Conditions: Osteoarthritis of Knee
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 397
Healthy volunteers: no

Brief summary:
This is a phase IIb, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of MM-II in subjects with symptomatic knee OA as compared to matching placebo.

Detailed description:

Arms:
arm 1: MM-II 1 ml arm 2: MM-II 3 ml arm 3: MM-II 6 ml arm 4: Placebo 1ml arm 5: Placebo 3ml arm 6: Placebo 6ml

Interventions: intervention 1: MM-II dose I intervention 2: MM-II dose II intervention 3: MM-II dose III intervention 4: Placebo intervention 5: Placebo intervention 6: Placebo
Intervention descriptions: intervention 1: Intra-articular injection intervention 2: Intra-articular injection intervention 3: Intra-articular injection intervention 4: Intra-articular injection intervention 5: Intra-articular injection intervention 6: Intra-articular injection

Protocol document:
Prot_000.pdf: 
Official title: A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, Single-administration, 
Multiple-Dose Study to Demonstrate the Efficacy and Safety of MM-II for Treatment of Knee Pain in 
Subjects With Symptomatic Knee Osteoarthritis   
Document: Clinical Study Protocol  
NCT number: NCT04506463 
Document date: 18 Jun 2021 


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CLINICAL STUDY PROTOCOL 
 
A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, 
Single-administration, Multiple-Dose Study to Demonstrate the 
Efficacy and Safety of MM-II for Treatment of Knee Pain in 
Subjects with Symptomatic Knee Osteoarthritis 
 
Protocol No.:   
CLR_17_17  
 
Test Product: 
MM-II (large liposomes of DMPC & DPPC) 
Indication: 
 Treatment 
of 
Knee 
Pain 
in 
Subjects 
with 
Symptomatic Knee Osteoarthritis 
Sponsor: 
Sun Pharmaceutical Industries Limited. 
 
Sun House, Plot No 201 B/1,  
 
Western Express Highway,  
 
Goregaon (E) - 400063, 
 
Mumbai, Maharashtra, India. 
Development Phase: 
Phase IIb 
Sponsor Signatory: 
 
 
2 Independence Way 
 
Princeton, NJ 08540 
Sponsor Medical Expert: 
 
 
2 Independence Way 
 
Princeton, NJ 08540 
Initial protocol, A0 - date: 
18 Aug 2020 
Amendment no. - date: 
2 – 18 Jun 2021  
 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator, or consultant for review by you, your staff, and applicable Independent Ethics 
Committee and/or Institutional Review Board.  It is understood that the information will not be 
disclosed to others without written authorization from Sun Pharmaceutical Industries Ltd. (SPIL) 
except to the extent necessary to obtain informed consent from those persons to whom the 
treatment may be administered. 


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1 
SIGNATURE PAGES 
1.1 
SPONSOR SIGNATURE PAGE 
 
PROTOCOL TITLE: A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, Single-
administration, Multiple-Dose Study to Demonstrate the Efficacy and Safety of MM-II for 
Treatment of Knee Pain in Subjects with Symptomatic Knee Osteoarthritis 
 
PROTOCOL NUMBER: CLR_17_17 
 
SPONSOR: Sun Pharmaceutical industries Ltd. (SPIL) 
 
 
 
 
 




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checked in blinded fashion, and the sample size could be increased. The sample will not be increased 
more than a maximal total of N=609.  If increase in the sample size is required post blinded sample size 
re-estimation, enrolment of the additional patients  after accrual of 348 patients would be done using an 
allocation ratio of 3:3:3:1:3:1. Enrolment for the study will then continue until the new target sample size 
is reached. The enrolment size at each site will be capped at no more than 20% of the overall sample size.  


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TABLE OF CONTENTS 
1 
SIGNATURE PAGES ................................................................................................... 2 
1.1 
SPONSOR SIGNATURE PAGE ..................................................................... 2 
1.2 
General Information ......................................................................................... 3 
1.3 
Signature of Investigator .................................................................................. 4 
2 
STUDY SYNOPSIS ...................................................................................................... 5 
TABLE OF CONTENTS .......................................................................................................... 14 
LIST OF TABLES .................................................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 19 
3 
INTRODUCTION ....................................................................................................... 22 
3.1 
Background..................................................................................................... 22 
3.2 
Discussion of Study Design............................................................................ 23 
3.3 
Rationale ......................................................................................................... 23 
3.3.1 
Rationale for Dose ..................................................................................... 24 
3.3.2 
Rationale for Study .................................................................................... 25 
3.3.3 
Risk/Benefit and Ethical Assessment ........................................................ 25 
3.3.4 
Statistical Justification ............................................................................... 26 
4 
STUDY OBJECTIVES ............................................................................................... 27 
4.1 
Primary Efficacy Objective ............................................................................ 27 
4.2 
Primary Safety Objective ............................................................................... 27 
4.3 
Secondary Objectives ..................................................................................... 27 
 
 
5 
INVESTIGATIONAL PLAN ...................................................................................... 29 
5.1 
Overall Study Design and Plan....................................................................... 29 
5.1.1 
Description ................................................................................................. 29 
5.1.2 
Adaptive Increase in Sample Size ............................................................. 30 
5.1.3 
Study Assessments ..................................................................................... 31 
5.1.4 
Schedule of Assessments ........................................................................... 31 
5.1.4.1 
Screening Period (-28 Days to Day 0) and Baseline 
Assessments ............................................................................... 34 
5.1.4.2 
Unscheduled Visits ..................................................................... 37 
5.2 
Selection of Study Population ........................................................................ 37 
5.2.1 
Inclusion Criteria ....................................................................................... 37 
5.2.2 
Exclusion Criteria ...................................................................................... 38 
5.2.3 
Strategies for Subject Recruitment and Retention ..................................... 41 
5.2.4 
Withdrawal of Subjects .............................................................................. 42 




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8.1.5 
Vital Signs ................................................................................................. 52 
8.1.6 
Pregnancy testing ....................................................................................... 53 
8.2 
Definitions ...................................................................................................... 54 
8.2.1 
Adverse Event/Reaction ............................................................................ 54 
8.2.2 
Serious Adverse Event ............................................................................... 54 
8.2.3 
Suspected Unexpected Serious Adverse Reactions and Unexpected 
Adverse Reactions ..................................................................................... 55 
8.2.4 
Overdose .................................................................................................... 55 
 
 
8.2.6 
Abnormal laboratory values/vital signs/electrocardiograms ..................... 55 
8.2.7 
Anaphylaxis ............................................................................................... 56 
8.3 
Causality of AEs ............................................................................................. 56 
8.4 
Assessment of severity, outcome and expectedness of Adverse Events ........ 58 
8.5 
Eliciting, Documentation and Reporting of Adverse Events ......................... 58 
8.6 
Reporting of Serious Adverse Events, Adverse Events of Special Interest ... 59 
8.6.1.1 
Safety Reporting to Sponsor ....................................................... 60 
8.6.1.2 
Safety Reporting to Health Authorities, Independent Ethics 
Committees/Institutional Review Boards and Investigators ...... 60 
8.7 
24/7 Medical Emergency Coverage ............................................................... 61 
 
 
 
 
 
 
9 
STATISTICAL EVALUATION ................................................................................. 62 
9.1 
Study Arms Description ................................................................................. 62 
9.2 
Randomization ................................................................................................ 62 
 
 
 
 
 
 
 
 
 
 
 
Safety Analysis Set .................................................................................... 64 
9.5.4 
Pharmacokinetic Analysis Set ................................................................... 64 
9.6 
Endpoints ........................................................................................................ 64 
 
 
9.6.2 
Primary Efficacy Endpoint ........................................................................ 64 
9.6.3 
Secondary Efficacy Endpoints (up to Week 26) ........................................ 64 
 
 


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9.7 
Description of Statistical Analyses ................................................................. 66 
9.7.1 
General Statistical Methods ....................................................................... 66 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 
DIRECT ACCESS TO SOURCE DATA/NOTES ..................................................... 70 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 71 
11.1 
Conduct of the Study ...................................................................................... 71 
11.2 
Study Monitoring............................................................................................ 71 
12 
ETHICS ....................................................................................................................... 72 
12.1 
Independent Ethics Committee/Institutional Review Board .......................... 72 
12.2 
Written Informed Consent .............................................................................. 72 
 
 
13 
DATA HANDLING AND RECORD KEEPING ....................................................... 74 
13.1 
Case Report Forms/Source Data Handling..................................................... 74 
13.2 
Retention of Essential Documents .................................................................. 74 
14 
FINANCING AND INSURANCE .............................................................................. 75 
15 
PUBLICATION POLICY ........................................................................................... 76 
16 
CONFLICT OF INTEREST POLICY ........................................................................ 77 
17 
REFERENCE LIST ..................................................................................................... 78 
18 
APPENDIX ................................................................................................................. 80 
18.1 
SYNOPSIS OF AMERICAN COLLEGE OF RHEUMATOLOGY 
CRITERIA FOR OSTEOARTHRITIS .......................................................... 80 
18.2 
WOMAC SCALE ........................................................................................... 81 




