), or nephropathy. Uncomplicated, stable 
diabetes that is well controlled and actively managed 
is not exclusionary. Haemoglobin A1c levels above 
8.5 are exclusionary.
Clarification of the 
exclusionary levels of 
HbA1C for participants 
with diabetes
Substantial
5.2 Exclusion 
Criteria
24
Known or suspected systemic 
infection, including HIV, HBV, HCV, or TB 
should be excluded. If QuantiFERON test is 
positive at screening, participants will be 
excluded from the study. 
24
Known or suspected systemic infection, 
including HIV, HBV, HCV, or TB should be 
excluded. If QuantiFERON test is positive at 
screening, participants will be excluded from the 
study except for the cases when the QuantiFERON 
test remains positive after the successful treatment of 
TB as confirmed and documented by the relevant 
specialist. 
Provision to include 
participants with a 
positive QuantiFERON 
test after successful 
treatment of active or 
latent TB, as it is 
possible that the 
QuantiFERON test 
remains positive after 
successful treatment.
Substantial
5.2 Exclusion 
Criteria
26
History or evidence of any significant 
autoimmune disease or demyelinating disorder, 
including multiple sclerosis, optic neuritis, 
transverse myelitis, peripheral demyelinating 
neuropathy; history or current diagnosis of 
epilepsy; current diagnosis of autonomic 
neuropathy; active liver disease; or history of any 
underlying condition that predisposes participant 
to infections (such as splenectomy or primary or 
secondary immunodeficiency syndrome)
26
History or evidence of any significant 
autoimmune disease or demyelinating disorder, 
including multiple sclerosis, optic neuritis, transverse 
myelitis, peripheral demyelinating neuropathy; 
history or current diagnosis of epilepsy; current 
diagnosis of autonomic neuropathy; active liver 
disease; or history of any underlying condition that 
predisposes participant to infections (such as 
splenectomy or primary or secondary 
immunodeficiency syndrome)
Exclusionary 
autoimmune diseases 
are captured in 
exclusion criterion 12; 
exclusionary 
neuropathies are 
captured in exclusion 
criterion 18, 
exclusionary 
predisposition to 
infection is captured in 
exclusion criterion 31 
for consistency. 
Participants with 
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Non-substantial
autoimmune diseases 
other than those listed 
in exclusion criterion 12 
might be enrolled at the 
investigator's discretion 
provided that other 
eligibility criteria are 
met.
5.2 Exclusion 
Criteria
27
History of severe 
allergy/hypersensitivity reactions or ongoing 
allergy/hypersensitivity reactions, including a 
history of hypersensitivity to immunisations or 
immunoglobulins and/or biological therapies (eg, 
etanercept)
27
History of anaphylactic/severe
hypersensitivity reactions, history of hypersensitivity 
to immunisations or immunoglobulins and/or 
biological therapies (eg, etanercept) or ongoing 
hypersensitivity reactions
Clarification that not all 
severe allergic reactions 
in the medical history 
are exclusionary 
Substantial
5.2 Exclusion 
Criteria
28
History of cancer or diagnosis of 
cancer between screening and randomisation
28
Lifetime history of haematopoietic 
malignancies, history of other cancers within 5 years 
prior to screening except for cervical carcinoma in 
situ, in situ colon cancer, or non-invasive malignant 
colon polyps treated by excision at least 2 years ago 
with no evidence of recurrence . History of cancer or 
d Diagnosis of any cancer between screening and 
randomisation
To make the eligibility 
criteria more relevant 
for the older population 
with OA with common 
comorbidities including 
medical history of 
successfully treated 
cancer.
Clarified that diagnosis 
of any cancer between 
screening and 
randomization is 
exclusionary.
Substantial
5.2 Exclusion 
Criteria
29
Transient ischaemic attack or stroke in 
the last 12 months prior to screening
29
Transient ischaemic attack in the last 
6 months prior to screening or stroke in the last 
12 months prior to screening; transient ischaemic 
attack or stroke between screening and randomisation
Possibility to decrease 
the time elapsed from 
transient ischemic 
attack to 6 months is 
aligned with the 
evaluation of potential 
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Substantial/ 
Non-substantial
risks related to 
MEDI7352 exposure 
Additional text to 
clarify exclusion of 
participants who have a 
transient ischaemic 
attack or stroke during 
the period between 
screening and 
randomisation.
5.2 Exclusion 
Criteria
30
History of substance use disorders 
(SUD) including alcohol or recreational drugs 
according to the criteria in the Diagnostic and 
Statistical Manual of Mental Disorders (fifth 
edition) within 2 years prior to screening (with 
the exception of tobacco SUD)
30
History of substance use disorders (SUD) 
including alcohol or recreational drugs according to 
the criteria in the Diagnostic and Statistical Manual of 
Mental Disorders (fifth edition) within 2 years prior to 
randomisation screening (with the exception of 
tobacco SUD)
Text added to clarify 
that SUD prior to 
randomisation is 
exclusionary (including 
the period between 
screening and 
randomisation).
Substantial
5.2 Exclusion 
Criteria
31
Current active infection, chronic or 
persistent systemic infection, or serious or severe 
localized or systemic infection within 3 months 
prior to screening or between screening and 
randomisation. Note that: 
- Any history of severe COVID-19 infection (eg, 
requiring hospitalisation, intensive care unit care, 
or assisted ventilation) or any prior COVID-19 
infection with unresolved sequelae is 
exclusionary. Any acute SARS-COV-2/COVID-
19 infection, including asymptomatic, mild, or 
moderate (lab confirmed or suspected based on 
clinical symptoms) within the last 6 months prior 
to screening is also exclusionary.
31
Current active infection, chronic or 
persistent systemic infection, or serious or severe 
localized or systemic infection within 3 months prior 
to screening or between screening and randomisation, 
or history of any underlying condition that 
predisposes participant to infections (such as 
splenectomy or primary or secondary 
immunodeficiency syndrome). Note that: 
- Any history of severe COVID-19 infection (eg, 
requiring hospitalisation, intensive care unit care, or 
assisted ventilation) or any prior COVID-19 infection 
with unresolved sequelae is exclusionary. Any acute 
SARS-COV-2/COVID-19 infection, including 
asymptomatic, mild, or moderate (lab confirmed or 
suspected based on clinical symptoms) within the last 
3 6 months prior to screening or between screening 
and randomisation is also exclusionary.
Moved from exclusion 
criterion 26.
Evolving knowledge of 
COVID-19 infection as 
well as data about the 
safety profile of 
MEDI7352 allows for 
restriction of the 
exclusionary period for 
asymptomatic, mild, or 
moderate SARS-COV-
2/COVID-19 infection 
to 3 months prior to 
screening or between 
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Non-substantial
screening and 
randomisation
5.2 Exclusion 
Criteria
32
Current serious or unstable clinically 
important illness, including respiratory, 
cardiovascular, gastrointestinal, endocrinologic, 
immunologic, haematologic, or neurological or 
other major disease that is likely to deteriorate or 
affect the participant’s safety or ability to 
complete the study, as judged by the investigator
32
Current serious or unstable clinically 
important illness, including respiratory, 
cardiovascular, gastrointestinal, endocrinologic, 
immunologic, haematologic, or neurological or other 
major disease that is likely to deteriorate or affect the 
participant’s safety or ability to complete the study, as 
judged by the investigator. Note: current diagnosis of 
cirrhosis of the liver is exclusionary.
Additional text added to 
clarify the exclusion of 
participants with 
cirrhosis of the liver.
Substantial
5.2 Exclusion 
Criteria
New criterion added as exclusion criterion 33
33
Family history of long QT syndrome
Subsequent exclusion criteria renumbered
Moved from 
ECG-related criterion 
44
Non-
substantial
5.2 Exclusion 
Criteria
34
Nondiagnostic arthroscopy performed 
on the target knee joint within 180 days prior to 
screening; diagnostic arthroscopy performed 
within 90 days prior to screening
35 34
History of surgery to a knee, hip, or 
shoulder within 1 year prior to screening or between 
screening and randomisation except for arthroscopy.
Note: Nondiagnostic arthroscopy performed on the 
target knee joint within 180 days prior to screening; 
or diagnostic arthroscopy performed on the target 
knee joint within 90 days prior to screening are 
exclusionary. Arthroscopy performed between 
screening and randomisation is exclusionary.
Moved from exclusion 
criterion 14 for 
consistency
Additional text to 
clarify exclusion of 
participants who have 
surgery to the knee, hip, 
or shoulder during the 
period between 
screening and 
randomisation.
Substantial
5.2 Exclusion 
Criteria
37
Intra-articular platelet-rich plasma 
treatment on the target joint within 6 months 
prior to screening
37
Intra-articular platelet-rich plasma treatment 
on the target joint within 6 months prior to screening 
or between screening and randomisation.
Additional text to 
clarify exclusion of 
participants who 
received intra-articular 
platelet-rich plasma 
treatment on the target 
joint during the period 
between screening and 
randomisation.
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Substantial/ 
Non-substantial
5.2 Exclusion 
Criteria
Exclusion criterion 44
•
A corrected QT interval by Fredericia 
(QTcF) interval measurement of 
> 470 milliseconds or family history of 
long QT syndrome
Exclusion criterion 45 44
•
Note that a corrected QT interval by Fredericia 
(QTcF) interval measurement 
of◦>◦470◦milliseconds or family history of long 
QT syndrome is exclusionary.
To clarify exclusion 
criterion. Family history 
text moved to medical 
history exclusion 
criterion.
Non-
substantial
5.2 Exclusion 
Criteria
45
Participant with > 2 × upper limit of 
normal (ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), or alkaline phosphatase 
(ALP) or > ULN total bilirubin (> 1.5 × ULN if 
known Gilbert’s syndrome)
∀
If a participant has elevations in total 
bilirubin only that are > ULN and < 1.5 × 
ULN, fractionated bilirubin should be 
checked to identify possible undiagnosed 
Gilbert’s syndrome (eg, direct bilirubin < 
35%).
46 45
Participant with > 2 × upper limit of normal 
(ULN) of any of the following: alanine 
aminotransferase (ALT), aspartate aminotransferase 
(AST), or alkaline phosphatase (ALP) or > 1.5 × ULN 
total bilirubin (> 1.5 × ULN if known Gilbert’s 
syndrome)
∀
If a participant has elevations in total bilirubin 
only that are > ULN and < 1.5 × ULN, 
fractionated bilirubin should be checked to 
identify possible undiagnosed Gilbert’s 
syndrome (eg, direct bilirubin < 35%).
Participants with 
baseline total bilirubin 
levels  ≤ 1.5 × ULN due 
to the reasons that are 
not contradictory with 
other exclusion criteria 
are good candidates for 
the study. 
Substantial
5.2 Exclusion 
Criteria
46
Estimated creatinine clearance 
< 60 ml/min at screening
47 46
Estimated creatinine clearance ≤ 50
< 60 ml/min at screening
Less stringent creatinine 
clearance cut-off to 
assess MEDI7352 
safety in the relevant 
OA population where 
creatinine clearance 50 
to 60 ml/min is a 
common finding.
Substantial
5.2 Exclusion 
Criteria
50
Participant requires aspirin at doses 
greater than 100 mg/day for cardiovascular 
prophylaxis or requires treatment with vitamin  
K dependent anticoagulant (eg, warfarin, 
coumadin), or nonvitamin K dependent novel 
oral anticoagulants (eg, dabigatran, rivaroxaban, 
apixaban, and edoxaban).
51 50
Participant requires aspirin at doses greater 
than 325 100 mg/day for cardiovascular prophylaxis 
or requires treatment with vitamin  K dependent 
anticoagulant (eg, warfarin, coumadin), or nonvitamin 
K dependent novel oral anticoagulants (eg, 
dabigatran, rivaroxaban, apixaban, and edoxaban).
To make the eligibility 
criteria more relevant 
for the broader OA 
population with 
common comorbidities 
and medications 
required for their 
treatment
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Substantial/ 
Non-substantial
6.5.1 Permitted 
Concomitant 
Therapy
The following treatments are permitted, with 
restrictions:
… 
•
Medications for the treatment of 
nonexcluded medical conditions (eg, 
depression, hypertension, and diabetes 
mellitus) are permitted, including 
antihypertensive, cholesterol-lowering, and 
antidiabetic medications; antidepressants; 
and sedative/hypnotics as judged clinically 
acceptable by the investigator and the 
medical monitor.
The following treatments are permitted, with 
restrictions:
… 
•
Medications for the treatment of nonexcluded 
medical conditions (eg, depression, 
hypertension, and diabetes mellitus) are 
permitted, including antihypertensive, 
cholesterol-lowering, and antidiabetic 
medications; antidepressants; and 
sedative/hypnotics as judged clinically 
acceptable by the investigator and the medical 
monitor.
Consultation with the 
medical monitor about 
all medications for 
non-exclusionary 
conditions is not 
mandatory. The new 
text on conditions when 
consultation with 
medical monitor about 
concomitant 
medications is advisable 
is added to this section.
Non-
substantial
6.5.1 Permitted 
Concomitant 
Therapy
The following treatments are permitted, with 
restrictions:
…
•
Low-dose aspirin up to 100 mg/day is 
permitted for cerebrovascular or 
cardiovascular prophylaxis.
The following treatments are permitted, with 
restrictions:
…
•
Low-dose aspirin up to 325 100 mg/day is 
permitted for cerebrovascular or cardiovascular 
prophylaxis.
To permit aspirin at the 
doses that are 
commonly used for 
cerebrovascular or 
cardiovascular 
prophylaxis
Substantial
6.5.1 Permitted 
Concomitant 
Therapy
New text added under “The following treatments 
are permitted, with restrictions:”
The following treatments are permitted, with 
restrictions:
•
Limited (no more than 10 days per 8-week 
period) concomitant use of prescription or OTC 
NSAIDs may be allowed on an occasional basis 
for self-limiting conditions not related to 
osteoarthritis (eg, migraine attack), after the 
Week 18 FU visit. The study medical monitor 
should be contacted for approval prior to use 
whenever possible, and all doses and days of 
use will be recorded in the eCRF.
Provision for limited 
use of NSAIDs during 
the FU period (after 
Week 18) to treat 
potential comorbidities 
with NSAIDs/ 
COX-inhibitors.
Substantial
6.5.1 Permitted 
Concomitant 
Therapy
New text added
If a new medication has to be introduced or the dose 
of concomitant medication needs to be changed 
during the double-blind treatment period, consultation 
with the medical monitor is advisable.
Clarification when 
investigators are 
expected to discuss 
concomitant therapy 
with a medical monitor.
Non-
substantial


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Non-substantial
6.5.1 Permitted 
Concomitant 
Therapy
However, intra-articular injections/interventions, 
NSAIDs, COX-2 inhibitors, and aspirin (in doses 
that exceed 100 mg/day) are prohibited until after 
the last FU visit (Visit 13).
However, intra-articular injections/interventions, 
NSAIDs, COX-2 inhibitors, and aspirin (in doses that 
exceed 325 100 mg/day) are prohibited until after the 
last FU visit (Visit 14 13).
To align with the 
updated allowed dose of 
aspirin, and updated 
visit schedule
Substantial 
(consequential)
6.5.2 Prohibited 
Concomitant 
Medications
The following treatments are prohibited during 
the study:
•
Vitamin K-dependent anticoagulants (eg, 
warfarin, coumadin) or nonvitamin K 
dependent novel oral anticoagulants (eg, 
dabigatran, rivaroxaban, apixaban, and 
edoxaban)
•
The use of NSAIDs, COX-2 inhibitors, or 
aspirin (> 100 mg/day) at any time from 
the start of the washout period until after 
the last FU visit (Week 32) is prohibited. 
This includes OTC pain medications and 
topical analgesics that contain an NSAID 
or COX 2 inhibitor. For participants who 
discontinue IP early, NSAIDs, COX-2 
inhibitors, or aspirin use is described in 
Section 7.1.2.
•
Use of analgesics other than paracetamol 
(including but not limited to weak opioids 
and topical applications of capsaicin and 
formulations containing local anaesthetic 
(eg, lidocaine) is prohibited from the start 
of the washout period until the Week 18 
FU visit.
•
Any other investigational drug or device, 
including other immunotherapeutics
•
Live viral or attenuated bacterial vaccines 
are disallowed from 28 days prior to the 
first IP dose, during IP administration, and 
for 2 months after the last IP 
administration.
•
Oral, IV, intramuscular, or any other 
parenteral steroids (Note that inhaled 
The following treatments are prohibited during the 
study:
•
Vitamin K-dependent anticoagulants (eg, 
warfarin, coumadin) or nonvitamin K dependent 
novel oral anticoagulants (eg, dabigatran, 
rivaroxaban, apixaban, and edoxaban)
•
The use of analgesics other than rescue 
medication (paracetamol) including but not 
limited to opioids, topical applications of 
capsaicin, and formulations containing local 
anaesthetic for OA pain treatment is prohibited 
from the start of the washout period until the 
Week 18 FU visit.
•
The use of NSAIDs, COX-2 inhibitors for OA 
treatment, or use of aspirin (> 325 100 mg/day) 
at any time from the start of the washout period 
until after the last FU visit (Week 36 32) is 
prohibited. This includes OTC pain medications 
and topical analgesics that contain an NSAID or 
COX 2 inhibitor. For participants who 
discontinue IP early, NSAIDs, COX-2 
inhibitors, or aspirin use is described in Section 
7.1.2.
•
Use of analgesics other than paracetamol 
(including but not limited to weak opioids and 
topical applications of capsaicin and 
formulations containing local anaesthetic (eg, 
lidocaine) is prohibited from the start of the 
washout period until the Week 18 FU visit.
•
Any other investigational drug or device, 
including other immunotherapeutics
•
COVID-19 vaccines
Amended in line with 
exclusion criteria 
updates.
Reordered for clarity 
(medication prohibited 
during all study periods 
vs medications 
prohibited during 
prespecified study 
periods).
As pre-screening 
restrictions are covered 
in the exclusion criteria, 
only restrictions 
applicable for the study 
should be detailed here.
Clarification by 
removing medications 
use before participation 
in the study that is 
covered in exclusion 
criterion 2.
Substantial 
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steroids for well-controlled chronic 
obstructive pulmonary disease or asthma or 
topical steroids for eczema are permitted). 
(Also refer to exclusion criteria 2 and 3.)
•
Any drug of abuse including but not 
limited to amphetamine, barbiturate, 
cannabis, cocaine, methadone, 
methaqualone, opiate, phencyclidine, or 
propoxyphene, with the following 
exceptions:
!
Sedative/hypnotics used as described 
above
!
Barbiturates as a constituent of 
antimigraine medication (eg, 
Fioricet)
!
Short-term sedation and/or analgesia 
if needed to perform study procedure 
(eg, MRI). (Note: These should not 
be given within 48 hours prior to a 
study visit or during the collection of 
ePRO pain data from Day -7 to 
Day -1 [inclusive] for baseline NRS 
pain evaluation.)
•
Muscle relaxants, anticonvulsants, anti-
Parkinsonian medications, or neuroleptic 
medications, unless used for nonexcluded 
conditions such restless leg syndrome, are 
prohibited. 
•
Corticosteroid injection or intra-articular 
hyaluronic acid injection on the target knee 
within 12 weeks prior to screening, 
corticosteroid injection on a nontarget joint 
within 12 weeks prior to screening, or 
intra-articular hyaluronic acid injection on 
a nontarget joint within 6 weeks prior to 
screening are prohibited. These therapies 
!
If a study participant is being considered 
for enrolment into the study and also for 
COVID-19 vaccination, the participant 
must not be randomised until 30 days 
after the last dose of COVID-19 vaccine 
or ‘booster dose’ (whichever is required to 
consider vaccination complete in line with 
applicable guidance). Note that this is 
applicable only to COVID-19 vaccines, 
irrespective of their modality, which are 
currently approved by Health Authorities 
or otherwise approved under relevant 
regulations, eg, emergency use 
authorisation (FDA)/conditional 
marketing authorisation (European 
Medicines Agency)/temporary supply 
(Medicines and Healthcare Products 
Regulatory Agency).
•
Live viral or attenuated bacterial vaccines are 
disallowed from 28 days prior to the first IP 
dose, during IP administration, and for 2 months 
after the last IP administration.
•
Oral, IV, intramuscular, or any other parenteral 
steroids (Note that inhaled steroids for well
controlled chronic obstructive pulmonary 
disease or asthma or topical steroids for eczema 
are permitted). (Also refer to exclusion criteria 2 
and 3.)
•
Any drug of abuse including but not limited to 
amphetamine, barbiturate, cannabis, cocaine, 
methadone, methaqualone, opiate, 
phencyclidine, or propoxyphene, with the 
following exceptions:
!
Sedative/hypnotics used as described 
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(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
are also prohibited during the study. (Note: 
Intra-articular injections are not permitted 
during the study with the exception of 
cases of ET when this treatment option is 
deemed necessary by the investigator. In 
such cases, initiation of intra-articular 
corticosteroid injections should be deferred 
until at least 8 weeks after the last IP 
administration.)
•
The following therapies are prohibited 
from 12 months prior to screening and 
during the study: 
!
Etanercept and medications known to 
interact with etanercept, specifically 
anakinra, abatacept, and sulfasalazine
!
Other DMARDs, including but not 
limited to golimumab, certolizumab, 
infliximab, adalimumab, rituximab, 
tocilizumab, and tofacitinib
!
Any other form of anti-TNF or anti-
NGF therapy 
!
Other immunosuppressants are 
prohibited from within 6 months 
prior to screening and during the 
study. The restrictions related to use 
of intra-articular corticosteroid 
injections are mentioned above.
•
COVID-19 vaccines
!
If a study participant is being 
considered for enrolment into the 
study and also for COVID-19 
vaccination, the participant must not 
be randomised until 30 days after the 
last dose of COVID-19 vaccine or 
‘booster dose’ (whichever is required 
!
Barbiturates as a constituent of 
antimigraine medication (eg, Fioricet)
!
Short-term sedation and/or analgesia if 
needed to perform study procedure (eg, 
MRI). (Note: These should not be given 
within 48 hours prior to a study visit or 
during the collection of ePRO pain data 
from Day 7 to Day 1 [inclusive] for 
baseline NRS pain evaluation.)
•
Muscle relaxants, anticonvulsants, anti
Parkinsonian medications, or neuroleptic 
medications, unless used for nonexcluded 
conditions such restless leg syndrome, are 
prohibited. 
•
Corticosteroid injection or intra-articular 
hyaluronic acid injection on the target knee 
within 12 weeks prior to screening, 
corticosteroid injection on a nontarget joint 
within 12 weeks prior to screening, or intra
articular hyaluronic acid injection on a 
nontarget joint within 6 weeks prior to 
screening are prohibited. These therapies are 
also prohibited during the study. (Note: Intra-
articular injections are not permitted during the 
study, including the screening period, with the 
exception of cases of ET when this treatment 
option is deemed necessary by the investigator. 
In such cases, initiation of intra-articular 
corticosteroid injections should be deferred until 
at least 8 weeks after the last IP 
administration.)
•
The following therapies are prohibited from 
12 months prior to screening and during the 
study starting from the screening period (please 
also refer to exclusion criteria 2, 5, 36, 51): 


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
212 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
to consider vaccination complete in 
line with applicable guidance). Note 
that this is applicable only to 
COVID-19 vaccines, irrespective of 
their modality, which are currently 
approved by Health Authorities or 
otherwise approved under relevant 
regulations, eg, emergency use 
authorisation (FDA)/conditional 
marketing authorisation (European 
Medicines Agency)/temporary 
supply (Medicines and Healthcare 
Products Regulatory Agency).
!
Etanercept and medications known to 
interact with etanercept, specifically 
anakinra, abatacept, and sulfasalazine
!
Other DMARDs, including but not limited 
to golimumab, certolizumab, infliximab, 
adalimumab, rituximab, tocilizumab, and 
tofacitinib
!
Any other form of anti-TNF or anti-NGF 
therapy 
!
Other immunosuppressants are prohibited 
from within 6 months prior to screening 
and during the study. The restrictions 
related to use of intra-articular 
corticosteroid injections are mentioned 
above.
!
Vitamin K-dependent anticoagulants (eg, 
warfarin)
!
Oral, IV, intramuscular, or any other 
parenteral steroids (Note that inhaled 
steroids for well-controlled chronic 
obstructive pulmonary disease or asthma 
or topical steroids for eczema are 
permitted).
!
Any drug of abuse including but not 
limited to amphetamine, barbiturate, 
cannabis, cocaine, methadone, 
methaqualone, opiate, phencyclidine, or 
propoxyphene, with the following 
exceptions:
- Sedative/hypnotics used as described 
above
- Barbiturates as a constituent of 
antimigraine medication (eg, Fioricet)


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
213 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
- Short-term sedation and/or analgesia if 
needed to perform study procedure (eg, 
MRI). (Note: These should not be given 
within 48 hours prior to a study visit or 
during the collection of ePRO pain data 
from Day -7 to Day -1 [inclusive] for 
baseline NRS pain evaluation.) 
!
Muscle relaxants, anticonvulsants, anti-
Parkinsonian medications, or neuroleptic 
medications, unless used for nonexcluded 
conditions, such as restless leg syndrome, 
are prohibited.
!
Any other investigational drug or device, 
including other immunotherapeutics  
•
COVID 19 vaccines
!
If a study participant is being considered 
for enrolment into the study and also for 
COVID 19 vaccination, the participant 
must not be randomised until 30 days 
after the last dose of COVID 19 vaccine 
or ‘booster dose’ (whichever is required to 
consider vaccination complete in line with 
applicable guidance). Note that this is 
applicable only to COVID 19 vaccines, 
irrespective of their modality, which are 
currently approved by Health Authorities 
or otherwise approved under relevant 
regulations, eg, emergency use 
authorisation (FDA)/conditional 
marketing authorisation (European 
Medicines Agency)/temporary supply 
(Medicines and Healthcare Products 
Regulatory Agency).


