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
Phase: PHASE2
Conditions: Osteoarthritis of Knee
Sponsor: Sun Pharmaceutical Industries Limited

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 
dependency or treatment abuse. 

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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