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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADAMTS 
A disintegrin and metalloproteinase with thrombospondin motifs 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
Anti-CCP Ab 
Anti-cyclic citrullinated peptide antibodies 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
CI 
Confidence interval 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
COX II 
Cyclooxygenase-II 
CP 
Conditional power 
CRO 
Contract research organization 
CTX 
C-terminal crosslinking telopeptide of collagen 
DMPC 
Dimyristoylphosphatidylcholine 
DPPC 
Dipalmitoylphosphatidylcholine 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EoS 
End of Study 
ESR 
Erythrocyte sedimentation rate 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
HbA1c 
Glycated hemoglobin 
HIV 
Human immunodeficiency virus 
huARGS 
Aggrecanase degraded aggrecan 
IA 
Intra-articular 
ICH 
International Council for Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 


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INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional review board 
ISC 
Independent statistical center 
IXRS 
Interactive voice/web response system 
LTBI 
Latent tuberculosis infection 
MACE 
Major adverse cardiovascular event 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MMPs 
Matrix metalloproteinases 
MLVs 
Multilamellar vesicles 
NOAEL 
No-observed-adverse-effect-level 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OA 
Osteoarthritis 
PA 
Posterior-anterior 
PC 
Phosphatidylcholines 
PD 
Pharmacodynamics 
PFS 
Pre-filled syringe 
PGA 
Physician global assessment 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PN 
Preferred name 
PPAS 
Per protocol analysis set 
PRN 
As needed (pro re nata) 
PT 
Prothrombin time 
PtGA 
Patient global assessment 
QTcF 
Qtc corrected according to the Fridericia formula 
RF 
Rheumatoid factor 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SIB 
Suicidal ideation and behavior 
T1/2 
Half-life  
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 


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Tmax 
Time of maximal concentration 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
WBC 
White blood cells 
WHO 
World health organization 
WOMAC 
Western Ontario and McMaster universities osteoarthritis index 
β-hCG 
Beta human chorionic gonadotropin 
 




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3.2 
 Discussion of Study Design 
This is a randomized, double-blind, placebo-controlled, single administration, multiple-dose, 
Phase IIb study to evaluate the efficacy of MM-II administered by a single IA joint injection of 
either MM-II or placebo in subjects with symptomatic knee OA. The study has been developed 
based on design features used in the completed first-in-human study for the symptomatic knee 
OA indication. The primary efficacy endpoint is based on the change from Baseline of WOMAC 
A pain score. Secondary efficacy endpoints are based on evaluation of other measures of pain 
scores, disease activity scores, and weekly cumulative exposure to rescue medication, which are 
all accepted measures for the evaluation of clinical outcome. 
 
 
 
 
3.3 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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3.3.2 Rationale for Study 
Osteoarthritis of the knees is the most common form of arthritis, both inflammatory and non-
inflammatory in nature, particularly after the age of 45. The pathophysiology of OA is poorly 
understood. Therefore, currently available medication regimens for OA, including non-opioid 
analgesics such as acetaminophen/paracetamol and NSAIDs, focus on providing transient 
palliative anti-inflammatory and pain-relieving benefits for OA, as opposed to curative effects.  
However, long-term use of these agents is associated with a wide range of side effects involving 
multi-organ systems. Furthermore, these agents have often provided limited and temporary pain 
relief. Therefore, effective and safer alternative treatments for OA are urgently needed.  This 
Phase IIb, randomized, double-blind, placebo-controlled, single-administration, multiple-dose 
study is designed to demonstrate the efficacy and safety of MM-II for treatment of knee pain, 
and to identify an optimal dose in a large population of subjects with symptomatic knee OA.  
The subjects in the proposed study will receive either MM-II (1 mL, 3 mL, or 6 mL) or placebo 
(1 mL, 3 mL, or 6 mL) in a single IA joint injection of the knee.  
3.3.3 Risk/Benefit and Ethical Assessment 
Given that efficacy benefits were reported for subjects with concurrent OA in the completed 
first- in-human study in symptomatic knee OA, there is an expectation that MM-II will improve 
OA knee pain and measures of quality of life in a larger OA subject population at Week 12.  
Furthermore, rescue medication is allowed for additional pain control during the study for 
subjects who experience breakthrough knee pain caused by knee OA.  
The study has also been designed to minimize potential risks to subjects; all subjects will 
undergo screening procedures aimed at reducing the likelihood and impact of any such risks, for 
example, subjects on anticoagulation or have a history of coagulopathy are excluded from this 
study due to a need for IA knee injection.  In addition, regular safety monitoring during the 
evaluation period for all subjects will ensure that any unanticipated effects of study participation 
are identified promptly and managed appropriately. 
An independent Data Safety Monitoring Board (DSMB) will review selected data across the 
study.  The DSMB in conjunction with the Sponsor is empowered to make recommendations 
regarding continuation, termination or modification of the study, as appropriate. 
Overall, based on data from non-clinical and clinical studies of MM-II to date and the risk 
minimization strategies discussed above, the risk: benefit profile of the current study is 
considered acceptable. 








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5 
INVESTIGATIONAL PLAN 
5.1 
Overall Study Design and Plan 
5.1.1 Description 
This is a 27-week, phase IIb, randomized, double-blind, placebo-controlled single-
administration, multiple-dose study to evaluate the efficacy and safety of a single IA joint 
injection of MM-II in subjects with symptomatic knee OA who have failed to respond 
adequately to simple analgesics as compared to matching placebo.  The design of the study is 
illustrated in Figure 5-1 below.  The study will be multinational and performed in a number 
of study centers.  Screening of subjects for eligibility will take place during a period of up to 28 
days, followed by randomization and a single IA joint injection of the index knee on Day 0 
(Week 0) and then a 26-week follow-up period.  
 
 Approximately 348 subjects with symptomatic knee OA will be randomized to 
receive a single IA injection of MM-II or placebo into the index knee at a volume of 1 mL, 3 mL, 
or 6 mL in this study. 
 
 
 
 
 
n the Standard Protocol for IA 
Injection.  The subject is blinded for the duration of the study. 
The primary endpoint is the change from Baseline in WOMAC A pain score (See Appendix 
18.2) at Week 12.  Secondary efficacy endpoints will include change from Baseline WOMAC A 
score at Week 26, WOMAC stiffness and disability sub-scores at Weeks 12, 26, and over time, 
knee joint pain by VAS at measured time points, global pain score by VAS at measured time 
points, the weekly cumulative amount of rescue medication (acetaminophen/paracetamol) used, 
and PtGA of disease activity. 
 
 
 
 
 
 
 
 
 
 
 




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5.1.3 Study Assessments 
The schedule of study assessments is presented in Table 5-1 and details of the study procedures 
are provided in Sections 5.1.4, 7, and 8. The Sponsor or designee and CRO will be notified 
immediately of any critical deviation from study procedures. All protocol deviations will be 
routinely examined by the Sponsor or designee and CRO. 
The study will consist of a Screening Period and Baseline assessments, followed by the Active 
Treatment, and Follow-up Period: 
x Screening (Day -28 to Day 0), followed by Baseline assessments and randomization, 
x Active Treatment: Double-blind, placebo-controlled period (Day 0, Week 0), 
x  Follow-up Period (Day 0, Week 0 to Week 26), starting immediately after the IP 
administration. 
 
 
 
 
 
 
 
  
5.1.4 Schedule of Assessments 
The Schedule of Assessments is presented in Table 5-1. 






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5.2 
Selection of Study Population 
5.2.1 Inclusion Criteria 
Subjects may be included in the study if they meet all of the following criteria: 




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2. Concomitant moderate or large size synovial fluid effusion of the index knee at Screening or 
Baseline. 
3. Known diagnosis of infection in the index knee in the past five years prior to Screening. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








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5.2.5 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
5.2.8 Replacement of subjects 
Subjects who drop out after randomization will not be replaced. 
5.2.9 Premature discontinuation of the complete study 
If the trial is prematurely terminated or suspended for any reason, the investigator/institution 
should promptly inform the trial subjects, should assure appropriate therapy and follow-up for 
the subjects, and, where required by the applicable regulatory requirement(s), should inform the 
regulatory authority(ies). 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.3 
Procedures for Monitoring Subject Compliance 
The dosage, timing and mode of administration of study treatment may not be changed. Any 
departures from the intended regimen must be recorded in the eCRF.  
 
 
 
 
6.3.1 Blinding and Randomization of Study Treatment(s) 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   


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Should a situation arise where unblinding is required, the Investigator at that site may perform 
immediate unblinding via the IWRS with or without following an attempt for communication 
with the Sponsor depending on local legislature. This can only occur in emergency situations 
(Section 6.4). 
 
