Clinical trial NCT02534896
Conditions: Active Rheumatoid Arthritis
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2015-11-01; Completion date: 2018-06-01
Enrollment: 150 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designated to evaluate the safety and efficacy of Sunpharma1505 in subjects with active rheumatoid arthritis who are experiencing a flare/exacerbation.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Treatment I intervention 2: Treatment II intervention 3: Treatment III
Intervention descriptions: intervention 1: Sunpharma1505 and Placebo intervention 2: Sunpharma1505 and Placebo intervention 3: Reference1505 and Placebo

Protocol documents:
Prot_SAP_000.pdf: 
CLR_15_05  
  
 
V3.1 25 September 2017 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
A Phase III, Randomized, Double-Blind, Double Dummy, Active Controlled, 
Multi-Center Study To Evaluate The Efficacy And Safety Of Intravenous 
Pegylated Liposomal Prednisolone Sodium Phosphate (Nanocort) Compared 
With Intramuscular Injection Of Methylprednisolone Acetate In Subjects With 
Active Rheumatoid Arthritis 
 
 
 
V3.1 25 September 2017 
 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
 
PROTOCOL TITLE 
 
 
A Phase III, Randomized, Double-Blind, Double Dummy, Active Controlled, 
Multi-Center Study To Evaluate The Efficacy And Safety Of Intravenous 
Pegylated Liposomal Prednisolone Sodium Phosphate (Nanocort) Compared 
With Intramuscular Injection Of Methylprednisolone Acetate In Subjects With 
Active Rheumatoid Arthritis 
 
 
Protocol ID 
CLR_15_05 
Version / Date 
V3.1 25 September 2017 
Amendment / Date 
Amendment 2 / CZE specific amendment 
Short title 
 
Phase III Double-Blind, Comparator study of 
intravenous Nanocort vs intramuscular Depo-Medrol® 
in subjects with active RA 
EudraCT number  
2015-002924-17  
Coordinating Investigator 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
Clinical Research Organisation: 
 
 
 
 
 
 
Sponsor 
 
 
Vishwanath Kenkare 
Manager Business Development 
Sun Pharma Global FZE  
Office No. 43, Block-Y, SAIF Zone 
P.O. Box No. 122304 
Sharjah, United Arab Emirates 
Ph: 00 971 4 454 8627 
Fax: 00 971 4 454 8465 
Email: vishwanath.kenkare@sunpharma.com  


CLR_15_05  
  
 
V3.1 25 September 2017 
 
 
Sponsor’s Clinical representative Shantanu Mehta MD  
Deputy General Manager- Clinical Research 
Sun Pharma Advanced Research Company Ltd,  
17-B, Mahal Industrial Estate, 
Mahakali Caves Road, Andheri (E) 
Mumbai, India - 400 093 
e-mail: shantanu.mehta@sparcmail.com 
T: + 9122 66455645 ext 5635 
Quality Assurance 
 
 
 
 
 
Laboratory sites (central/local 
laboratory, pharmacokinetics 
analytical facility), Data 
management/statistical facility 
Will be documented separately 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor: 
Vishwanath Kenkare 
 
 
Medical Monitor: 
Cornelis Wortel, MD, PhD 
 
 
Sponsor’s Clinical Representative: 
Shantanu Mehta MD 
 
 
Coordinating Investigator: 
Prof. Dr. J.W.J. Bijlsma 
 
 
Biostatistician: 
 Erich Geschwentner 
 
 
Medical Writer: 
Leonie Middelink 
 
 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
5 of 71 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
.................................................. 
8 
SUMMARY ............................................................................................................................... 
11 
1. INTRODUCTION AND RATIONALE 
................................................................................ 
15 
2. OBJECTIVES 
.................................................................................................................... 
17 
3. STUDY DESIGN 
............................................................................................................... 
18 
4. STUDY POPULATION 
...................................................................................................... 
19 
4.1  Population 
 ............................................................................... 
19 
4.2  Inclusion criteria 
 ............................................................................... 
19 
4.3  Exclusion criteria 
 ............................................................................... 
20 
4.4  Sample size calculation 
 ............................................................................... 
23 
5. TREATMENT OF SUBJECTS 
.......................................................................................... 
25 
5.1  Investigational medicinal products ............................................................................ 
25 
5.1.1 Nanocort arm 
...................................................................................................... 
25 
5.1.2 Depo-Medrol arm ............................................................................................... 
25 
5.1.3 Blinding 
............................................................................................................... 
25 
5.2  Use of co-intervention 
 ............................................................................... 
26 
5.2.1 Allowed Medications 
........................................................................................... 
26 
5.2.2 Prohibited Medications 
....................................................................................... 
27 
5.2.3 Escape medication 
............................................................................................. 
27 
5.2.4 Other RA medication 
.......................................................................................... 
27 
6. INVESTIGATIONAL MEDICINAL PRODUCT 
.................................................................. 
28 
6.1  Name and description of investigational medicinal product(s) ................................. 
28 
6.2  Summary of findings from non-clinical studies 
.......................................................... 
29 
6.3  Summary of findings from clinical studies 
................................................................. 
29 
6.4  Summary of known and potential risks and benefits ................................................ 
29 
6.4.1 Evaluation of the Risks 
....................................................................................... 
29 
6.5  Description and justification of route of administration and dosage 
......................... 
30 
6.6  Dosages, dosage modifications and method of administration 
................................ 
30 
6.7  Preparation and labelling of Investigational Medicinal Product 
................................ 
31 
7. COMPARATOR ................................................................................................................ 
32 
7.1  Name and description of comparator product(s) ...................................................... 
32 
7.2  Description and justification of route of administration and dosage 
......................... 
32 
7.3  Dosages, dosage modifications and method of administration 
................................ 
32 
7.4  Preparation and labelling of comparator 
................................................................... 
33 
7.5 Use of saline 
 ............................................................................... 
33 
8. METHODS ........................................................................................................................ 
34 
8.1  Study parameters/endpoints 
 ............................................................................... 
34 
8.1.1 
Main study parameter/endpoint ......................................................................... 
34 
8.1.2  Key Secondary study parameters/endpoints 
..................................................... 
34 
8.2  Randomisation, blinding and treatment allocation 
.................................................... 
35 
8.3  Study procedures 
 ............................................................................... 
36 
8.3.1 Overview of Assessments by Study Day 
........................................................... 
39 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
6 of 71 
8.4  Drug accountability 
 ............................................................................... 
48 
8.5  Withdrawal of individual subjects .............................................................................. 
49 
8.6  Follow-up of subjects withdrawn from treatment ...................................................... 
50 
8.7  Premature termination of the study 
........................................................................... 
50 
9. SAFETY REPORTING 
...................................................................................................... 
51 
9.1  Disadvantageous event 
 ............................................................................... 
51 
9.2 
AEs, SAEs and SUSARs 
 ............................................................................... 
51 
9.2.1  Adverse events (AEs)......................................................................................... 
51 
9.2.2  Serious adverse events (SAEs) 
......................................................................... 
53 
9.2.3  Suspected unexpected serious adverse reactions (SUSARs) 
.......................... 
54 
9.3 
Follow-up of adverse events  ............................................................................... 
56 
9.4 
Data Safety Monitoring Board (DSMB) / Safety Committee 
..................................... 
56 
10.  STATISTICAL ANALYSIS 
............................................................................................. 
57 
10.1 General 
 ............................................................................... 
57 
10.2 Primary study parameter 
 ............................................................................... 
57 
10.3 Key Secondary parameters 
 ............................................................................... 
57 
10.4 Secondary study parameters  ............................................................................... 
58 
10.4.1 EULAR Response 
.................................................................................................. 
58 
10.4.2 DAS28 mean and % change 
................................................................................. 
58 
10.4.3 Time to first EULAR response (moderate or good) 
............................................... 
58 
10.4.4 ACR 20/50/70 response scores............................................................................. 
58 
10.4.5 Tender and swollen joint counts 
............................................................................ 
58 
10.4.6 Visual Analog Score (VAS) 
.................................................................................... 
58 
10.4.7 Quality of Life and RA activity questionnaires 
....................................................... 
59 
10.4.8 Maintenance of Improvement at 12 Weeks 
........................................................... 
59 
10.4.9 Safety assessments 
............................................................................................... 
59 
10.5 PK analysis 
 ............................................................................... 
59 
10.6 Other study parameters 
 ............................................................................... 
60 
10.7 Interim analysis 
 ............................................................................... 
60 
10.8 Analysis Populations 
 ............................................................................... 
60 
10.9  Missing Data 
 ............................................................................... 
61 
11.  ETHICAL CONSIDERATIONS ..................................................................................... 
62 
11.1 Regulation statement 
 ............................................................................... 
62 
11.2 Recruitment and consent 
 ............................................................................... 
62 
11.3 Objection by minors or incapacitated subjects (if applicable) 
................................... 
62 
11.4 Compensation for injury 
 ............................................................................... 
63 
11.5 Incentives 
 ............................................................................... 
63 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
.......................... 
64 
12.1 Handling and storage of data and documents 
.......................................................... 
64 
12.1.1 Data Handling 
..................................................................................................... 
64 
12.1.2 Data Coding 
........................................................................................................ 
64 
12.1.3 Data Confidentiality 
............................................................................................ 
64 
12.1.4 Data Storage ...................................................................................................... 
65 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
7 of 71 
12.2 Monitoring and Quality Assurance ............................................................................ 
65 
12.3 Amendments 
 ............................................................................... 
66 
12.4 Annual progress report 
 ............................................................................... 
67 
12.5 End of study report 
 ............................................................................... 
67 
12.6 Public disclosure and publication policy 
.................................................................... 
68 
13. REFERENCES 
.............................................................................................................. 
69 
14 
APPENDICES ............................................................................................................... 
70 
14.1 SF-36 
 ............................................................................... 
70 
14.2 HAQ 
 ............................................................................... 
70 
14.3 FACIT 
 ............................................................................... 
70 
14.4 Health Economics Questionnaire 
.............................................................................. 
70 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
8 of 71 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
ACR 
American College of Rheumatology 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANCOVA Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CK 
Creatine kinase 
Ca++ 
Calcium 
CIOMS 
Council for International Organizations of Medical Sciences 
CRF 
Case report form 
CRP 
C-reactive protein 
DAS28 
Disease Activity Score in 28 Joints 
DMARDs Disease-modifying antirheumatic drugs 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
e.g. 
exempli gratia (for example) 
EMA 
European Medicines Agency 
EOS 
End of study 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
EudraCT 
European drug regulatory affairs Clinical Trials  
FACIT 
The Functional Assessment of Chronic Illness Therapy 
GC 
Glucocorticoid 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamy
l Transpeptidase  
HAQ 
Health Assessment Questionnaire 
HbA1c 
Hemoglobin A1c 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
IBD 
Inflammatory Bowel Disease 
ICF 
Informed Consent Form 
ICH 
International conference on harmonization 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
9 of 71 
i.e. 
id est (that is) 
IEC 
Independent Ethics Committee 
IM 
Intramuscular 
IMP 
Investigational Medicinal Product  
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
IV 
Intravenous 
IWRS 
Interactive Web-based Randomization System 
K+ 
Potassium 
Kg 
Kilogram(s) 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MCTD 
Mixed Connective Tissue Disease 
Mg 
Milligram(s) 
Min 
Minute(s) 
mL 
Milliliter(s) 
MM 
Medical Monitor 
MTX 
Methotrexate 
MS 
Multiple sclerosis 
Na+ 
Sodium 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PE 
Physical examination 
PEG 
Polyethylene glycol 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PLP 
Prednisolone sodium phosphate 
PP 
Per protocol  
PRO 
Patient Reported Outcome 
PV 
Pharmacovigilance 
QA 
Quality Assurance  
QoL 
Quality of Life 
RA 
Rheumatoid Arthritis 
RBC 
Red blood cells 
RF 
Rheumatoid Factor 
SAE 
Serious Adverse Event  
SAF 
Safety 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SF-36 
Short Form 36 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SLE 
Systemic lupus erythematosus 
SPC 
Summary of Product Characteristics 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
10 of 71 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VAS 
Visual Analogue Scale 
WBC 
White blood cells 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
11 of 71 
SUMMARY 
 