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
214 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
6.5.3 Rescue 
Medication
Participants who develop unacceptable pain 
during any stage of the study (including during 
the washout period and the period between 
completion of washout and randomisation) will 
be permitted to initiate rescue analgesic therapy 
with paracetamol using a dosing regimen that is 
aligned with local standards of prescribing 
practice and as described in the patient 
information leaflet and approved by the 
investigator.
Participants who develop unacceptable pain during 
any stage of the study until the Week 18 visit or ET 
visit, whichever is earlier (including during the 
washout period and the period between completion of 
washout and randomisation) will be permitted to 
initiate rescue analgesic therapy with paracetamol 
using a dosing regimen that is aligned with local 
standards of prescribing practice and as described in 
the patient information leaflet and approved by the 
investigator.
Wording amended to 
correct an inconsistency 
and to align with the 
study design where 
participants may be 
given standard of care 
therapy after the Week 
18 visit (for participants 
who have completed 
treatment) or the ET 
visit (for participants 
for whom IP 
administration has been 
discontinued earlier) so 
there is no need to use 
paracetamol as rescue 
medication after those 
visits.  
Non-
substantial
7.1.1 Subject-
specific Criteria for 
Discontinuation of 
Investigational 
Product
For any individual participant, further 
administration of IP will be stopped if any of the 
following scenarios occur:
•
Reports of drug-related SAE(s) or drug-
related AE(s) including but not necessarily 
limited to:
… 
#
Renal toxicity, defined as serum 
creatinine ≥ 1.5 × ULN
For any individual participant, further administration 
of IP will be stopped if any of the following scenarios 
occur:
•
Reports of drug-related SAE(s) or drug-related 
AE(s) including but not necessarily limited to:
… 
#
Renal toxicity, defined as serum 
creatinine ≥ 1.5 × ULN
Criterion removed to 
address the changes in 
exclusion criteria 
Substantial 
(consequential)
7.1.2 Procedures for 
Early 
Discontinuation of 
Investigational 
Product
However, initiation of NSAIDs, COX-2 
inhibitors, and aspirin (in doses that exceed 100 
mg/day) is prohibited until after 5 half-lives 
following the last IP administration (ie, 
approximately 3 weeks).
However, initiation of NSAIDs, COX-2 inhibitors, 
and aspirin (in doses that exceed 325 100 mg/day) is 
prohibited until after 5 half-lives following the last IP 
administration (ie, approximately 3 weeks).
To align with the 
updated allowed dose of 
aspirin 
Substantial 
(consequential)


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
215 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
7.1.2 Procedures for 
Early 
Discontinuation of 
Investigational 
Product
All participants prematurely discontinued from 
IP are expected to complete the ET visit and the 
20 week FU period, which consists of 3 FU 
clinic visits and 3 phone calls at the times 
indicated below:
…
•
FU visit 2: Week 28 assessments to be 
performed 18 weeks after the last IP 
administration
•
FU visit 3: Week 32 assessments to be 
performed 22 weeks after the last IP 
administration 
All participants prematurely discontinued from IP are 
expected to complete the ET visit and the 24 20-week 
FU period, which consists of 3 FU clinic visits and 4
3 phone calls at the times indicated below:
…
•
FU phone call 4 visit 2: To be conducted Week 
28 assessments to be performed 18 weeks after 
the last IP administration
•
FU visit 2 3: Week 32 assessments to be 
performed 22 weeks after the last IP 
administration
•
FU visit 3: Week 36 assessments to be 
performed 26 weeks after the last IP 
administration
Number and time points 
of visits updated due to 
change in the duration 
of the FU period
Substantial 
(consequential)
7.1.3 Temporary 
Discontinuation of 
Investigational 
Product
Withholding IP administration temporarily may 
be considered in the following cases:
...
•
AE suggestive of peripheral neuropathy
Withholding IP administration temporarily may be 
considered in the following cases:
...
•
AE suggestive of new occurrence or worsening 
of peripheral neuropathy
Updated criterion in 
line with updated 
exclusion criterion 18 
Substantial 
(consequential)
7.1.3 Temporary 
Discontinuation of 
Investigational 
Product
Participants with AEs suggestive of peripheral 
neuropathy as per investigator’s neurological 
assessment should be evaluated by a neurologist 
as soon as possible.
…
The participant should not be dosed with the 
subsequent dose of IP until (if applicable) the 
absence of sensory abnormalities, sympathetic 
dysfunction, peripheral neuropathy or Class 3 or 
Class 4 (NYHA 1994) heart failure have been 
confirmed, or RPOA, SIF, primary 
osteonecrosis, or pathological fracture have been 
excluded.
Participants with AEs suggestive of new occurrence 
or worsening of peripheral neuropathy as per 
investigator’s neurological assessment should be 
evaluated by a neurologist as soon as possible.
…
The participant should not be dosed with the 
subsequent dose of IP until (if applicable) the absence 
of sensory abnormalities, sympathetic dysfunction, 
new occurrence or worsening of peripheral 
neuropathy or Class 3 or Class 4 (NYHA 1994) heart 
failure have been confirmed, or RPOA, SIF, primary 
osteonecrosis, or pathological fracture have been 
excluded.
Updated in line with 
updated exclusion 
criterion 18
Substantial 
(consequential)


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
218 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
•
AE of abnormal sensation such as 
allodynia, burning sensation, dysesthesia, 
hyperesthesia, hypoesthesia, neuralgia, 
paresthesia, or sensory loss 
•
AE of new occurrence or worsening of
abnormal sensation such as allodynia, burning 
sensation, dysesthesia, hyperesthesia, 
hypoesthesia, neuralgia, paresthesia, or sensory 
loss
inclusion of some 
non-exclusionary 
neuropathies
8.2.2 Neurological 
Examinations
None: new text
For participants with clinical manifestations 
consistent with worsening of pre-existing neuropathy, 
follow-up nerve conduction studies should be 
performed and documented at the time points deemed 
appropriate by the neurologist, but at least once 
during participation in the study.
Guidance on FU of 
worsening of 
non-exclusionary 
neuropathy added.
Substantial
8.2.2 Neurological 
Examinations
The participant should not be dosed with the 
subsequent dose of IP until the absence of 
peripheral neuropathy or another neurological 
condition that meets prespecified criteria for IP 
discontinuation has been confirmed.
The participant should not be dosed with the 
subsequent dose of IP until the absence of the
peripheral neuropathy or another neurological 
condition that meets prespecified criteria for IP 
discontinuation has been confirmed.
Language on the FU of 
peripheral neuropathy 
during the study has 
been amended to align 
with the possibility of 
inclusion of some 
non-exclusionary 
neuropathies
Substantial
8.2.4
Electrocardiograms
On all other dosing days, ECG recording will be 
performed at 30 to 60 minutes prior to IP 
administration; thereafter, ECGs will be recorded 
at Week 12 and Week 28.
On all other dosing days, ECG recording will be 
performed at 30 to 60 minutes prior to IP 
administration; thereafter, ECGs will be recorded at 
Week 12 and Week 32 28.
Time points of visits 
updated due to change 
in the duration of the 
FU period
Substantial 
(consequential)
8.2.6.1
Radiographic 
(X-ray) Assessment
At the Week 28 visit, safety X-ray imaging will 
be performed on the knee and hip joints. Any 
potentially clinically significant findings 
detected on X-ray performed at Week 28 will be 
further assessed and adjudicated (if needed) by 
the final FU visit (Week 32).
At the Week 32 28 visit, safety X-ray imaging will be 
performed on the knee and hip joints. Any potentially 
clinically significant findings detected on X-ray 
performed at Week 32 28 will be further assessed and 
adjudicated (if needed) by the final FU visit (Week 36
32).
Time points of visits 
updated due to change 
in the duration of the 
FU period
Substantial 
(consequential)
8.2.9 Injection Site 
Reactions
On Day 1, injection site reactions will be 
monitored at 5, 15, 30, 45, and 60 minutes and 2 
and 4 hours after IP administration.
On Day 1, injection site reactions will be monitored at 
approximately 5, 15, 30, 45, and 60 minutes and 2 and 
4 hours after completion of IP administration.
Clarification to allow 
for the practicalities of 
assessment taking into 
Non-
substantial


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
219 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
consideration 2 IP 
injections
8.2.10 Procedures 
for Subjects 
Undergoing Joint 
Replacement
Participants who permanently discontinue IP will 
be asked to complete study assessments at the 
ET visit as soon as possible and then to enter the 
FU period.
It is recommended to have at least 3 weeks between 
IP administration and joint replacement surgery. 
Participants who permanently discontinue IP will be 
asked to complete study assessments at the ET visit as
soon as possible and then to enter the FU period.
Recommendation on the 
minimum period 
between IP 
administration and joint 
replacement surgery 
added
Substantial
8.2.10 Procedures 
for Subjects 
Undergoing Joint 
Replacement
None: new text
Wherever possible, the surgeon’s assessment of 
procedural difficulty (uneventful; minor 
complications (including but not limited to impaired 
wound healing); or major complications (taking into 
consideration the participant’s  medical history and 
physical condition prior to surgery) should be 
collected as well.
Additional information 
that is expected to be 
collected in joint 
replacement surgery 
cases added
Substantial
8.2.10 Procedures 
for Subjects 
Undergoing Joint 
Replacement
AEs that led to joint replacement surgery should 
be followed up by the investigator for as long as 
medically indicated but no less than up to the 
end of the FU period.
AEs that led to joint replacement surgery should be 
followed up by the investigator for as long as 
medically indicated but no less than up to the end of 
the FU period or 4 months since joint replacement 
surgery (whichever is longer). Data on additional or 
corrective procedures (for example a revision or 
implant replacement) that were necessary after total 
joint replacement and their outcomes should be 
collected wherever possible as well.
The minimal duration 
of FU period to assess 
joint replacement 
surgery outcomes and 
additional information 
that is expected to be 
collected in joint 
replacement surgery 
cases is added
Substantial
8.2.11.3 Urine Drug 
Screen
The urine drug test will be performed only at 
screening (Table 1).
The urine drug test will be performed at the time 
points shown in only at screening (Table 1).
To clarify time points in 
the text and correct 
discrepancy with Table 
1
Non-
substantial
8.3.5 Adverse 
Events of Special 
Interest
The following AESIs have been identified 
specifically for this MEDI7352 protocol and are 
to be reported as described in Section 8.3.1
through Section 8.3.4.
The following AESIs have been identified specifically 
for this MEDI7352 protocol and are to be reported as 
described in Section 8.3.1 through Section 8.3.4.
•
…
Additional events have 
been added to AESIs 
for safety data 
collection and 
monitoring purposes
Substantial


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
222 of 253
Section # and 
Name
Initial Wording under Amendment 1
Amended or New Wording under Amendment 2
(Deletions are strikethrough, and additions are 
underlined)
Brief Rationale
Substantial/ 
Non-substantial
The precise committee membership, 
responsibilities, and procedures applicable to the 
Independent Efficacy Review Committee will be 
detailed in its charter.
Review Group Committee will be detailed in its 
charter.
Appendix I
Footnote a for Table I11:
Scheduled X-ray at Week 28 is required for hips 
and knees only.
Footnote a for Table I11:
Scheduled X-ray at Week 32 28 is required for hips 
and knees only.
Time points of visits 
updated due to change 
in the duration of the 
FU period
Substantial 
(consequential)
Appendix I
Table I12:
Knee: At screening and at Week 28 (or FU clinic 
Visit 2 for participants who discontinued IP 
early) and as clinically indicated during the study
Hip: At screening and at Week 28 (or FU clinic 
Visit 2 for participants who discontinued IP 
early) and as clinically indicated during the study 
a
Table I12:
Knee: At screening and at Week 32 28 (or FU clinic 
Visit 2 for participants who discontinued IP early) and 
as clinically indicated during the study
Hip: At screening and at Week 32 28 (or FU clinic 
Visit 2 for participants who discontinued IP early) and 
as clinically indicated during the study a
Time points of visits 
updated due to change 
in the duration of the 
FU period
Substantial 
(consequential)
Abbreviations are found in Appendix L.


Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
223 of 253
Amendment 1 (11 March 2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
This global amendment 1 supersedes all global or country-specific protocol addendums dated 
prior to the date of this amendment as it incorporates the requirements detailed in these 
addendums.
Overall Rationale for the Amendment:
This protocol (study D5680C00003) has been amended to outline the approaches to 
COVID-19 vaccination in the current clinical study protocol (CSP) in the context of the 
current pandemic of coronavirus respiratory disease (COVID-19) caused by the novel severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2); to correct and/or clarify 
inclusion/exclusion criteria, timing of assessments on Day 1, timing for rescreening subjects, 
rescreening procedures, and to revise, add, or remove minor text as needed to increase clarity 
or correct interpretation of the protocol.