 
 
6.4 
Procedure for Breaking the Randomization Code 
Subjects, Investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until all subjects complete 
their double-blind follow-up (Week 26 visit) and the study database has been cleaned and 
locked. 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
subject safely and efficaciously. Most often, knowledge of the possible treatment assignments is 
sufficient to treat a study subject who presents with an emergency condition. Emergency code 
breaks are performed using the IWRS. The detailed procedure of emergency code breaking and 
unblinding the subject is described in the eCRF/IWRS completion guideline available to study 
site and staff prior to study start.  
 
 
 
 
 
 


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7 
ASSESSMENT OF EFFICACY 
The following efficacy assessments will be undertaken, as outlined in the Schedule of 
Assessments (Table 5-1 
). 
7.1 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
.  
7.1.2 WOMAC Evaluation of Knee Osteoarthritis 
The current WOMAC survey is comprised of 24 items divided into three subscales: Pain (5 
items), stiffness (2 items), and physical function (17 items). Subjects are asked a range of 
questions about their knee pain, knee stiffness, their ability to carry out daily activities such as 
using the stairs, rising from sitting, lying in bed and conducting light or heavy domestic duties. 
All the items are scored on a scale of 0-4 (lower scores indicate lower levels of symptoms or 
physical disability). Values are summed up for a combined WOMAC score (WOMAC total 
score) or subscores (WOMAC A pain score, etc), and means can be calculated for total and 
subscores on the 0-4 scale. This is a common method used, although other aggregation methods 
have been used. The higher the score, the higher the amount of pain, stiffness, and a high level of 
functional limitations. 








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8.1.6 Pregnancy testing 
For female subjects of childbearing potential, a serum pregnancy test will be performed at the 
Screening visit. A
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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Pregnancies must be reported to the CRO within 24 hours of awareness. 
8.2 
 Definitions  
8.2.1 Adverse Event/Reaction 
An AE is defined as “any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of an investigation product, whether or 
not related to the investigational product”. 
 
 
 
 
 
 
 
 
An adverse treatment reaction is an “untoward and unintended response to an IP related to any 
dose administered”.  All AEs judged by either the reporting Investigator or the Sponsor as having 
a reasonable causal relationship to an IP qualify as adverse treatment reactions.  The expression 
of “reasonable causal relationship” means to convey in general that there are facts or arguments 
which suggest a causal relationship. 
8.2.2 Serious Adverse Event 
A SAE is any untoward medical occurrence that, at any dose 
x results in death 
x is life-threatening 
x requires in-subject hospitalization or prolongation of existing hospitalization* 
x results in persistent or significant disability/incapacity 
x is a congenital anomaly/birth defect 
x important medical event: Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered as SAEs when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.), 
convulsions that do not result in hospitalization, or the development of treatment 
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Possibly 
A clinical event, including 
laboratory test abnormality, with 
a reasonable time sequence to  
administration of the treatment, 
but which could also be 
explained by concurrent disease 
or other treatments or chemicals. 
Information on treatment 
withdrawal may be lacking or 
unclear. 
1. It follows a reasonable temporal sequence from 
administration of the treatment. 
2.  It could also be explained by patient's concurrent 
disease, environmental factors, medical history and 
other concomitant treatments or chemicals (including 
food-treatment interactions). 
3. There is no information or uncertainty with regard 
to what has happened after stopping the treatment. 
Probably 
A clinical event, including 
laboratory test abnormality, with 
a reasonable time sequence to 
administration of the treatment, 
unlikely to be attributed to 
concurrent disease or other 
treatments or chemicals, and 
which follows a clinically 
reasonable response on 
withdrawal (dechallenge). 
Rechallenge information is not 
required to fulfil this definition. 
1. It follows a reasonable temporal sequence from 
administration of the treatment. 
2. It could not be readily explained (unlikely) by the 
patient’s concurrent disease, environmental factors, 
medical history and other concomitant treatments or 
chemicals including food-treatment interactions. 
3. It disappears or decreases in severity on cessation 
or reduction in dose or on administration of a specific 
antagonist wherever possible. There are important 
exceptions when an AE does not disappear upon 
discontinuation of the treatment, yet treatment 
relatedness clearly exists. 
4. No rechallenge information is available or possible. 
Certainly 
A clinical event, including 
laboratory test abnormality, 
occurring in a plausible time 
relationship to treatment 
administration, and which cannot 
be explained by concurrent 
disease or other treatments or 
chemicals. The response to 
withdrawal of the treatment 
(dechallenge) should be clinically 
plausible. The event must be 
definitive pharmacologically or 
phenomenologically, using a 
satisfactory rechallenge 
procedure if necessary. 
1. It follows a plausible time sequence to treatment 
intake, this means that there is a positive argument in 
sufficient detail to support the view that the treatment 
is causally involved, pharmacologically or 
pathologically e.g. pharmacokinetics and type of 
reaction. 
2. It could not be explained by patient's concurrent 
disease, environmental factors, medical history and 
other concomitant treatments or chemicals including 
food-treatment interactions (i.e. no alternative causes). 
3. It disappears or decreases in severity on cessation 
or reduction in dose or on administration of a specific 
antagonist wherever possible. 
4. It is an objective and specific medical disorder or a 
recognized pharmacological phenomenon for instance 
‘grey baby syndrome’ and chloramphenicol or 
anaphylaxis immediately after the administration of a 
treatment that had been given previously. This means 
that any other event is automatically excluded and 
can never qualify for ‘Certain’ (even in the case of a 
positive rechallenge observation). 
5. It reappears on readministration of the treatment 
(only if ethically correct i.e. in case of non-serious, 
and easily treatable AEs). 


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Assessments of Unlikely and Unrelated do not meet the threshold for reasonable suspected 
causal relationship and are therefore classified as Unrelated for regulatory reporting and 
within a binary scale of Related/Not Related. 
The Investigator should consider the following before reaching a decision on causality 
assessment: 
x Time relationship between IP use and event’s onset 
x Medical history 
x Study treatment 
x Mechanism of action of IP 
x Class effect 
x Concomitant treatments in use 
x Lack of efficacy/worsening of existing condition 
x Erroneous treatment with study treatment or concomitant medication 
x Protocol-related process 
8.4 
Assessment of severity, outcome and expectedness of Adverse Events 
The severity of an AE will be characterized as: 
x Mild: AE which is easily tolerated 
x Moderate: AE sufficiently discomforting to interfere with daily activity. 
x Severe:  AE, which prevents normal daily activities. 
x Life-threatening: The subject is at risk of death due to the AE as it occurred. This does 
not refer to an event that hypothetically might have caused death if it were more severe. 
x Death: Death related to AE 
Event outcome is categorized as: fatal, resolved, resolved with sequelae, resolving, not resolved, 
or unknown.  
Action taken with respect to study treatment due to an AE is categorized as: none, unknown, or 
not applicable. 
Other actions taken are categorized as: none, specific therapy/medication, surgical medical 
procedure, or (Prolonged) hospitalization. 
Assessment of Expectedness will be determined by the version of the IB effective at the time of 
onset of the adverse event 
8.5 
Eliciting, Documentation and Reporting of Adverse Events 
Information on AEs will be derived by questioning the subjects in general terms (e.g. "How do 
you feel?” or “How have you been feeling since the last questioning?” respectively), by subjects' 
spontaneous reports, or by observation. 
AEs will be documented on the source document. Trained monitors will check the entries on the 
source document. The AE will be transcribed to the AE eCRF-sections. The following 
information will be given for each AE: Description of the AE, start date, stop date, severity, 


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pattern, action taken, outcome, seriousness, dose of study treatment, and relationship to the study 
treatments. The dose of study treatment assigned to an AE will be the dose the subject was 
assigned to take on the date the subject reported the AE first began.   
8.6 
 Reporting of Serious Adverse Events, Adverse Events of Special Interest 
All SAEs must be reported according to ICH guidelines on GCP or local regulations, applying 
the regulation with the stricter requirements. 
 
 
 
 
 
 
 
 
   
All AEs/SAEs will be recorded on the AE Report Form in the eCRF and source documents.  The 
Investigator is responsible for informing the IEC or IRB of the SAE as per local requirements. 
SAE forms should be completed at the site and faxed/emailed to the relevant Sponsor / 
designated CRO or emailed to the global email distribution list within 24 hours of awareness of 
the event.  The Investigator is responsible for informing the IEC or IRB of the SAE as per local 
requirements. 
SAE and AESI reports should be sent to: 
Central Receipt mail box:
 
If the report is sent via email then the completed and signed SAE or Pregnancy Report Form 
must be attached to the email.  A notification email of the event describing it in the email text is 
not sufficient. 
There may be situations when an SAE (or AESI) has occurred and the Investigator has minimal 
information to include in the initial SAE report.  However, it is very important that the 
Investigator always makes an assessment of causality for every event prior to transmission of the 
SAE Report Form. Minimum criteria are identifiable subject (number), a suspect product (i.e., IP 
or concomitant medication), an identifiable reporting source (Investigator/study site 
identification), and an event or outcome that can be identified as serious.  The Investigator may 
change his/her opinion of causality in the light of follow-up information, amending the SAE 
report form accordingly.  The causality assessment is the criteria used when determining 
regulatory reporting requirements for SAEs. 