Rationale: 
Inflammatory disorders, such as rheumatoid arthritis (RA), are chronic, progressive, and 
debilitating diseases that often lead to disability. Adequate treatment is difficult and costly, 
and hospitalization often occurs [1]. Prednisolone and some other glucocorticoids (GCs) can 
be highly effective in treating joint inflammation, but their systemic application is limited 
because of a high incidence of serious adverse effects, especially related to long-term 
treatment [2, 3]. Besides a poor safety profile, also poor localization in inflamed areas in the 
body limits the usefulness of glucocorticoids in the patient [4]. Prednisolone sodium 
phosphate (PLP) encapsulated in long-circulating liposomes (Nanocort®) is being developed 
with the prospect of providing enhanced localized exposure over ex
isting systemic 
formulations of glucocorticoids in certain “flare-ups” of inflammatory diseases that currently 
benefit from prednisolone administrations. As a result, Nanocort might be able to significantly 
reduce frequency of administration and use of the glucocorticoids compared to the treatment 
with intramuscular (IM) corticosteroids and so has a safety advantage.  
This study is designed to evaluate the safety and efficacy of intravenous (IV) polyethylene-
glycosylated (PEG)-liposomal prednisolone sodium phosphate (Nanocort) in RA subjects 
with flare/exacerbation. 
Objective: 
Primary objective: To assess efficacy and safety (treatment of signs and symptoms) of 
Nanocort in subjects with active rheumatoid arthritis who are experiencing a 
flare/exacerbation in comparison to a standard of care medication (Depo-Medrol).  
Secondary objectives: Patient Reported Outcomes and an assessment of pharmacokinetic 
parameters in a subset population from each treatment group.   
Study design:  
The study is a randomized, double- blind, double dummy, active controlled, parallel, multi-
center study in which IV Pegy
lated Liposomal Prednisolone Sodium Phosphate (Nanocort) 
will be compared with IM injection of methylprednisolone acetate (Depo-Medrol®) to evaluate 
efficacy and safety.  Each patient will receive an infusion and an IM injection containing either 
an active treatment or a dummy treatment. Opaque IV lines, sleeved bags and opaque 
syringes will be used to maintain blinding of either liposomal product or reference product. 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
12 of 71 
All subjects will be provided an informed consent form (ICF) containing information about the 
study. After fully understanding of the ICF, subjects will voluntarily sign the ICF. Subjects will 
enter a screening period for up to 14 Days to assess laboratory values and other 
inclusion/exclusion criteria. Medical history and serious medical conditions as determined by 
the Principal Investigator (PI) will be reviewed during screening. In addition, the screening 
period will include a physical examination, blood and urine collection for laboratory 
assessments, vital signs, electrocardiogram (ECG) and confirmation of RA diagnosis (flare 
criteria).  
Subjects with active RA who meet all eligibility criteria will undergo Baseline visit (Day 1) 
assessments. At this visit, prior to receiving treatments, subjects will be assessed for 
baseline parameters and then will be randomized into one of three groups: 
 Nanocort 75 mg IV infusion and IM saline injection on Day 1 and Day 15  
 Nanocort 150 mg IV infusion and IM saline injection on Day 1 and Day 15  
 Depo-Medrol® 120 mg IM injection and IV saline infusion on Day 1 and Day 15  
Dosing will occur on Baseline (Day 1) and Week 2 (Day 15). Study visits will occur at Week 
1, Week 2, Week 3, Week 4, Week 6, Week 8 and Week 12 / End of Study (EOS) to assess 
efficacy and safety evaluations as indicated in the Schedule of Assessments. Subjects 
receiving any treatment dose will be followed till Week 12 for safety if possible. 
Study population:  
Male and female subjects (≥ 18 years) with diagnosed active RA who are experiencing a 
flare / exacerbation defined as recently switched from a period with -well documented- 
remission or low disease activity to an active disease (DAS28 ≥ 3.2). This documentation is 
either based on available detailed DAS28 values (increase in DAS28 > 1.2 or > 0.6 if DAS28 
≥ 3.2 compared to last DAS28 measurement (max
imum 06 months before screening), or on 
a clear description of the previous low disease state by the treating physician (max
imum 06 
months before screening). The increase in disease activity has to be RA related. 
Intervention:  
A total of up to 330 subjects will be enrolled and randomized into 3 groups indicated below: 
 Nanocort 75 mg IV infusion and IM saline injection (110 subjects) 
 Nanocort 150 mg IV infusion and IM saline injection (110 subjects) 
 Depo-Medrol® 120 mg IM injection and IV saline infusion (110 subjects) 
Subjects in this trial will be randomized to receive an IM injection of 120 mg 
methy
lprednisolone acetate (Depo-Medrol®) or 75 mg/infusion of Nanocort administered as 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
13 of 71 
an IV infusion or 150 mg/infusion of Nanocort administered as an IV infusion, on Day 1 and 
15.  
 
Study endpoints/parameters:  
Primary Endpoint: European League Against Rheumatism (EULAR) responder (moderate 
and good combined) rate at Week 1 (Day 8) 
Key Secondary Endpoints: 
 EULAR responder (only good) rate at Week 1 (Day 8) 
 EULAR responder (moderate and good combined) rate at Week 2 (Day 15) 
 EULAR responder (only good) rate at Week 2 (Day 15) 
Secondary Endpoints/Parameters: 
 EULAR response at Week 1, 2, 3, 4, 6, 8 and 12.  
 DAS28 mean and % change  at Week 1, 2, 3, 4, 6, 8 and 12 
 Time to first EULAR response (moderate/good)  
 American College of Rheumatology (ACR) 20/50/70 response scores at Week 1, 2, 3, 
4, 6, 8 and 12 
 Tender joint counts at Week 1, 2, 3, 4, 6, 8 and 12 
 Swollen joint counts at Week 1, 2, 3, 4, 6, 8 and 12 
 Patient Pain and Global Visual Analog Score (VAS) score at Week 1, 2, 3, 4, 6, 8 and 
12 
 Investigator Global Visual Analog Score (VAS) score  at Week 1, 2, 3, 4, 6, 8 and 12 
 Short Form 36 (SF-36) to assess physical and mental component at Week 1, 2, 4, 6, 
and 12. 
 Health Assessment Questionnaire (HAQ) at Week 1, 2, 3, 4, 6, 8 and 12. 
 The Functional Assessment of Chronic Illness Therapy (FACIT) at Baseline, Week 4 
and 6  
 Health Economics Questionnaire at Week 12 
 Maintenance of Improvement at 12 Weeks assessed during a blinded review by the 
Medical Monitor (MM) and Principal Investigator (PI) at the end of the study 
 Pharmacokinetics (PK) assessment in subset of patient population at Baseline, Week 
1, 2, 3, 4 and 6 
 AEs ( including glucocorticoid related AEs),  AEs leading to withdrawal, AEs leading 
to discontinuation of medication, and AEs due to infusion reactions) 
 Vital signs 
 Physical examinations 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
14 of 71 
 Laboratory 
 ECG 
 Assessment by monitoring cortisol levels at Screening, Baseline, 6 and 12 weeks  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness:  
The study consists of 9 visits to the clinic in 14 Weeks; at each of these visits blood samples 
are taken; at each visit a physical examination (PE) will take place; at each visit the subjects 
have to fill out questionnaires. For details please see Table 2, Schedule of Assessments. 
Nanocort, as a single infusion of 300 mg or two infusions of 150 mg each with a 6-10 or 14 
Day interval between infusions, appears to be well tolerated by subjects. Overall, few 
adverse events (AEs) typically associated with the administration of glucocorticoids have 
been observed [5]. 
Too rapid an infusion of PEG-liposomal products could cause a pseudo-allergic infusion 
reaction. These acute infusion-related reactions, are typically characterized by flushing, 
shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest and 
throat, and/or hypotension, and are related to complement activation. The likelihood of the 
occurrence of such infusion reactions has been described for liposomes (empty placebo as 
well as drug-loaded) and is not unlike that for other colloidal formulations and biologics, with 
an incidence of about 5-10% of patients [5]. The slower infusion speed used in the later 
Nanocort trials has resulted in a lower infusion reaction incidence.  This study will involve an 
even slower rate of infusion over a 2.5 hour period. 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
15 of 71 
1. INTRODUCTION AND RATIONALE 
 