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Clinical Study Protocol – Global Amendment 3
MEDI7352 - D5680C00003
Version 4.0 28 June 2022
CONFIDENTIAL AND PROPRIETARY
226 of 253
Section # and 
Name
Initial Wording under Version 1
Amended or New Wording under Amendment 1
Brief Rationale
Substantial/ 
Non-
substantial
COVID-19 
Pandemic
4.1.2 Additional 
Risk-Mitigation 
Procedures 
Implemented in the 
Context of the 
SARS‑CoV-2/ 
COVID-19 
Pandemic
• No earlier than 72 hours prior to each dosing visit, 
COVID-19 nose swab and/or throat/saliva swab will 
be performed according to local laboratory standards 
and protocols for sample acquisition.
• No earlier than Within 72 hours prior to each dosing 
visit, COVID-19 nose swab and/or throat/saliva swab 
will be performed according to local laboratory 
standards and protocols for sample acquisition.
To provide clarity on 
definition of SARS-
CoV-2/COVID-19 
testing 72 hours before 
a visit
Non-
substantial
5.1 Inclusion 
Criteria 
(Diagnostic)
12 Participant has a documented history of 
inadequate pain relief from past or ongoing 
treatment with NSAIDs/COX-2 inhibitors, 
acetaminophen (paracetamol), and opioids (weak or 
strong). The participant is expected to have tried all 
specified analgesic classes either consecutively or 
simultaneously (including in combination products) 
within recommended dosing guidelines for at least 
2 weeks unless contraindicated (see below).
•
Participants who have intolerability or 
contraindications to NSAIDs/COX-2 inhibitors 
must have documented history that 
acetaminophen (paracetamol) and opioid 
treatment, either consecutively or 
simultaneously (including in combination 
products) within recommended dosing 
guidelines for at least 2 weeks, at any time, has 
not provided sufficient pain relief.
•
Participants who have intolerability or 
contraindications to opioids must have 
documented history that acetaminophen 
(paracetamol) and NSAID/COX-2 inhibitors 
treatment, either consecutively or 
simultaneously (including in combination 
products) within recommended dosing 
12 Participant has a Documented history of inadequate 
pain relief from past or ongoing treatment according to 
the recommended dosing guidelines with 
acetaminophen (paracetamol) and oral 
NSAIDs/COX-2 inhibitors unless contraindicated/not 
tolerated and opioids unless (a) opioids are 
contraindicated/not tolerated, (b) there is no access to 
opioids as per local standards of care, or (c) the patient 
is unwilling to take opioids. (Note that ongoing strong 
opioids are exclusionary.) with NSAIDs/COX 2 
inhibitors, acetaminophen (paracetamol), and opioids 
(weak or strong). The participant is expected to have 
tried all specified analgesic classes either consecutively 
or simultaneously (including in combination products) 
within recommended dosing guidelines for at least 2 
weeks unless contraindicated (see below).
•
Participants who have intolerability or 
contraindications to NSAIDs/COX 2 inhibitors 
must have documented history that 
acetaminophen (paracetamol) and opioid 
treatment, either consecutively or simultaneously 
(including in combination products) within 
recommended dosing guidelines for at least 2 
weeks, at any time, has not provided sufficient 
pain relief.
To provide opportunity 
for inclusion of 
difficult-to-treat 
patients who are 
unwilling to take 
opioids or when there is 
no access to opioids for 
treatment of 
osteoarthritis pain
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guidelines for at least 2 weeks, at any time, has 
not provided sufficient pain relief.
•
Participants who have intolerability or 
contraindications to NSAIDs/COX-2 inhibitors 
and opioids must have documented history that 
acetaminophen (paracetamol) within 
recommended dosing guidelines for at least 
2 weeks, at any time, has not provided 
sufficient pain relief.
•
Participants who have intolerability or 
contraindications to opioids must have 
documented history that acetaminophen 
(paracetamol) and NSAID/COX-2 inhibitors 
treatment, either consecutively or simultaneously 
(including in combination products) within 
recommended dosing guidelines for at least 2 
weeks, at any time, has not provided sufficient 
pain relief.
•
Participants who have intolerability or 
contraindications to NSAIDs/COX 2 inhibitors 
and opioids must have documented history that 
acetaminophen (paracetamol) within 
recommended dosing guidelines for at least 
2 weeks, at any time, has not provided sufficient 
pain relief.
5.2 Exclusion 
Criteria (General)
2. Previously received any form of anti-NGF, anti-
TNF, or other biological DMARDs (including but 
not limited to golimumab, certolizumab, infliximab, 
adalimumab, etanercept, rituximab, abatacept, 
tocilizumab, and tofacitinib) for 12 months prior to 
screening or received other immunosuppressants for 
6 months prior to screening
2. Previously received any form of anti-NGF, anti-
TNF, or other biological DMARDs (including but not 
limited to golimumab, certolizumab, infliximab, 
adalimumab, etanercept, rituximab, abatacept, 
tocilizumab, and tofacitinib) for within 12 months prior 
to screening or received other immunosuppressants for
within 6 months prior to screening (with the exception 
of inhaled or topical corticosteroids; for exclusionary 
intra-articular corticosteroids use, refer to exclusion 
criterion 37).
To clarify that the 
duration of the listed 
medications is not the 
important aspect for 
exclusion but the 
exposure relative to 
screening date; to 
clarify non-systemic 
corticosteroid use
Non-
substantial
5.2 Exclusion 
Criteria (General)
None: new exclusion criterion
4. Administration of COVID-19 vaccine (regardless of 
modality or vaccine delivery platform, eg, vector, lipid 
nanoparticle) within 30 days prior to randomisation 
(from last vaccination or booster dose, whichever is 
required to consider vaccination complete in line with 
applicable guidance)
To reflect changes in 
the clinical study 
management of 
prospective study 
participants who may 
have access to 
COVID-19 vaccination
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Non-
substantial
5.2 Exclusion 
Criteria (General)
5. Plasma donation within 28 days of screening or 
any blood donation or blood loss > 50 mL within 
2 months of screening
6. Plasma donation within 28 days of prior to screening 
or any blood donation or blood loss > 50 500 mL 
within 2 months of prior to screening
To clarify exclusion 
criterion; study team 
considers that it is
appropriate to restrict 
blood loss to 500 mL 
within 2 months of 
screening; also minor 
correction in wording to 
increase clarity
Substantial
5.2 Exclusion 
Criteria (Medical 
History)
12. The following conditions (including screening 
imaging results suggestive of these conditions as per 
central reader evaluation) should be excluded: 
RPOA, primary osteonecrosis (including 
spontaneous osteonecrosis of the knee), subchondral 
insufficiency fractures, avascular necrosis, 
osteoporotic fractures, atrophic or hypotrophic OA, 
hip dislocation, excessive malalignment of the target 
knee or pathological fractures.
13. The following conditions (including screening 
imaging results suggestive of these conditions as per 
central reader evaluation) should be excluded: RPOA, 
primary osteonecrosis (including spontaneous 
osteonecrosis of the knee), subchondral insufficiency 
fractures, avascular necrosis, osteoporotic fractures,
atrophic or hypotrophic OA, hip dislocation, congenital 
hip dysplasia with degenerative joint disease, excessive 
malalignment of the target knee (anatomical axis angle 
greater than 10 degrees), pathological fractures, stress 
fracture or reaction, vertical tear of the posterior 
meniscal root, or large or extensive subchondral cysts. 
To clarify exclusionary 
conditions based on 
central reader's 
evaluation that 
represent joint 
pathology other than 
OA or have a potential 
impact on the accurate 
assessment of joint-
related safety events 
Substantial
5.2 Exclusion 
Criteria (Medical 
History)
23. Known or suspected systemic infection, 
including HIV, HBV, HCV, or TB should be 
excluded. If QuantiFERON test is positive at 
screening, participants will be excluded from the 
study. Other tests could be performed if deemed 
necessary by the investigators to exclude systemic 
infection.
24. Known or suspected systemic infection, including 
HIV, HBV, HCV, or TB should be excluded. If 
QuantiFERON test is positive at screening, participants 
will be excluded from the study. Other tests could be 
performed if deemed necessary by the investigators to 
exclude systemic infection. Note: Positive results for 
hepatitis B surface antigen (HBsAg) or antibody to 
hepatitis B core antigen (anti-HBc) are exclusionary.
To clarify exclusion 
criteria based on results 
from Hepatitis B testing
Non-
substantial
5.2 Exclusion 
Criteria
(Medical History)
30. Active infection and clinically important 
infection, including chronic, persistent, or acute 
infection within 3 months of screening or between 
screening and randomisation. Note that: 
31. Current active infection, and clinically important 
infection, including chronic, or persistent, or acute
systemic infection, or serious or severe localized or 
systemic infection within 3 months of prior to
To clarify exclusion 
criterion related to 
ongoing infections and 
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Non-
substantial
•
Participants with clinical signs and symptoms 
consistent with COVID-19 infection or active 
COVID-19 infection and participants with a 
previous COVID-19 infection, irrespective of 
severity or symptomatology, are not eligible to 
participate in the study.
screening or between screening and randomisation. 
Note that: 
•
Participants with clinical signs and symptoms 
consistent with COVID-19 infection or active 
COVID 19 infection and participants with a 
previous COVID 19 infection, irrespective of 
severity or symptomatology, are not eligible to 
participate in the study.
•
Any history of severe COVID-19 infection (eg, 
requiring hospitalisation, intensive care unit care, 
or assisted ventilation) or any prior COVID-19 
infection with unresolved sequelae is 
exclusionary. Any acute SARS-COV-2/ 
COVID-19 infection, including asymptomatic, 
mild, or moderate (lab confirmed or suspected 
based on clinical symptoms) within the last 
6 months prior to screening is also exclusionary.
infections in medical 
history
5.2 Exclusion 
Criteria 
(Procedural 
Contraindications)
36. Corticosteroid injection or intra-articular 
hyaluronic acid injection on target knee within 
6 months of screening or on a nontarget joint within 
3 months of screening. If a participant has had 
multiple injections within the year prior to screening, 
then the total dose of corticosteroid used should be 
no more than 180 mg of triamcinolone, 
methylprednisolone, or their equivalent.
37. Corticosteroid injection or intra-articular 
hyaluronic acid injection on target knee within 
6 months of 12 weeks prior to screening, or
corticosteroid injection on a nontarget joint within 
3 months of 12 weeks prior to screening, or intra-
articular hyaluronic acid injection on nontarget joint 
within 6 weeks prior to screening. If a participant has 
had multiple injections within the year prior to 
screening, then the total dose of corticosteroid used 
should be no more than 180 mg of triamcinolone, 
methylprednisolone, or their equivalent.
Revision added as study 
team considers 
appropriate to reduce 
time elapsed from 
corticosteroid and 
hyaluronic acid intra-
articular injection to 
screening
Substantial
5.2 Exclusion 
Criteria (Physical 
examination, vital 
signs, ECG, 
laboratory values, 
and imaging)
42. Orthostatic hypotension (defined as a sustained 
reduction of systolic BP of at least 20 mmHg and/or 
diastolic BP of at least 10 mmHg within 3 minutes 
of standing from a supine position)
43. Orthostatic hypotension (defined as a sustained 
reduction of systolic BP of at least 20 mmHg and/or 
diastolic BP of at least 10 mmHg within 3 minutes of 
standing from a supine position, provided that supine 
BP is stable). If supine BP results are not stable, the 
measurements can be repeated on the same day or at a 
subsequent screening visit. If it is not possible to 
To clarify eligibility of 
the subjects for whom it 
is not possible to 
achieve a stable supine 
blood pressure for 
monitoring of 
orthostatic hypotension
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substantial
establish stable supine BP, then subject is not eligible 
for the study.
5.2 Exclusion 
Criteria (Physical 
examination, vital 
signs, ECG, 
laboratory values, 
and imaging)
43. Any clinically significant abnormality in ECG 
rhythm, conduction, or morphology as judged by the 
investigator 
•
A corrected QT interval by Fredericia (QTcF) 
interval measurement of > 470 microseconds 
or family history of long QT syndrome
44. Any clinically significant abnormality in ECG 
rhythm, conduction, or morphology as judged by the 
investigator 
•
A corrected QT interval by Fredericia (QTcF) 
interval measurement of > 470 microseconds
milliseconds or family history of long QT 
syndrome
To correct typo 
Non-
substantial
5.4.1 Rescreening
One rescreening visit is permitted within the 45-day 
screening period. Baseline X-ray and MRI 
assessments will remain valid for a maximum period 
of 45 days prior to Day 1. 
The following screening procedures should be 
performed at the rescreening visit:
•
X-ray/MRI if these have not been performed at 
screening
•
Recent medical history
•
Concomitant medications review
•
Physical examination
•
Neurological examination
•
12-lead ECG
•
Screening pain NRS at the rescreening visit 
•
TNSn
•
Vital signs and orthostatic BP
•
AEs
•
Urine drug screen
•
Laboratory tests (haematology, clinical 
chemistry, coagulation, serology, and 
pregnancy)
A participant who is rescreened is not required to 
sign another ICF as the rescreening must occur 
within the 45-day screening period.
One rescreening attempt is permitted for each 
participant. 
For the participants who have undergone X-ray 
assessments during the screening period (and provided 
that there were no triggering events [eg, trauma] 
affecting the joints or any clinically significant changes 
in joint condition since the X-ray evaluation during the 
screening period based on the investigator’s 
assessment), then rescreening, if deemed necessary, 
must occur within 90 days from this first screening 
X-ray assessment. If it is not possible to assess such 
changes in clinical condition over the above mentioned 
period, then the participants should not be rescreened. 
Note: There is no rescreening option beyond the above-
mentioned 90 days for participants who have been 
exposed to X-rays during screening.
For the study participants who were considered screen 
failures before any X-ray images were obtained, one 
rescreening attempt is allowed at any time point while 
the study is ongoing. 
All screening procedures and assessments (except for 
X-ray/MRI if performed at screening) should be 
repeated for the rescreened participants. A participant 
should sign a new ICF if they have been rescreened for 
any reason. visit is permitted within the 45 day 
To provide one 
rescreening opportunity 
for study participants
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substantial
screening period. Baseline X ray and MRI assessments 
will remain valid for a maximum period of 45 days 
prior to Day 1. 
The following screening procedures should be 
performed at the rescreening visit:
•
X ray/MRI if these have not been performed at 
screening
•
Recent medical history
•
Concomitant medications review
•
Physical examination
•
Neurological examination
•
12 lead ECG
•
Screening pain NRS at the rescreening visit 
•
TNSn
•
Vital signs and orthostatic BP
•
AEs
•
Urine drug screen
•
Laboratory tests (haematology, clinical 
chemistry, coagulation, serology, and pregnancy)
A participant who is rescreened is not required to sign 
another ICF as the rescreening must occur within the 
45 day screening period.
6.5.2 Prohibited 
Concomitant 
Medications
• Corticosteroid injections or intra-articular 
hyaluronic acid injections performed on the target 
knee within 6 months of screening are prohibited. 
Corticosteroid injections or intra-articular hyaluronic 
acid injections performed on a nontarget joint within 
2 months of screening are prohibited.
• Corticosteroid injections or intra-articular hyaluronic 
acid injections performed on the target knee within 
6 months of 12 weeks prior to screening are prohibited, 
corticosteroid injections on a nontarget joint within 
12 weeks prior to screening, or intra-articular 
hyaluronic acid injections performed on a nontarget 
joint within 2 months of 6 weeks prior to screening are 
prohibited.
To ensure consistency 
with exclusion 
criterion 37
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substantial
6.5.2 Prohibited 
Concomitant 
Medications
• The following therapies are prohibited from 
12 months prior to screening and during the study: 
!
Etanercept and medications known to 
interact with etanercept, specifically 
anakinra, abatacept, and sulfasalazine
!
Other DMARDs, including but not limited 
to golimumab, certolizumab, infliximab, 
adalimumab, rituximab, tocilizumab, and 
ofacitinib
!
Any other form of anti-TNF or anti-NGF 
therapy 
!
Other immunosuppressants with the 
exception of systemic corticosteroids that 
are prohibited from 6 months prior to 
screening and during the study.
• The following therapies are prohibited from 
12 months prior to screening and during the study: 
!
Etanercept and medications known to interact 
with etanercept, specifically anakinra, 
abatacept, and sulfasalazine
!
Other DMARDs, including but not limited to 
golimumab, certolizumab, infliximab, 
adalimumab, rituximab,  tocilizumab, and 
tofacitinib
!
Any other form of anti-TNF or anti-NGF 
therapy 
!
Other immunosuppressants with the exception 
of systemic corticosteroids that are prohibited 
from within 6 months prior to screening and 
during the study. The restrictions related to use 
of intra-articular corticosteroid injections are 
mentioned above.
To correct the 
discrepancy with the 
exclusion criterion 
related to 
immunosuppressants 
and corticosteroids use
Substantial
6.5.2 Prohibited 
Concomitant 
Medications
None: new bullet
• COVID-19 vaccines: If a study participant is being 
considered for enrolment into the study and also for 
COVID-19 vaccination, the participant must not be 
randomised until 30 days after the last dose of 
COVID-19 vaccine or ‘booster dose’ (whichever is 
required to consider vaccination complete in line with 
applicable guidance). Note that this is applicable only 
to COVID-19 vaccines, irrespective of their modality, 
which are currently approved by Health Authorities or 
otherwise approved under relevant regulations, eg, 
emergency use authorisation (FDA)/conditional 
marketing authorisation (European Medicines 
Agency)/temporary supply (Medicines and Healthcare 
Products Regulatory Agency).
To reflect changes in 
the clinical study 
management of 
prospective study 
participants who may 
have access to 
COVID-19 vaccination
Substantial
7.1
Discontinuation of 
None: New bullet
• If a study participant is vaccinated with a COVID-19 
vaccine during the treatment period of the study, he/she 
To clarify 
discontinuation criteria 
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Non-
substantial
Investigational 
Product
should be discontinued from IP administration. The 
study participant will still be required to attend 
scheduled safety visits and to complete the follow-up 
period of the study (Please refer to Section 7.1.2 for 
“Procedures for Early Discontinuation of 
Investigational Product”). If a study participant is 
vaccinated during the follow-up period, they should 
continue participation in the follow-up period of the 
study.
for study participants 
receiving COVID-19 
vaccination during the 
treatment or follow-up 
periods of the study
7.1.1 Subject-
specific Criteria 
for 
Discontinuation of 
Investigational 
Product
!
A positive test for SARS-CoV-2 RNA at any 
time point
!
A positive test for SARS-CoV-2 RNA at any 
time point
To provide more 
options for SARS-
CoV-2 testing once new 
tests with acceptable 
standards would 
become available.
Non-
substantial
7.1.1 Subject-
specific Criteria 
for 
Discontinuation of 
Investigational 
Product
• Any of the following are criteria for immediate 
and permanent discontinuation of IP 
(Section 8.2.11.1):
!
ALT or AST ≥5 × ULN 
!
ALT or AST ≥3 × ULN and coexisting total 
bilirubin ≥2 × ULN (Hy’s Law [HL]). Hy’s 
law is described in Section 8.3.8 and FU of 
HL cases is provided in Appendix F.
!
ALT or AST ≥3 × ULN and associated with 
symptoms (which may be either transient or 
persistent) of hepatitis or hypersensitivity. 
Hepatitis symptoms include fatigue, nausea, 
vomiting, right upper quadrant pain or 
tenderness. Hypersensitivity symptoms 
include eosinophilia (≥5%), rash, and fever 
without clear alternative cause. 
• Any of the following are criteria for immediate and 
permanent discontinuation of IP (Section 8.2.11.1):
!
ALT or AST ≥> 5 × ULN for more than 2 weeks
!
ALT or AST ≥3 × ULN and coexisting total 
bilirubin ≥2 × ULN (Hy’s Law [HL]). Hy’s law 
is described in Section 8.3.8 and FU of HL cases 
is provided in Appendix F.
!
ALT or AST ≥3 × ULN and coexisting 
normalised ratio (INR) > 1.5 
!
ALT or AST ≥3 × ULN and associated with 
symptoms (which may be either transient or 
persistent) of hepatitis or hypersensitivity. 
Hepatitis symptoms include fatigue, nausea, 
vomiting, right upper quadrant pain or 
tenderness. Hypersensitivity symptoms include 
eosinophilia (≥5%), rash, and or fever without 
clear alternative cause. 
To align with 
AstraZeneca’s guidance 
for detection, 
assessment, and 
management of drug-
induced liver injury
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substantial
7.1.1 Subject-
specific Criteria 
for 
Discontinuation of 
Investigational 
Product
None (new bullet)
!
Cases when sympathetic neuropathy is not 
confirmed but orthostatic hypotension remains 
symptomatic for more than 14 days
To further clarify the 
language related to IP 
discontinuation criteria 
due to orthostatic 
hypotension when 
sympathetic neuropathy 
is not confirmed
Substantial
7.1.3 Temporary 
Discontinuation of 
Investigational 
Product
None (new bullet)
• When follow-up on cases of abnormal liver function 
is needed before the decision on permanent IP 
discontinuation is made (eg, identification of potential 
HL (PHL) cases needed or further evaluation in order 
to exclude HL required, or ALT or AST ≥5 × ULN for 
less than 2 weeks)
To provide guidance on 
temporary IP 
discontinuation before 
the decision about 
permanent IP 
discontinuation made
Substantial
7.1.3 Temporary 
Discontinuation of 
Investigational 
Product
None (new text)
Please refer to the Appendix F for guidance on follow-
up procedures for PHL and HL cases and 
Section 8.2.11.1 for management of other cases of 
abnormal liver function
To indicate where (1) 
follow-up guidance for 
PHL and HL cases and 
(2) management of 
other cases of abnormal 
liver function are found 
in the CSP 
Non-
substantial
7.1.4 Procedures 
for Handling 
Incorrectly 
Enrolled or 
Randomised 
Subjects
A participant may be rescreened once and then be 
withdrawn if he/she still do not meet the eligibility 
criteria (Section 5.4.1).
Where a participant does not meet all the eligibility 
criteria but is randomised in error, or incorrectly 
started on IP, the investigator should inform the 
sponsor’s study physician or designee immediately, 
and a discussion should occur between the study 
physician and the investigator.
If the agreed decision is to discontinue IP, the 
participant will be asked to complete the assessments 
at the early termination visit and then enter the 
A participant may be rescreened once and then be 
withdrawn screen failed if he/she still does not meet the 
eligibility criteria (Section 5.4.1).
Where a participant does not meet all the eligibility 
criteria but is randomised in error, or incorrectly started 
on IP, the investigator should inform the sponsor’s 
study physician or designee immediately and a 
discussion should occur between the study physician 
and the investigator.
If the agreed decision is to discontinue IP, the 
participant will be asked to complete the assessments at 
the early termination visit and then enter the follow up 
Minor revision and 
several sentences 
deleted to remove 
language that could 
indicate acceptance of 
protocol deviations
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follow up period (Table 1). Procedures for early 
discontinuation of IP are provided in Section 7.1.2.
The decision to discontinue/continue IP must be 
appropriately documented, including rationale, 
particularly if the agreed decision is to continue IP.
period (Table 1). Procedures for early discontinuation 
of IP are provided in Section 7.1.2.
The decision to discontinue/continue IP must be 
appropriately documented, including rationale, 
particularly if the agreed decision is to continue IP 
treatment.
8 Study 
Assessments and 
Procedures (Data 
reporting)
New text: new section added
Data Reporting
The primary modality for study participants to capture 
daily information as well as complete all the study 
questionnaires during the study will be an ePRO hand-
held device. In the event that there is a problem with 
the ePRO device or its availability, a digital alternative, 
electronic clinical outcomes assessment (eCOA) At-
Home Web Back Up will be used for collecting eCOA 
data directly from patients when their provisioned 
device is not available.
To notify and provide 
guidance on the use of 
paper copies of the 
daily patient diary and 
questionnaires at the 
start of the study for 
collecting data until the 
ePRO devices become 
available for subject use
Non-
substantial
8 Study 
Assessments and 
Procedures 
(Double-blind 
Treatment Period)
The following procedures will be performed on 
Day 1 prior to randomisation:
•
Inclusion and exclusion criteria confirmation
•
Urine pregnancy test (for women who are not 
surgically sterile only; the results must be 
negative in order to proceed with IP 
administration)
•
WOMAC index 
•
Daily pain diary (NRS) 
•
DSIS
•
Physical and neurological examination
•
Supine BP and pulse rate …
•
Orthostatic BP …)
•
Body temperature (prior to any blood draw)
•
Respiratory rate (prior to any blood draw)
•
ECG …
The following procedures will be performed on Day 1 
prior to randomisation:
•
Inclusion and exclusion criteria confirmation
•
Urine pregnancy test (for women who are not 
surgically sterile only; the results must be 
negative in order to proceed with IP 
administration)
•
WOMAC Index
•
Daily pain diary (NRS) 
•
DSIS
•
TNSn
•
Physical and neurological examination
•
Supine BP and pulse …
•
Orthostatic BP …
•
Body temperature (prior to any blood draw)
•
Respiratory rate (prior to any blood draw)
Move WOMAC and 
haematology/chemistry/
coagulation to after 
randomisation and 
pre-IP and TNSn to 
prior to randomisation 
because of the amount 
of time required to 
complete assessments
Non-
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used in the SF-36; fixed 
in-text citation
8.1.8 Assessment 
of Healthcare 
Resource 
Utilisation
The utilisation of healthcare resources (eg, doctor 
office visits, hospitalisations, surgeries, or other 
procedures) used by participants prior to entering the 
study (ie, 3 months prior to baseline) will be 
assessed at the times indicated in the SoA (Table 1).
Healthcare resource utilisation data associated with 
medical encounters will be collected by the 
investigator and study-site personnel for all 
participants throughout the study. Protocol-
mandated procedures, tests, and encounters are 
excluded. The question should be asked with a recall 
period of 3 months.
The utilisation of healthcare resources (eg, doctor 
office visits, hospitalisations, surgeries, or other 
procedures) used by participants prior to entering the 
study (ie, 3 months prior to baseline) and during the 
study will be assessed at the times indicated in the SoA 
(Table 1).
Healthcare resource utilisation data associated with 
medical encounters will be collected by the investigator 
and study-site personnel for all participants throughout 
the study. Protocol-mandated procedures, tests, and 
encounters are excluded. After the baseline assessment, 
the question should be asked with a recall period of 3 
months by recalling the period between visits.
To increase objectivity 
and accuracy of recall 
period by reducing 
recall period to the 
period between visits.
Non-
substantial
8.2.3.2 Orthostatic 
Blood Pressure 
Measurements and 
Follow-up of 
Confirmed 
Orthostatic 
Hypotension
If the BP measurements do not meet the criteria for
orthostatic hypotension, no additional measurement 
is needed. If the BP measurement meets any of the 
criteria shown in Table 6, investigators will repeat 
the supine and standing measurements up to 
2 additional times.
If the BP measurements do not meet the criteria for 
orthostatic hypotension, no additional measurement is 
needed (refer to exclusion criterion 43 for screening 
visit and Visit 2 assessments and Table 6 for the 
assessments after Visit 2). If BP measurements taken at 
the screening visit or Visit 2 meet exclusion 
criterion 43, then the subject in not eligible for 
participation in the study. After Visit 2 (Day 1), if the 
initial BP measurement meets any of the criteria shown 
in Table 6, investigators will repeat the supine and 
standing measurements up to 2 additional times.
To clarify when 
orthostatic blood 
pressure measurements 
outlined in the Table 6 
and follow-up of 
confirmed orthostatic 
hypotension are 
applicable
Non-
substantial
8.2.6.1
Radiographic (X-
ray) Assessment
Details of the image acquisition and review criteria 
will be described in the Radiology Technical 
Manual.
Details of the image acquisition and review criteria will 
be described in the Radiology Technical Manual
Procedure Manuals for X-ray and MRI Image 
Acquisition.
To align with the title 
and content of manuals 
for X-ray and MRI 
image acquisition
Non-
substantial
8.2.6.2 Magnetic 
Resonance 
Imaging
MRI of the bilateral knee joints must be done during 
the screening period (Table 1). An MRI should also 
be performed during the screening period for the 
MRI of the bilateral knee joints must be done during 
the screening period (Table 1) except for the cases 
when a study participant has undergone a total joint 
#1: To clarify that MRI 
should not be obtained 
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joints with a KL grade at baseline of ≥3 as per 
screening X-ray assessment.
Eligibility (absence of specified joint abnormalities) 
will be determined by a central imaging reader. 
In addition, unscheduled MRIs should be done “for 
cause” in the knee joints or the joints with a KL 
grade at baseline of ≥3 to follow up on any newly 
occurring symptoms or worsening of symptoms 
considered clinically significant by the investigator. 
replacement and has an artificial nontarget joint or 
when a knee joint is no longer present due to leg
amputation. In that case only acquire MRI images of 
the opposite (target) knee. An MRI should also be 
performed during the screening period for the joints 
with a KL grade at baseline of ≥3 as per screening 
X-ray assessment.
Eligibility (absence of specified joint abnormalities) 
will be determined by a central imaging reader. 
In addition, unscheduled MRIs should be done “for 
cause” in the knee joints or the joints with a KL grade 
at baseline of ≥3 to follow up on any newly occurring 
symptoms or worsening of symptoms considered 
clinically significant by the investigator (except for the 
cases when a study participant has undergone a total 
joint replacement and has an artificial joint).
for nontarget knee with 
an artificial joint
#2: To clarify that MRI 
should not be obtained 
for an artificial joint
8.2.6.2 Magnetic 
Resonance 
Imaging
Details of the image acquisition and review criteria 
will be described in the Radiology Technical 
Manual.
Details of the image acquisition and review criteria will 
be described in the Radiology Technical Manual 
Procedure Manuals for X-ray and MRI Image 
Acquisition
To align with the titles 
of the site manuals for 
X-ray and MRI image 
acquisition.
Non-
substantial
8.2.11.1 Guidance 
for Evaluation of 
Abnormal Liver 
Function Tests
Table 8
AST or ALT: ≥3 × ULN
Total bilirubin: ≥2 × ULN
Symptom of hepatitis or hypersensitivity: NA
Consultation required: Hepatology consultation d;
Case must be discussed with the medical monitor 
ASAP
Actions: Immediate and permanent discontinuation 
of IP
Tests: Essential: must have liver chemistry values 
and additional testing completed ASAP 
Table 8
AST or ALT: ≥3 × ULN
Total bilirubin: ≥2 × ULN
Symptom of hepatitis or hypersensitivity: NA
Consultation required: Hepatology consultation d;
Case must be discussed with the medical monitor 
ASAP
Actions: Immediate and permanent discontinuation of 
IP
Tests: Essential: must have liver chemistry values and 
additional testing completed ASAP (Appendix F7) or 
To clarify that follow-
up on PHL cases is also 
needed as per 
Appendix F
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(Appendix F7) or follow up events of Hy’s law, if 
applicable as per Appendix F4)
Evaluation: Monitoring of liver chemistry values at 
least twice per week until values normalise, stabilise, 
or return to within baseline
level e
follow-up events of PHL or HL, if applicable as per 
Appendix F 4)
Evaluation: Monitoring of liver chemistry values at 
least twice per week until values normalise, stabilise, 
or return to within baseline
level e
8.2.11.1 Guidance 
for Evaluation of 
Abnormal Liver 
Function Tests
Table 8
AST or ALT: ≥3 × ULN
Total bilirubin: NA
Symptom of hepatitis or hypersensitivity: Yes
Consultation required: Hepatology consultation d;
Case must be discussed with the medical monitor 
ASAP
Actions: Immediate and permanent discontinuation 
of IP
Tests: Essential: must have liver chemistry values 
and additional testing completed ASAP 
(Appendix F7) or follow up events of Hy’s law, if 
applicable as per Appendix F4)
Evaluation: Monitoring of liver chemistry values at 
least twice per week until values normalise, stabilise, 
or return to within baseline
level e
Table 8
AST or ALT: ≥3 × ULN
Total bilirubin: NA
Symptom of hepatitis or hypersensitivity: Yes
Consultation required: Hepatology consultation d;
Case must be discussed with the medical monitor 
ASAP
Actions: Immediate and permanent discontinuation of 
IP
Tests: Essential: must have liver chemistry values and 
additional testing completed ASAP (Appendix F7) or 
follow-up events of PHL or HL, if applicable as per 
Appendix F 4)
Evaluation: Monitoring of liver chemistry values at 
least twice per week until values normalise, stabilise, 
or return to within baseline
level e
To clarify that follow-
up on PHL cases is also 
needed as per 
Appendix F
Non-
Substantial
8.2.11.1 Guidance 
for Evaluation of 
Abnormal Liver 
Function Tests
Table 8
AST or ALT: ≥5 × ULN
Total bilirubin: NA
Symptom of hepatitis or hypersensitivity: NA
Consultation required: Hepatology consultation d;
Case must be discussed with the medical monitor 
ASAP
Table 8
AST or ALT: ≥5 × ULN
Total bilirubin: NA < 2 × ULN f
Symptom of hepatitis or hypersensitivity: NA No
Consultation required: Hepatology consultation d; Case 
must be discussed with the medical monitor ASAP
Actions: Immediate and permanent IP discontinuation 
of IP required; Permanent IP discontinuation required 
To align with 
AstraZeneca’s guidance 
for detection, 
assessment, and 
management of drug-
induced liver injury
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Actions: Immediate and permanent discontinuation 
of IP
Tests: Essential: must have liver chemistry values 
and additional testing completed ASAP 
(Appendix F7) or follow up events of Hy’s law, if 
applicable as per Appendix F4)
Evaluation: Monitoring of liver chemistry values at 
least twice per week until values normalise, stabilise, 
or return to within baseline
level e
if follow-up tests reveal AST or ALT ≥3 × ULN and 
INR > 1.5, or ALT or AST > 5 × ULN for more than 
2 weeks
Tests: Essential: Must have liver chemistry values and 
additional testing completed ASAP (Appendix F7) or 
follow up events of Hy’s law, if applicable as per 
Appendix F4)
Evaluation: Hepatology consultation d; Monitoring of 
liver chemistry values at least twice per week until 
values normalise, stabilise, or return to within baseline 
level e
8.2.11.1 Guidance 
for Evaluation of 
Abnormal Liver 
Function Tests
Table 8
AST or ALT: ≥3 × ULN (and ≥2 × baseline) 
and < 5 × ULN
Total bilirubin: < 2 × ULN
Symptom of hepatitis or hypersensitivity: No
Consultation required: Discussion with medical 
monitor required
Actions: Immediate discontinuation of IP not 
required unless deemed necessary by the investigator
Tests: Not required unless otherwise medically 
indicated (at the discretion of the investigator)
Evaluation: Monitoring of liver chemistry values at 
least twice per week until values normalise, stabilise, 
or return to within baseline level e
Table 8
AST or ALT: ≥3 × ULN (and ≥2 × baseline) 
and < 5 × ULN
Total bilirubin: < 2 × ULN f
Symptom of hepatitis or hypersensitivity: No
Consultation required: Discussion with medical 
monitor required
Actions: Temporal Immediate IP discontinuation of IP
needed for the period required for obtaining not
required unless repeated liver function tests and INR. 
Permanent discontinuation of IP required if follow-up 
tests reveal AST or ALT ≥3 × ULN and INR > 1.5 or 
as deemed necessary by the investigator
Tests: Measure ALT, AST, ALP, GGT, and bilirubin 
(total and direct), INR, albumin in 48-72 hours. Other 
tests might be performed as  Not required unless 
otherwise medically indicated (at the discretion of the 
investigator)
Evaluation: If the tests reveal AST or ALT ≥3 × ULN 
and INR > 1.5, then hepatology consultation and 
monitoring of liver chemistry values required at least 
To align with 
AstraZeneca’s guidance 
for detection, 
assessment, and 
management of drug-
induced liver injury
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twice per week until values normalise, stabilise, or 
return to within baseline level
8.2.11.1 Guidance 
for Evaluation of 
Abnormal Liver 
Function Tests
None (new footnote)
f All bilirubin values since the start of IP exposure 
should be checked to exclude PHL criteria 
(Appendix F2). If the PHL criteria are met, IP should 
be immediately discontinued, and the case needs to be 
reported and followed-up as per guidance in 
Appendix F.
Wording added to 
ensure that potential HL 
cases are not missed 
Non-
substantial
8.2.11.1 Guidance 
for Evaluation of 
Abnormal Liver 
Function Tests
The criteria below makes provision for the 
continuation of IP treatment at the discretion of the 
investigator. 
•
Participants with ALT or AST ≥3 × ULN 
(and ≥2 × baseline) and < 5 × ULN, total 
bilirubin < 2 × ULN with no symptoms of 
hepatitis (Table 8).
The criteria below makes provision for the continuation 
of IP treatment at the discretion of the investigator. 
•
Participants with ALT or AST ≥3 × ULN 
(and ≥2 × baseline) and < 5 × ULN, total 
bilirubin < 2 × ULN and INR ≤1.5 with no 
symptoms of hepatitis or hypersensitivity 
(Table 8).
Minor changes to align 
with Table 8
Non-
substantial
8.3.5 Adverse 
Events of Special 
Interest
An AESI is an AE of scientific and medical interest 
specific to understanding of the effects of the IP and 
may require close monitoring …
An AESI is an a treatment-emergent AE of scientific 
and medical interest specific to understanding of the 
effects of the IP and may require close monitoring …
To clarify definition of 
an AESI
Non-
substantial
8.3.5 Adverse 
Events of Special 
Interest
The following AESIs have been identified 
specifically for this MEDI7352 protocol and are to 
be reported as described in Section 8.3.1 to 
Section 8.3.4.
•
Positively-adjudicated possible or probable 
RPOA, subchondral insufficiency fracture, 
primary osteonecrosis, or pathological fracture 
•
Systemic infections
•
Anaphylactic reactions and injection site 
reactions that lead to discontinuation of 
administration of IP
Adverse events of special interest irrespective of 
their severity should be reported immediately using 
the same procedure as for SAE reporting 
(Section 8.3.9.)
The following AESIs have been identified specifically 
for this MEDI7352 protocol and are to be reported as 
described in Section 8.3.1 to through Section 8.3.4.
•
Positively-adjudicated possible or probable 
RPOA, subchondral insufficiency fracture, 
primary osteonecrosis, or pathological fracture 
•
Systemic infections
•
Infections that meet SAE or severe AE criteria* 
•
Anaphylactic reactions and injection site 
reactions that lead to 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 8.3.9).
To further clarify 
infection-related AESI
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*Note: A serious infection is any infection that meets 
the SAE criteria in CSP Appendix C2 “Definition of 
Serious Adverse Event.” 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.
8.3.9 Reporting of 
Serious Adverse 
Events 
All SAEs have to be reported, whether or not 
considered causally related to the IP or to the study 
procedure(s). All SAEs will be recorded in the 
eCRF.
If any SAE occurs in the course of the study, 
investigators or other site personnel will inform the 
appropriate AstraZeneca representative within one 
day, ie, immediately but no later than 24 hours of 
when he or she becomes aware of it by completing, 
signing, and dating the SAE Report Form, verifying 
the accuracy of the information recorded in the form 
with the source documents and eCRF, and sending 
the SAE form to AstraZeneca representative.
•
Email: drugsafety@mmsholdings.com
•
Fax number: +1 734 468 0850
The designated AstraZeneca representative will 
work with the investigator to ensure that all the 
necessary information is provided to the 
AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-
threatening events and within 5 calendar days of 
initial receipt for all other SAEs.
All SAEs have to be reported, whether or not 
considered causally related to the IP or to the study 
procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, 
investigators or other site personnel will inform the 
appropriate AstraZeneca representative within one day, 
ie, immediately but no later than 24 hours of when he 
or she becomes aware of it by completing the 
appropriate forms in the electronic data capture (EDC) 
system and submitting electronically to the safety team. 
Any follow-up information received must also be 
updated within the system and resubmitted within 
24 hours of being made aware. SAE reporting via 
paper forms will only serve as backup if the EDC 
system were to be temporarily unavailable for any 
unforeseen reasons. In such cases, the electronic SAE 
form can be completed within the EDC system when it 
becomes available. This will ensure safety events are 
still reported within 24 hours of any site staff being 
made aware. The paper SAE report forms are available 
in the investigator site files and must be completed by 
the principal investigator by signing, and dating the 
SAE Report Form, verifying the accuracy of the 
information recorded in the form with the source 
To clarify that SAE 
reporting process; SAEs 
will be reported via 
EDC, not paper 
reporting.
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documents and eCRF, and sending the SAE form to the 
AstraZeneca representative.
•
Email: drugsafety@mmsholdings.com
•
Fax number: +1 734 468 0850
The designated AstraZeneca representative will work 
with the investigator to ensure that all the necessary 
information is provided to the AstraZeneca Patient 
Safety data entry site or representative within 
one calendar day of initial receipt for fatal and life-
threatening events and within 5 calendar days of 
initial receipt for all other SAEs.
8.3.10 Pregnancy
A woman who becomes pregnant during IP 
treatment or within 30 days of discontinuing the IP 
will be immediately withdrawn from study 
participation. The investigator must report the 
pregnancy to AstraZeneca or representative as if it 
were an SAE within 24 hours of learning of the 
pregnancy using the pregnancy notification and 
outcome form via the same fax number and/or email 
address as for SAE reporting.
All pregnancies and their subsequent outcome 
(spontaneous miscarriage, elective termination, 
ectopic pregnancy, normal birth or congenital 
abnormality) should be reported to AstraZeneca or 
representative.
•
Email: drugsafety@mmsholdings.com
•
Fax number: +1 734 468 0850
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 FU
information must be reported to AstraZeneca or 
A woman who becomes pregnant during IP treatment 
or within 30 days of discontinuing the IP will be 
immediately withdrawn from study participation. The 
investigator must report the pregnancy to AstraZeneca 
or representative as if it were an SAE (within 24 hours 
of learning of the pregnancy) using the pregnancy 
notification and outcome form. by completing the 
appropriate forms in the EDC system and submitting 
electronically to the safety team. Pregnancy reporting 
via paper forms will only serve as backup if the EDC 
system were to be temporarily unavailable for any 
unforeseen reasons, as described in Section 8.3.9. The 
paper pregnancy notification and outcome forms are 
available in the investigator site files.
All pregnancies and their subsequent outcome 
(spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) 
should be reported to AstraZeneca or representative via 
the EDC system. If paper pregnancy notification and 
outcome forms are used as backup, these must be 
completed by the principal investigator, and sent via 
the same fax number and/or email address as for SAE 
reporting
To clarify pregnancy 
reporting process
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substantial