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8.6.1.1 Safety Reporting to Sponsor 
Designated CRO will forward the SAE and Pregnancy report to the following Sponsor’s safety 
representatives within 1 business day or 3 calendar days (whichever is earlier) of becoming 
aware of it. 
 
 
 
 
 
 
8.6.1.2 Safety 
Reporting 
to 
Health 
Authorities, 
Independent 
Ethics 
Committees/Institutional Review Boards and Investigators 
Designated CRO will notify the Sponsor or designee of any SAE and will perform follow-up 
activities with the concerned site.  The Sponsor will bear responsibility of expedited and periodic 
reporting to the Health Authorities according to national requirements. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) to the IEC/IRB that approved the study.  Investigators 
should provide written documentation of IEC/IRB notification for each report to the Designated 
CRO. 
In accordance with ICH GCP, Designated CRO will inform the Investigators of findings that 
could adversely affect the safety of patients, impact the conduct of the study, or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study, as assessed by the Sponsor.  In 
particular and in line with respective regulations, Designated CRO will inform the Investigators 
of SAEs.  The Investigator should place copies of Safety Reports in the Investigator Site File.  
National regulations with regard to Safety Report notifications to Investigators will be taken into 
account. 
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC/IRB and will maintain records of these 
notifications.  When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor and of filing copies of all related correspondence in 
the Investigator Site File. 


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8.7 
24/7 Medical Emergency Coverage 
In a study-related emergency situation occurring outside of usual business hours, when site 
Investigators cannot be reached by a caller, assigned Medical Monitors, followed by an on-call 
physician can be reached 24 hours per day, 7 days per week. 
 
 
 
 
 
 
Any
 
 
 
  
 






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 Safety Analysis Set 
The Safety Analysis Set will include all randomized subjects who received the single dose of IP.  
Analyses will be based on the actual treatment received. 
9.5.4 Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects in the
 
 
9.6 
Endpoints 
 
 
 
 
 
 
9.6.2 Primary Efficacy Endpoint 
The primary efficacy endpoint is: 
x The change from Baseline in the WOMAC A pain score at Week 12. 
9.6.3 Secondary Efficacy Endpoints (up to Week 26) 
The secondary efficacy endpoints are as follows: 
x To assess the effect of a single IA joint injection of MM-II in subjects with symptomatic OA 
as measured by the change from Baseline for: 




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These parameters will be assessed using the PK Analysis Set.  
9.7 
Description of Statistical Analyses 
9.7.1 General Statistical Methods 
Summary statistics will be presented by treatment group.  For continuous variables, unless 
otherwise stated, the number of available observations (n), mean, SD, median, and range will be 
provided.  For categorical variables, the number and percentage in each category will be 
displayed. 
Assessments of change from Baseline to post-Baseline will include only those subjects with both 
Baseline and post-Baseline measurements.  The last value of a variable taken before the single 
dose of IP will be used as the Baseline value.  Unless otherwise specified, missing or dropout 
data will not be imputed for the purpose of data analysis. 
A more detailed description of study analyses will be presented in the SAP that will be finalized 
before the sample size reassessment. 
9.7.2 Analysis of Primary Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 




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Physical Examination 
 
 
 
 
 


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10 DIRECT ACCESS TO SOURCE DATA/NOTES 
The Investigator/institution shall provide direct access to source data/documents for study-related 
monitoring, audits, IEC/IRB review and regulatory inspection. 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Conduct of the Study 
Sponsor and CRO shall implement and maintain quality control and quality assurance procedures 
with written Standard Operating Procedures and study manuals to ensure that the study is 
conducted and data are generated, documented and reported in compliance with the protocol, 
ICH GCP R2 and applicable regulatory requirements. 
This study shall be conducted in accordance with the provisions of the Declaration of Helsinki 
(October 2013)10, Food and Drug Administration (FDA) (CFR, Sections 312.50 and 312.56), EU 
(Annex 1, Directive 2001/83/EC) and UK regulations (The Medicines for Human Use [Clinical 
Trials] Regulations 2004 [no.1031]), and with ICH GCP R2 (CPMP 135/95). 
The Investigator may not deviate from the protocol without a formal protocol amendment having 
been established and approved by an appropriate IEC/IRB, except when necessary to eliminate 
immediate hazards to the subject or when the change(s) involve(s) only logistical or 
administrative aspects of the study.  Any deviations may result in the subject having to be 
withdrawn from the study and render that subject non-evaluable. 
11.2 Study Monitoring 
The Investigator shall permit the Sponsor/designated CRO Site Monitor to review study data as 
frequently as deemed necessary to ensure that data are being recorded in an adequate manner and 
that protocol adherence is satisfactory. 
The Investigator will provide access medical records for the monitor in order that entries in the 
eCRF may be verified.  The Investigator, as part of his/her responsibilities, is expected to 
co-operate with Sponsor/designated CRO in ensuring that the study adheres to GCP 
requirements. 
 


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12 ETHICS 
12.1 Independent Ethics Committee/Institutional Review Board 
Prior to the start of the study, the Investigator is responsible for ensuring that the protocol and 
consent form have been reviewed and approved by a relevant IEC/IRB.  The IEC/IRB shall be 
appropriately constituted and perform its functions in accordance with FDA, ICH GCP and local 
requirements as applicable. 
The IEC/IRB shall approve all protocol amendments, written informed consent forms and 
document updates, subject recruitment procedures (e.g., advertisements), written information to 
be provided to the subjects, Investigator's Brochure, available safety information, the 
Investigator's curriculum vitae and/or other evidence of qualifications and any other documents 
requested by the IEC/IRB and Regulatory Authority (Competent Authority) as applicable. 
12.2 Written Informed Consent 
The nature and purpose of the study shall be fully explained to each subject (or their legally 
responsible guardian). 
Written informed consent must be obtained from each subject (or guardian) prior to any study 
procedures being performed.  The process of obtaining informed consent must be documented in 
the subject source documents. 
The consent documents to be used for the study shall include all the elements of informed 
consent as outlined in accordance with FDA, ICH GCP and local requirements as applicable and 
be reviewed and approved by the appropriate IEC/IRB prior to use. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13 DATA HANDLING AND RECORD KEEPING 
13.1 Case Report Forms/Source Data Handling 
All required study data must be entered in the eCRF created for the study.  This data collection 
tool is a validated electronic data capture (EDC) system that contains a system generated audit 
trail.  Data required according to this protocol are recorded by investigational site personnel via 
data entry into the internet based EDC software system.  The Investigator shall ensure that all 
data from subject visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. The Investigator must sign each eCRF to verify the integrity of the data 
recorded. All internal Sponsor/designated CRO and external investigational site personnel 
seeking access to the eCRF are supported by the CRO data manager. At the end of the study all 
data captured electronically will be provided to the Investigator for archiving at the 
investigational site. 
A list of the normal ranges for all laboratory tests to be undertaken forms part of the 
documentation to be collated prior to study start.  If a central laboratory has been selected to 
conduct any or all tests, it is essential that all samples be analyzed at that laboratory, unless 
otherwise specified (e.g., ESR). 
The Investigator must maintain source documents, such as laboratory reports, X-rays, ECGs, 
consultation reports, and complete medical history and physical examination reports. All 
information in the eCRF must be traceable to the source documents in the subject’s file. 
13.2 Retention of Essential Documents 
The Investigator/institution should maintain the study documents as specified in the ICH 
guidelines on GCP and as required by the applicable regulatory requirements. The 
Investigator/institution should take measures to prevent accidental or premature destruction of 
these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IP. These documents should be retained for a 
longer period, however, if required by the applicable regulatory requirements or by an agreement 
with the Sponsor.  It is the responsibility of the Sponsor to inform the Investigator/institution as 
to when these documents no longer need to be retained. 


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14 FINANCING AND INSURANCE 
The Sponsor shall carry an insurance policy to cover compensation of subjects’ health injuries 
arising from the study.  If a subject incurs a study-related injury, the subject may be treated (and 
other necessary measures taken) at the study site and/or another medical institution.  If it is 
necessary to compensate for the treatment, the Sponsor will cover the cost.  The Sponsor shall 
not impose on the subject the burden of proving the causal relation between the study and the 
injury. 
If any of the following is confirmed, the Sponsor may refuse or restrict the payment of the 
compensation: 
1. 
A serious GCP or protocol deviation by the Investigator or Sub-Investigator (except 
deviation medically necessary to avoid an immediate hazard to the study subjects) 
2. 
Intentional act or negligence on the part of the Investigator or Sub-Investigator or 
malpractice thereby 
3. 
Injury caused by unlawful act or delinquency of a third party 
4. 
Injury caused by intentional act or negligence of the subject 
If compensation becomes necessary for a study-related injury, the site will promptly notify the 
Sponsor and will co-operate with the Sponsor and its insurer (or their legal representatives) in 
their handling thereof. 
 