Rheumatoid arthritis is a chronic, serious progressive and debilitating inflammatory disease 
characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to 
severe disability and premature mortality. RA is considered as an auto immune disease [6].  
The current modern standard of care is based on the knowledge of the severity of the natural 
history of RA. Patients are treated early using aggressive treatment strategies, with 
methotrexate (MTX) as anchor drug, biological targeted therapies in those with inadequate 
response, and tight control aiming for remission and low disease activity [7], according to the 
2012 American College of Rheumatology (ACR) Update [8] the European League Against 
Rheumatism (EULAR) recommendations [9] and European Medicines Agency (EMA) 
Guideline on clinical investigation of medicinal products other than Non-Steroidal Anti- 
Inflammatory Drugs (NSAIDs)  for the treatment of rheumatoid arthritis (draft 2015 [10]). 
Glucocorticoids (GCs) have been – and still are – a cornerstone in the treatment of rheumatic 
diseases for many decades [11, 12]. In RA, the general view is that GCs are to be used at 
the lowest doses possible in order to minimize their systemic exposure and their related side 
effects. In order to reach higher local concentrations of GCs, while minimizing potential 
systemic adverse effects, intra-articular (IA) injections of high dose GCs are frequently used 
in the management of RA.  
However, it is impractical to inject multiple joints in a patient with an exacerbation of RA. 
Thus there is a clear and well established need for GCs to be administered in a way that 
multiple joints receive high local concentrations of the drug after a single systemic treatment 
while the healthy organ exposure to active drug upon such treatment remains in line with that 
of an established low systemic GC maintenance dosing schedule that is generally considered 
to be safe in RA. Nanocort is such a novel GC therapy.  
Nanocort is being developed to enable selective local delivery of GC to sites of inflammation 
targeting all inflamed joints upon one or two IV administrations of liposomal entrapped 
prednisolone (as inactive sodium phosphate). Enclosing prednisolone in small, carefully 
designed lipid vesicles is designed to allow selective accumulation in inflamed tissues 
following IV administration. This effect is thought to occur by virtue of the locally increased 
permeability of blood vessel walls, while limiting systemic exposure down to acceptable 
levels. 
To date, data are available for 65 subjects who have received Nanocort in single doses of up 
to 300 mg. Of most relevance for the proposed indication, an investigator-initiated, two-part 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
16 of 71 
clinical trial (ENLA001) has been completed in 22 subjects with active RA, 14 received 
Nanocort. The first part of the study was an open-label, two dose level escalation (37.5 and 
75 mg) in 3 subjects with each dose. The second part was a 12-Week, double-blind, parallel 
group comparison in 16 subjects of a single 150-mg IV dose of Nanocort and a single 120-
mg IM dose of methy
lprednisolone (Depo-Medrol). Nanocort was found to be safe and well-
tolerated and in the second part of the study, showed statistically significant reduction in the 
DAS28 when compared to Depo-Medrol. Data are also available from a clinical study 
(GLPG0303-CL-204) in 15 subjects with active multiple sclerosis (MS) in which doses of 300 
mg single dose were administered to 8 subjects in total. 
Other studies with Nanocort have been initiated in patients with atherosclerosis, peripheral 
artery disease, and ulcerative colitis. In addition, radio-labeled PEG liposomes, such as those 
in the Nanocort formulation, have also been successfully used for imaging in patients with 
RA, Inflammatory Bowel Disease (IBD) and other focal infection/inflammation in the body 
[13]. 
The safety and efficacy profile attributed to Nanocort warrant further clinical investigation of 
Nanocort for the treatment of RA, MS, and IBD. The population of patients to be enrolled in 
this trial with an exacerbation / flare of RA has been selected, as this is the population which 
is currently being treated with GC and is exceptionally well suited for a targeted, short term 
treatment approach with Nanocort. 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
17 of 71 
2. OBJECTIVES 
 
Primary Objective: 
To assess efficacy and safety (treatment of signs and symptoms) of Nanocort in subjects 
with active rheumatoid arthritis who are experiencing a flare/exacerbation in comparison to a 
standard of care medication (Depo-Medrol).  
Secondary Objective(s):   
 To evaluate patient-reported outcomes in subjects with Active Rheumatoid Arthritis 
who are experiencing a flare/exacerbation receiving IV Nanocort as compared with 
subjects receiving IM injections of methylprednisolone acetate. 
 To assess PK parameters, in a subset population from each treatment group.   
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
18 of 71 
3. STUDY DESIGN 
 
This is a randomized, double-blind, double dummy, active controlled, parallel, multi-center 
study in which IV Pegylated Liposomal Prednisolone Sodium Phosphate (Nanocort) will be 
compared with IM injection of methy
lprednisolone acetate (Depo-Medrol) to evaluate efficacy 
and safety.  Each patient will receive treatment on Day 1 and Day 15 both an infusion and an 
IM injection containing either an active treatment or a dummy treatment. The total duration of 
the trial is 14 weeks maximum for each subject (up to 2 weeks of screening period and 12 
weeks of treatment with follow up). 
During this 14 weeks study, the dosage of any 
 
should not be changed (in case the subject is receiving such treatment at 
screening). 
The use of Depo-Medrol 120 mg IM for the control group and the short duration of treatment 
are selected in order to use standard of care treatment for exacerbations / flares in subjects 
with RA. Furthermore, the total GC exposure is the same in the 120 mg Depo-Medrol and 
150 mg Nanocort arms. Additional Nanocort 75 mg arm is included. 
 
 
 
 
 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
19 of 71 
4. STUDY POPULATION 
 
4.1 Population  
The study will be conducted at approximately 25 sites in the Netherlands,  Belgium and the 
Czech Republic. Sites will be selected based on previous study experience in RA and 
accessibility to study required populations. It is expected that each research centre will be 
able to identify sufficient subjects that meet all the inclusion and exclusion criteria.  
The study population will consist of male and female subjects (≥ 18 years old) with active RA 
who are experiencing a flare / exacerbation defined  as recently switched from a period with -
well documented- remission or low disease activity to an active disease (DAS28 ≥ 3.2). This 
documentation is either based on available detailed DAS28 values (increase in DAS28 > 1.2 
or > 0.6 if DAS28 ≥ 3.2 compared to last DAS28 measurement (max
imum 06 months before), 
or on a clear description of the previous low disease state by the treating physician 
(max
imum 06 months before). The increase in disease activity has to be RA related. 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
1) Male or female ≥ 18 years old. 
2) Known Diagnosed RA according to the revised 2010 ACR/EULAR Rheumatoid 
Arthritis Classification Criteria. Secondary Sjögren’s syndrome with RA is permitted. 
3) Male and female subjects recently switched from a period with -well documented- 
remission or low disease activity to an active disease (DAS28 ≥ 3.2). This 
documentation is either based on available detailed DAS28 values (increase in 
DAS28 > 1.2 or > 0.6 if DAS28 ≥ 3.2 compared to last DAS28 measurement 
(max
imum 06 months before), or on a clear description of the previous low disease 
state by the treating physician (maximum 06 months before). The increase in 
disease activity has to be RA related.  
4) Willing and able to comply with the study protocol visits, assessments and 
accessible for follow up. 
5) Subjects naïve to treatment and/or currently not treated for at least 8 Weeks prior to 
the Screening Visit and willing to continue without non-study treatment for 12 
Weeks, or subjects on stable treatment with DMARD (including biologicals) for at 
least 8 Weeks prior to the Screening Visit and willing to continue current stable 
treatment for 12 Weeks.  