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representative using a new pregnancy notification 
and outcome form.
•
Email: drugsafety@mmsholdings.com
•
Fax number: +1 734 468 0850
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 FU 
information must be reported to AstraZeneca or 
representative (MMS) by submitting using a new
pregnancy notification and outcome EDC report form.
8.3.10.1 Maternal 
Exposure
Should a pregnancy still occur, the IP should be 
discontinued immediately and the pregnancy 
reported to AstraZeneca or its representative.
Should a pregnancy still occur, the IP should be 
discontinued immediately and the pregnancy reported 
to AstraZeneca or its representative via the EDC 
system.
To clarify pregnancy 
reporting process
Non-
substantial
8.3.10.2 Paternal 
Exposure
Pregnancy in a participant’s partner is not considered 
to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or 
congenital abnormality), occurring from the date of 
the first dose of IP until 3 months and 20 days after 
the last dose of IP should, if possible, be followed up 
and documented in the pregnancy report form. 
Consent from the partner must be obtained before 
the pregnancy report form is completed.
Pregnancy in a participant’s partner is not considered 
to be an AE. However, the outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality), 
occurring from the date of the first dose of IP until 
3 months and 20 days after the last dose of IP should, if 
possible, be followed up and documented in the 
pregnancy EDC report form. The site will update the 
information within the EDC system and submit to 
AstraZeneca or representative (MMS). Consent from 
the partner must be obtained before the pregnancy 
report form is completed.
To clarify pregnancy 
reporting process
Non-
substantial
8.4 Overdose
The maximal dose of IP should not be exceeded 
during the study. The investigator must report any 
overdose to an AstraZeneca representative within 
24 hours of learning of the overdose using the 
overdose report form. 
The maximal dose of IP should not be exceeded during 
the study. The investigator must report any overdose to 
an AstraZeneca representative within 24 hours of 
learning of the overdose using the overdose report form
by completing the appropriate forms in the EDC 
system and submitting electronically to the safety team. 
Drug overdose reporting via paper forms will only 
serve as backup if the EDC system were to be 
To clarify overdose 
reporting process
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substantial


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temporarily unavailable for any unforeseen reasons, as 
described for SAE reporting (Section 8.3.9). The paper 
forms are available in the investigator site files and 
must be completed by the principal investigator. 
9.4.3.1 Adverse 
events
Treatment-emergent AEs are defined as:
•
AEs with onset at the time of or following the 
start of IP through the FU visit or ET visit, 
whichever occurs first, or
•
AEs starting prior to the start of IP 
administration but increasing in severity or 
relationship at the time of, or following, the 
start of IP through the FU visit or ET visit, 
whichever occurs first,
Treatment-emergent AEs are defined as:
•
AEs with onset at the time of or following the 
start of IP through the FU last visit or ET visit, 
whichever occurs first, or
•
AEs starting prior to the start of IP administration 
but increasing in severity or relationship at the 
time of, or following, the start of IP through the 
FU last visit or ET visit, whichever occurs first,
To simplify language 
and increase clarity
Non-
substantial
Appendix B 3
Informed Consent
A participant who is rescreened is not required to 
sign another ICF as the rescreening must occur 
within the 45-day screening period.
A participant who is rescreened is not required to sign 
another a new ICF as the rescreening must occur within 
the 45-day screening period.
To clarify and to be 
consistent with changes 
in the rescreening 
section
Non-
substantial
Appendix B 5
Committees 
Structure
Rapidly Progressive Osteoarthritis Adjudication 
Committee 
The role of the Rapidly Progressive Osteoarthritis 
Adjudication Committee (RPOA-AC) is to 
independently review, interpret, and adjudicate 
possible or probable joint safety events including but 
not limited to RPOA, subchondral insufficiency 
fracture, primary osteonecrosis, or pathological 
fracture cases that are experienced by the study 
participants. The adjudication committee will review 
all cases of suspected joint safety events to 
determine whether or not they meet accepted 
diagnostic criteria. The RPOA-AC will review and 
adjudicate all joint safety events that meet SAE or 
severe AE criteria or AEs that led to joint 
replacement or other arthroplasty procedures. Joint 
safety events will be identified preliminarily by the 
Rapidly Progressive Osteoarthritis Adjudication 
Committee 
The role of the Rapidly Progressive Osteoarthritis 
Adjudication Committee (RPOA-AC) is to 
independently review, interpret, and adjudicate 
possible or probable joint safety events including but 
not limited to RPOA, subchondral insufficiency 
fracture, primary osteonecrosis, or pathological fracture 
cases that are experienced by the study participants. 
The adjudication committee will review all cases of 
suspected joint safety events to determine whether or 
not they meet accepted diagnostic criteria. The RPOA-
AC will review and adjudicate all joint safety events 
that meet SAE or severe AE criteria or AEs that led to 
joint replacement or other arthroplasty procedures to 
determine whether or not they meet accepted 
diagnostic criteria. Joint safety events will be identified 
Redundant sentence 
removed as joint safety 
events that will be 
reviewed by RPOA-AC 
are specified: RPOA, 
subchondral 
insufficiency fracture, 
primary osteonecrosis, 
or pathological fracture 
and all joint safety 
events that meet SAE or 
severe AE criteria or 
AEs that led to joint 
replacement or other 
arthroplasty procedures
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investigators, and also by AstraZeneca/sponsor 
personnel or during the RPOA-AC process as 
specified in the committee’s charter. 
preliminarily by the investigators, and also by 
AstraZeneca/sponsor personnel or during the RPOA-
AC process as specified in the committee’s charter. 
Appendix B 10
Publication Policy
The results of this study may be published or 
presented at scientific meetings. The investigator 
must agree to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the 
sponsor to protect proprietary information and to 
provide comments.
The results of this study may be published or presented 
at scientific meetings. Publications developed and 
managed by the investigator will be shared with the 
sponsor for review and approval before submission.
The investigator must agree to submit all manuscripts 
or abstracts to the sponsor before submission. This 
allows the sponsor to review the publication for 
accuracy and to ensure protect any proprietary 
information is protected. and to provide comments.
Revised in response to 
German Ethics 
Committee (EC) query 
as to clarify that the 
purpose of the 
publication policy is to 
identify and remove any 
proprietary information 
from the publication
Non-
substantial
Appendix I
Summary of 
Imaging 
Assessments 
(Table I11)
Imaging Assessments to be Performed 
During the Study
Joints/
indications
X-ray (plain 
radio-
graphs
MRI
Shoulders 
(both)
E and S
for joints with 
KL grade 3 or 
more
Imaging Assessments to be Performed During 
the Study
Joints/
indications
X-ray (plain 
radiographs)
MRI
Shoulders 
(both)
E and S
for joints with 
KL grade 3 or 
more
When further 
clarification of 
imaging 
findings needed
To clarify that MRI of 
shoulder joints will be 
performed only when 
deemed necessary based 
on central reader 
evaluation of X-ray data 
and when it is clinically 
indicated during the 
study (due to issues 
with accurate definition 
of KL grade 3 in 
shoulder joints)
Non-
substantial


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Section # and 
Name
Initial Wording under Version 1
Amended or New Wording under Amendment 1
Brief Rationale
Substantial/ 
Non-
substantial
Appendix I
Summary of 
Imaging 
Assessments
(Table I12)
Schedule of Assessments - Imaging
Imaging
Knee
Hip
Shoulder
MRI
Both knee 
joints at 
screening 
and as 
clinically 
indicated 
during the 
study
Joints with 
KL grade 3 
or more at 
screening 
and as 
clinically 
indicated 
during the 
study 
For joints 
with KL 
grade 3 or 
more at 
screening 
and as 
clinically 
indicated 
during the 
study
Schedule of Assessments - Imaging
Imaging
Knee
Hip
Shoulder
MRI
Both knee 
joints at 
screening 
and as 
clinically 
indicated 
during the  
study
Joints with 
KL 
grade 3 or 
more at 
screening 
and as 
clinically 
indicated 
during the 
study 
For joints 
with KL 
grade 3 or 
more at 
screening 
and As 
clinically 
indicated 
during the 
study
To clarify that MRI of 
shoulder joints will be 
performed only when 
clinically indicated 
during the study
Non-
substantial
Abbreviations are found in Appendix L.


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11
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SAP_001.pdf: 
Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 1 of 95 
 
 
Statistical Analysis Plan 
Study Code 
D5680C00003 
Edition Number 
Final v3.0 
Date 
13SEP2023 
A Randomised, Double-blind, Placebo-controlled, Dose-response 
Study of the Efficacy and Safety of MEDI7352 in Subjects with 
Painful Osteoarthritis of the Knee 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 7 of 95 
 
 
3.3.3 
OMERACT-OARSI responder index ................................................................... 31 
3.4 
Pharmacokinetic and immunogenicity variables .................................................. 32 
3.4.1 
Pharmacokinetics .................................................................................................. 32 
3.4.2 
Immunogenicity .................................................................................................... 32 
3.5 
Exploratory variables ............................................................................................ 33 
3.5.1 
Supportive efficacy and health related quality of life variables ........................... 33 
3.5.1.1 
Daily Sleep Interference Scale (DSIS) ................................................................. 33 
3.5.1.2 
European Quality of Life-5 Dimensions (EQ-5D-5L).......................................... 34 
3.5.1.3 
36-Item Short Form Health Survey Questionnaire ............................................... 34 
3.5.1.4 
Work Productivity and Activity Impairment questionnaire for OA (WPAI:OA) 35 
3.5.1.5 
Healthcare Resource Utilisation (HCRU) ............................................................ 35 
3.5.1.6 
Lack of efficacy endpoints.................................................................................... 35 
3.5.1.7 
Rescue medication use .......................................................................................... 36 
3.5.2 
Biomarker and Pharmacodynamic variables ........................................................ 36 
3.5.3 
Ambulatory blood pressure monitoring (ABPM) variables ................................. 37 
3.6 
Safety variables ..................................................................................................... 38 
3.6.1 
Adverse events ...................................................................................................... 38 
3.6.1.1 
Adverse events of special interest......................................................................... 39 
3.6.1.2 
Adverse events based on signs and symptoms ..................................................... 39 
3.6.1.3 
Adverse events based on examinations and tests ................................................. 40 
3.6.1.4 
Pregnancy ............................................................................................................. 40 
3.6.2 
Physical examination ............................................................................................ 40 
3.6.2.1 
Weight................................................................................................................... 40 
3.6.3 
Neurological examination ..................................................................................... 40 
3.6.4 
Total neuropathy score- nurse (TNSn) variables .................................................. 41 
3.6.5 
Vital Signs ............................................................................................................ 42 
3.6.5.1 
Orthostatic blood pressure .................................................................................... 42 
3.6.6 
Survey of Autonomic Symptoms (SAS)............................................................... 42 
3.6.7 
Electrocardiograms ............................................................................................... 43 
3.6.8 
Laboratory data ..................................................................................................... 43 
3.6.9 
Injection site reactions .......................................................................................... 44 
3.6.10 
Radiographic (X-ray) and magnetic resonance imagining (MRI) assessments.... 44 
3.6.10.1 
X-ray assessments ................................................................................................. 44 
3.6.10.2 
MRI assessments .................................................................................................. 45 
3.6.11 
Study treatments ................................................................................................... 45 
3.6.11.1 
Exposure of study treatment ................................................................................. 45 
3.6.11.2 
Compliance ........................................................................................................... 45 
4 
ANALYSIS METHODS ...................................................................................... 46 
4.1 
General principles ................................................................................................. 47 
4.1.1 
Imputation Rules ................................................................................................... 47 
4.1.1.1 
Imputation of the primary and key secondary efficacy endpoints ........................ 47 
4.1.1.2 
Imputation of other study variables ...................................................................... 50 
4.1.1.3 
Handling of missing/incomplete dates ................................................................. 50 
4.2 
Efficacy analysis ................................................................................................... 51 
4.2.1.1 
Multiple testing strategy ....................................................................................... 53 




Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 9 of 95 
 
 
LIST OF TABLES 
Table 1 Analysis sets ............................................................................................................... 20 
Table 2 Intercurrent events and imputation strategy ............................................................... 29 
Table 3 Threshold values for the SF-36v2 scale and summary measures ............................... 35 
Table 4 Acceptable ABPM ranges .......................................................................................... 37 
Table 5 Normal ABPM ranges ................................................................................................ 38 
Table 6 Vital signs reference ranges........................................................................................ 42 
Table 7 Study treatments ......................................................................................................... 45 
Table 8 Pre-planned statistical analyses to be conducted ........................................................ 52 
Table 9 Pre-defined hypothesis and hierarchy to be tested ..................................................... 53 
 
LIST OF FIGURES 
Figure 1 Study design .............................................................................................................. 19 
Figure 2 Formal statistical testing strategy .............................................................................. 54 
 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 13 of 95 
 
 
AMENDMENT HISTORY 
Category*: 
Change refers to 
Date 
Description of change 
In line with the 
CSP? 
Rationale 
 Other secondary endpoints  
10AUG23 
All dosing visits will be 
used in analysis and 
summary statistics.  
No 
Provided the data is available it was 
decided to analyse it despite the 
protocol pre-defined timepoints.  
Data presentation  
15AUG23 
The document was 
updated throughout 
following the dry run 
prior to unblinding and 
final database lock.  
Yes/ No 
Data presentation was updated to 
allow more appropriate evaluation 
of the available data.  
In cases where such updates would 
deviate from the protocol, details 
are provided in section 6 of this 
document.   
Other  
15AUG23 
Clarifications added 
throughout the 
document.   
Yes 
To support programming. 
Other  
12SEP23 
Updated references to 
tables so that numbering 
aligns.  
NA 
Not applicable. 
* Pre-specified categories are  
Primary or secondary endpoints; Statistical analysis method for the primary or secondary endpoints; Derivation of primary or secondary endpoints; Multiple 
Testing Procedure; Data presentations; Other 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 14 of 95 
 
 
1 
STUDY DETAILS 
This statistical analysis plan (SAP) contains a more detailed description of the final analyses 
as described in the clinical study protocol (CSP) version 4.0, dated 28th June 2022. The final 
analyses will be split into two sections: 
Accelerated final efficacy analysis 
This analysis will be performed once all participants complete or discontinue the treatment 
period by completing week 12 (EOT/ET) visit. This threshold will indicate a potential data 
cut-off (DCO) date that will be confirmed by the study team. This confirmed DCO date will 
be used for analysis purposes and data cleaning will be focused on critical data up to and 
including the DCO date. Therefore, any data with a date in-between the DCO and database 
export dates will not be used for accelerated analysis purpose.  
The accelerated final efficacy analyses will consist primarily of the primary and secondary 
statistical analyses and formal statistical testing of the primary endpoint and one key 
secondary endpoint namely the Change in the WOMAC pain subscale from baseline to Week 
12. In addition, the supportive and other statistical analyses of those two endpoints will be 
executed. Specific outputs that will be produced for this analysis will be summarised in the 
accelerated final efficacy shells file that will be approved prior to the accelerated final efficacy 
analysis database lock. 
The accelerated final efficacy outputs will be prepared by the blinded IQVIA biostatistics 
team. The unblinding of the accelerated final efficacy analysis will be done by an independent 
unblinded IQVIA biostatistics team. The unblinded IQVIA biostatistics team will share the 
fully unblinded accelerated final efficacy analysis package with AstraZeneca via the restricted 
EntimICE unblinded folder. More details on the process and preserving the blind can be found 
in the biostatistical data transfer guidelines (DTG) and the unblinding plan. 
Final analysis  
This analysis will be performed at the end of the study once all participants either discontinue 
or complete the whole study including the follow-up period as defined in the clinical study 
protocol (CSP). This analysis will consist of the statistical analyses and formal statistical 
testing of the remaining key secondary endpoints and other statistical analyses that were not 
assessed nor performed during the accelerated final efficacy analysis. Outputs produced for 
this analysis will be summarised in the study specific shells file that will also include the 
specification of the outputs produced during the accelerated final efficacy analysis. Those 
outputs produced for the accelerated final efficacy analysis would be also rerun to ensure that 
only expected changes occurred (e.g., no ongoing participants in the study, changes associated 
with post treatment period). If any unexpected changes are observed, then the root cause 
analyses will be performed.   
  