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15 PUBLICATION POLICY 
The Sponsor shall retain the ownership of all data. When the study is complete the Sponsor shall 
arrange the analysis and tabulation of data.  A clinical study report shall then be prepared, which 
may be used for publication, presentation at scientific meetings or submission to regulatory 
authorities. All proposed publications based on this study must be subject to the Sponsor's 
approval requirements. 
The Sponsor assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. 


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16 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design conduct, analysis, publication, or any aspect of this study will be 
disclosed and managed.  Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
study.  The study leadership in conjunction with the Sponsor has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest. 


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17 REFERENCE LIST 
1. Mehta, C and Pocock, SJ. Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statistics in Medicine. 2011; 30(28): 3267-3284. 
2. Zhang Y and Jordan JM.  Epidemiology of osteoarthritis.  Clin Geriatr Med.  2010;26:355-
369. 
3. Osteoarthritis. National Institute of Arthritis and Musculoskeletal and Skin Diseases. April 
2015. Archived from the original on 18 May 2015. Retrieved 13 May 2015. Available at 
https://web.archive.org/web/20150518090102/http:/www.niams.nih.gov/health_info/Osteoart
hritis/default.asp 
4. Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, and Carr AJ.  
Osteoarthritis. Lancet. 2015; 386: 376–387. 
5. Armitage P, Berry G. Stat. Methods in Medical Research. London: Blackwell Scientific 
Publications; 1987 
6. Lemeshow S, Hosmer DW, Klar J, Lwange SK. Adequacy of Sample Size in Health Studies. 
Chjichester, New York, Brisbane, Singapore: John Wiley & Sons; 1990 
7. Schneider H, Braun A, Füllekrug J, Stremmel W, and Ehehalt R.  Lipid Based Therapy for 
Ulcerative Colitis—Modulation of Intestinal Mucus Membrane Phospholipids as a Tool to 
Influence Inflammation.  Int. J. Mol. Sci. 2010;11:4149-4164. 
8. Paik J, Duggan ST, and Keam SJ. Triamcinolone Acetonide Extended-Release: A Review in 
Osteoarthritis Pain of the Knee.  Drugs.  2019;79:455–462. 
9. Maurer W, Hothorn LA, Lehmacher W. Multiple comparisons in drug clinical trials and 
preclinical assays: a-priori ordered hypotheses In: Vollmar J, ed. Biometrie in der chemisch-
pharmazeutischen Industrie 6, Testprinzipien in klinischen und praklinischen Studies. 
Stuttgart, Jena, New Yprk: Gustav Fischer Verlag; 1995 
10. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human 
Subjects (https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-
for-medical-research-involving-human-subjects/). 


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18 APPENDIX 
18.1 SYNOPSIS OF AMERICAN COLLEGE OF RHEUMATOLOGY CRITERIA FOR 
OSTEOARTHRITIS  
    (https://www.rheumatology.org/Portals/0/Files/Idiopathic%20OA%20of%20the%20Knee.pdf) 
 
Clinical and laboratory 
Clinical and radiographic 
Clinical 
Knee pain 
Knee pain 
Knee pain 
+at least 5 of 9 
+at least 1 of 3 
+at least 3 of 6 
-Age >50 years 
-Age >50 years 
-Age >50 years 
-Stiffness <30 min 
-Stiffness <30 min 
-Stiffness <30 min 
-Crepitus 
-Crepitus 
-Crepitus 
-Bony tenderness 
+Osteophytes 
-Bony tenderness 
-Bony enlargement 
 
-Bony enlargement 
-No palpable warmth 
 
-No palpable warmth 
-ESR <40 mm/hour 
 
 
 


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18.2 WOMAC SCALE  
 

SAP_001.pdf: 
Official title: A Phase IIb, Randomized, Double-Blind, Placebo-Controlled, Single-administration, 
Multiple-Dose Study to Demonstrate the Efficacy and Safety of MM-II for Treatment of Knee Pain in 
Subjects With Symptomatic Knee Osteoarthritis   
Document: Statistical Analysis Plan 
NCT number: NCT04506463 
Document date: 30-Sep-2022 


Statistical Analysis Plan
Sponsor:
Sun Pharmaceutical Industries Limited
Protocol No:
CLR_17_17
Protocol Title:
A Phase IIb, Randomized, Double-Blind, 
Placebo-Controlled, Single-administration, 
Multiple-Dose Study to Demonstrate the 
Efficacy and Safety of MM-II for Treatment of 
Knee Pain in Subjects with Symptomatic Knee 
Osteoarthritis
Document Date:
30-Sep-2022


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Confidential Document




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Confidential Document
TABLE OF CONTENTS
LIST OF ABBREVIATIONS ...................................................................................................... 6
1.
INTRODUCTION ................................................................................................................. 8
1.1
Background ...................................................................................................................... 8
1.2
Study Design .................................................................................................................... 9
1.3
Rationale........................................................................................................................... 9
2.
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 10
3.
PRIMARY ESTIMAND ..................................................................................................... 12
4.
STATISTICAL METHODOLOGY .................................................................................. 12
4.1
General Principles .......................................................................................................... 12
4.2
Randomization ............................................................................................................... 13
4.3
Sample Size Considerations........................................................................................... 13
4.4
Sample Size Reassessment............................................................................................. 14
4.5
Analysis Sets .................................................................................................................. 14
4.5.1
All Randomized Set................................................................................................ 14
4.5.2
Full Analysis Set..................................................................................................... 14
4.5.3
Per Protocol Analysis Set........................................................................................ 15
4.5.4
Safety Analysis Set ................................................................................................. 15
4.5.5
Pharmacokinetic Analysis Set................................................................................. 15
4.6
Subject Disposition ........................................................................................................ 15
4.7
Subject Demographics and Baseline Characteristics ..................................................... 15
4.8
Prior and Concomitant Medications............................................................................... 16
4.9
Primary Endpoint Analysis ............................................................................................ 16


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4.9.1
Sensitivity Analysis ................................................................................................ 18
4.10
Secondary Endpoint Analyses........................................................................................ 19
4.11
Exploratory Endpoint Analysis...................................................................................... 21
4.12
Subgroup Analysis ......................................................................................................... 21
4.13
Plasma Concentration and Pharmacokinetic Analyses .................................................. 21
4.14
Safety Analyses.............................................................................................................. 22
4.14.1
Adverse Events ....................................................................................................... 22
4.14.2
Vital Signs Measurements ...................................................................................... 23
4.14.3
Clinical Laboratory Tests........................................................................................ 23
4.14.4
ECGs....................................................................................................................... 24
4.14.5
Physical Examinations............................................................................................ 24
5.
DATA HANDLING............................................................................................................. 24
5.1
Baseline, Pre-Dose, and Study Visits............................................................................. 24
5.2
Pooling of Sites .............................................................................................................. 25
5.3
Missing Data .................................................................................................................. 25
5.4
Unscheduled Data .......................................................................................................... 26
5.5
Presentation Conventions............................................................................................... 26
5.5.1
Significant Figures.................................................................................................. 26
6.
DEVIATIONS FROM THE PROTOCOL ....................................................................... 27


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Confidential Document
LIST OF ABBREVIATIONS
Abbreviation
Definition
ADAMTS
A disintegrin and metalloproteinase with thrombospondin motifs
AE
Adverse event
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of covariance
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve from time zero to time of last 
quantifiable concentration
BMI
Body mass index
Cmax
Maximum observed concentration
COX II
Cyclooxygenase II
CS
Clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CTX
C-terminal crosslinking telopeptide of collagen
CV
Coefficient of variation
DMPC
Dimyristoylphosphatidylcholine
DPPC
Dipalmitoylphosphatidylcholine
ECG
Electrocardiogram
eCRF
Electronic case report form
EoS
End of Study
FAS
Full Analysis Set
huARGS
Aggrecanase degraded aggrecan
IA
Intra-articular
IP
Investigational product
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MACE
Major adverse cardiovascular event
MMPs
Matrix metalloproteinases
MMRM
Mixed model repeated measures
NCS
Not clinically significant


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Abbreviation
Definition
NSAIDs
Non-steroidal anti-inflammatory drugs
OA
Osteoarthritis
PC
phosphatidylcholines
PK
pharmacokinetic
PN
Preferred name
PPAS
Per Protocol Analysis Set
PT
Preferred term
PtGA
Patient Global Assessment
SOC
System organ class
SD
Standard deviation
TEAE
Treatment emergent adverse event
Tmax
Time to maximum observed concentration
VAS
Visual Analog Scale
WHO
World Health Organization
WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index