CLR_15_05  
  
 
V3.1 25 September 2017 
 
20 of 71 
6) Subjects able and willing to give written informed consent (or legally acceptable 
representative or impartial witness when applicable) and is available for entire 
study.  
7) Subjects of child bearing potential should be non-lactating and must be practicing 
an acceptable method of birth control as judged by the Investigator. Medically 
acceptable methods of birth control include bilateral tubal ligation or the use of 
either a contraceptive implant, a contraceptive injection (e.g., Depo-Provera™), 
sexual abstinence (sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study drug. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the subject), an intrauterine device, vasectomized partner, an oral 
contraceptive taken continually within the past three months and which the subject 
agrees to continue using during the study  
 To adopt another birth control method, or a double-barrier method which 
consists of a combination of any two of the following: diaphragm, cervical cap, 
condom, or spermicide at least 2 months prior to study entry and must continue 
to use contraception for the duration of the study 
 Subjects who are postmenopausal for at least 1 year or surgically sterile 
(bilateral tubal ligation, bilateral oophorectomy, or hysterectomy has been 
performed on the subject) may participate in study.  
 All female subjects of child-bearing potential must have a negative urine 
pregnancy test    
8) Male subjects enrolled in the study are advised to prevent passage of semen to 
their sexual partner during intercourse using acceptable methods as judged by the 
investigator, like condoms, , abstinence or  vasectomy.  
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
1) Rheumatic autoimmune disease other than RA, e.g., systemic lupus erythematosus 
(SLE), mixed connective tissue disease (MCTD), scleroderma, polymyositis.  
2) Current inflammatory joint disease other than RA (e.g., gout, reactive arthritis, 
psoriatic arthritis, spondyloarthritis, Lyme disease, osteoarthritis). 
3) Subjects who are pregnant or intend to become pregnant during the study. 
4) Have a family history (more than one first degree relative) of multiple thrombotic 
events (more than one per person) or a personal history of any venous or arterial 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
21 of 71 
thrombotic event including deep vein thrombosis, stroke, myocardial infarction, 
pulmonary embolus, and peripheral arterial thromboembolic events or abnormal ECG 
which may impact the subject’s safety as per Investigator’s opinion. 
5) Subject with positive hepatitis panel (including hepatitis B surface antigen [HBsAg], 
and / or anti-hepatitis B core antibodies, and / or hepatitis C virus antibody [anti-
HCV]), and / or a positive Human immunodeficiency virus (HIV) antibody screen, 
based on the current medical data of the patient. Subjects with active or latent 
tuberculosis are also excluded. 
6) Abnormal  hepatic  function 
[alanine  aminotransferase (ALT)/aspartate 
aminotransferase (AST) or bilirubin > 2 x upper limit of normal] at the time of the 
Screening Visit. 
7) Abnormal renal function [Blood Urea Nitrogen (BUN) or creatinine >1.25 x upper limit 
of normal] at the time of the Screening Visit. 
8) Clinically significant out-of-range values on hematology panel, at discretion of the PI.  
9) Treatment with oral, rectal or injectable (including intra-articular) glucocorticoids 
(GCs) within 8 Weeks prior to Screening Visit. Inhaled glucocorticoids are allowed. 
Topical steroids are allowed, however subjects should not have received more than 
100 gram of a mild to moderate topical corticosteroid cream per Week, 50 gram of a 
potent corticosteroid cream per Week or 30 gram of a very potent topical 
corticosteroid cream per Week in the 4 
Weeks prior to the Screening Visit. 
10) 
 Subjects who have received an investigational drug within 30 Days prior to the 
Screening visit. 
11) 
 Previous treatment with IV gamma globulin, plasmapheresis or Prosorba® column 
within 3 months prior to Screening. 
12) 
 Known sensitivity to any component of the study drug or previous hypersensitivity 
reaction or other clinically significant reaction to IV medications, biologic therapy or IV 
radiocontrast agents. 
13) 
Contraindication for glucocorticoids as judged by Investigator. 
14) 
 Subjects who have previously received Nanocort. 
15) 
 Neuropathies or other painful conditions that might interfere with pain evaluation, as 
judged by the Investigator.   
16) 
 Active infection requiring systemic treatment. 
17) 
 Planned surgery during the study period or had undergone major surgery within the 
60 Days prior to the Screening visit. 
18) 
 Requirement for immunizations or vaccinations during the treatment  period.  
19) 
 Subjects with poor peripheral venous access as per Investigator or site personnel 
opinion. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
22 of 71 
20) History of substance abuse or alcohol abuse. 
Additional exclusion criteria for subjects participating in PK subset study:  
Blood donation by subjects within 6 months before screening. 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
23 of 71 
4.4 Sample size calculation 
A total of 330 subjects will be enrolled and randomized into 3 groups of 110 subjects.  
 
The EULAR response will be considered as primary parameter.  
There is a special interest in the percentage of subjects with an EULAR response category of 
good or moderate (good and moderate combined) and the percentage of subjects with an 
EULAR response category of only good. These subjects will be called EULAR responders 
and EULAR good-responders, respectively. 
 
Primary endpoint: 
 
the percentage of EULAR responders (good and moderate combined) at Day 8 
 
Key secondary endpoints: 
 
The percentage of EULAR good-responders at Day 8 
 
The percentage of EULAR responders at Day 15 
 
The percentage of EULAR good-responders at Day 15 
 
 
The sample size calculation for this study is based on group comparisons of  EULAR 
responder rates (Nanocort 150 mg compared to Depo-Medrol® and Nanocort 75 mg 
compared to Depo-Medrol®) at Day 8. The study is called positive if one of the primary null 
hypotheses will be rejected.
The following primary null hypotheses will be considered: 
H0,1 : EULAR responder rate at Day 8 for Nanocort 150 mg = EULAR responder rate at Day 8 for Depo-Medrol® 
H0,2 : EULAR responder rate at Day 8 for Nanocort 75 mg = EULAR responder rate at Day 8 for Depo-Medrol® 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
24 of 71 
Taking a drop-out rate of approx
imately 10% into consideration, a sample size of 110 
subjects per treatment arm will be sufficiently large to show superiority of Nanocort compared 
to Depo-Medrol® in EULAR responders at Day 8 and to assess the safety of Nanocort in this 
study.  
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
25 of 71 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational medicinal products 
Eligible subjects will be randomized to one of three treatment groups: 
 Nanocort 75 mg IV infusion and IM saline injection, or 
 Nanocort  150 mg IV infusion and IM saline injection, or 
 Depo-Medrol 120 mg IM injection and IV saline infusion. 
Subjects in this trial will be randomized to receive either Nanocort (75 mg/infusion or 150 
mg/infusion) administered as an IV infusion, or 120 mg methy
lprednisolone acetate (Depo-
Medrol®) administered as an IM injection. Subjects will receive treatment on Day 1 and Day 
15 with additional study visits on Weeks 1, 2, 3, 4, 6, 8 and 12. Compliance will be recorded 
after dosing of Investigational Medicinal Product (IMP) at Day 1 and Day 15 (week 2). 
IV infusion (either Nanocort/Placebo) will be administered over approx
imate 2.5 hours, with 
an increasing infusion rate over the whole infusion period. If required, infusion rate can be 
modified in case of infusion related reactions as per PI opinion. A detailed instruction will be 
documented the in the Investigational Medicinal Product (IMP) manual. 
5.1.1 Nanocort arm 
Prior to Nanocort administration, the contents of the requisite number of vials will be diluted 
up to 500 mL with normal saline (NaCl 0.9% w/v) and will be administered as IV infusion  
In addition, these patients will receive IM normal saline (as placebo) in 3 ml in the same visit.  
5.1.2 Depo-Medrol arm 
On Day 1 and Day 15 subjects will receive IM injection of Depo-Medrol (3 ml) and 500 ml 
normal saline (as placebo) as IV infusion in the same visit. 
The details of the preparation and administration of the IMP will be documented in the IMP 
manual.  
5.1.3 Blinding 
The study will be performed in a double blind, double dummy fashion. Each patient will 
receive an infusion and an IM injection containing either an active treatment or a dummy 
treatment. Opaque IV lines, sleeved bags and opaque syringes will be used to maintain 
blinding. The IMP preparation will be done by an independent unblinded person (pharmacist 
or designated person) in order to keep the Investigator and other site personnel blinded. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
26 of 71 
Proper care has to be taken so that the patient’s treatment will not be disclosed to the 
patient, Investigator or other site personnel. 
5.2  Use of co-intervention 
Any medication the subject takes other than the study drug is considered a concomitant 
medication (co-medication). All co-medications must be recorded in the Electronic Case 
Report Form (eCRF). The following information must be recorded in the eCRF for each co-
medication: generic name, route of administration, start date, stop date, dosage, and 
indication. Any changes in the dosage or regimen of a concomitant medication must be 
recorded in the eCRF. The subject should not take any concomitant treatment without the 
Investigator’s knowledge. Investigator will instruct patients about co-medications and diet if 
required. 
At Screening, subjects will be asked to provide details of all medications they have taken 
during the last 8 weeks. At each subsequent study visit (as listed in the Schedule of 
Assessments), subjects will be asked what co-medications they are currently taking. 
During the study co-medications may be administered at the discretion of the Investigator in 
order to provide the subject with the best possible medical care. However, it is recommended 
that changes in ongoing treatments or introduction of new therapies are kept to a minimum. 
The risk/benefit to the subject should be carefully assessed and consideration given to the 
timing of any necessary introductions during the study period. 
5.2.1 Allowed Medications 
Co-medications that are allowed during this study include:  
 Concomitant therapies taken for the long term treatment of pre-existing conditions (as 
per Investigator’s opinion) may be continued during the study. However, these should 
be stabilized prior to entry and continued wherever practical without variation of dose 
or regimen during the study. 
 Prescription medications for contraception and/or those medications deemed 
acceptable by the Investigator and Sponsor, or designee.  
 Topical glucocorticoid GC creams are allowed, however subjects should not receive 
more than 100 gram of a mild to moderate topical corticosteroid cream per Week, 50 
gram of a potent corticosteroid cream per week or 30 gram of a very potent topical 
corticosteroid cream per week in the 4 weeks prior to the Screening Visit and 
throughout the duration of the study. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
27 of 71 
 Inhaled glucocorticoids are allowed. 
 Stable treatment with DMARD for at least 8 weeks prior to the Screening Visit and 
willing to continue current treatment for 12 weeks/throughout the study (this includes 
biologicals). 
 Ritux
imab is only allowed when on a fixed dosing scheme of every 6 months. 
5.2.2 Prohibited Medications 
The following medication use is restricted and/or will exclude the subject from enrolment in 
this trial: 
 Exposure to an experimental treatment or use of investigational product within the 
past 30 days prior to Screening, or is still within a washout period of a previous 
clinical trial. 
 Last treatment with oral, rectal or injectable (including intra-articular) glucocorticoids 
(GCs) must be discontinued for at least 8 weeks prior to Screening Visit and may not 
be taken throughout the duration of the study. 
 Previous treatment with IV gamma globulin, plasmapheresis or Prosorba® column 
within 3 months prior to screening and during the study. 
 Systemic antibiotics and/ or anti-viral medications for treatment of an active infection 
required at the time of screening.  
 Immunizations or vaccinations during the study period.  
 Medications that may cause drug-drug interactions with methylprednisolone in opinion 
of investigator 
5.2.3 Escape medication  
Investigator can use medicines in safeguard of patient if required. 
5.2.4 Other RA medication 
All subjects will be followed for 12 weeks. Subjects who do not reach at least a moderate 
EULAR response at week 2 or at any visit thereafter, may receive other RA medication. In 
this case, several QoL measurements may be skipped, see footnote in Table 2, Schedule of 
Assessments. The infusion at week 2 will take place and the patients remain in the study for 
the remaining visits for safety follow up.  
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
28 of 71 
6. INVESTIGATIONAL MEDICINAL PRODUCT  
 