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 15 of 95 
 
 
1.1 
Study objectives 
1.1.1 
Primary objective 
Primary Objective 
Estimand description/endpoint 
To assess the efficacy of 
MEDI7352 compared to 
placebo on chronic pain in 
participants with painful OA of 
the knee at Week 12 
Population: 
Adults with moderate-to-severe chronic OA pain of the 
knee, persistent for 3 months or longer, not adequately 
controlled by standard-of-care treatments 
Primary endpoint:  
Change in weekly average of daily NRS pain scores from 
baseline to Week 12 
Intercurrent events:  
• 
Discontinuation due to lack of efficacy or an adverse 
event (AE) 
• 
Discontinuation due to other reasons such as loss to 
follow-up or external circumstances 
• 
Taking prohibited pain medication during the 
treatment period 
• 
Taking excessive permitted rescue medication 
Summary measures:  
• 
Difference in mean changes in weekly average daily 
NRS pain scores between MEDI7352 doses and 
placebo 
• 
An ‘attributable’ estimand strategy will be adopted 
for primary endpoint data missing or affected by any 
of the above intercurrent events: Missing or affected 
primary endpoint values will be imputed, but the 
method of imputation will differ depending upon the 
intercurrent event. Specifically, data missing due to 
discontinuation, due to lack of efficacy or an AE will 
be imputed assuming an unfavourable outcome. 
Similarly, data affected by prohibited or excessive 
rescue medication will be set to missing and imputed 
assuming an unfavourable outcome. 
AE, adverse event; NRS, numerical rating scale; OA, osteoarthritis. 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 16 of 95 
 
 
1.1.2 
Secondary objectives 
Secondary Objectives 
Estimand descriptions/endpoints 
To assess the efficacy of 
MEDI7352 compared to 
placebo on additional measures 
of efficacy in participants with 
painful OA of the knee 
Key secondary endpoints:  
• 
Change in the WOMAC pain subscale from baseline 
to Week 12 
• 
Change in the WOMAC physical function subscale 
from baseline to Week 12 
• 
Change in the PGA of OA from baseline to Week 12 
Other secondary endpoints:  
• 
Change in the WOMAC pain subscale from baseline 
to Weeks 2, 4, 6, 8, 10, and 18 
• 
Change in the WOMAC physical function subscale 
from baseline to Weeks 2, 4, 6, 8, 10, and 18 
• 
Change in the WOMAC overall scores from baseline 
to Weeks 2, 4, 6, 8, 10, 12, and 18 
• 
Change in the WOMAC stiffness scores from 
baseline to Weeks 2, 4, 6, 8, 10, 12, and 18 
• 
Change in PGA of OA from baseline to Weeks 2, 4, 
8, 10, and 18 
• 
Percentage of responders as measured by the OARSI 
responder index using the OMERACT-OARSI 
definition (Pham et al 2004) at Weeks 2, 4, 8, 12, and 
18 
• 
Percentage of participants who have achieved an 
improvement of ≥ 2 points in PGA of OA at Weeks 
2, 4, 8, 12, and 18 
• 
Change in the weekly average of daily NRS pain 
scores from baseline to Weeks 2, 4, 6, 8, 10, and 18 
• 
Percentage of participants who have achieved ≥ 30% 
and ≥ 50% reductions in the weekly average of daily 
NRS pain scores from baseline to Weeks 2, 4, 8, 12, 
and 18 
• 
Percentage of participants who have achieved ≥ 30% 
and ≥ 50%, reductions in WOMAC pain subscale 
scores at Weeks 2, 4, 8, 12, and 18. 
• 
Percentage of participants who have achieved ≥ 30% 
and ≥ 50% reductions in WOMAC physical function 
subscale at Weeks 2, 4, 8, 12, and 18 
To assess the PK of 
MEDI7352 in participants with 
painful OA of the knee 
• 
Serum concentration of MEDI7352 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 17 of 95 
 
 
Secondary Objectives 
Estimand descriptions/endpoints 
To assess immunogenicity of 
MEDI7352 in participants with 
painful OA of the knee 
• 
Presence of ADA to MEDI7352 
• 
ADA titre 
ADA, anti-drug antibody; NRS, numerical rating scale; OA, osteoarthritis; OARSI, Osteoarthritis Research 
Society International; OMERACT-OARSI, Outcome Measures in Rheumatology-Osteoarthritis Research Society 
International; PGA, Patient’s Global Assessment; PK, pharmacokinetics; WOMAC, Western Ontario and 
McMaster Universities Osteoarthritis. 
 
1.1.3 
Safety objectives 
Safety Objectives 
Estimand descriptions/endpoints 
To assess the safety and 
tolerability of MEDI7352 
compared with placebo in 
participants with painful OA of 
the knee 
 
Safety and tolerability will be evaluated based on AEs, 
vital signs, and clinical laboratory assessments, including 
but not limited to: 
• 
AEs and SAEs  
• 
Physical examinations 
• 
Neurological examinations 
• 
Total Neuropathy Score-nurse 
• 
Weight 
• 
Vital signs (supine and standing BP, pulse rate, 
temperature, respiratory rate) 
• 
Survey of Autonomic Symptoms 
• 
12-lead ECGs 
• 
Clinical laboratory testing (haematology, chemistry, 
coagulation, and urinalysis) 
• 
CRP (inflammatory biomarker) 
• 
Concomitant medications and therapies 
• 
Injection site reactions 
• 
X-ray or/and MRI of large joints a 
a Detailed information about the joints to be evaluated by X-ray and/or MRI as noted in the protocol section 8.2.6 
Appendix I. 
AE, adverse event; BP, blood pressure; CRP, C-reactive protein; ECG, electrocardiogram; MRI, magnetic 
resonance imaging; OA, osteoarthritis; SAE, serious adverse event. 
 
 
 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 21 of 95 
 
 
Analysis set 
Definition 
Full analysis set  
All randomised participants. Participants will be analysed 
according to the intent-to-treat principle whereby their randomised 
study treatment will be analysed regardless of the study treatment 
actually received. This set will be used for demographics and other 
baseline characteristics, medication description and all efficacy 
analyses. 
Safety analysis set  
All participants who received at least one dose of double-blind 
study treatment. Participants will be analysed according to their 
actual study treatment received, regardless of the randomised study 
treatment. This set will be used for safety analyses.  
PK analysis set 
All participants who received at least one dose of double-blind 
study treatment per the protocol for whom any post-baseline PK 
data are available and who do not violate or deviate from the 
protocol in ways that would significantly affect the PK analyses. 
Participants will be analysed according to their actual study 
treatment received, regardless of the randomised study treatment. 
PK, pharmacokinetics. 
 
The assignment of actual treatment if an incorrect IP is administered will follow the below 
criteria: 
• If a participant randomised to placebo receives at least one dose of MEDI7352 XX mg 
during the entire double-blind treatment period then the actual treatment arm = 
MEDI7352 XX, where XX corresponds to the lowest dose of MEDI7352 that 
participant received during the double-blind treatment period. 
• If a participant took only MEDI7352 XX mg treatment during the entire double-blind 
treatment period, then the actual treatment arm = MEDI7352 XX, where XX 
corresponds to the dose of MEDI7352 that participant took during the entire double-
blind treatment period regardless of what treatment participant was randomized to.  
• If a participant took a mix of MEDI7352 XX mg treatments during the entire double-
blind treatment period, then the actual treatment arm = MEDI7352 XX, where XX 
corresponds to the lowest dose of MEDI7352 that participant received during the 
double-blind treatment period regardless of what treatment participant was randomized 
to. 
• If a participant randomised to an active treatment receives only placebo during the 
entire double-blind treatment period, then the actual treatment arm = Placebo. 
 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 22 of 95 
 
 
2.2 
Violations and deviations 
AstraZeneca use International Conference on Harmonization (ICH) E3 terminology for 
protocol deviations (PDs), which are all important deviations related to study inclusion or 
exclusion criteria, conduct of the trial, participant management or participant assessment. All 
protocol deviations (PDs) identified during monitoring of the study are recorded in the clinical 
trial management system (CTMS). Important protocol deviations (IPDs) are a subset of 
protocol deviations that may significantly impact the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a participant’s rights, safety, or 
well-being.  
The reporting of PDs and hence the CTMS changed on 16MAY2022. The main changes were 
the addition of the flag identifying the IPDs as well as changes to the PD categories.  
A detailed description of how PDs and IPDs are collected and identified is referenced in the 
Protocol Deviation Management Plan.  
The final list of IPDs will be documented prior to unblinding the study data for the final DBL 
and re-visited if required once the study is unblinded (for example, incorrect IP 
administration). This list may include, but not limited to the following categories:    
 
• 
Inclusion Criteria Deviations 
• 
Exclusion Criteria Deviations 
• 
Discontinuation Criteria for study product met but participants not withdrawn from study 
treatment 
• 
Discontinuation Criteria for overall study withdrawal met but participant not withdrawn 
from study 
• 
Deviations from IP management and administration  
• 
Prohibited Medications Taken 
• 
Deviations related to study procedure such as informed consent 
• 
Other Important Deviations 
o 
Scheduled study assessments not done or incorrectly performed which could impact 
the primary or key secondary endpoints 
o 
Unblinding of treatment assignment for reasons unrelated to participant safety 
o 
Other severe non-compliance (such deviations will be clearly described in the CSR) 
 
The IPDs will be listed including the full PD text as entered in the CTMS by site staff or 
CRAs and summarised by randomised treatment group including the old and new categories 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 23 of 95 
 
 
depending on when the PD was reported (before or after 16MAY2022). IPDs will also be 
summarised separately by whether they are due to COVID-19 or not.   
None of the deviations will lead to participants being directly excluded from the analysis sets 
described in section 2.1. The only exception being for the PK analysis set, if the deviation is 
considered to significantly impact upon PK assessments. That is:  
• If a participant randomised to an active treatment receives only placebo, then such 
participant would be excluded from the PK analysis set. 
• If a participant randomised to placebo receives only active treatment, then such 
participant would also be excluded from the PK analysis set (per protocol PK samples 
from participants randomised to placebo are not to be analysed). 
• If a participant randomised to placebo receives only placebo, but has any post-baseline 
PK data available, such participant will be excluded from the PK analysis set.    
• If a participant randomised to an active treatment receives an incorrect dose or placebo 
during the treatment period then such participant would be included in the PK analysis 
set, but PK assessment(s) after such dose would be excluded from summary outputs.   
• Participants with missed IP dose will be included in the PK analysis set, but such 
participants will be discussed case by case prior to unblinding to agree on the PK 
assessments use. The generic rule would be to not include assessment(s) made after the 
missed dose in summary outputs. Such data would be set to missing on the ADaM 
level so that there is traceability (but will be included in the SDTMs). 
• Participants that don’t receive a full volume of the IP will be included in the PK 
analysis set if more than 80% of the volume was administered. If less than 80% of the 
volume was administered, then such cases will be reviewed prior to unblinding and 
handled case by case. 
In addition, if a participant does not receive IP, this would lead to their exclusion from the 
safety set. A per protocol analysis excluding participants with specific important protocol 
deviations is not planned.  


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3.1.6.3 
Post treatment  
Post treatment is defined from last IP+15 days through to the date of last study assessment.  
3.1.7 
Reference start date  
The reference start date is defined as the date of the first dose of investigational product. 
• 
If the date of the assessment/event is on or after the reference date, then: 
Relative study day = (date of event – reference date) + 1  
• 
If the date of the assessment/event is prior to the reference date, then:  
Relative study day = (date of event – reference date) 
In the situation where the assessment/event date is partial or missing, relative study day and 
corresponding durations will appear partial or missing in the data listings. 
3.1.8 
Analysis visits – Retests and Unscheduled Assessments  
By-visit summaries will be presented by scheduled electronic case report form (eCRF) visit in 
form of a Day and a Week with a corresponding timepoint where applicable, unless otherwise 
specified. No analysis visit windowing will be applied unless otherwise specified.  
If more than one assessment coincides with the date of the scheduled visit as per the eCRF 
visit form, then the following will apply: 
• If assessment is associated with a scheduled timepoint as per the protocol, then such 
assessment will be used for analysis.  
• If more than one assessment per specific visit is associated with a scheduled timepoint 
as per the protocol, then the latest assessment according to the assessment date/time 
with non-missing result will be used for analysis.   
• If for such assessments a timepoint is not defined in the protocol, then the latest 
assessment according to the assessment date/time with non-missing result will be used 
for analysis.  
In addition, due to the extension of the follow-up period as per the protocol amendment 2 
dated 14OCT21, certain assessments were performed only during the Week 32 as supposed to 
Week 28 as done in the previous versions of the protocol. Provided that no windowing is 
applied some of such assessments will be mapped to Week 28 and some to Week 32 
depending on at what visit the assessment was actually performed as per the eCRF visit form. 
Consequently, the by-visit summaries will include both visits. 
NRS daily scores and DSIS will be mapped so that all assessments prior to Day 1 visit will be 
mapped to screening, the NRS daily score which date coincides with the Day 1 visit will be 


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collected during the follow-up period as well as prior to the first IP administration will be 
considered and summarised. 
3.2 
Primary efficacy variables 
The primary efficacy variable is the change in weekly average of daily NRS pain scores from 
baseline to Week 12. 
The NRS is an 11-point Likert scale used to assess pain, where participants are asked to 
describe their average pain in the target knee by identifying a number from 0 = “no pain” to 
10 = “most severe pain imaginable over the previous 24 hours”. This will be recorded on a 
daily basis at approximately the same time every morning. The daily NRS pain scores will be 
recorded via electronic patient recorded outcome (ePRO) diary.  
The relevant visit associated with the daily NRS scores will be derived based on the date of 
NRS pain scores that coincide with the relevant visit date as recorded on the electronic case 
report form (eCRF). Therefore, the Week 12 weekly average of daily NRS pain scores is the 
average of the daily NRS pain scores of 7 days up to and including the date on which the week 
12 (EOT/ET) visit occurred.  
For participants that discontinue the treatment period, the date of the ET visit as recorded on 
the eCRF in form of the week 12 (EOT/ET) visit will be associated with the protocol defined 
visit based on the study day, and the 7-day average for that specific visit will be derived using 
the same approach as described above for the Week 12 average. If the ET visit coincides with 
the target study day of the EOT visit, then this ET average will not be derived as it cannot 
represent a valid Week 12 average. In other words, only participants that complete the 
treatment will have Week 12 average derived. For those who prematurely withdraw from the 
treatment the Week 12 average will be imputed. At least four of the seven daily scores need to 
be recorded by the participant to obtain a weekly average value including baseline for the 
statistical analyses.  
If there are less than four daily scores for the Week 12 average due to an inappropriate visiting 
schedule of Week 11 (Week 11 and Week 12 in close succession), the derivation of the Week 
12 average will take priority over the Week 11 average. The weekly average will be derived in 
the same manner as described above but daily scores that may have been used for derivation 
of the Week 11 average would instead be used for derivation of the Week 12 average to 
ensure that at least 4 scores are available. 
For the primary endpoint, an attributable estimand strategy will be adopted for missing or 
unevaluable data accounted for by any of the defined intercurrent events. Missing or 
unevaluable primary endpoint values will be imputed, but the method of imputation will differ 
depending upon the intercurrent event, as detailed in Table 2 below.  


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Primary endpoint data missing due to other reasons than those summarised in Table 2 will be 
imputed using missing-at-random (MAR) multiple imputation approach, as outlined in section 
4.1.1.1. 
In addition, only single LOCF imputation will be applied as specified in section 4.1.1.1. 
Unevaluable data of the primary and key secondary variables are defined as cases where: 
• Participant’s cumulative daily dose of rescue medication of at least 4000 mg or 
prohibited pain medication were taken for a minimum of 4 days over the 7-day period 
that is being considered for deriving the weekly NRS average. In this instance the NRS 
average will be set to missing. 
• Participant’s cumulative daily dose of rescue medication of at least 4000 mg was taken 
within 24h prior of the WOMAC and PGA assessment or prohibited pain medication 
was taken a day before the WOMAC and PGA assessment. In this instance the 
WOMAC and PGA score is set to missing.   
In addition, all daily NRS scores affected by use of prohibited pain medication or paracetamol 
intake of cumulative daily dose of at least 4000 mg will be set to missing and not used for 
derivation of the weekly averages.  
Furthermore, there is potential for unevaluable primary and key secondary variable data in 
cases where prohibited pain medication was taken for less than 4 days over the 7-day period 
that is being considered for deriving the weekly NRS average or more than one day prior to 
WOMAC or PGA assessment. 
Participants with potentially unevaluable data will be reviewed prior to study unblinding by 
the study team who will confirm whether the data is deemed unevaluable or not. Only 
evaluable data for such participants will be included in the analyses. 
Table 2 Intercurrent events and imputation strategy 
Intercurrent event 
Single imputation strategy  
(Used for tabulation purposes)  
Multiple imputation 
strategy  
(Used for formal 
analyses) 
Discontinuation due to lack 
of efficacy or an AE 
Missing data imputed assuming an 
unfavourable outcome, that is the 
BOCF imputation 
MNAR: BOCF 
approach 
Taking prohibited pain 
medication during the 
treatment period 
Data affected will be set to missing 
and then imputed assuming an 


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Taking excessive permitted 
rescue medication 
unfavourable outcome, that is the 
BOCF imputation 
Discontinuation due to other 
reasons such as loss to 
follow-up or external 
circumstances 
Missing data imputed assuming 
missing at random, that is the LOCF 
imputation 
MAR approach  
BOCF, baseline-observation-carried-forward; LOCF, last-observation-carried-forward; MAR, missing at 
random; MNAR, missing not at random. 
More details concerning the imputation of missing or unevaluable primary endpoint data can 
be found in section 4.1.1.1. 
3.3 
Secondary efficacy variables 
The following are the key secondary efficacy endpoints: 
• Change in the WOMAC pain subscale from baseline to Week 12 
• Change in the WOMAC physical function subscale from baseline to Week 12 
• Change in the PGA of OA from baseline to Week 12 
The same attributable estimand strategy as well as single LOCF imputation as for the primary 
efficacy endpoint will be applied for these key secondary efficacy endpoints. In addition, 
missing Week 12 WOMAC pain subscale scores will be imputed using a differing MI 
approach as described in section 4.1.1.1., as a supportive analysis to compare with previously 
published studies. 
The other secondary efficacy endpoints are summarised in section 1.1.2. However, data of all 
available per protocol visits will be used for analysis and summarised (Weeks 2, 4, 6, 8, 10, 12 
and 18) unless otherwise specified.     
Finally, the ET assessments of all secondary endpoints will be handled in the same manner as 
for primary endpoint that is will be reassigned based on the study day.   
3.3.1 
WOMAC multiscale index 
The Western Ontario and McMaster Universities Osteoarthritis (WOMAC) multiscale index is 
used to assess pain, stiffness, and joint functionality in the past 48 hours in participants with 
OA of the knee or hip. The WOMAC questionnaire will be completed for the target knee at 
Visit 2 (Week 0, baseline), Visit 4 (Week 2), Visit 5 (Week 4), Visit 6 (Week 6), Visit 7 
(Week 8), Visit 8 (Week 10), Visit 11 (EOT or ET Week 12) and Visit 12 (Week 18) for only 
those participants who complete the treatment period. On dosing days, the WOMAC 
questionnaire will be completed prior to IP administration.  


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3.3.1.1 
WOMAC pain subscale 
The WOMAC pain subscale consists of 5 questions assessing the participant’s pain due to OA 
in the target knee. Each question is scored on an NRS scale from 0 to 10, where higher scores 
represent higher pain. The WOMAC pain subscale score is calculated as the mean score from 
all 5 questions.  
3.3.1.2 
WOMAC physical function subscale 
The WOMAC physical function (PF) subscale consists of 17 questions assessing the 
participant’s difficulty in performing activities of daily living due to OA in the target knee. 
Each question is scored on an NRS scale from 0 to 10, and the WOMAC PF subscale score is 
calculated as the mean score from all 17 questions, where higher scores represent worse 
function. 
3.3.1.3 
WOMAC stiffness subscale 
The WOMAC stiffness function subscale consists of 2 questions assessing stiffness due to OA 
in the target knee. Stiffness is defined as a sensation of decreased ease of movement in the 
target knee. Each question is scored on an NRS scale from 0 to 10, and the WOMAC stiffness 
function subscale score is calculated as the mean score from the 2 questions, where higher 
scores represent higher stiffness.  
3.3.1.4 
WOMAC overall score 
The WOMAC overall score consists of all 24 questions reported in the WOMAC 
questionnaire to assess: i) pain subscale, ii) PF subscale and iii) stiffness subscale. WOMAC 
overall score is calculated as the mean score from all 24 questions where higher scores 
represent worse outcome. 
3.3.2 
Patient’s Global Assessment (PGA) of Osteoarthritis (OA) 
The PGA of OA is a 5-point Likert scale used to assess symptoms and activity impairment 
due to OA of the knee. Participants are asked to identify a number from 1 = “very good 
(asymptomatic and no limitation to normal activities)” to 5 = “very poor (very severe 
symptoms which are intolerable and inability to carry out all normal activities)” based on the 
question “Considering all the ways that OA of the knee affects you, how are you feeling 
today?”. The PGA questionnaire will be administered at the time points specified in the CSP 
(Refer to CSP Table 1). Participants who discontinue IP early will have their last PGA of OA 
assessment at the ET visit. On dosing days, the PGA assessment will be completed prior to IP 
administration. 
3.3.3 
OMERACT-OARSI responder index  
The OMERACT-OARSI responder index is calculated from the WOMAC Pain subscale, the 
WOMAC Physical Function Subscale and the PGA of OA. A participant is classified as a 
responder if either of the below occurs: 


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1. ≥2-point absolute change from Baseline to Week X or a ≥50% improvement is 
reported in the WOMAC Pain or the Physical Function subscales. 
2. At least 2 of the following 3 conditions are true: 
• ≥1-point absolute change from Baseline to Week X or ≥20% improvement is 
reported in the WOMAC Pain subscale. 
• ≥1-point absolute change from Baseline to Week X or ≥20% improvement is 
reported in the WOMAC Physical Function subscale. 
• ≥1-point absolute change from Baseline to Week X is reported in the PGA of 
OA.  
 