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1.
INTRODUCTION
1.1
Background
Osteoarthritis (OA) is the most common form of joint diseases, and is characterized by articular 
cartilage degradation, osteophyte formation, bone remodeling, joint space narrowing, and joint 
inflammation.  It is estimated that 80% of the population will have radiographic evidence of OA 
by the age of 65 years, although only 20% of those will be symptomatic.  The etiology of OA is 
unknown, but is believed to be multifactorial, including hereditary, metabolic causes, mechanical 
damages, and inflammatory in nature.  Osteoarthritis of the knees has higher prevalence than any 
other joints.  Clinical manifestations of OA in the knees include pain in and around the joint, 
particularly on weight-bearing of the knee joint, stiffness of the joint after rest, and limited joint 
motion due to pain and/or stiffness of the joint.  The end result of all forms of OA is often loss of 
function of the joint or limb, imposing significant economic burden on the individuals as well as 
the society.  Diagnosis of OA is based on signs and symptoms, and is often confirmed with imaging 
studies or using laboratory tests to rule out concomitant inflammatory causes. Since the 
pathophysiology of OA is unknown, current recommendations for managing OA focus on 
relieving pain and stiffness, and improving physical function as important goals of therapy.  Non-
surgical treatment of OA focuses on reducing overloading of joints, physiotherapy, and alleviation 
of pain and inflammation, usually by topical, systemic, or intra-articular (IA) joint administration 
of drugs.
Currently available medication regimens for most OA include non-opioid analgesics such as 
acetaminophen/paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), and injectable 
hyaluronic acid.  These pharmaceutical agents can provide transient pain relief quite effectively, 
but long-term use of NSAIDs has been found to be associated with increased risk of 
gastrointestinal bleeding, hypertension, cardiovascular events, congestive heart failure, and renal 
insufficiency, etc.  Long-term opioid use for OA is generally discouraged due to lack of 
information on benefits as well as risks of addiction and other side effects.  The NSAIDs in the 
form of topical application and cyclooxygenase II (COX II) inhibitors are considered somewhat 
safer than other NSAIDs in terms of gastrointestinal side effects, although COX II inhibitors are 
contraindicated in patients with a history of coronary artery disease.  Because of the high incidence 
of side effects associated with long-term therapy of both nonselective and COX II selective 
NSAIDs, effective and safer alternative treatments for OA are urgently needed.
MM-II is composed of two surface active phospholipids 
 
 
 
 




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Osteoarthritis of the knees is the most common form of arthritis, both inflammatory and non-
inflammatory in nature, particularly after the age of 45.  The pathophysiology of OA is poorly 
understood.  Therefore, currently available medication regimens for OA, including non-opioid 
analgesics such as acetaminophen/paracetamol and NSAIDs, focus on providing transient 
palliative anti-inflammatory and pain-relieving benefits for OA, as opposed to curative effects.  
However, long-term use of these agents is associated with a wide range of side effects involving 
multi-organ systems.  Furthermore, these agents have often provided limited and temporary pain 
relief.  Therefore, effective and safer alternative treatments for OA are urgently needed.  This 
Phase IIb, randomized, double-blind, placebo-controlled, single-administration, multiple-dose 
study is designed to demonstrate the efficacy and safety of MM-II for treatment of knee pain, and 
to identify an optimal dose in a large population of subjects with symptomatic knee OA.  The 
subjects in the proposed study will receive a single IA joint injection of either MM-II or placebo.  
Specifically, subjects will be randomized to one of the following treatment arms:
Arm A:  MM-II 1 mL IA joint injection,
Arm B:  MM-II 3 mL IA joint injection,
Arm C:  MM-II 6 mL IA joint injection,
Arm D:  Placebo 1 mL IA joint injection,
Arm E:  Placebo 3 mL IA joint injection, or
Arm F:  Placebo 6 mL IA joint injection.
2.
STUDY OBJECTIVES AND ENDPOINTS
Primary Efficacy Objective
Endpoint(s)
To determine the optimal dose of an 
IA joint injection of MM-II in the 
treatment of knee pain in subjects with 
symptomatic knee OA
Change from Baseline of WOMAC A pain score at Week
12
Primary Safety Objective
Endpoint(s)
To assess the safety and tolerability of 
a single IA joint injection of MM-II in 
the treatment of knee pain in subjects 
with symptomatic knee OA at Week 
12
x
AEs
x
Laboratory assessments
x
Vital signs
x
ECG
x
Physical examination




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3.
PRIMARY ESTIMAND
Primary Estimand
Primary scientific 
question of interest
What is the optimal dose of a single IA joint injection of MM-II as 
compared to placebo in the treatment of knee pain in subjects with 
symptomatic knee OA?
Target Population
Defined through appropriate inclusion/exclusion criteria as listed in the 
study protocol.
Treatments of Interest
x
Single IA joint injection of 1 mL MM-II
x
Single IA joint injection of 3 mL MM-II
x
Single IA joint injection of 6 mL MM-II
Outcome Variable
Change from Baseline in WOMAC A pain score at Week 12
Summary Measure
Least square mean difference between active doses and 3 mL placebo and 
associated p-values from a mixed model repeated measures (MMRM) with 
fixed effects for treatment, visit, and treatment-by-visit interaction and 
covariates site, Baseline WOMAC A pain score, and randomization 
stratification factors adjusting for multiplicity using Dunnett’s step-down 
procedure
Intercurrent Events
No adjustments to the primary estimand will be made based on intercurrent 
events
4.
STATISTICAL METHODOLOGY
4.1
General Principles
All collected study data will be presented in listings.  All derivations and statistical analyses will 
be performed using SAS® software Version 9.4.  Prior and concomitant medications will be coded 
using World Health Organization (WHO) Drug Dictionary Enhanced September 1, 2020.  Adverse 
events (AEs) and medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.1.
Unless stated otherwise, descriptive summaries for continuous variables will include n (number of 
subjects with non-missing results), mean, standard deviation (SD), median, minimum, and 






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Safety Analysis Set
The Safety Analysis Set will include all randomized subjects who received the single dose of IP.  
Analyses will be based on the actual treatment received.
 
 
 
 
4.6
Subject Disposition
The number of subjects screened and in each of the analysis sets will be summarized by treatment, 
site, and overall, where applicable.
The number and percentage of subjects who completed the study will be presented by treatment, 
site, and overall for the All Randomized Set.  Frequency and percentage of subjects who withdrew 
or discontinued from the study, and the primary reason for withdrawal, will also be summarized 
by treatment and overall.
4.7
Subject Demographics and Baseline Characteristics
Demographic data and subject characteristics at Baseline will be summarized descriptively.  These 
characteristics will include age, sex, reproduction status, contraception method used, ethnicity, 
race, weight (kg), height (cm), BMI, Rhuematoid Factor, Anti-CCP, Index Knee X-ray, Analgesic 






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4.9.1 Sensitivity Analysis
Multiple sensitivity analyses will be performed for the change from Baseline in WOMAC A pain 
score.  One will repeat the primary analysis using the PPAS.  The primary analysis will also be 
repeated for the FAS, but pooling the three placebo groups such that treatment in the model has 
four levels (1 mL, 3 mL, and 6 mL MM-II and pooled placebo).  Comparisons of MM-II will be 
made against pooled placebo for this analysis.
An additional sensitivity analysis will be performed on the change from Baseline in WOMAC A 
pain score that imputes missing data using multiple imputations (MI) methodology.  For the 
multiple imputations, subjects on MM-II that discontinue due to lack of efficacy will be imputed 
according to results for subjects randomized to 3 mL placebo. All other missing data will be 
imputed according to the subject’s randomized treatment.
The multiple imputation method will be applied to missing WOMAC A pain scores from Baseline
through Week 12 only.  The imputation procedure will first begin by generating 100 imputed 
datasets for subjects that did not discontinue due to lack of efficacy or that were randomized to 
placebo.  The 100 imputed datasets for the WOMAC A pain scores will be generated separately 
for each randomized treatment with a fully conditional specification (FCS) model using the 
regression method.  The model will include covariates Baseline BMI group (<30 kg/m2, ≥30 kg/m2
and <35 kg/m2, ≥35 kg/m2) and Baseline VAS group (≤74, ≥75).  Following these initial 
imputations, 100 copies of the non-missing WOMAC A pain scores for subjects on MM-II that 
discontinue due to lack of efficacy will be generated.  One of these copies will be added to each of 
the 100 imputed datasets generated for the 3 mL placebo group.   A single imputation will then be 
generated for each of these 100 combined sets of data using the same FCS model as above.  This 
will result in 100 imputed datasets for all subjects.
Change from Baseline to Week 12 in WOMAC A pain score from each of the 100 imputed datasets 
will be analyzed separately using an ANCOVA model with effect treatment and covariates site, 
Baseline WOMAC A pain score, Baseline BMI group (<30 kg/m2 , ≥30 kg/m2 and <35 kg/m2, ≥35 
kg/m2), and Baseline VAS group (≤74, ≥75).  For each comparison of interest, estimates and their 
associated standard errors from the ANCOVA models will be combined to produce a single overall 