6.1 Name and description of investigational medicinal product(s) 
Nanocort is provided as a sterile, white to off-white, translucent liposomal dispersion for IV 
infusion, in 20 mL glass, single use vials. Each vial contains nominally 5.0 mg/mL +/- 5% 
Prednisolone sodium phosphate, encapsulated inside the liposomes, dispersed in 10% w/v 
sucrose solution, buffered with phosphate buffer at a pH of 7.4 and a tonicity range of 280 to 
400 mOsm/kg. The product needs to be stored refrigerated between 2 and 8 °C. Freezing 
needs to be avoided. 
Name of Finished Product: 
Pegy
lated Liposomal Prednisolone Sodium Phosphate (Nanocort) 
Figure 1.  Drug Product Diagram 
 
 
 
Description of Investigational Medicinal Product: 
Nanocort is a novel formulation containing prednisolone sodium phosphate [PhEur] as the 
drug substance encapsulated in PEGylated liposomes of approximately 100 nm (range 80 to 
120 nm) that comprise a lipid bilayer of dipalmitoyl phosphatidyl choline (DPPC), cholesterol, 
and mPEG2000-distearoyl phosphatidyl ethanolamine (mPEG2000-DSPE) in a mass ratio of 
approximately 3.5:1:1. Coating of the liposome lipid bilayer with PEG improves the properties 
and performance of the formulation, including physical stability and prolonged circulation time 
in vivo. The lipid bilayer encloses an aqueous compartment in which the water-soluble 
sodium phosphate derivative of prednisolone is entrapped. The proposed formulation also 
includes the compendial excipients sucrose, sodium dihydrogen phosphate dihydrate, 
disodium hydrogen phosphate, absolute ethanol (removed during diafiltration process), and 
Water for Injection.  
 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
29 of 71 
6.2 Summary of findings from non-clinical studies 
Nonclinical pharmacology studies with Nanocort have been performed in rodent arthritis 
models including rat adjuvant-induced arthritis (AIA) and mouse collagen-induced arthritis 
(CIA) [15,
Histology of the inflamed joints showed a 
beneficial effect both at the level of inflammation (complete resolution of joint cavity exudate 
and inflammatory cellular infiltrate) and a significant delay of the process of cartilage erosion.  
Please refer to Investigator’s Brochure (IB) for more detailed information on the non-clinical 
studies. 
6.3 Summary of findings from clinical studies 
Based on the five studies so far in different indications, clinical safety data on Nanocort are 
currently available for 65 patients (14 with RA and 8 with MS, 20 with Atherosclerotic 
Disease, 7 with Peripheral Artery Disease and 16 with Acute Ulcerative Colitis). In these 
studies Nanocort was found to be safe and well-tolerated. Approximately 9.7% of patients in 
studies with Nanocort to date have experienced an infusion reaction (verbatim term) and/or 
infusion related reaction (verbatim term) and 2.7% of patients experienced an acute infusion 
reaction (verbatim term). 
6.4 Summary of known and potential risks and benefits 
The risk-benefit assessment of the administration of Nanocort to humans is informed by 
preclinical and clinical evaluations [19]. Taken together these data provide a risk-benefit 
profile favourable to study Nanocort compared to the standard of care, Depo-Medrol, for use 
in RA. 
 
6.4.1 Evaluation of the Risks 
Too rapid an infusion of Nanocort could cause a pseudo-allergic infusion reaction. The 
slower speed used in the ongoing trials has resulted in a low infusion reaction incidence.  
The likelihood of the occurrence of infusion reactions has been described for liposomes 
(empty placebo as well as drug-loaded) and is not unlike that for other colloidal formulations 
and biologics, with an incidence of about 5-10% of patients. 
Due to the small overall sample size, which includes uncontrolled study data, it is difficult to 
assess the relationship of the observed AEs to Nanocort at this time of development. The 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
30 of 71 
following AEs were observed in > 5% of subjects: ALT increased, AST increased, blood 
lactate dehydrogenase increased, chills, cough, diarrhea, dizziness, fatigue, glycosuria, 
haematoma, headache, hot flush, hyperhidrosis, infusion related reaction, nasopharyngitis, 
nausea, paraesthesia, pharyngolaryngeal pain, pyrexia, rash, skin ulcer, and sleep disorder. 
However, many of these AEs may not have a pathophysiological relationship with Nanocort. 
At this time, with the limited exposure to Nanocort, there have not been any significant 
changes in the assessment of benefit or risk to subjects in the clinical trials that have not 
been previously described. There are no emerging potential safety issues that require a 
change in the current development program or require additional assessments in the on-
going studies or in any subsequent studies.   
6.5 Description and justification of route of administration and dosage 
Nanocort® (Pegy
lated Liposomal Prednisolone Sodium Phosphate) is provided as a sterile, 
white to off-white, translucent liposomal dispersion for IV infusion, in 20 mL glass, single use 
vials.  
Route of administration: The IV route is selected for this study based on previous study 
experience.  
Dose: The 75 mg and 150 mg doses are selected based on prior experience with Nanocort.  
6.6 Dosages, dosage modifications and method of administration 
Dosages and method of administration 
Subjects in this trial will be randomized to receive either an IM injection of 120 mg 
methy
lprednisolone acetate (Depo-Medrol), or 75 mg/infusion of Nanocort administered as 
an IV infusion or 150 mg/infusion of Nanocort administered as an IV infusion, on Day 1 and 
15.  
Nanocort will be infused over approximately 2.5 hours. The details of Nanocort preparation 
and administration is given in IMP manual. 
If an infusion reaction occurs, the infusion rate can be lowered or the infusion can be 
temporarily halted. The infusion reactions can be treated with standard of care and infusion 
can be resumed as per Investigator’s opinion. If an infusion reaction occurred during the first 
infusion, the subject will receive standard pre-treatment before the start of the second 
infusion. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
31 of 71 
6.7 Preparation and labelling of Investigational Medicinal Product 
Prior to Nanocort administration, the contents of the requisite number of vials will be diluted 
with normal saline (NaCl 0.9% w/v).  
 
 
Example Label: 
 
20 mL vial label: 
Protocol No: CLR_15_05 
Contents: Nanocort – 5 mg/mL 
Solution for Intravenous use 20 mL per vial 
Batch/Lot #: XXXXXXX 
 
FOR CLINICAL TRIAL USE ONLY 
Store at 2-8°C Vial Number: XXXX 
Expiration date/Retest Date: DD/MMM/YYYY 
Sponsor: Sun Pharma Global FZE  
ADDRESS:  Sharjah, United Arab Emirates 
 
 
 
 
 
 
 
 
 
 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
32 of 71 
7. COMPARATOR  
 
7.1 Name and description of comparator product(s) 
DEPO-MEDROL is an anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft 
tissue or intralesional injection.  
DEPO-MEDROL Sterile Aqueous Suspension contains methylprednisolone acetate which is 
the 6-methyl derivative of prednisolone. Methylprednisolone acetate is a white or practically 
white, odorless, crystalline powder which melts at about 215° with some decomposition. It is 
soluble in dioxane, sparingly soluble in acetone, in alcohol, in chloroform, and in methanol, 
and slightly soluble in ether. It is practically insoluble in water [18]. 
The chemical name for methy
lprednisolone acetate is pregna-1,4-diene-3,20-dione, 21 
(acety
loxy)-11,17-dihydroxy-6-methyl-,(6α,11β) and the molecular weight is 416.51. The 
structural formula is represented below: 
 
 
 
See Package Insert for Depo-Medrol. 
7.2 Description and justification of route of administration and dosage 
DEPO-MEDROL will be administered by IM injection at the dose of 120 mg. This dosage was 
selected as this is the standard of care treatment for exacerbations / flares. Furthermore, the 
120 mg IM of Depo-Medrol is equipotent to 150 mg IV of Nanocort [19].  
7.3 Dosages, dosage modifications and method of administration 
Placebo: All subjects will also receive saline (placebo): either IM sterile saline or IV sterile 
saline on Day 1 and Day 15.  Therefore, subjects that are randomized to receive one of the 2 
doses of Nanocort will also receive an IM injection of placebo (0.9% saline), and the subjects 
that are randomized to receive IM injection of Depo-Medrol will receive an IV infusion of 
placebo (0.9% saline). Appropriate care will be taken to use opaque lines for drug 
administration equipment. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
33 of 71 
Subjects in this trial will be randomized to receive an IM injection of 120 mg 
methy
lprednisolone acetate (Depo-Medrol), or 75 mg/infusion of Nanocort administered as 
an IV infusion or 150 mg/infusion of Nanocort administered as an IV infusion, on Day 1 and 
15.  
7.4 Preparation and labelling of comparator 
DEPO-MEDROL® is an anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft 
tissue or intralesional injection. It is available in three strengths: 20 mg/mL; 40 mg/mL; 80 
mg/mL. Sodium Chloride was added to adjust tonicity. When necessary, pH was adjusted 
with sodium hydroxide and/or hydrochloric acid. The pH of the finished product remains 
within the USP specified range; e.g., 3.5 to 7.0. See Package Insert for additional 
information. Labelling shall be performed separately for Depo-Medrol. 
7.5 Use of saline 
The dummy product (commercially available Saline 0.9%) will be purchased by the Sponsor 
and supplied to the clinical sites. All subjects will also receive placebo either IM saline or IV 
saline on Day 1 and Day 15.  Therefore, subjects that are randomized to receive one of the 2 
doses of Nanocort will also receive an IM injection of placebo (0.9% saline), and the subjects 
that are randomized to receive IM injection of Depo-Medrol will receive an IV infusion of 
placebo (0.9% saline).  
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
34 of 71 
8. METHODS 
 