3.4 
Pharmacokinetic and immunogenicity variables   
Blood samples for PK and ADA assessments will be analysed by bioanalytical test sites. All 
serum samples will be collected prior to study treatment administration (on dosing days) at the 
time points specified (See CSP Table 1). On non-dosing days, PK and ADA samples will be 
collected in the morning and the time of sample collection must be recorded. Note that 
participants who discontinue IP early will have their last PK sampling at the ET visit. 
3.4.1 
Pharmacokinetics 
The serum MEDI7352 concentrations will be determined only for participants randomised to 
an active treatment. 
At a visit/time point for a specific cohort where less than or equal to 50% of the concentration 
values are not quantifiable (NQ) that is are below the lower limit of quantification (LLOQ), all 
such values will be set equal to the LLOQ value, and all descriptive statistics will be 
calculated accordingly (using the value of the LLOQ that will be included in the summary 
statistics). 
At a visit/time point for a specific cohort where more than 50% (but not all) of the values are 
NQ, the gmean, gmean ± gSD and gCV% will be set to NC. The maximum value will be 
reported from the individual data, and the minimum and median will be set to NQ. 
If all concentrations are NQ for a specific cohort at a visit/time point, no descriptive statistics 
will be calculated for that time point. The gmean, minimum, median and maximum will be 
reported as NQ and the gCV% and gmean ± gSD as NC. 
3.4.2 
Immunogenicity  
For immunogenicity analysis, the presence of detectable (i.e., positive) anti-drug antibodies 
(ADAs) against MEDI7352 will be reported. ADA results from each sample are reported as 
either positive or negative.  In addition, the ADA titer result will be reported for samples 
confirmed positive for the presence of ADAs. A participant is defined as being ADA-positive 


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if at least one positive ADA result is available at any time (including baseline and all post-
baseline measurements); otherwise ADA negative. 
The following ADA categories will be determined: 
• 
ADA positive if a collected sample is tested positive at any time during the study, 
including baseline and/or post-baseline. (The percentage of these participants in a 
population is known as ADA prevalence) 
• 
Treatment-emergent ADA positive (TE-ADA+): A positive post-baseline result and 
either of the following statements holds: 
− 
Baseline is ADA negative and at least one post-baseline assessment is ADA positive. 
This is called treatment-induced ADA positive.  
− 
Baseline is ADA positive, and the baseline titre is boosted by greater than the 
variability of the assay (i.e. ≥ X-fold increase, commonly 4-fold) at ≥1 post-baseline 
timepoint. This is called treatment-boosted ADA positive.  
(The percentage of these participants in a population is known as ADA incidence) 
• 
Non-Treatment-emergent ADA positive (non-TE-ADA+): Participants who are ADA 
positive but not fulfilling the conditions for TE-ADA+ 
• 
Treatment-emergent Persistently ADA positive: ADA negative at baseline and having 
at least 2 post-baseline ADA positive measurements with ≥ 16 weeks (112 days) between 
first and last positive, or an ADA positive result at the last available post-baseline 
assessment 
• 
Treatment-emergent Transiently ADA positive: ADA negative at baseline and at least 
one post-baseline ADA positive measurement and not fulfilling the conditions for 
persistently positive 
• 
ADA positive post-baseline and positive at baseline. 
• 
ADA not detected post-baseline and positive at baseline. 
ADA evaluable participants are defined as the participants in the safety analysis set who have 
a non-missing baseline and at least one non-missing post-baseline ADA results. 
 
3.5 
Exploratory variables 
3.5.1 
Supportive efficacy and health related quality of life variables 
The supportive efficacy and health related quality of life endpoints are summarised in section 
1.1.4. 
3.5.1.1 
Daily Sleep Interference Scale (DSIS) 
DSIS is an 11-point Likert scale used to assess how pain interferes with participants’ sleep 
where 0= pain did not interfere with sleep and 10 = pain completely interfered with sleep. 
This will be recorded on a daily basis (upon awakening) via electronic patient recorded 


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outcome (ePRO) diary until Week 18 unless participants discontinue the IP early in which 
case last recording DSIS would be at ET visit.   
The derivation of the averages will be the same as for the NRS pain score described in section 
3.2 including the handling of the ET assessments. However, the average will be derived 
regardless of how many daily scores are available. 
3.5.1.2 
European Quality of Life-5 Dimensions (EQ-5D-5L) 
The EQ-5D-5L questionnaire assesses 5 dimensions of health (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression). For each dimension, respondents will 
select which statement best describes their health on that day from a possible 5 options of 
increasing levels of severity (no problems, slight problems, moderate problems, severe 
problems, and extreme problems). 
In addition to the descriptive system, the participants are asked to rate their health on the day 
of assessment on a visual analogue scale (VAS), ranging from 0 (worst imaginable health) to 
100 (best imaginable health). This score is reported separately. 
The European Quality of Life-5 Dimensions (EQ-5D-5L) may be analysed separately and not 
form part of this SAP. 
3.5.1.3 
36-Item Short Form Health Survey Questionnaire 
The 36-Item Short Form Health Survey Questionnaire version 2 (SF-36v2) is a 36-item 
questionnaire on functional health and well-being, with a 1- to 4-week recall period. 
Responses to 35 of the 36 items are used to compute an 8-domain scores and two component 
summary measures. The remaining item (the ‘health transition’ item), asks participants to rate 
how their current state of health compares to their state of health one year ago. This item is not 
used to calculate domain scores.  
The 8-domains are: Physical Functioning (PF), Role Limitations due to Physical Health (RP), 
Bodily Pain (BP), General Health Perceptions (GH), Vitality (VT), Social Functioning (SF), 
Role Limitations due to Emotional Problems (RE), and Mental Health (MH). The component 
summary measures (physical component summary [PCS] and mental health component 
summary [MCS]) are computed from domain scores to give a broader metric of physical and 
mental health-related quality of life. The transformed score range for each of the 8 domains 
and for PCS and MCS is 0-100; higher scores indicate better health state. 
The change from baseline in SF-36v2 (PCS and MCS) scores will be calculated. 
The threshold values for the SF-36v2 PCS, MCS, and domain scores listed in Table 3 are 
suitable for interpreting change at the participant level and are referred to as the responder 
thresholds or responder definitions (Maruish 2011).  


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Table 3 Threshold values for the SF-36v2 scale and summary measures  
  
SF-36v2 score  
Threshold  
PCS 
MCS 
PF 
RP 
BP 
GH 
VT 
SF 
RE 
MH 
Group difference  
2 
3 
3 
3 
3 
2 
2 
3 
4 
3 
Individual change  
3.4 
4.6 
4.3 
3.4 
6.2 
7.2 
6.2 
6.9 
4.5 
6.2 
BP, bodily pain; GH, general health perceptions; MCS, mental health summary; MH, mental health; PCS, 
physical component summary; PF, physical functioning; RE, emotional problems; RP, role limitations due to 
physical health; SF, social functioning; VT vitality. 
Categorical analyses of the change in each of the SF-36v2 scales and summary measures will 
be compared to its respective individual change threshold (see Table 3) to indicate whether 
each participant experienced a change deemed clinically significant and important. A 
participant will be classified as a responder if the change from baseline ≥ individual change 
threshold, or a non-responder if change from baseline < individual change threshold. If data 
are missing, then the participant will be classified as a non-responder. 
3.5.1.4 
Work Productivity and Activity Impairment questionnaire for OA 
(WPAI:OA) 
The WPAI:OA is a self-administered tool comprised of 6 questions that measure absenteeism, 
presenteeism, work productivity, and activity impairment due to OA of knee. This tool 
captures data from the past 7 days. Each subscale score is expressed as a percentage 
impairment from 0 to 100, where higher numbers indicate greater impairment and less 
productivity.  
The following WPAI:OA impairment scores are defined: i) Percent activity impairment due to 
Osteoarthritis, ii) Percent impairment while working due to osteoarthritis, iii) Percent overall 
work impairment due to osteoarthritis and iv) Percent work time missed due to Osteoarthritis. 
Further details about the questions and derivations of those endpoints are shown in Appendix 
A1. 
3.5.1.5 
Healthcare Resource Utilisation (HCRU) 
Healthcare resource utilisation information (e.g., doctor office visits, hospitalisations, 
surgeries, or other procedures) used by each participant are collected by the investigator and 
study-site personnel for all participants at baseline (i.e., collecting data up to 3 months before) 
and various time points during the study as specified (See CSP Table 1).  Protocol-mandated 
procedures, tests, and encounters are excluded. The responses and scores to the HRCU 
questionnaire are presented in Appendix A2 with questions recalling the period between visits 
reported in weeks for all visits except for baseline. 
3.5.1.6 
Lack of efficacy endpoints 
The investigator is responsible to determine if a participant should discontinue treatment due 
to lack of efficacy and report the same on the DS_EOT page of eCRF.  


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For each participant, the time to permanent discontinuation of IP due to lack of efficacy will 
be determined as follows: 
(Date of IP discontinuation as reported on the DS_EOT page of eCRF) – (date of first IP 
administration) +1 
3.5.1.7 
Rescue medication use 
Rescue medication (paracetamol) use will be collected via the participant eDiary from Day -
14 until Week 18. Participants who discontinue IP early, will stop recording rescue medication 
after the ET visit. 
The following variables will be derived and/or summarised: 
• 
Number of participants using the rescue medication 
• 
Reason for using rescue medication  
• 
Total number of days rescue medication was used 
− 
Each day on which rescue medication was used at least once is counted 
• 
Cumulative consumption (mg) of rescue medication use 
− 
Calculated as the total dose of rescue medication (mg) 
• 
Average daily dose (mg) of rescue medication use 
− 
Calculated as: cumulative consumption of rescue medication (mg) /total number of 
days rescue medication was used 
In addition to the above and in order to evaluate the changes in rescue medication use (number 
of days and cumulative consumption) over time, the daily collected data will be assigned to a 
specific study week. This assignment will use the same principles as deriving the NRS pain 
scores. For details refer to the section 3.2.  
 
3.5.2 
Biomarker and Pharmacodynamic variables  
The biomarker endpoints are defined in the section 1.1.4.  
However, only the below will be considered for analyses and CSR reporting depending on 
data availability at the end of the study (final clinical database lock): 
• Total NGF measurements in serum over time (also denominated as pharmacodynamic 
variable/endpoint)  
• Baseline biomarkers/pharmacodynamics namely Total NGF, TNF alpha, IL-1 beta, IL-
6 and high sensitivity C-reactive protein (CRP)  
Additional endpoints may be analysed providing such data are available. 


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Samples for biomarker research are required and will be collected from all participants in this 
study as specified (see CSP Table 1). Note that participants who discontinue IP early will have 
their last pharmacodynamics/biomarkers sampling at the ET visit. 
3.5.3 
Ambulatory blood pressure monitoring (ABPM) variables 
The ABPM endpoints are presented in section 1.1.4. 
During ABPM, the systolic BP, diastolic BP, pulse pressure, pulse rate recorded as heart rate 
by the vendor, and mean arterial pressure readings will be recorded over a period of 24 hours 
with frequency of readings during the day (every 15 minutes) and overnight (every 30 
minutes). Participants will wear the ABPM device for a period of 24 hours at 2 separate times 
during the study: one time during the screening period and one time during the double-blind 
treatment period (between Weeks 8 and 12 inclusive).  
An average of the individual readings during the day as well as the night will be determined 
for each participant. The 24-hour assessments will be derived as an overall average of all 
readings of a specific parameter for each participant for that specific visit (screening or visit 
within Weeks 8 and 12). 
Individual readings with missing or zero values or values out of the acceptable ranges as 
identified in Table 4 below as well as those set to ‘not done’ will not be included in the 
calculation of averages.  
Table 4 Acceptable ABPM ranges 
Parameter 
ABPM acceptable ranges  
Systolic blood pressure (SBP) 
10 - 250 mmHg 
Diastolic blood pressure (DBP) 
5 - 200 mmHg 
Pulse Pressure (PP) 
5- 250 mmHg  
Mean Arterial Pressure (MAP) 
10 – 250 mmHg 
Heart Rate (HR) 
1 - 200 bpm 
 
In addition, the entire set of the readings for a specific visit will be considered of poor quality 
and hence not used for analysis if any of the following is met:  
• There is less than 20h of the total readings available for a specific parameter and visit 
for each participant 


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• There are less than 70% of valid measurements out of the total measurements recorded 
for a specific parameter and visit for each participant  
Such readings that should be excluded will be identified by the vendor according to the above-
mentioned criteria.   
ABPM will be classified as normal if average is within normal reference range presented in 
Table 5 below and abnormal if the average is outside of this reference range. 
Table 5 Normal ABPM ranges  
Parameter 
ABPM normal reference ranges 
Day/Night/24-hours SBP 
70 - 240 mmHg 
Day/Night/24-hours DBP 
40 - 150 mmHg 
Pulse Pressure (PP) 
20 - 150 mmHg 
Mean Arterial Pressure (MAP) 
40 - 200 mmHg 
Day/Night/24-hours HR 
20 - 200 bpm 
 
3.6 
Safety variables 
Safety and tolerability of MEDI7352 will be evaluated based on the AEs, physical and 
neurological examination, total neuropathy scores, vital signs, survey of autonomic symptoms, 
electrocardiograms, injection site reactions, radiographic and magnetic resonance imagining 
assessment and clinical laboratory assessment.  
3.6.1 
Adverse events 
AEs and serious AEs (SAEs) as defined in the protocol appendix C will be collected from the 
screening, throughout the study, and including the follow-up period. The Medical Dictionary 
for Regulatory Activities (MedDRA) will be used to code the AEs, using the latest version. 
AEs will be graded according to the Common Terminology Criteria for AEs (CTCAE version 
5).   
A treatment emergent adverse event (TEAE) is defined as:   
• 
any AE with an onset at the time of or following the start of study treatment through the 
end of study participation as per DS page in eCRF;  


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• 
any AE starting prior to the start of study treatment administration but increasing in 
severity at the time of, or following, the start of study treatment through end of study 
participation as per DS page in eCRF.  
 
Any AE occurring before the first dose of study treatment and without worsening after the 
first dose will be included in the data listings but will not be included in the AE summary 
tables.  
The causal relationship between IP and each AE will be recorded. For SAEs, causal 
relationship will be assessed for other medication and study procedures. 
 
3.6.1.1 
Adverse events of special interest 
An AE of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring and collecting additional 
information by the investigator. An AESI may be serious or nonserious. The rapid reporting of 
AESIs allows ongoing surveillance of these events to characterise and understand them in 
association with the use of MEDI7352.  
AESIs for MEDI7352 include, but are not limited to: 
• Positively-adjudicated possible or probable Rapidly Progressive Osteoarthritis 
(RPOA), Subchondral Insufficiency Fracture (SIF), primary osteonecrosis, or 
pathological fracture 
• Infections that meet SAE or severe AE criteria (see CSP Appendix C 2) 
• Anaphylactic reactions; serious or severe hypersensitivity reactions; or injection site 
reactions that lead to permanent discontinuation of administration of IP 
• Other – includes AESIs that do not meet any of the above criteria, but are deemed of 
interest by the study team  
AESIs irrespective of their severity and seriousness should be reported immediately using the 
same procedure as for SAE reporting (See CSP section 8.3.9). 
3.6.1.2 
Adverse events based on signs and symptoms  
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: ‘Have you had any health problems since the 
previous visit/since you were last asked?’ or revealed by observation will be collected and 
recorded in the eCRF. 


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3.6.1.3 
Adverse events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
will only be reported as AEs if they fulfil any of the SAE criteria, are the reason for 
discontinuation of treatment with the IP or are considered to be clinically relevant as judged 
by the investigator (see CSP section 8.3.7).  
In addition, occurrences in liver biochemistry of AST or ALT ≥ 3 × ULN together with total 
bilirubin ≥ 2 × ULN will be reported as SAEs as per Hy’s Law (see CSP Appendix F).  
3.6.1.4 
Pregnancy  
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. A woman who becomes pregnant 
during IP treatment or within 30 days of discontinuing the IP will be immediately withdrawn 
from study participation. Every pregnancy will be documented in EDC using the pregnancy 
report (PREGREP) page in eCRF.    
3.6.2 
Physical examination  
The following assessments will be performed as part of the physical examination: 
General appearance, skin, head and neck, examination of the oral cavity for any lesions, 
lymph nodes, thyroid, abdomen (bowel sounds, liver, and spleen palpation), back 
(including costovertebral angle tenderness), musculoskeletal/extremities, cardiovascular, 
and respiratory systems. 
The physical examination will be performed during screening, treatment period and follow-up 
period, as indicated in CSP (Table 1).   
3.6.2.1 
Weight  
Weight will be measured at screening and at Week 12 as well as when change is suspected, or 
fluid retention occurs.   
3.6.3 
Neurological examination 
The neurological examination performed ideally by a neurologist include: 
Assessment of mental status, cranial nerves, motor examination (muscle strength and 
tone), upper and lower extremity deep tendon reflexes, plantar responses, sensory system 
examination, coordination, and gait. 
The neurological examination will be performed during screening, treatment period and 
follow-up period, as indicated in CSP (Table 1).   


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For participants with clinical manifestations consistent with worsening of pre-existing 
neuropathy, follow-up nerve conduction studies should be performed and documented at the 
time points deemed appropriate by the neurologist, but at least once during participation in the 
study. 
3.6.4 
Total neuropathy score- nurse (TNSn) variables 
The total neuropathy score – nurse (TNSn) assessment is collected as scores as follows: 
• 
Sensory symptom score 
− 
Sensory symptoms consist of six questions, each rated from 0 to 4. 
− 
Sensory symptom score is determined as the maximum of the six scores. 
• 
Motor symptom score 
− 
Motor symptoms consist of four questions, each rated from 0 to 4. 
− 
Motor symptom score is determined as the maximum of the four scores. 
• 
Autonomic symptom score 
− 
Autonomic symptoms consist of six symptoms rated as present of not (yes/no) 
− 
Autonomic symptom score is determined as the number of symptoms present, with a 
maximum score of 4 assigned for four or more symptoms present. 
• 
Pin sensibility score 
− 
Pin sensibility is scored as 0 to 4 in upper and lower limbs both left and right, 
therefore four areas in total. 
− 
Pin sensibility score is determined as the maximum of the four scores. 
• 
Vibration sensibility score 
− 
Vibration sensibility is scored as 0 to 4 in upper and lower limbs both left and right, 
therefore four areas in total. 
− 
Vibration sensibility score is determined as the maximum of the four scores. 
• 
TNSn total 
− 
The total score is determined as the sum of the five aforementioned scores. 
The TNSn assessment will be performed during screening, treatment period and follow-up 
period, as indicated in CSP (Table 1).  
The ET assessments will be handled in the same manner as for primary endpoint that is will be 
reassigned based on the study day.   


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3.6.5 
Vital Signs 
Blood pressure (BP) and pulse rate will be measured at each clinic visit with details about the 
method, time and frequency described in CSP section 8.2.3.1. Body temperature and 
respiratory rates will be measured at different time points as indicated in CSP (Table 1). 
Absolute values will be compared to the reference ranges in Table 6 and classified as low 
(below range), normal (within range or on limits) or high (above range). All values (absolute) 
falling outside the reference ranges will be flagged. 
Table 6 Vital signs reference ranges 
Parameter 
Standard Unit 
Lower Limit 
Upper Limit 
Diastolic Blood Pressure 
mmHg 
60 
120 
Systolic Blood Pressure 
mmHg 
100 
160 
Pulse Rate 
Beats/min 
40 
120 
Respiratory Rate 
Breaths/Min 
8 
28 
Body Temperature 
Celsius 
36.5 
38 
 
3.6.5.1 
Orthostatic blood pressure  
Orthostatic (BP) measurements will be obtained at all clinic visits and taken after scheduled 
supine measurements (1 and 3 minutes after the participant stands) and prior to any required 
blood draw or study treatment administration (and prior to randomisation on Day 1). 
After stable BP is achieved in supine position (see CSP section 8.2.3.2), the participant will 
stand, and a BP measurement will be taken at 1 and 3 minutes after the participant stands. If 
the BP measurements also referred to as postural changes do not meet the criteria for 
orthostatic hypotension, no additional measurement is needed. If the BP measurement meets 
any of the criteria shown in CSP Table 6, investigators will repeat the supine and standing 
measurements up to 2 additional times. Blood pressure changes meeting the pre-specified 
criteria and confirmed will be designated as a confirmed orthostatic hypotension episode. 
3.6.6 
Survey of Autonomic Symptoms (SAS) 
The SAS is an instrument that measures autonomic symptoms used for assessing autonomic 
neuropathies in clinical trials.  
The SAS evaluates the presence of a symptom and the degree of its severity. It consists of 11 
questions in women and 12 in men.  
Each question has a “Yes” or “No” answer to symptoms occurring 6 months prior to IP 
administration. Questions answered with “Yes” are further rated from 1 to 5 by asking the 


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participant how much each symptom is bothering him or her. Each answer is scored on a scale 
from 1 to 5 where 1 = “not at all” and 5 = “a lot”, and a total symptom impact score is 
determined as the sum of the ratings provided for all reported symptoms, that is questions 
answered with ‘Yes”. 
The following domains are assessed:  
Orthostatic, sudomotor symptoms, vasomotor, gastrointestinal, urinary, and sexual 
dysfunction. 
The assessment is done at Day 1 and Week 36 only.  
3.6.7 
Electrocardiograms 
Electrocardiograms (ECGs) will be obtained during screening, during treatment period and 
follow-up period as indicated in CSP (Table 1).  
The investigator will judge the overall interpretation as normal or abnormal clinically non-
significant or abnormal clinically significant, and this evaluation will be reported in the eCRF. 
3.6.8 
Laboratory data 
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
serology, drug screening, pregnancy tests, and urinalysis will be taken at the visits indicated in 
CSP Table 1. 
Blood and urine samples for haematology, serum chemistry, coagulation, urinalysis, and 
serology will be sent to a central laboratory for analysis. Urine drug screens will be conducted 
at the study sites. Serum pregnancy test will be conducted at the central laboratory; urine 
pregnancy test will be conducted at study sites. 
Samples for laboratory tests will include the following:  
• 
Haematology: haemoglobin, haematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular haemoglobin, mean corpuscular haemoglobin concentration, platelet count 
(or estimate), white blood cell count, and white blood cell differential 
• 
Serum chemistry: albumin, total and direct bilirubin, total protein, calcium, alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma glutamyl transferase (GGT), blood urea nitrogen (BUN), creatinine*, glucose, 
sodium, potassium, chloride, bicarbonate, calcium, phosphorus, lactate dehydrogenase 
(LDH), uric acid, C-reactive protein (CRP), cholesterol, triglycerides, creatine 
phosphokinase.  
• 
Coagulation panel: prothrombin time, activated partial thromboplastin time, fibrinogen  
• 
Urinalysis: pH, specific gravity, blood, leukocytes, glucose, protein, ketones, bilirubin  


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• 
Urine drug screen: including but not limited to amphetamine, barbiturate, cannabinoids, 
cocaine, methadone, methaqualone, opiate, phencyclidine, and propoxyphene.  
• 
Urine pregnancy test (only in female participants not surgically sterile) 
• 
Serology: human immunodeficiency virus (HIV), hepatitis B, and hepatitis C screen, 
tuberculosis (TB) (QuantiFERON), and anti-citrullinated protein antibodies (ACPA) 
(screening only) 
• 
Endocrinology: follicle-stimulating hormone (FSH) (Female < 50 years of age only and at 
screening only, to confirm menopausal state), β-HCG beta human chorionic gonadotropin 
(female participants, not surgically sterile only, at screening only). 
• 
Other: haemoglobin A1c  
*Note: Serum chemistry reports should include calculation of creatinine clearance using the 
Cockcroft-Gault equation. 
 
HIV, hepatitis B and C and TB QuantiFERON data is considered sensitive and as such, the 
data will remain at the sites and will not be transferred further hence will not be part of the 
analysis.  
Change from baseline in hematology, chemistry, coagulation, urinalysis, and haemoglobin 
A1c variables will be calculated for each post-dose visit as per the protocol defined schedule. 
 
3.6.9 
Injection site reactions 
Injection site reactions occurring during or immediately following study treatment 
administration will be evaluated. Local reaction to injectable product will be evaluated for 
pain, tenderness, erythema/redness, and induration/swelling, and classified as mild, moderate 
or severe as per CSP (Table 7).  
In addition, 
• 
For erythema/redness, the measurement associated to the local reaction at the greatest 
single diameter should be recorded as a continuous variable. 
• 
Induration/swelling should be evaluated as the actual measurement. 
 
3.6.10 
Radiographic (X-ray) and magnetic resonance imagining (MRI) 
assessments  
3.6.10.1 
X-ray assessments  
All participants should undergo diagnostic x-ray on the shoulder, knee, and hip joints during 
screening period while at Week 32 visit, x-ray imagining is performed on the knee and hip 
joints. Any potentially clinically significant findings detected on X-ray performed at week 32 
will be further assessed and sent for adjudication. In addition, unscheduled X-ray should be 
performed “for cause” to follow up on any worsening symptoms. These assessments will aid 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 48 of 95 
 
 
Single imputation  
Single imputation will be used for tabulation of the primary and key secondary endpoints as 
well as ANCOVA analysis of primary and key secondary endpoints. In this case the missing 
or unevaluable data at Week 12 will be imputed using: 
• A single imputation method LOCF or BOCF as specified in Table 2 for tabulation 
only. 
• A single LOCF imputation method for ANCOVA supplementary analysis and 
tabulation. 
Multiple imputation  
Generally, it will be assumed that missing observations for the primary and key secondary 
endpoints are missing at random. The exception are observations that are missing due to lack 
of efficacy or an AE, also values that are invaluable or missing due to taking prohibited pain 
medication or excessive use of permitted rescue medication as presented in Table 2. Those 
observations are assumed to be missing not at random (MNAR). Consequently, the pattern 
mixture framework (Ratitch B. and O’Kelly M., 2011) will be implemented by multiple 
imputation using steps summarized below, where 100 imputed datasets will be created across 
which the Rubin’s rule will be applied to combine the estimates. Execution details are 
provided in Appendix B1. However, prior to executing the below steps, missing baseline of 
the primary and key secondary endpoints will be imputed using the SAS PROC MI statement 
MONOTONE REG with seed number =568000003 with number of iterations set to 100. KL 
grade as reported by Bioclinica also referred to as Clario will be included in the imputation 
model.  
Step 1: Intermediate missing data imputation  
The non-monotone missing values will be imputed using the Markov chain Monte 
Carlo method assuming MAR and multivariate normality. This step will be executed 
using the SAS procedure PROC MI with the MCMC option with seed 
number=568000003 and number of iterations set to 1 and number of burn-in iterations 
fixed at 200. The treatment and Kellgren and Lawrence (KL) grade variables will be 
included in the imputation model. 
 