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estimate and standard error.  Associated two-sided 95% confidence intervals and p-values will
then be generated as appropriate.
The SAS® MI procedure will be utilized for imputing data.  The first imputation step as described 
above will be implemented as follows.
Proc MI NIMPUTE=100 SEED=1867004294 MINIMUM=. . 0 0 0 0 0
        MAXIMUM=. . 4 4 4 4 4;
  by trt;
  class bmi vas;
  var bmi vas w0 w1 w2 w4 w8 w12;
  fcs reg(w0) reg(w1) reg(w2) reg(w4) reg(w8) reg(w12);
run;
Where:
  trt = Treatment (Arms A, B, C, D, E, F)
  bmi = Baseline BMI group
  vas = Baseline VAS group
  w0 = Baseline WOMAC A pain score
  w1 = Week 1 WOMAC A pain score
  w2 = Week 2 WOMAC A pain score
  w4 = Week 4 WOMAC A pain score
  w8 = Week 8 WOMAC A pain score
  w12 = Week 12 WOMAC A pain score
The imputation step for subjects randomized to MM-II that discontinued due to lack of efficacy 
will be as above except with SEED=454120304, NIMPUTE=1, and without “by trt” since 
imputation will be based on a single treatment group.
4.10 Secondary Endpoint Analyses
 
 
 
Additionally, change from Baseline in WOMAC A pain score will be analyzed separately at each 
visit through Week 26 using an ANCOVA model with effect treatment and covariates site, 


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VAS knee pain and global pain scores are collected daily.  Weekly post-baseline average daily 
scores will calculated for all weeks through Week 26 regardless of whether or not there was a 
scheduled visit at that week.  Weeks will be calculated according to actual study days.  Since the 
Day 1 assessment is scheduled to be collected prior to dosing, Week 1 will be calculated from 
VAS scores collected on Days 2 through 8, Week 2 from Days 9 through 15, etc.  Daily VAS 
global pain score is only collected prior to dosing on Day 1.  Per the definition of baseline in 
Section 5.1, the last daily VAS global pain score collected prior to the date and time of dosing will 
be considered baseline for the change from baseline analyses.  Daily VAS knee pain score is 
collected daily leading up to Day 1.  Baseline daily VAS knee pain score will be calculated as the 
average of the assessments on Day 1, if prior to dosing, and the previous six days.  Day 1 
assessments of average daily knee pain and average daily global pain that are collected after dosing 
will be excluded from baselin and the Week 1 daily average determination.  Weekly averages will 
be calculated based on the number of days in the week with non-missing pain scores.
The weekly cumulative amount of rescue medication will be based on information from the rescue 
medication dispensing and accountability eCRF pages only.  Weekly cumulative amount of rescue 
medication will be calculated between each scheduled visit.  At each visit, rescue medication is 
returned and accounted for from the previous visit and new rescue medication is dispensed.  It will 
be assumed that no rescue medication was taken on the day of return unless rescue medication was 
also dispensed on that date.  If so, then the dosage taken for that day will be based on the 
accountability for the newly dispensed rescue medication.  The amount of rescue medication taken 
between visits will be based on the “number of tablets consumed” and the associated “dosage per 
tablet” as captured on the eCRFs.  For a given period (dispensing through return), the average daily 
dose of rescue medication will be calculated.  It will be assumed that the subject consumed this 
average daily dose of rescue medication on each date in the period.  Dates for which a subject is 
in the study, but do not fall within one of the dispensing and return periods or the date of return 
where no new rescue medication was dispensed, will be assumed to have no rescue medication
received.  The days associated with a given visit include the date of the previous visit through the 
day prior to the current visit.  Weekly cumulative amount of rescue medication for a given visit 
will be calculated by summing up the daily doses within the period, dividing by the number of 
days in the period, and then multiplying by seven.  Subjects with missing information for a given 
period will have their weekly cumulative amount of rescue medication set to missing for that 
period.  Subjects discontinuing early will be analyzed in the MMRM analysis only through the last 
scheduled visit.  However, rescue medication usage after this visit through the date of early 
termination will be summarized under the heading “Last Visit”.  Subjects completing the study 


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that have a calculable Week 26 weekly cumulative amount of rescue medication will have their 
Week 26 results summarized under Week 26 and “Last Visit”.
 
 
 
  
4.12 Subgroup Analysis
The primary endpoint and WOMAC C disability sub-scores will be analyzed using separate mixed 
model repeated measures for the following subgroups:
x
Baseline WOMAC A pain score (≤median, > median)
x
BMI (<30 kg/m2, ≥30 kg/m2 and < 35 kg/m2, and ≥35 kg/m2)
x
Baseline Index Knee Pain (VAS: ≤74, ≥75)
The median for the Baseline WOMAC A pain score will be calculated based on the FAS.
Change from Baseline to Week 12 in WOMAC A pain score will be summarized descriptively for 
the following groups:
x
Age (≤65 years, > 65 years)
x
Sex (Male, Female)
x
Race (White, Non-White)
x
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
x
Site
x
Region (US Sites, Denmark Sites, Hong Kong Site)
4.13 Plasma Concentration and Pharmacokinetic Analyses
Plasma DMPC and DPPC concentration data will be listed by individual subject and summarized 
by time and MM-II dose group. PK parameters of AUC, Cmax, Cmin, and Tmax will be summarized 
with descriptive statistics (n, mean, SD, geometric mean, coefficient of variation (CV), minimum, 
first, second (i.e., median) and third quartiles, and maximum). The PK Analysis Set will be used 
for the analysis.  PK analysis will only be conducted at US sites.
AUC will be determined from the linear trapezoidal method using non-compartmental analysis. 
Pre-dose concentrations will be analyzed at time 0. All other concentrations will be analyzed using 
their actual time post-dose.  Concentrations below the lower limit of quantification (LLOQ)


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occurring before the first quantifiable concentration will be analyzed as 0. Concentrations below 
the LLOQ occurring after the first quantifiable concentration will be considered missing. If a 
quantifiable concentration during the elimination phase occurs after an elimination phase 
concentration that is below the LLOQ, the concentration will be examined to determine if the 
concentration should be included in the calculation.
4.14 Safety Analyses
Safety will be assessed by adverse events, laboratory assessments, vital sign measurements, ECG 
data, index knee examination, and physical examination abnormalities using the Safety Analysis 
Set.
4.14.1Adverse Events
An AE is defined as “any untoward medical occurrence in a subject, or clinical investigation 
subject administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, 
symptom or disease temporally associated with the use of an investigation product, whether or not 
related to the investigational product”. 
Any relevant observations made (including physical examination findings, clinically relevant 
abnormal vital signs, clinically relevant laboratory abnormalities, and clinically relevant ECG 
findings) prior to or after administration of the single dose of IP are to be recorded on the AE 
eCRF.  An AE relating to a pre-existing condition will only be recorded if there is a worsening of 
the pre-existing condition during study conduct with regard to nature, severity or frequency.  An 
event will be considered a treatment-emergent AE (TEAE) if the start or worsening of the event 
was on or after the administration of IP.  Summaries of adverse events will be limited to TEAEs, 
but listings of all events will be provided.  A serious adverse event is an event recorded as ‘Serious’ 
on the adverse event eCRF page.  Adverse events will be classified by MedDRA SOC and PT.
The overall summary of TEAEs will include frequencies and percentages and will be presented 
for the following:
x
Overview of adverse events;
x
All adverse events by SOC and PT;
x
Serious adverse events SOC and PT;
x
Adverse events by SOC, PT, and severity;
x
Adverse events related to study treatment by SOC and PT