8.1 Study parameters/endpoints 
The objective of the current trial is to assess efficacy and safety (treatment of signs and 
symptoms) of Nanocort in subjects with active rheumatoid arthritis who are experiencing a 
flare/exacerbation in comparison to a standard of care medication. Efficacy will be measured 
by comparing the therapeutic effect of 75 mg or 150 mg IV administration Nanocort with the 
therapeutic effect of an IM administration of 120 mg methy
lprednisolone (Depo-Medrol) as 
measured by the EULAR response as well as other measures of RA activity. 
8.1.1 Main study parameter/endpoint 
The Primary parameter that will be measured is the EULAR response at Week 1 (Day 8). 
Primary Endpoint: EULAR responder (moderate and good combined) rate at Week 1 (Day 8) 
8.1.2 Key Secondary study parameters/endpoints  
  EULAR responder (only good) rate at Week 1 (Day 8) 
 EULAR responder (moderate and good combined) rate at Week 2 (Day 15) 
 EULAR responder (only good) rate at Week 2 (Day 15) 
 
Secondary study parameters/endpoints 
The secondary endpoints that will be measured are: 
 EULAR response at Week 1, 2, 3, 4, 6, 8 and 12  
 DAS28 mean and % change  at Week 1, 2, 3, 4, 6, 8 and 12 
 Time to first EULAR response (moderate/good)  
 ACR 20/50/70 response scores  at Week 1, 2, 3, 4, 6, 8 and 12 
 Tender joint counts at Week 1, 2, 3, 4, 6, 8 and 12 
 Swollen joint counts at Week 1, 2, 3, 4, 6, 8 and 12 
 Patient pain and Global Visual Analog Score (VAS) score at Week 1, 2, 3, 4, 6, 8 and 
12 
 Investigator Global Visual Analog Score (VAS) score  at Week 1, 2, 3, 4, 6, 8 and 12 
 Short Form 36 (SF-36) to assess physical and mental component at Week 1, 2, 4, 6, 
and 12. 
 Health Assessment Questionnaire (HAQ) at Week 1, 2, 3, 4, 6, 8 and 12. 
 The Functional Assessment of Chronic Illness Therapy (FACIT) at Baseline, Week 4 
and 6  
 Health Economics Questionnaire at Week 12 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
35 of 71 
 Maintenance of Improvement at 12 Weeks assessed during a blinded review by the 
Medical Monitor (MM) and Principal Investigator (PI) at the end of the study 
 AEs (including glucocorticoid related AEs,  AEs leading to withdrawal, AEs leading to 
discontinuation of medication, and AEs due to infusion reactions) 
 Vital signs 
 Physical examinations 
 Laboratory 
 ECG 
 
 Assessment by monitoring cortisol levels at Screening, Baseline, 6 and 12 weeks  
8.2 Randomisation, blinding and treatment allocation 
Subject randomization will take place before the start of administration of the IMP.  
Subjects will be randomized in a 1:1:1 ratio to the three treatment arms and stratified by site.  
Randomization of the subjects will be performed by an Interactive Web-based Randomization 
System (IWRS) by an independent party. The randomization number will be recorded on the 
eCRF. Once the numbers have been assigned they cannot be reassigned.  
Subjects in this trial will be randomized in a 1:1:1 ratio to receive one of three dose groups:  
• Nanocort 75 mg IV infusion and IM saline injection on Day 1 and Day 15, or 
• Nanocort 150 mg IV infusion and IM saline injection on Day 1 and Day 15, or 
• Depo-Medrol 120 mg IM injection and IV saline infusion on Day 1 and Day 15 
Blinding: 
Prior to the start of the study, a copy of the master randomization code will be stored in 
confidential manner up to the unblinding after database lock. A separate unblinded 
Pharmacovigilance Medical Reviewer and unblinded Pharmacovigilance Associate will be 
available for triage, review and submission of safety events.  
Any reported Suspected Unexpected Serious Adverse Reactions (SUSARs) will be triaged 
by the Medical Monitor in a blinded fashion and forwarded for full processing to the unblinded 
Medical Reviewer and unblinded Pharmacovigilance Reviewer for processing and reporting 
to the Competent Authority (CA) and Independent Ethics Committee (IEC) per regulations.  
Unblinding to Investigator and subject will occur only after database closure at the end of the 
study. The study blind will only be broken after database lock except in the case of 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
36 of 71 
emergency to protect subject’s safety. The code may be broken in case of an emergency, 
preferably after discussion with the MM. Any code break will be recorded and a copy retained 
within the study file. 
The blind will be preserved throughout the study unless, in the opinion of the Investigator, the 
lack of this information places the subject at undue risk. In general, this will occur only if an 
adverse event occurs for which the subject’s physician requires knowledge of the treatment 
assigned. In this case, the Sponsor should be notified as soon as possible and un-blinded 
information for the subject’s treatment group will be provided. 
Premature unblinding of study drug may occur to reveal whether a subject has been 
receiving Nanocort or Depo-Medrol. This should occur only in an emergency and if the 
information is considered by the Investigator (or other treating physician) as medically 
necessary.  If unblinding occurs prior to notification of the Medical Monitor the circumstances 
leading to the unblinding must be clearly documented and promptly reported by telephone or 
in writing to the Medical Monitor. Unblinding will be performed by the IWRS responsible 
person. 
8.3 Study procedures 
The Schedule of Assessments (Table 2) included in the protocol summarizes the timing of 
the efficacy and safety measurements.  
The Day of the first dose administered to a subject is considered Day 1 for that individual 
subject. Other study Days are calculated with Day 1 as the reference point. Screening will 
consist of period up to 2 Weeks (14 Days) and those subjects that are still eligible after the 
screening visit will be randomized to one of the three treatment groups.  
Treatment will be given on Day 1 and Day 15. The patient will be followed up for 12 Weeks or 
End of Study visit. In the event of early termination, subjects are asked to return for the Week 
12 assessments if possible. Otherwise, the subjects are assessed as per Week 12 
assessment schedule on the Day of termination. Infusion related reactions will be monitored 
during the infusion and at the end of infusion. 
Physical Examination 
A full physical examination should include: General appearance, Skin, Head and Neck, Eyes-
Ears-Nose, Throat, Lymph Nodes palpation, Cardiovascular, Lungs & Chest, Abdomen, 
Musculoskeletal, and Neurological Function. All other body systems should be assessed at 
the Investigator’s discretion. A full physical examination will be done at Screening, Baseline 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
37 of 71 
and End of study. For remaining visits it will be up to the judgement of the Investigator if a full 
or abbreviated exam is completed.  
Vital Signs 
Vitals signs will be taken supine (for 5 minutes) and include heart rate, respiratory rate, blood 
pressure (BP), and temperature. The method of temperature assessment must remain 
consistent for each individual subject throughout the study. 
Subject blood pressure and heart rate will be measured using an automatic device 
(whenever possible) after the subject has rested (supine) comfortably for 5 min. Vital signs 
will be measured at the time points specified in the Schedule of Assessments (Table 2). 
Weight will be recorded as per Table 2. 
Disease Activity Score in 28 Joints (DAS28) 
The DAS28 is a composite index for measuring disease activity in RA and is calculated at 
each study visit. The index includes swollen (range 0-28) and tender joint counts (range 0-
28), acute phase response erythrocyte sedimentation rate (ESR), and general health status 
(range 1-100). The DAS28, which uses a 28 joint count including shoulders is derived from 
the original DAS, which includes a 44 swollen joint count. The DAS28 has been validated in 
RA. The index is calculated using the formula from the EULAR website: 
http://emeunet.eular.org/links.cfm?catID=19. 
The DAS28 ranges from 0 to 9.3, where higher scores represent higher disease activity. 
Joint Tenderness and Swelling Assessments 
An assessor at each site will be used to evaluate tenderness and swelling of the 28 joints 
specified by the DAS28 scoring system. Scoring for each joint will be based on whether or 
not the joint is swollen (1=yes, 0= no) and whether the joint is tender (1=yes, 0= no).  The 
CRF will also have the options Not done and Not Evaluable. Evaluations will be done at all 
study visits. 
Health Assessment Questionnaire (HAQ) 
The HAQ is a patient-reported outcomes (PRO) questionnaire based on 5 patient-centered 
dimensions; disability, pain, medication effects, costs of care, and mortality. The version used 
for this trial is the “short” or 2-page HAQ comprised of the HAQ disability module and the 
global and pain visual analog scales [20]. The HAQ may be completed directly by the subject 
or by an interviewer. HAQ will be collected at Baseline and all post dose study visits. 
[Appendix 14.2] 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
38 of 71 
Short Form-36 (SF-36) Survey 
The Short Form (36) Health Survey is a patient-reported survey of patient health [21]. The 
SF-36 is a measure of health status. SF-36 surveys may be completed directly by the subject 
or by an interviewer. SF-36 surveys will be collected at Baseline and Week 1, 2, 4, 6, and 12. 
 [Appendix 14.1] 
Functional Assessment of Chronic Illness Therapy (FACIT) Score 
"FACIT" (Functional Assessment of Chronic Illness Therapy) was adopted as the formal 
name of the measurement system in 1997 to portray the expansion of the familiar "FACT" 
(Functional Assessment of Cancer Therapy) questionnaires into other chronic illnesses and 
conditions [22]. Questionnaires may be completed directly by the subject or by an 
interviewer. The FACIT questionnaire will be collected at Baseline, Week 4 and Week 6. 
[Appendix 14.3] 
EULAR Response 
Comparing the DAS28 from one patient on two different time points, it is possible to define 
moderate or good response [14]. The EULAR response criteria are defined as follows: 
DAS28 improvement → 
> 1.2 
> 0.6 and ≤ 1.2 
≤ 0.6 
Present DAS28↓ 
≤ 3.2 
good response 
moderate response no response 
> 3.2 and ≤ 5.1 
moderate response moderate response no response 
> 5.1 
moderate response no response 
no response 
The EULAR response will be calculated at all visits after Baseline. 
American College of Rheumatology 20/50/70 (ACR 20/50/70) 
ACR score is a scale to measure change in rheumatoid arthritis symptoms. It is named after 
the American College of Rheumatology. Different degrees of improvement are referred to as 
ACR20, ACR50, ACR70. The following definition of improvement was selected: 20% 
improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 
remaining ACR core set measures: patient and physician global assessments, pain, 
disability, and an acute-phase reactant [23]. ACR 50 and ACR 70 criteria are defined in a 
manner similar to that for ACR 20, but with improvement of at least 50 percent and 70 
percent in the individual measures, respectively.  
Visual Analog Scale (VAS) 
The visual analogue scale or visual analog scale (VAS) is a psychometric response scale 
which can be used in questionnaires. It is a measurement instrument for subjective 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
39 of 71 
characteristics or attitudes that cannot be directly measured. When responding to a VAS 
item, respondents specify their level of agreement to a statement by indicating a position 
along a continuous line between two end-points. Four VAS measurements will be at each 
study visit; the subject will assess their current pain level and general health, the subject will 
assess their RA Activity levels, and a trained blinded site evaluator will independently assess 
the subjects RA Activity levels. 
Subjects will be given an explanation on use of different scales at screening. 
8.3.1 Overview of Assessments by Study Day 
Screening Visit (up to 14 Days prior to dosing) 
 Informed Consent 
 Medical and surgical history including history of RA diagnosis 
 Demographic information [date of birth, race, height, smoking history, Rheumatoid 
Factor (RF)] 
 Inclusion/exclusion criteria 
 Previous and all current drug record review 
 Full physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature) 
 Weight 
 12 lead Electrocardiogram (ECG) 
 Visual Analog Scale (VAS) experience of pain (patient) and General Health 
 VAS Rheumatoid Arthritis (RA activity patient’s and Investigator’s evaluation) 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 Disease flare 
 Extensive laboratory:  
o Hematology: Hemoglobin (Hgb), Hematocrit (HCT), Red blood cells (RBC), 
White blood cells (WBC), differential count, platelet count, erythrocyte 
sedimentation rate (ESR) 
o Chemistry: Sodium (Na
+), potassium (K
+), chloride, total bilirubin, alkaline 
phosphatase (ALP), ALT [Serum glutamic pyruvic transaminase (SGPT)], 
AST [Serum glutamic oxaloacetic transaminase (SGOT)], Gamma 
Glutamyl Transpeptidase (GGT), Lactate dehydrogenase (LDH), C-