Step 2: Imputation of missing patterns  
The missing/unevaluable values of each pattern that are defined by the intercurrent 
events as specified in Table 2 will be imputed via the sequential regression method 
using the SAS PROC MI statement MONOTONE REG with seed number 
=568000003 as follows:  
• MAR -The missing/unevaluable week 12 values of primary and key secondary 
endpoints will be estimated from the observed and imputed data from step 1 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 49 of 95 
 
 
using the sequential modelling approach. That is, prior outcomes of the primary 
or key secondary endpoints at each visit will be considered for imputing 
missing week 12 values under the MAR assumption. In addition, the treatment 
and KL grade variables will be included in the model. 
• MNAR – The missing/unevaluable week 12 values of primary and key 
secondary endpoints will be estimated from the observed and imputed data 
from step 1 using the baseline observation carried forward approach. Non-
missing baseline records from participants from both the placebo and active 
treatment arms will be used to impute post-discontinuation records from both 
the placebo and active treatment arms with KL grade included in the model. 
 
Step 3: Combining the imputed outcomes and Statistical analyses  
The imputed data from first two steps along with observed data will be analysed using 
the MCP-Mod and analysis of covariance (ANCOVA) model as described in section 
4.2 
 
MCP-Mod 
The estimated dose response parameters (µො(𝑞𝑞)) with their covariance matrices (𝑆𝑆̂(𝑞𝑞)) 
from each imputed dataset 𝑞𝑞=  1, … , Q   obtained from ANCOVA model as specified 
in section 4.2 will be combined using Rubin’s rule (as elaborated by Shomaker and 
Heumann, 2014). For more information refer to Appendix C.  
Dose-response model will be selected using the estimates combined above. 
 
ANCOVA 
The estimates obtained from the ANCOVA models will be combined using the 
MIANALYZE SAS procedure with adjusted degrees of freedom (EDF = option) based 
on the Rubin’s method (Barnard and Rubin 1999). 
 
In addition to the above, the missing Week 12 WOMAC pain subscale scores will be 
multiply imputed using sampling from a normal distribution approach (Appendix B2) 
depending on the reason for missing data as follows: 
 
• Discontinuation due to lack of efficacy or an AE or death:  
Sampling from normal distribution with mean of participant’s baseline score 
and standard deviation of the observed WOMAC pain subscale scores at Week 
12 over all participants in FAS regardless of treatment assignment.  
 
• Missing data due to reasons other than those stated above: 
Sampling from normal distribution with mean of participant’s last available 
score and standard deviation of the observed WOMAC pain subscale scores at 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 50 of 95 
 
 
Week 12 over all participants in FAS regardless of treatment assignment. It is 
possible that participant’s last available score would be baseline score, in 
which case this score would be used.  
  
Missing baseline of WOMAC pain subscale score will be also imputed using the same 
approach of imputing missing baseline of primary and key secondary endpoints 
described in the first paragraph of the multiple imputation section above. In addition, 
this MI with seed number =568000003 will also generate 100 imputed datasets. 
Each imputed dataset will be used for ANCOVA analysis, and its estimates combined 
using the MIANALYZE SAS procedure with adjusted degrees of freedom (EDF = 
option) based on the Rubin’s method (Barnard and Rubin 1999).    
4.1.1.2 
Imputation of other study variables 
Age at randomization will be derived for analysis purpose from the date of birth (DM module) 
and the randomization date (IE1 module) on the eCRF at screening as: year (randomization 
date) – year (date of birth), -1 if “day and month” of the randomization date is before “day and 
month” of the date of birth.  
Participants with a partial date of birth (i.e., for those countries where year of birth only is 
given due to local regulatory constraints) will have an assumed date of birth of 1st Jan ([given 
year]).  
Unless otherwise specified, safety assessment values of the form of “< x” (i.e. below the lower 
limit of quantification) or “> x” (i.e. above the upper limit of quantification) will be imputed 
as “x” in the calculation of summary statistics but displayed as “< x” or “> x” in the listings.  
 
Adverse events: all AEs will be considered as treatment-emergent unless the opposite can be 
clearly stated. Imputation will be done only in the context of identifying TEAEs. 
Medications/therapies: all medications will be considered as concomitant unless the opposite 
can be clearly stated. 
Additionally, AEs that have missing causality (after data querying) will be assumed to be 
related to study treatment. 
 
4.1.1.3 
Handling of missing/incomplete dates 
The original incomplete or missing dates will be presented in the listings. 
In practice, partial AE or medication start dates will be imputed as follows: 
• Missing day: Impute the 1st of the month unless month is same as month of first dose 
of study drug then impute first dose date. If the onset is before the first dose of study 
drug then impute with date of informed consent 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 51 of 95 
 
 
• Missing day and month: impute 1st January unless year is the same as first dose date 
then impute first dose date 
• Completely missing – impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end 
date 
When imputing a start date, ensure that the new imputed date is sensible i.e., is prior to the 
end date of the AE or medication. 
 
Partial AE or medication end dates will be imputed as follows: 
• Missing day: impute day as the earlier of either the end date of the study or the last day 
of the month 
• Missing day and month: as the earlier of either the end date of the study or the last day 
of the year 
• Completely missing: if the event is not ongoing then input as the date of the last visit 
unless the start date is prior to first dose date in which case this date would be used for 
imputation 
 
The same logic presented above will be used to impute partial dates of the start of the OA in 
order to derive the duration of OA based on the available date parts.  
If a participant is known to have died where only a partial death date is available, then the date 
of death will be imputed as the latest of the last date known to be alive +1 from the database 
and the death date using the available information provided: 
• For missing day only – using the 1st of the month 
• For missing day and month – using the 1st of January 
• For missing year – the analysis date will not be imputed 
No other imputation will be made. 
Conversions 
• 
1 year=365.25 days 
• 
1 month=30.4573 days 
 
4.2 
Efficacy analysis  
Results of all statistical analyses will be presented using a two-sided 95% confidence interval 
(CI) and one-sided nominal p-value, unless otherwise stated. In addition, for all primary and 
key secondary endpoints the asymmetric confidence intervals will be produced as per Frewer 
P. et. al., 2016, unless otherwise stated. Finally, details of all participants affected by 
intercurrent events will be summarized in the key participant information output and 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
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PROC IML will be used to calculate the test statistics and corresponding p-values since it 
allows for the multiplication of vectors and matrices and sampling from a multivariate normal 
distribution. The seed 568000003 will be used when sampling from the multivariate normal 
distribution. Example SAS code is also included in Appendix D2. 
If none of the candidate models are statistically significant, the procedure stops, suggesting 
that a dose-response relationship cannot be established from the observed data. However, in 
such circumstances the dose-response model corresponding to the MCP test contrast with the 
lowest p-value will still be estimated.  
Step 4: Model selection  
Out of the statistically significant candidate models the most appropriate one will be selected 
using the model selection criteria gAIC. Additional information alongside an example code 
can be found in Appendix D3.  
 
The best/optimal model will be the one with the minimum gAIC criterion. The gAIC for each 
model will be displayed in the table and the optimal model with the minimum gAIC will be 
indicated.   
 
Step 5: Dose-response and dose estimation (Target dose selection)  
The estimates from the optimal dose-response model will be used to calculate the minimum 
effective dose (MED), ED50, 90% of the Emax (ED90) and dose to achieve selected target 
effects if/when applicable. The MED is defined as the minimum dose that the chosen model 
predicts will achieve 1.0, 1.2 and 1.5-point improvements over placebo. For details concerning 
the derivations of MED and other parameters refer to the  Appendix D4.1. 
To obtain the 95% CIs for the MED and estimates other than model estimates of the treatment 
effect at doses studied, the asymptotic normal distribution of the estimates from the optimal 
dose-response model will be determined as per Appendix D4.2.1. 10,000 samples from the 
asymptotic normal distribution will then be drawn (using seed 568000003) with each set of 
samples used to create a dose response curve and corresponding MED. The 0.025 and 0.975 
percentiles of the MED values will be used to form the 95% confidence intervals. Same 
approach will be used to obtain the 95% CIs for estimates other than model estimates of the 
treatment effect at doses studied.  
The 95% CIs for estimates associated with treatment comparisons will be constructed using 
the delta method described in Appendix D4.2.2.   
Finally, the MCP-Mod process will be reported in a summary table including:  
o Candidate dose-response models test statistics (including adjusted p-value) 
o gAIC values for all candidate dose-response models (lowest value shows 
model with best fit) 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 60 of 95 
 
 
The same summary outputs including listing will be produced as produced for the primary 
endpoint detailed in section  4.2.1.2.1. 
4.2.1.2.2.3 Change in PGA of OA scores  
The same analysis as applied to the primary endpoint, excluding the MCP-MOD analysis, will 
be applied to the change from baseline to Week12 in PGA of OA scores.  
The same summary outputs including listing will be produced as produced for the primary 
endpoint detailed in section  4.2.1.2.1. 
4.2.2 
Other secondary efficacy endpoints 
For each endpoint reported under the other secondary efficacy variables detailed in section  
3.3, a separate summary table for observed cases only will be produced, as described in 
section  4.1. That is, for other continuous secondary endpoints, the outputs will present the 
summary statistics for baseline and the change from baseline to corresponding Weeks.  
Other continuous secondary endpoints will be analysed by observed cases only.  The 
ANCOVA model with dose, baseline score and KL grade will be used, and results tabulated 
following the same presentation used for key secondary endpoints except for the asymmetric 
CI.     
For binary secondary endpoints, a logistic regression analysis will be performed with the same 
covariates as for the respective continuous endpoints. That is, for example the logistic 
regression for the OMERACT-OARSI endpoint will include baseline WOMAC pain and 
physical function subscales scores, baseline PGA score and KL grade as covariates in the 
model. The results will be tabulated so that the number and percent of responders with odds 
ratios, 95% CIs and nominal p-values will be presented for each week of interest.    
Finally, listings will be produced for all other secondary efficacy endpoints.  
4.2.3 
Exploratory analysis 
A summary table will be produced for the change in DSIS score from baseline to Weeks 2, 4, 
6, 8, 10, 12, and 18 as specified in section  4.1 following the same presentation used for 
summary statistics of primary endpoint. 
A summary table will present the change from baseline to Weeks 6, 12, 18 and 32 in the 
overall health utility score from the EQ-VAS questionnaire, by treatment group. Data will be 
listed.  
The number and percentage of participants above and below the threshold values for the SF-
36v2 Scale domains, PCS and MCS will be presented as well as descriptive summary statistics 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 61 of 95 
 
 
for scores and change from baseline will be produced by treatment group and visit. Data will 
be listed.  
A separate summary table will be produced for each of the four WPAI:OA endpoints defined 
in section 3.5.1.4 for the change from baseline to Weeks 12,18 and 32. Data will be listed.  
A summary table will be produced for the following HCRU endpoints due to OA at baseline 
and Weeks 12, 18, and 32: any type of medical service received, use of emergency room and 
frequency, hospitalisation, and length of stay in hospital, use of any aids or devices, any job 
loss and length of time. Data will be listed.  
A table summarising the incidence and time to discontinuation due to lack of efficacy will be 
produce.  
A summary table with use of rescue medication from baseline to Weeks 2, 4, 6, 8, 10, 12, and 
18 will be produced. A separate listing will be produced also. 
4.2.3.1 
ABPM 
Three ABPM parameters (systolic and diastolic blood pressure and pulse rate) will be 
evaluated separately for during daytime, night-time and over the 24-hour period as follows:  
• Baseline and change from baseline will be summarised descriptively as per section 4.1 
• ANCOVA for change from baseline with treatment and baseline ABPM as covariates 
will be fitted and results including 95% CIs and nominal p-values tabulated. 
Absolute mean ABPM values and ABPM mean change from baseline for readings mentioned 
in section 3.5.3 will be listed for each participant. Abnormal values as defined in section 3.5.3 
will be flagged within the listing.  
4.2.3.2 
Pharmacodynamic analysis 
Only total NgF concentrations will be included and will be listed and summarised by 
treatment group and timepoint (further subset by ADA status), with the following descriptive 
statistics presented: n, N<LLOQ, Arithmetic mean and SD, Geometric mean (gSD) and CV% 
(gCV%), median, minimum and maximum. 
Furthermore, the influence of the baseline total NgF on changes in NRS pain scores and any 
interaction with treatment will be assessed. 
In addition, a figure of geometric mean (with and without gSD) total NGF serum 
concentration over time by treatment group will be generated on a linear and a semilog scales 
as well as spaghetti plot of individual participant profiles by treatment group (both further 
subset by ADA status). Available data will be listed. 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 62 of 95 
 
 
Total NGF serum concentrations from the initial assay (Q2 assay) will be only listed using the 
latest raw dataset as provided by Q2. This data will not be mapped to SDTM nor ADaM and 
hence will not be included in any summary tables or figures nor included in any analyses. 
4.2.3.3 
Biomarker analysis  
Biomarkers (i.e. soluble biomarkers (e.g., cytokines, chemokines), genomic biomarkers (e.g., 
RNA, microRNA) and urinary CTX‐II concentration (cartilage degradation marker)) and their 
effects on PK, PD, and efficacy may be investigated. However, any such exploratory analyses 
will be performed and presented separately from the CSR.  
Available biomarker data at time of DBL (e.g., baseline TNF alpha, IL-1 beta, IL-6 and high 
sensitivity CRP) will however be listed for each participant and summarised using descriptive 
statistics by cohort.  Furthermore, the influence of the baseline biomarkers on changes in NRS 
pain scores and any interaction with treatment will be assessed. 
4.2.4 
Pharmacokinetic analysis 
PK concentration data will be listed for each participant and each dosing day and timepoint, 
and descriptive summary statistics (same descriptive statistics as for total NGF concentrations) 
will be provided by treatment group and timepoint for all evaluable participants (PK analysis 
set) and further subset by ADA status.  
For the calculation of the descriptive statistics refer to section 3.4.1. 
In addition, a figure of geometric mean (with and without gSD) serum MEDI7352 
concentration over time by treatment group will be generated on a linear and a semilog scales 
as well as spaghetti plot of individual participant profiles by treatment group (further subset 
by ADA status). Available data will be listed.  
The population PKPD analysis of the study data will be described in a separate modelling 
analysis plan and will be reported separately from the main CSR. 
4.2.5 
Immunogenicity analysis  
The number and percentage of participants who display detectable ADA within each ADA 
response category listed in section 3.4.2 will be summarized by treatment group and 
MEDI7352 Total, based on the safety set for ADA-evaluable participants. Median and range 
of maximum titer will be provided as appropriate (if a participant has multiple titers, the max 
post-baseline titer is used for summary statistics calculation).  
A table providing ADA category definitions will be produced.   


Statistical Analysis Plan  
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A summary will be provided of the number and percentage of participants who display 
detectable ADA by visit. Median, Q1, Q3, minimum and maximum of ADA titres by visit will 
also be included. 
Impact of ADA on PK and total NGF concentrations will be explored by presenting serum 
MEDI7352 concentrations and total NGF concentrations descriptive statistics in ADA-
positive and ADA-negative participants.  
Summary of TEAEs by ADA categories table will include the number and percentage of 
participants who had:  
• 
Any AE 
• 
Any AE with an outcome of death 
• 
Any SAE 
• 
Any AE leading to discontinuation of study treatment  
• 
Any AESI 
• 
Any AE leading to withdrawal from study. 
 
TEAEs in ADA positive participants will also be listed. 
Immunogenicity results will be listed by participant regardless of ADA-evaluable status. ADA 
titer will be listed for samples confirmed positive for the presence of ADA. 
4.2.6 
Safety analysis 
Safety summaries will be descriptive only. No formal statistical analyses are planned for 
safety data. All data will be reported using the safety population unless specified otherwise. 
The following sections describe the planned safety summaries for safety variables as defined 
in section  3.6. However, additional safety summaries (not specified in this SAP) may need to 
be produced to aid interpretation of the safety data.  
4.2.6.1 
Adverse Events  
Summary tables will include TEAEs as defined in section  3.6.1, unless otherwise specified. 
An AE overview summary table will be produced showing the number (%) of participants 
with at least one AE in each of the following categories: 
• 
Any AE 
• 
Any AE with an outcome of death 
• 
Any SAE 


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• 
Any AE leading to discontinuation of study treatment 
• 
Any severe AE 
• 
Any AESI 
• 
Any AE leading to withdrawal from study 
 
For all categories above, the number (%) of participants with at least one causally related AE 
in that category will also be provided. 
 
An additional table will be produced showing the incidence of participants with the following 
type of adjudicated events: 
• RPOA (type 1 and 2) 
• SIF 
• Primary osteonecrosis,  
• Pathological fracture 
The number of participants treated per treatment group will be used as the denominator to 
calculate percentages. 
 
Summary tables will be produced by MedDRA SOC and PT for the following categories: 
• 
AEs 
o 
By age group as defined in section 4.2.8 
o 
By sex 
o 
By periods as defined in section 3.1.6.   
o 
By ADA categories as defined in section 3.4.2 
• 
Severe AEs 
• 
By periods as defined in section 3.1.6.  Causally related AEs and SAEs 
o 
By periods as defined in section 3.1.6.   
• 
SAEs with outcome death 
• 
SAEs  
o 
By periods as defined in section 3.1.6.   
o 
By ADA categories as defined in section 3.4.2 
• 
AEs leading to discontinuation of study treatment 
• 
AESIs 
o 
By periods as defined in section 3.1.6 
o 
Separate table to be provided for each AESI category as defined in section 3.6.1.1 
 By periods as defined in section 3.1.6 
 Joint related AESI table by study periods will also include the exposure adjusted 
rates, where AE event rate (per 100 participant years) is defined as the number of 


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participants with that AE divided by the total number of days at risk for AEs 
across all participants in given treatment arm and multiplied by 365.25 x 100 to 
present in terms of per 100 participant years. 
• 
Most common non-serious AEs defined as AEs occurring in at least 5% of participants 
overall (in total column). For each SOC/PT, the number (%) of participants reporting at 
least one event at each level of summarisation will be presented. Participants with 
multiple occurrences of the same AE, the event will only be counted once per SOC/PT. 
Those will be sorted by international order for system organ class and in alphabetical 
order for preferred term. 
 
In addition, a table with AEs and event counts sorted by decreasing frequency on preferred 
term will be produced as well as AEs by maximum intensity on preferred term by SOC and 
PT.  
Additional table presenting mapping of AESIs will be produced.  
A separate table with key participant information will be produced for: 
• SAEs with outcome of death 
• SAEs 
• AEs leading to discontinuation of study treatment  
 
A separate listing will be produced for the following AE categories: 
• AEs 
• SAEs 
• AESIs 
• AEs leading to discontinuation of study treatment 
 
For any AE with change in intensity, listings will report all intensities as well as associated 
actions. 
4.2.6.2 
Joint replacement surgeries 
Incidence of participants with the joint replacement surgeries occurred during the study 
participation will be summarised by treatment group depending on whether the surgeries were 
elective or due to an AE.  
4.2.6.3 
Pregnancies 
Pregnancies entered on the pregnancy report (PREGREP) page in eCRF will be reconciled 
against safety database and the reconciled entries on (PREGREP) page in eCRF will be listed.  


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4.2.6.4 
Laboratory results 
Tables with descriptive summaries (mean, SD, median, minimum, and maximum) of actual 
(absolute) values and changes from baseline values will be produced for each treatment group 
at each visit. Tables will be produced for tests specified in section 3.6.8 except for urine drug 
screen, urine pregnancy test, serology, and endocrinology. Participants with abnormal results 
of these tests except for urine pregnancy test will be only listed including all available results.  
Central laboratory reference ranges will be used for the identification of abnormalities. Shift 
tables will be produced for the same parameters for which summary tables will be produced 
with the exception of urinalysis to display low, normal, and high values.  
The shift tables will present baseline and maximum/minimum on-treatment value, as 
applicable for each parameter and will include participants with both baseline and post-
baseline data. The exception would be Haemoglobin A1c that is evaluated only at baseline and 
Week 32 hence this shift table will present baseline and maximum/minimum value during the 
study.   
For urinalysis parameters collected as for example: Negative, Small, Moderate or Large, shift 
tables from baseline to maximum value during treatment will be provided. This will apply to 
bilirubin, blood, leucocytes, glucose, protein and ketones. Key participant information table 
listing only participants and assessments with abnormal values will be produced.  
Laboratory values will also be presented as box plots, for absolute values and changes from 
baseline. All protocol defined visits will be summarised.  
Each plot will show the following details: 
• 
Mean (symbol within each box) 
• 
Median (horizontal line within each box) 
• 
Q1 and Q3 (bottom and top of each box) 
• 
Whiskers extending to the most extreme observation within 1.5 times the interquartile 
range from the nearest quartile. 
• 
Outliers outside the whiskers displayed individually. 
• 
Reference ranges shown as dotted lines on the analysis value plots, not relevant to the 
change from baseline plot. If more than one reference range is available for an assessment 
(example: due to gender differences) then the narrowest range will be used in the graph.  
The plots will be prepared for each test within the laboratory categories: 
• 
Haematology: hemoglobin, hematocrit, RBC count, platelet count (or estimate), WBC 
count, WBC differential 


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• 
Serum chemistry: albumin, total and direct bilirubin, total protein, calcium, ALP, ALT, 
AST, GGT, BUN, creatinine, glucose, sodium, potassium, chloride, bicarbonate, 
phosphorus, LDH, uric acid, CRP, cholesterol, triglycerides, creatine phosphokinase. 
• 
Coagulation panel: prothrombin time, activated partial thromboplastin time, fibrinogen 
• 
Urinalysis: pH, specific gravity. 
 
In addition, listings of abnormal safety laboratory results will be prepared. The listings will 
include only participants and tests with at least one abnormal value reported. All available 
results for that specific test will be presented in order to see the change over time. 
4.2.6.4.1 
Liver enzyme elevations and Hy’s law 
Liver function laboratory tests assessments (scheduled and unscheduled) up to 30 days after 
the last dose of study treatment will be considered. 
The following summaries will include the number (%) of participants with at least one post-
baseline liver function assessment who have: 
• 
Elevated ALT, AST and total bilirubin as 
− 
ALT ≥3× to <5×, ≥5× to <10×, ≥10× to <20×, ≥20× upper limit of normal (ULN) 
− 
AST ≥3× to <5×, ≥5× to <10×, ≥10× to <20×, ≥20× ULN 
− 
Total bilirubin ≥2× ULN  
− 
ALT or AST ≥3× to <5×, ≥5× to <10×, ≥10× to <20×, ≥20× ULN  
− 
ALT or AST ≥3× ULN and total bilirubin ≥2× ULN (Potential Hy’s law): The onset 
date of ALT or AST elevation should be prior to or on the date of total bilirubin 
elevation. 
Percentages will be based on the number of participants who have at least one measurement 
available.  
To identify potential Hy’s Law cases, a listing of participants who have ALT or AST ≥3× 
ULN and total bilirubin ≥2× ULN (not necessarily at the same time) following first dose of 
study treatment will be provided. 
A shift table will also present maximum ALT and AST observed values by maximum total 
bilirubin observed value, expressed as multiples of ULN. Categories will be included for: 
− 
ALT <3, ≥3× to <5×, ≥5× to <10×, ≥10× to <20×, ≥20× ULN 
− 
AST <3×, ≥3× to <5×, ≥5× to <10×, ≥10× to <20×, ≥20× ULN 
− 
Total bilirubin <2×, ≥2× ULN 
Key participant information table of participants with potential Hy’s law will be produced.  