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An adverse event will be considered related to study drug if the relationship is “possibly”, 
“probably”, or “certainly”.  The severity of an adverse event will be rated by the investigator as 
“mild”, “moderate”, or “severe”. Subjects experiencing multiple instances of the same PT are only 
counted once within each SOC and PT combination.  Subjects experiencing multiple instances of 
the same PT will only be counted once according to the highest severity during the treatment 
emergent period when summarizing severity.
Serious adverse events, if present, also will be listed using verbatim and SOC/PT. Should any 
serious adverse events occur during the study, the serious adverse events are displayed in a table 
and a narrative for each serious adverse event included in the study report.
Adverse Events of Special Interest (AESIs) will be summarized descriptively. AESI-related safety 
endpoints include: 
x
Percent of subjects with severe infections, defined as any infection meeting the regulatory 
definition of a SAE, or any infection requiring IV antibiotics whether or not reported as a 
serious event, as per the regulatory definition 
x
Percent of subjects with malignancies (excluding carcinoma in situ of the cervix) 
x
Percent of subjects with non-melanoma skin cancer 
x
Percent of subjects with melanoma skin cancer 
x
Percent of subjects with major adverse cardiovascular event (MACE)
x
Percent of subjects with treatment-related hypersensitivity reactions (e.g. anaphylaxis, 
urticaria, angioedema, etc.) 
All AEs will be presented in full in a comprehensive listing including subject number, treatment 
regimen, severity, seriousness, action taken, outcome, relationship to treatment, onset/stop and 
duration. Details of SAEs and AEs leading to withdrawal will be listed separately.
4.14.2Vital Signs Measurements
Vital sign observed values and changes and shifts from Baseline will be summarized at each 
scheduled visit, where applicable. Shifts will be presented for parameters that are further classified 
as “Normal”, “Abnormal Not Clinically Significant (NCS)” and “Abnormal Clinically Significant 
(CS)”.  Abnormal NCS and Abnormal CS will be combined and displayed as “Abnormal” in the 
shift tables.  A listing of all clinically significant abnormal results will be presented.
4.14.3Clinical Laboratory Tests
Clinical laboratory parameters (e.g., albumin, etc.), including observed values and changes and 
shifts from Baseline, will be summarized at each scheduled visit, where applicable.  Laboratory 


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parameters may be classified as “Low”, “Normal”, or “High” (quantitative parameters) or 
“Abnormal” or “Normal” (qualitative parameters) by the central laboratory according to the 
reference ranges provided in the laboratory data transfer.  “Low”, “High”, and “Abnormal” results 
will be flagged in the listings of individual subject data.  Some parameters may not have normal 
ranges.
Urine drug, urine cotinine, urine alcohol, FSH, serology, coagulation, and pregnancy test results 
will also be presented in data listings.
4.14.4ECGs
The overall ECG interpretation will be summarized by presenting the number and percentage of 
subjects with “Normal”, “Abnormal, not clinically significant”, and “Abnormal, clinically 
significant”.   Shifts from Baseline in overall ECG interpretation will also be presented for 
“Normal” and “Abnormal”.  A listing of all clinically significant abnormal overall ECG 
interpretations will be presented.  Continuous ECG parameter (e.g., QTcF) observed values and 
changes from Baseline will be summarized per schedule.
4.14.5Physical Examinations
Physical examination results will be summarized with incidence of “Normal”, “Abnormal NCS”
and “Abnormal CS” by body system at each scheduled visit.  Shifts from Baseline will also be 
presented by body system for “Normal” and “Abnormal”.  A listing of all clinically significant 
abnormal results will be presented.
5.
DATA HANDLING
5.1
Baseline, Pre-Dose, and Study Visits
Baseline daily VAS knee pain score will be calculated as the average of the assessments on Day 1 
and the previous six days.  For all other parameters, the last non-missing value, including 
unscheduled, of a variable taken before the single dose of IP will be used as the Baseline value.    
Except for determination of the PK parameters, all post-Baseline unscheduled data will be 
excluded from the analyses and presented in the listings only.  Except for pharmacokinetic 
concentration data used to derive PK parameters, which will be analyzed at the actual sampling 
times, including unscheduled, all other analyses presented by collection day and/or by time point 
will be based on the schedule of assessments as planned in the protocol and recorded on the eCRFs.  
However, subjects who prematurely discontinue from the study having their final visit assessments
collected on the Week 26 eCRFs.  For these subjects, data collected under Week 26 will be mapped 
to one of the scheduled visits based on the following visit windows.  On a per data point basis, if 
no scheduled result exists for the mapped visit, then the Week 26 will be used in the analysis for 


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that visit.  If there is a scheduled result associated with the mapped visit, then the original scheduled 
result for that visit will be used in the analysis and the mapped Week 26 result will be presented 
in the listings only.
Visit
Target Study Day
Study Day Range
Week 1a
8
1 – 11
Week 2
15
12 – 22
Week 4
29
23 – 43
Week 8
57
44 – 71
Week 12
85
72 – 99
Week 16
113
100 – 127
Week 20
141
128 – 162
Week 26
183
≥163
a: Day 2 assessments are scheduled for specific hours on that day.  
Any subject discontinuing prior to Week 1 will have their early 
termination assessments mapped to Week 1 and not to specific 
hours on Day 2 regardless of the date.
5.2
Pooling of Sites
Sites contributing less than 16 subjects to the PPAS will be pooled within region (US Sites, 
Denmark Sites, Hong Kong Site).  Pooling will begin by sorting the sites within a region based on 
the number of subjects in the PPAS.  The site with the lowest number of subjects will be pooled 
with the site with the next lowest number of subjects.  If necessary, pooling with subsequent sites 
will continue until the pooled site contains at least 16 subjects in the PPAS.  Pooling for additional 
sites will continue until all sites/pooled sites within a region have at least 16 subjects in the PPAS.  
Pooled site will be used for all analyses (e.g., MMRM) containing site in the model or site as a 
stratification factor.  If a site does not have any subjects in the PPAS, then it will be combined with 
the pooled site containing the greatest number of individual sites within the same region.  If there 
is more than one pooled site with the greatest number of individual sites, then it will be combined 
with the pooled site with the fewest number of total subjects.
5.3
Missing Data
WOMAC A pain scores will be imputed as described in Section 4.9.1 for the sensitivity analysis 
based on multiple imputations.  All other analyses will based on available data.  Handling of 
plasma values that are BQL with respect to the pharmacokinetic analyses are described in Section
4.13.


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5.4
Unscheduled Data
Unscheduled PK collections will be used for the derivation of the PK parameters.  For all other 
data obtained from unscheduled assessments, results will only be considered for Baseline
determination; otherwise, unscheduled data will not be used in summary tables or included in the 
analyses.  All unscheduled data will be presented in the listings.
5.5
Presentation Conventions
For all parameters, where applicable: 
x
n: no decimal place,
x
CV% and CV% geometric mean will be displayed to one decimal place,
For the following pharmacokinetic parameters, where applicable:
x
Arithmetic mean, geometric mean, SD, median, minimum, and maximum:
o
tmax: two decimal places,
o
Cmax and AUC,: four significant figures.
All other parameters that are reported or derived at a fixed number of decimal points (e.g., vital 
sign measurements, including body mass index (BMI), clinical laboratory test parameters, and 
plasma drug concentrations), will be reported as follows:
x
Mean, median, and first and third quartiles will be displayed to one more decimal than the 
maximum number of decimal places reported for the original data,
x
SD will be reported to two more decimal places than the maximum number of decimal 
places reported for the original data,
x
Minimum and maximum will be reported to the maximum number of decimal places 
reported for the original data.
5.5.1 Significant Figures
When descriptive statistics are to be presented to a specific number of significant figures, the 
following conventions will be utilized:
x
Results of “0” will be displayed as “0”.
x
Results that cannot be displayed to the exact specified number of significant figures (in 
Section 3.5) without the use of scientific notation will be displayed using the maximum 
number of significant figures that is less than the specified number of significant figures. 


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E.g., “1000” and “1295” cannot be displayed to three significant figures without the use of 
scientific notation, so “1000” and “1300” would be presented, respectively.
x
All other results will be displayed to the specified number of significant figures in Section 
3.5. Examples of results displayed to three significant figures are presented below:
Original Result
Presentation Result
(3 Significant Figures)
12.34
12.3
0.01234
0.0123
0.12
0.120
10
10.0
1234
1230
6.
DEVIATIONS FROM THE PROTOCOL
The protocol specifies that the primary endpoint analysis will be performed by first testing for an 
overall treatment effect prior to testing pairwise comparisons using Fisher’s LSD Test.  
Comparisons between MM-II doses and 3 mL placebo will instead be analyzed using a step-down 
Dunnett testing method.
The wording of the subgroup analysis was clarified from the protocol as the subgroups themselves 
are not covariates but rather ways to separately analyze different subsets of the total subject 
population of interest.
The summary of physical examinations was changed to include Abnormal CS and Abnormal NCS 
to better reflect the information provided by the eCRF.
The protocol specified summarizing treatment compliance but was deemed unnecessary since this 
is a single injection study.
The reference to “confirmed” when discussing MACE was removed since MACE events will not 
be adjudicated.
The definition of the FAS in the protocol required subjects to have at least one post-Baseline 
primary efficacy assessment.  The definition of the FAS has been modified to no longer require 
subjects to have at least one post-Baseline primary efficacy assessment.


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The definition of the PPAS was modifed to require a non-missing Week 12 primary efficacy 
assessment instead of any non-missing post-baseline assessment and to exclude subjects with other 
factors that could influence the validity of the data for the primary efficacy variable that are not 
major protocol deviations.