CLR_15_05  
  
 
V3.1 25 September 2017 
 
40 of 71 
reactive protein (CRP), Creatinine Kinase (CK), Blood Urea Nitrogen 
(BUN), creatinine, glucose, uric acid, calcium (Ca++), phosphorous, total 
protein, albumin, Hemoglobin A1c (HbA1C), cholesterol, high-density 
lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, 
triglycerides, osteocalcin and serum cortisol 
o Urinalysis: Glucose, N-telopeptide and creatinine   
 Urine Pregnancy Test (as applicable) 
 Tuberculosis test : QuantiFERON TB-Gold test (QFT) (as per local regulation) 
Baseline Visit (Day 1) 
 Full Physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature)  
 Adverse events 
 Concomitant medication 
 Visual Analog Scale (VAS) experience of pain (patient) and RA activity, also 
recorded in patient diary on Day 2, 4 and 6 
 VAS Rheumatoid Arthritis RA activity Investigator’s evaluation and patient General 
Health) 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 Functional Assessment of Chronic Illness Therapy (FACIT)  
 Short Form 36 (SF-36) to assess physical and mental component and the Health 
Assessment Questionnaire (HAQ) 
 Extensive laboratory (fasting):  
o Hematology: Hgb, HCT, RBC, WBC, differential count, platelet count, ESR 
o Chemistry: Sodium, potassium, chloride, total bilirubin, ALP, ALT (SGPT), 
AST (SGOT), gamma GT (GGT), LDH, CRP, CK, BUN, creatinine, 
glucose, uric acid, calcium (Ca++), phosphorous, total protein, albumin, 
HbA1C, cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, 
osteocalcin and serum cortisol 
o Urinalysis: Glucose, N-telopeptide and creatinine   
 Urine pregnancy test (as applicable) 
 Re-Assess eligibility for enrollment 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
41 of 71 
 Randomization 
 Treatment / Dosing 
 
Week 1 (Day 8±1), Week 3 (Day 22±2), Week 4 (Day29±2) 
 Physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature)  
 Adverse events 
 Concomitant medication 
 EULAR and ACR Response  
 VAS experience of pain (patient) and General Health 
 VAS Rheumatoid Arthritis (RA activity patient’s and Investigator’s evaluation) 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 HAQ 
 SF-36 at Week 1 and Week 4 
 FACIT at Week 4 
 Limited laboratory:  
o Hematology: Hgb, HCT, RBC, WBC, differential count, platelet count, ESR  
o Chemistry: Sodium, potassium, chloride, ALT, CRP, creatinine, glucose, 
HbA1C, HDL-cholesterol, LDL cholesterol, triglycerides and serum cortisol 
o Urinalysis: Glucose 
Week 2 (Day 15±1) 
 Physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature)  
 Adverse events 
 Concomitant medication 
 EULAR and ACR Response  
 VAS experience of pain (patient) and RA activity, also recorded in patient diary on 
Day 16, 18 and 20 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
42 of 71 
 VAS Rheumatoid Arthritis RA activity Investigator’s evaluation and patient General 
Health 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 SF-36 and HAQ 
 Limited laboratory:  
o Hematology: Hgb, HCT, RBC, WBC, differential count, platelet count, ESR  
o Chemistry: Sodium, potassium, chloride, ALT, CRP, creatinine, glucose, 
HbA1C, HDL-cholesterol, LDL cholesterol, triglycerides and serum cortisol 
o Urinalysis: Glucose  
 Urine Pregnancy Test (as applicable) 
 Treatment / Dosing 
Week 6 (Day 43±3) 
 Physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature)  
 Adverse events 
 Concomitant medication 
 EULAR and ACR Response 
 Visual Analog Scale (VAS) experience of pain (patient) and General Health 
 VAS Rheumatoid Arthritis (RA activity patient’s and Investigator’s evaluation) 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 SF-36 and HAQ 
 FACIT 
 Extensive laboratory (fasting):  
o Hematology: Hgb, HCT, RBC, WBC, differential count, platelet count, ESR 
o Chemistry: Sodium, potassium, chloride, total bilirubin, ALP, ALT (SGPT), 
AST (SGOT), gamma GT (GGT), LDH, CRP, CK, BUN, creatinine, 
glucose, uric acid, calcium (Ca++), phosphorous, total protein, albumin, 
HbA1C, cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, 
osteocalcin and serum cortisol 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
43 of 71 
o Urinalysis: Glucose, N-telopeptide and creatinine   
Week 8 (Day 57±3)  
 Physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature)  
 Adverse events 
 Concomitant medication 
 EULAR and ACR Response 
 VAS experience of pain (patient) and General Health 
 VAS Rheumatoid Arthritis (RA activity patient’s and Investigator’s evaluation) 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 HAQ 
 Limited laboratory (fasting):  
o Hematology: Hgb, HCT, RBC, WBC, differential count, platelet count, ESR.  
o Chemistry: Sodium, potassium, chloride, ALT, CRP, creatinine, glucose, 
HbA1C, HDL-cholesterol, LDL cholesterol, triglycerides and serum cortisol 
o Urinalysis: Glucose  
Week 12 (Day 85± 3) (End of Study/ Early Termination) 
 Full Physical examination 
 Vital signs supine for 5 minutes (heart rate, blood pressure, respiration rate and 
body temperature)  
 Weight 
 Adverse events 
 Concomitant medication 
 EULAR and ACR Response 
 Visual Analog Scale (VAS) experience of pain (patient) and General Health 
 VAS Rheumatoid Arthritis (RA activity patient’s and Investigator’s evaluation) 
 Tender joint counts 
 Swollen joint counts 
 DAS28 
 SF-36 and HAQ 




CLR_15_05  
  
 
V3.1 25 September 2017 
 
45 of 71 
If the infusion is stopped or infusion rate is changed at any other time than 
already prescribed in the infusion instructions in the protocol, a PK sample should 
be obtained ASAP after the unscheduled change in infusion rate. 
These patients have an additional exclusion criterion (blood donation). The 
patients participating in the PK sub-study will be compensated for the time spent 
at site and for the additional blood collection. . 
Detailed operational procedures as well as information with regard to parameters, 
analytes for this PK sub-study are described in the PK manual.   


CLR_15_05  
  
 
V3.1 25 September 2017 
 
46 of 71 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
47 of 71 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
48 of 71 
 