Statistical Analysis Plan  
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4.2.6.5 
Vital signs results 
Table with descriptive summaries (n, mean, SD, median, minimum, maximum, Q1 and Q3) of 
observed values and changes from baseline values for each treatment group at each protocol 
scheduled time point will be produced for the following vital signs tests: 
• Systolic BP 
• Diastolic BP 
• Pulse rate 
• Respiratory rate 
• Temperature 
In addition, shift table from baseline to minimum/maximum value during treatment will be 
produced for all above mentioned parameters. The reference ranges provided in section 3.6.5 
will be used to determine whether the minimum/maximum value during treatment is within 
the normal range or not.   
A by-visit incidence summary of orthostatic hypotension will be prepared for the following 
result categories: 
• 
Criteria met 
• 
Confirmed 
• 
Symptomatic 
 
A table presenting the changes in postural BP at each timepoint/ visit will be produced. 
Consequently, the supine readings from VS (for non-dosing visits) and VS1 (for dosing visits) 
eCRF forms as well as postural readings from VS2 eCRF form will be summarised 
descriptively by cohorts at each visit and all available timepoints as per all three eCRF forms.  
In addition, a listing of confirmed and symptomatic orthostatic hypotension cases will be 
prepared. The listing will include all participants with at least one assessment indicated as a 
confirmed or symptomatic case of orthostatic hypotension. All available results will be 
presented in order to see the change over time. 
Vital signs data for participants/parameter with at least one abnormal result for the below 
mentioned parameters will be listed:  
• Systolic BP (Including assessments from VS2 page in the eCRF) 
• Diastolic BP (Including assessments from VS2 page in the eCRF) 
• Pulse rate 
• Respiratory rate 
• Temperature 


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4.2.6.6 
ECG results 
Overall evaluation of electrocardiogram (ECG) will be summarised at each timepoint/visit 
reporting the number (%) of participants presenting a normal, abnormal not clinically 
significant or abnormal clinically significant evaluation.  
In addition, a listing of abnormal ECG results will be prepared. The listing will include all 
participants with at least one abnormal value reported. All available results will be presented 
in order to see the change over time.  
4.2.6.7 
Physical examination findings 
Findings, that is data of participants/examinations with at least one abnormal result will be 
listed for all available visits including unscheduled visits for all participants.  
4.2.6.7.1 
Weight 
On top of listing the data as mentioned in section 4.2.6.7 above, the summary table presenting 
the actual (absolute) values and change from baseline to Week 12 will be prepared.   
4.2.6.8 
Neurological examination findings  
A summary of the overall assessments across all neurological evaluations will be provided by 
treatment arms for each visit.  
In addition, a key participant information table will be produced summarising data of all 
participants with at least one reported abnormality.   
4.2.6.9 
Total neuropathy score-nurse (TNSn) results 
A summary of the total neuropathy score – nurse (TNSn) results will be prepared, including 
results for each of the following categories: 
• 
Sensory symptom score 
• 
Motor symptom score 
• 
Autonomic symptom score 
• 
Pin sensibility score 
• 
Vibration sensibility score 
• 
TNSn total 
 
4.2.6.10 
Injection site reaction 
An incidence summary by severity (mild, moderate, severe) or presence (yes, no) and 
visit/timepoint will be prepared for the following injection site reactions: 
• 
Pain (mild, moderate, severe) 


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• 
Tenderness (mild, moderate, severe) 
• 
Erythema/redness (mild, moderate, severe) 
• 
Induration/swelling (mild, moderate, severe) 
• 
Necrosis (mild, moderate, severe) 
• 
Ulceration (yes, no) 
 
In addition, the quantitative result for erythema/redness and induration/swelling measurements 
(cm) will be summarised descriptively by visit/timepoint. 
4.2.6.11 
Survey of Autonomic Symptoms (SAS) 
The SAS scores will be summarised by treatment group for the total number of symptoms 
reported and the total impact score. The summary will be presented by visit and will include 
the change from baseline. 
4.2.6.12 
X-ray and MRI  
Summary table suggestive of abnormal findings for each treatment group at the protocol 
defined visits will be produced. 
All data of assessable imaging will be listed for each participant. In addition, a separate listing 
of participants whose data was sent for adjudication will be produced presenting the outcome 
of the adjudication review.  
4.2.7 
Treatment exposure and compliance  
The following summaries related to study treatment will be produced using the safety analysis 
set by actual treatment group and MEDI7352 Total: 
• Participants who received an IP dose  
• Maximum number of doses received 
o Participant will be included only in one category depending on the maximum 
number of doses received during the treatment period. That is if a participant 
receives only 4 doses during treatment, then this participant should be counted 
only once in the category ‘4’  
• Duration of exposure as defined in section 3.6.11.1 
• Number of participants with dose delay/interruption as reported on the eCRF 
• Reasons for dose delays/interruptions as reported on the eCRF 
• Cumulative exposure over time (in form of a graph) using the total treatment duration 
variable as defined in section 3.6.11.1.  
• Compliance 


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Administration of study treatment will also be listed for all participants in the safety analysis 
set. In addition, overdose cases, as reported by the investigator, will be listed. Also, the kit 
details of the study treatment that were administered will be listed.  
4.2.8 
Demographic and baseline characteristics 
Disposition, demographic data, and other baseline characteristics will be presented for 
participants in the FAS (unless otherwise specified below). No statistical testing will be 
carried out for demographic or other baseline characteristics. The following data will be 
summarized: 
 
• Participant disposition (Screening set) namely: 
o Enrolled (number of participants only) 
o Rescreened (number of participants only) 
o Randomised/not randomised (including reason) 
o Received study treatment/did not receive study treatment (including reasons) 
o Completed study treatment/discontinued study treatment (including reasons) 
o Completed study/withdrawn from study (including reasons) 
Percentages will be based on the randomised participants. 
A listing will provide details on participants who were withdrawn from the study and 
participants who were enrolled and were not randomised. Also, a listing will report 
participants who completed the study as well as the randomisation codes of all 
randomised participants.  
• Inclusion in analysis sets 
A listing will provide the reasons for exclusion from the analysis sets and the 
participant status for each of the analysis sets. 
• Screen failure reasons  
o Number and percentage of participants that did not meet specific 
inclusion/exclusion criteria  
In addition, a listing will provide the reason(s) for screen failures (inclusion/exclusion 
criteria not met), including rescreened participants.  
• Demographics namely: 
o Age (years) at the time of randomisation (derived) 
o Age groups (<65 and >=65) 


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o Sex  
 Childbearing potential presented for females 
 Reasons for not of childbearing potential included 
o Race 
o Ethnic group  
o Country 
 
• Participant characteristics at baseline namely: 
o Height (cm) 
o Weight (kg) 
o Body mass index (BMI) (kg/m2) 
o BMI group (kg/m2) (<18.5, >=18.5 - < 25, >=25 – < 30, >=30)  
 
• Participant recruitment by region, country, and site 
 
• Medical history and surgical history (as appropriate) 
o All medical/surgical history will be classified according to the latest version of 
the Medical Dictionary for Regulatory Activities (MedDRA). 
o The number (%) of participants with any medical/surgical history (records) will 
be tabulated by MedDRA system organ class (SOC) and PT.  A participant will 
only be counted once within a particular SOC/PT, regardless of multiple 
conditions/diseases/surgeries in the same SOC/PT. SOC and PT will be 
presented in alphabetical order. 
• All prior/concomitant medications will be coded using the latest World Health 
Organization (WHO) Drug Global B3-format dictionary. 
Summary tables of allowed and prohibited concomitant medications will present the 
number (%) of participants, using at least one medication by generic term within 
anatomical therapeutic chemical (ATC) classification. Participants will be counted 
once at each level of summarisation (ATC classification/generic term). 
• OA related medical history, as collected in the OA medical history eCRF form, 
namely: 
o Duration of OA (years) 
 Calculated as: Randomization date - OA start date (collected on the OA 
medical history form), presented in years. 
o Duration of target knee pain (years) 


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 Calculated as: Randomization date - target knee pain start date 
(collected on the OA medical history form), presented in years. 
o Target knee (left/right), n (%) 
 As collected on the OA medical history form. 
o Baseline KL grade 
 As reported by Bioclinica 
o Baseline pain intensity score (NRS) 
 As collected in the eDiary  
 
In addition, disease-related treatment at screening will be summarised and will include: 
• 
Previous/ongoing treatments 
o Nonsteroidal anti-inflammatory drugs (NSAIDs)/cyclooxygenase-2 (COX-2) 
inhibitors 
o Paracetamol 
o Opioids  
Pain relief history evaluated in terms of:  
o Not effective 
o Intolerability 
o Contraindication 
o No access to opioids (only for opioids) 
o Unwillingness to take opioids (only for opioids) 
The number (%) of participants will be presented. 
• 
Rescue medication variables defined in section 3.5.1.7 will be summarised by periods as 
defined in section 3.1.6. 
 
Demographic and baseline characteristics data will also be listed. 
4.2.9 
Accounting for the COVID-19 pandemic effects 
This study started during the severe acute respiratory syndrome coronavirus 2 
(SARSCoV2)/Coronavirus disease 2019 (COVID19) pandemic, confirmed on 12th March 
2020. The CSR will report how COVID-19 affected participants and/or study progression. 
COVID-19 assessments were carried out prior to the first IP administration and throughout the 
study and affected participants will be summarised.  
 
A table will be produced to summarise any COVID-19 related study disruptions. The 
participant disposition table will incorporate COVID-19 as a further reason for discontinuing 


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study treatment. Participants affected by COVID-19 will be listed as well as those reported as 
having issues due to the COVID-19 pandemic in CTMS. 
5 
INTERIM ANALYSES 
This section of the SAP is dedicated to the interim analyses (IA). Additional separate stand-
alone SAPs were created for the Data and Safety Monitoring Board (DSMB) analyses as well 
as the Interim analyses. 
The study incorporates two interim analyses: 
• 
Futility analysis (IA 1): 
− 
When approximately 25% of participants are evaluable for the primary endpoint 
− 
The likely success of the study outcome will be assessed.  
− 
This analysis will enable the sponsor to make a go/no-go decision regarding 
continuation of the study as described by Frewer P. et. al., 2016. That is, the primary 
endpoint and WOMAC pain subscale endpoint will be analysed by most appropriate 
candidate model as specified in section 4.2.1.2.1.1 from which the pairwise model-
based estimates versus placebo will be used for decision making purposes as follows: 
o 
Consider stopping the study if the lower limit of 1-sided 90% confidence interval 
for delta (MEDI7352 dose - Placebo) of change from baseline is below minus 1.5 
(the target value).     
o 
Consider initiate planning for phase 3 if upper limit of 1-sided 80% confidence 
interval for delta (MEDI7352 dose - Placebo) of change from baseline is below 
minus 0.8 (the lower reference value). 
− 
Primary endpoint would be the main determinant of go/no go decision. If the primary 
endpoint is in the consider zone, then WOMAC pain subscale endpoint may help to 
determine the final decision.  
− 
This analysis will include disposition, baseline characteristics, primary efficacy, and 
key secondary efficacy (supportive) endpoint, which is change in the WOMAC pain 
subscale from baseline to Week 12.  
 
• 
Interim analysis (IA 2): 
− 
When approximately 50% of participants are evaluable for the primary endpoint 
− 
This analysis will enable the sponsor to plan future project-related activities (without 
making any changes to the current study). At minimum, the same analyses as 
described for IA 1 will be performed. The decision making will proceed as follows:  


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o 
Consider initiate planning for phase 3 if upper limit of 1-sided 80% confidence 
interval for delta (MEDI7352 dose - Placebo) of change from baseline is below 
minus 0.8 (the lower reference value). 
− 
This analysis will include the same evaluations as covered by the first interim 
analysis plus additional outputs as specified within this version of the IA SAP v2.0 
and accompanying table shells. The interim analyses will be prepared by the blinded 
IQVIA biostatistics team. The unblinding of the interim analyses will be done by an 
independent unblinded IQVIA biostatistics team. The unblinded IQVIA biostatistics 
team will provide the unblinded interim analyses output to the Independent Efficacy 
Review Group (IERG). 
 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 77 of 95 
 
 
• 
An additional AESI category was defined in this SAP that does not feature in the 
protocol. This category was classed as ‘Other AESIs’ and has been defined as any other 
AEs that are deemed of an interest by the study team.  
 
 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 79 of 95 
 
 
8 
APPENDICES  
Appendix A Questionnaires derivations  
Appendix A1 WPAI:OA  
The table below summarize the six questions of the WPAI:OA questionnaire, and the 
derivations of the four endpoints of the effect of impairment on activity and impairment. 
Question Question Wording 
Scoring 
1 
Are you currently employed? [if No skip to 
question 6]  
Yes, No 
2 
During the past seven days, how many hours 
did you miss from work due to problems 
associated with your OA of the knee or hip? 
number of hours (free text) 
3 
During the past seven days, how many hours 
did you miss from work because of any other 
reason, such as vacation, holidays, time off to 
participate in this study? 
number of hours (free text) 
4 
During the past seven days, how many hours 
did you actually work? (if ‘0’ skip to Question 
6) 
number of hours (free text) 
5 
During the past seven days, how much did your 
OA of the knee or hip affect productivity while 
you were working? 
0 to 10 scale with 0 being ‘No 
effect on my work’ and 10 
being ‘Completely prevented 
me from working’ 
6 
During the past seven days, how much did your 
OA of the knee or hip affect your ability to do 
your regular daily activities, other than work at 
a job? 
0 to 10 scale with 0 being ‘No 
effect on my daily activities’ 
and 10 being ‘Completely 
prevented me from doing my 
daily activities’ 
 
WPAI endpoint 
Calculation 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 80 of 95 
 
 
Percent activity impairment due to 
Osteoarthritis 
Q6*10 
Percent impairment while working due to 
osteoarthritis 
Q5*10 
Percent overall work impairment due to 
osteoarthritis 
{
𝑄𝑄2
𝑄𝑄2+𝑄𝑄4 + [1 −ቀ
𝑄𝑄2
𝑄𝑄2+𝑄𝑄4ቁ](
𝑄𝑄5
10)} ∗100 
 
Percent work time missed due to 
Osteoarthritis 
𝑄𝑄2
𝑄𝑄2 + 𝑄𝑄4 ∗100 
 
Appendix A2 Responses and scores of the HCRU questionnaire  
Question 
Response 
Scoring 
During the last X weeks what services did you 
receive directly related to your osteoarthritis? 
• Primary Care Physician; 
• Neurologist; 
• Rheumatologist; 
• Physician Assistant or Nurse 
Practitioner; 
• Pain Specialist; 
• Orthopaedist; 
• Physical Therapist; 
• Chiropractor; 
• Alternative Medicine or Therapy 
(Concomitant Medications); 
• Podiatrist; 
• Nutritionist/Dietician; 
• Radiologist; 
• Home healthcare services; 
• Other; 
Number of visits Response not 
selected= 0 
Number of visits= 1-
999 
 
During the past X weeks, have you visited the 
emergency room due to your osteoarthritis? 
Yes, No 
No = 0 
Yes = 1 
How many times? 
Number of visits 0-999 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 81 of 95 
 
 
During the past X weeks, have you been 
hospitalized due to your osteoarthritis? 
Yes, No 
No = 0 
Yes = 1 
How many nights in total did you stay in 
hospital due to your osteoarthritis in the last X 
weeks? 
Number of 
Nights 
0-999 
Did you use these aids or devices to help you in 
doing things because of your osteoarthritis in 
the last X weeks? 
• Walking Aid 
• Wheelchair 
• Devices or utensils to help you dress, 
eat or bathe 
• Other 
Did not use any 
aids or devices 
never, rarely, 
sometimes, 
often, always 
Did not use any aids 
or devices= 0  
Device not selected= 0  
Never = 1 
Rarely = 2 
Sometimes = 3 
Often = 4 
Always = 5 
Did you quit your job because of your 
osteoarthritis? 
Yes, No 
No = 0 
Yes = 1 
 Not applicable = 2 
How long ago did you quit your job because of 
your osteoarthritis? 
Years and 
Months 
0-99 Years and 0-99 
Months (should be 
max of 11 months) 
 
 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 82 of 95 
 
 
Appendix B Multiple Imputation 
Appendix B1 The pattern mixture framework 
The MAR imputation will be performed for all participants, regardless of the intercurrent 
event, on the observed and imputed data from step 1 (intermediate missing data imputation), 
including the imputed baseline from step 0 also. The same will be performed for MNAR 
approach. This would result in two sets of multiply imputed datasets: one set under MAR 
assumption and one set under MNAR assumption.  
The final set that would then be used for further analysis will be compiled such that only 
imputed data from either MAR or MNAR sets would be selected based on the participants’ 
intercurrent event. For example, if a participant discontinues treatment due to an adverse 
event, then only data from the MNAR set would be included in the final set, whilst data of a 
participant who discontinues treatment due to their decision would come from only MAR set.  
 
Appendix B2 The sampling from normal distribution approach 
1. Obtain the standard deviation from observed WOMAC pain subscale scores at Week 
12 for all participants in FAS  
2. Sampling from normal distribution to be executed using the following data step: 
rand('NORMAL' BASE,stddev) or rand('NORMAL',LOCF,stddev)  
a. where the stddev is obtained in step 1  
b. BASE or LOCF are either participant’s baseline score or participant’s last 
observed WOMAC pain subscale score.  
3. Step 2 to be performed 100 times  
4. Data to be ordered by ParticipantID and imputation to have the same seed number and 
produce identical results on production and QC 
NOTE:  
• No intermediate missing data imputation step is needed.  
• For LOCF, consider available WOMAC pain subscale scores of all post-baseline visits 
(not just protocol defined visits), except unscheduled visits. That is, if participant has 
Week 11 WOMAC score, this score can be used as last observation for LOCF 
imputation.  
 


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Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 85 of 95 
 
 
Appendix DMCP-Mod Code 
Referenced in SAP section  4.2.1.2.1.1 
Appendix D1 Deriving optimum contrast coefficients 
 
The below code alongside the combined dose estimates and covariance matrix derived in 
appendix B can be used to obtain the optimum contrast coefficients. 
 
/*Specify doses*/ 
 
data doses; 
input dose @@; 
datalines; 
   0 7.5 25 75 150; 
; 
run; 
 
 
/*Specify candidate models*/ 
 
data models; 
 
length modnam $25; 
 
input modnam par1-par3; 
 
datalines; 
 
 
emax 10 . . 
 
 
emax 40 . . 
 
 
emax 80 . . 
 
 
linear . . . 
 
 
exponential 10 . . 
 
 
exponential 25 . . 
 
 
; 
run; 
 
/*Write optimal contrasts in data set optcontrasts and in global macro variable modcontr */ 
 
%optcont(models=models, dose=doses, sigma=scalemat, direction=incr, dosevarname=dose); 
 
proc print data optcontrasts label noobs; 
 
title “Optimal contrasts for defined models”; 
run; 
 
%optcont macro code 
 
%macro optcont(models=,doses=,sigma=,direction=,dosevarname=); 
 
/********************************************************************** 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 86 of 95 
 
 
Reading in models 
***********************************************************************/ 
data &models; 
set &models; 
length modspec $ 50; 
if compress(modnam)="emax" then do; 
modelnum=1; 
modspec="emax "!!compress("(ed50="!!par1!!")"); 
end; 
if compress(modnam)="exponential" then do; 
modelnum=2; 
modspec="exponential "!!compress("(delta="!!par1!!")"); 
end; 
if compress(modnam)="linear" then do; 
modelnum=3; 
modspec=modnam; 
end; 
if compress(modnam)="linlog" then do; 
modelnum=4; 
modspec="linlog "!!compress("(off="!!par1!!")"); 
end; 
if compress(modnam)="quadratic" then do; 
modelnum=5; 
modspec="quadratic "!!compress("(delta="!!par1!!")"); 
end; 
if compress(modnam)="sigEmax" then do; 
modelnum=6; 
modspec="sigemax "!!compress("(ed50="!!par1!!", h="!!par2!!")"); 
end; 
if compress(modnam)="betaMod" then do; 
modelnum=7; 
modspec="betamod "!!compress("(del1="!!par1!!", del2="!!par2!!",  
scal="!!par3!!")"); 
end; 
run; 
 
proc sql noprint; 
select count(distinct(dose))format=1.0 into :n_dose_ from &doses; 
quit; 
 
proc sql noprint; 
select count(modelnum) into :n_mod_ from &models; 
quit; 
 
proc sql noprint; 
select modnam into :mod1 - :mod%left(&n_mod_) from &models; 


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 87 of 95 
 
 
quit; 
 
proc sql noprint; 
select modspec into :modspec1 - :modspec%left(&n_mod_) from &models; 
quit; 
 
%if &direction=incr %then %do; %let dir=1; %end; 
%if &direction=decr %then %do; %let dir=-1; %end; 
 
/********************************************************************** 
Calculation of contrasts 
***********************************************************************/ 
proc iml ; 
/* read in doses, covariance mat, models/guesstimates and model names*/ 
use &doses var {dose }; 
read all into dose; 
use &sigma; 
read all into sigma; 
use &models; 
read all var{modelnum par1 par2 par3} into par; 
use &models; 
read all var{modnam} into modlist; 
 
/* Unity matrix */ 
unity=j(&n_dose_, 1, 1); 
 
/* Empty matrix for calculated mean vectors and contrasts */ 
meanmat=j(&n_dose_, &n_mod_+1, -88); 
meanmat[, 1]=dose; 
 
/* row labels */ 
contmat=j(&n_dose_, &n_mod_, -88); 
 
/* calculation of stand. mean-vector for each model*/ 
do j=2 to &n_mod_+1; 
modnum=par[j-1, 1]; 
do i=1 to &n_dose_; /* for each dose*/ 
if modnum=1 then meanmat[i, j]=dose[i]/(par[j-1, 2] + dose[i]); 
if modnum=2 then meanmat[i, j]=exp(dose[i]/par[j-1, 2]) - 1; 
if modnum=3 then meanmat[i, j]=dose[i]; 
if modnum=4 then meanmat[i, j]=log(dose[i] + par[j-1, 2]); 
if modnum=5 then meanmat[i, j]=dose[i] + par[j-1, 2]*dose[i]**2; 
if modnum=6 then meanmat[i, j]=dose[i]**par[j-1, 3]/(par[j-1,  
2]**par[j-1,3] + dose[i]**par[j-1, 3]); 
if modnum=7 then do; 
maxDens=(par[j-1, 2]**par[j-1, 2]) * (par[j-1,3]**par[j-1,3])   


Statistical Analysis Plan  
AstraZeneca 
D5680C00003  Final v3.0 
13SEP2023 
CONFIDENTIAL AND PROPRIETARY 
 88 of 95 
 
 
/((par[j-1, 2] + par[j-1,3])**(par[j-1, 2] + par[j-1, 3])); 
standdose=dose[i]/par[j-1, 4]; 
meanmat[i, j]=1/maxDens * (standdose**par[j-1, 2]) * 
(1 - standdose)**par[j-1, 3]; 
end; 
end; 
end; 
invsigma=inv(sigma); 
 
do j=2 to &n_mod_+1; /* calculation of contrasts*/ 
mean_t=t(meanmat[, j]); 
_1=mean_t*invsigma*unity; 
_2=t(unity)*invsigma*unity; 
_3=_1/_2; 
_4=_3*unity; 
_5=meanmat[, j]-_4; 
contrast=invsigma*_5; 
c_norm=sqrt(ssq(contrast)); 
contmat[, j-1]=&dir*contrast/c_norm; 
end; 
create optcontrasts from contmat; 
 
/* Export the final contrasts to dataset*/ 
append from contmat; 
quit; 
data &models; 
set &models; 
i=_n_; 
run; 
 
data _null_; 
set &models; 
do j=1 to &n_mod_; 
if j=i then do; 
call execute (" 
data optcontrasts; set optcontrasts; 
attrib col"!!compress(j)!!" label='"!!compress(modnam)!!"'; 
run;"); 
end; 
end; 
 
data optcontrasts; 
merge &doses(keep=dose) optcontrasts; 
run; 
 
 


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