8.4 Drug accountability 
The Sponsor will supply the clinical Investigator with the investigational product, and other 
clinical drug supplies as agreed upon for the timely completion of the clinical study described 
above. 
The investigational products (Nanocort and Depo-Medrol, as well as the placebo dummies) 
will be delivered to the study pharmacy. Study pharmacists will be unblind. It will be the 
responsibility of the study pharmacist to prepare the individual treatments based on 
randomization, treatment group and dose. Preparation on site is required to ensure the study 
blind. The investigational products will be dispensed only under the restricted conditions 
defined in the present protocol. Drugs will be administered by blinded personnel only. Time 
(start and end time of infusion) and date of administration and initials of the person 
administering the drug will be documented. 
The pharmacist will record and acknowledge receipt of all shipments of the investigational 
product and document the lot numbers and condition of each shipment. The investigational 
products must be kept in a locked area with restricted access. The investigational products 
must be stored and handled in accordance with the manufacturer’s instructions. The 
Investigator is responsible for maintaining documentation showing the amount of 
investigational product provided to the investigational site, and administered to and collected 
from each study patient. Discrepancies in investigational product accountability must be 
explained and documented. An inventory of investigational products will be maintained. The 
unblinded monitor will be responsible for verifying the Investigator’s documentation on 
receipt, use and return of investigational products. The unblinded monitor will check drug 
accountability at sites on an ongoing basis from the start of the study. At the end of the study, 
it must be possible to reconcile delivery records with records of used and returned study 
treatments. An account of any discrepancies must be provided. The unblinded monitor will 
prepare a final report of the accountability of the investigational product for filing in the 
investigator file.  
Nanocort should be stored between 2 and 8°C, protected from light and kept in an 
appropriate secure area (e.g., a locked cabinet). All other related material can be stored at 
room temperature or per manufacturer’s instructions.  
The Sponsor (or designee) can provide the framework for documenting study treatment 
accountability throughout the study. The Investigational site must maintain an accurate 
written record of the shipment, dispensing, and return of study treatments. And an accurate 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
49 of 71 
record of the date and amount of study drug dispensed to each subject must be available for 
inspection at any time.  
At the conclusion of the study and after inspection by the unblinded monitor the Investigator 
will return all drug containers, drug labels, and a copy of the completed drug accountability 
form to the monitor for transfer to the appropriate parties. Sites may destroy medications 
locally at an appropriate time point, if previously agreed with the Sponsor. 
8.5 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The Investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
Reasons for subjects to be withdrawn from the study include, but are not limited to;   
 The subject withdraws consent. 
 Violation of eligibility criteria (if the violation is detected prior to drug administration). 
 At the Investigator’s or MM’s discretion to protect subject safety and well-being. 
 Subjects may also be discontinued due to the following: change in compliance with 
inclusion/exclusion criterion that is clinically relevant and affects safety, occurrence 
of AEs, intake of non-permitted concomitant medication that might affect safety or 
study assessments/objectives, etc. 
Reasons for discontinuation will be recorded.  
Once dosing is complete, subsequent violation of the protocol should not be considered 
grounds for withdrawal.  All subjects treated should be followed up for safety evaluation, if at 
all possible. If withdrawn due to an AE, subjects must be followed until resolution of all their 
AEs or until the unresolved AEs are judged by the Investigator is stabilized.  In all cases, the 
date the subject is withdrawn from the study and the reason(s) for withdrawal must be 
recorded on the electronic case report form (eCRF).  
In the case of incomplete drug administration, subjects should not be withdrawn from the 
study, but should undergo all planned follow-up visits. 
If a subject is withdrawn from the study for any reason, the Investigator must make every 
effort to perform the evaluations described for the End of Study/Early Termination Visit at 
Day 85 (Week 12), as soon as possible but preferably within 30 Days after their last study 
drug administration. Subjects withdrawn because of adverse experiences will undergo a 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
50 of 71 
physical examination and laboratory tests planned at the follow-up visit (if required). A follow-
up of AEs will also be undertaken. 
Replacement of individual subjects after withdrawal 
No subjects will be replaced.  If any of the subjects is withdrawn from the study,   the reason 
for withdrawal will have to be recorded in the case report form (eCRF) for all withdrawn 
subjects. 
8.6 Follow-up of subjects withdrawn from treatment 
All subjects treated should be followed up for safety evaluation if at all possible. If withdrawn 
due to an AE, subjects must be followed until resolution of all their AEs or until the 
unresolved AEs are judged by the Investigator and MM to have stabilized. In all cases, the 
date the subject is withdrawn from the study and the reason(s) for withdrawal must be 
recorded on the case report form (eCRF).  
In the case of incomplete drug administration, subjects should not be withdrawn from the 
study, but should undergo all planned follow-up visits. 
If a subject is withdrawn from the study for any reason, the Investigator must make every 
effort to perform the evaluations described for the End of Study/Early Termination Visit at 
Day 85 (Week 12), as soon as possible but preferably within 30 Days after their last study 
drug administration. 
8.7 Premature termination of the study 
The study may be discontinued at the discretion of the Principal Investigator, Sponsor, or 
Independent Ethics Committee (IEC) based on the occurrence of the following (but not 
limited to): 
 AEs unknown to date with respect to their nature, severity, and duration; 
 Increased frequency and/or severity and/or duration of known AEs; 
 Medical or ethical reasons affecting the continued performance of the study; 
 Difficulties in recruitment; 
 Cancellation of drug development; 
 Notification by regulatory authorities  
The written information concerning premature termination of the study will be provided to 
applicable recipients, such as Investigators, Sponsor or IECs. 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
51 of 71 
9. SAFETY REPORTING 
9.1  Disadvantageous event 
In accordance to applicable legislation and guidelines, the Investigator will inform the 
subjects and the reviewing accredited ethical committee if anything occurs, on the basis of 
which it appears that the disadvantages of participation may be significantly greater than was 
foreseen in the research proposal. The study will be suspended pending further review by the 
accredited ethical committee, except insofar as suspension would jeopardise the subject’s 
health. The Investigator will take care that all subjects are kept informed.  
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
An adverse event (AE) is any untoward medical occurrence in a subject who has received 
study drug, or any untoward or unintended response to an experimental intervention which 
does not necessarily have a causal relationship with the treatment. Adverse Events include:  
  Any new undesirable medical experience or an unfavourable and unintended change of 
an existing condition that occurs during or after treatment. 
  Untoward clinically significant manifestations of laboratory abnormalities (e.g., clinical 
chemistry, haematology, urinalysis, etc.) or other abnormal assessments (e.g., 
electrocardiogram, vital signs) independent of the underlying medical condition. If 
possible, abnormal laboratory findings with these characteristics should be reported as a 
clinical diagnosis rather than the abnormal value itself (e.g., "anemia" rather than 
"decreased blood count"). 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalisation for 
elective surgery, social and/or convenience admissions) do not represent AEs.  
Subjects will be carefully monitored throughout the study for AEs. At each study visit, 
subjects will be asked to report any AE. All AEs are followed until they are resolved or 
stabilized, or until all attempts to determine resolution of the event are exhausted. The 
investigator will use his/her discretion in ordering additional tests as necessary to monitor the 
resolution of such events.  
Each collected AE, regardless of the relationship to study drug, will be recorded in the AE 
eCRF. All entries should contain an event term, date of onset, date of resolution, severity, 
action taken, outcome, relationship to study drug, and a seriousness assessment. The 
investigator will document all AEs in the subject’s source document. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
52 of 71 
Severity will be assessed by Investigator according to the following definitions: 
Mild: The event is of little concern to the subject and/or of no clinical significance. The 
event is not expected to have any effect on the subject’s health or wellbeing. 
Moderate: The subject experienced discomfort enough to cause interference with 
usual activity, and/or the condition required specific treatment. The event is of some 
concern to the subject’s health or wellbeing. The event may require medical 
intervention. 
Severe: The subject is incapacitated and unable to work or participate in many or all 
usual activities. The event is of definite concern to the subject and/or poses 
substantial risk to the subject’s health or wellbeing. The event is likely to require 
medical intervention and/or close follow-up. 
Life-threatening: The subject is at risk of death due to the adverse event as it 
occurred. This does not refer to an event that hypothetically might have caused death 
if it were more severe. 
Death: Death related to adverse event. 
Action taken is categorized as “none”, “study drug discontinued”, “study drug discontinued 
and restarted”, “dose modified”, “required concomitant medication”, “required procedure”, or 
“other”. 
Event outcome at resolution, or time last follow-up was recorded is categorized as: “event 
resolved”; “resolved with sequelae”; “ongoing”; “lost to follow-up”; or “death”. 
The investigator will determine the relationship of the event to the study drug according to the 
following criteria: 
 Not related: The event was most likely caused by other factors such as the 
subject’s clinical condition, intercurrent illness, or concomitant drugs, and did 
not follow a known response pattern to the study drug, or the temporal 
relationship of the event to study drug administration made a causal 
relationship unlikely. 
 Unlikely: A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease provide 
plausible explanations. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
53 of 71 
 Possibly related: The event followed a reasonable temporal sequence from 
the time of drug administration, and/or followed a known response pattern to 
the study drug, but could have been produced by other factors such as the 
subject
's clinical condition, intercurrent illness, or concomitant drugs. 
 Probably related: The event followed a reasonable temporal sequence from 
the time of drug administration, and/or followed a known response pattern to 
the study drug, and could not be reasonably explained by other factors such 
as the subject
's clinical condition, intercurrent illness or concomitant drugs.  
 Related: The event follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected response pattern 
to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any dose:  
- results in death; 
- is life threatening (at the time of the event); 
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- results in persistent or significant disability or incapacity; 
- is a congenital anomaly or birth defect; 
- Any other important medical event that may not result in death, be life threatening, 
or require hospitalization, may be considered a serious adverse experience when, 
based upon appropriate medical judgement, the event may jeopardize the subject 
or may require an intervention to prevent one of the outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether an AE is serious in 
other instances, such as an important medical event that may not be immediately life-
threatening or resulting in death, or a hospitalisation that may jeopardize the subject or 
require intervention to prevent one of the above outcomes. 
All serious adverse events will be reported by the investigator to the Accelovance 
Pharmacovigilance (PV) within 24 hours of first knowledge of the Investigator via the Fax:      
 All SAEs will be reported by 
submitting a completed SAE Report Form. Whenever possible, diagnoses should be given 
when signs and symptoms are due to a common etiology. It is critical that the information 
provided on the Sponsor’s SAE Report Form matches the information recorded in AE eCRF 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
54 of 71 
for the same event. In addition, the same information is to be recorded in the source 
documents. 
The Investigator must also notify the Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) in writing as soon as is practical, but at least within 15 Days after the 
Investigator has first knowledge of the serious adverse events.  
Accelovance PV will notify Sponsor of all SAE’s within 24 hrs of its initial receipt. 
The Council for International Organizations of Medical Sciences (CIOMS) Form prepared by 
Accelovance PV will be shared with Sponsor for review and approval. 
Pregnancy test will be performed at screening and at visits specified in the protocol. Subjects 
with a positive test at screening or during the study period will be excluded from the study. 
Women of child-bearing potential will be instructed to practice an acceptable method of birth 
control for the duration of the study. However, if subject becomes pregnant during the study, 
pregnancy will be recorded as a significant medical event and reported per SAE reporting 
procedure. The outcome of a pregnancy should be followed up carefully and any abnormal 
outcome of the pregnancy should be reported. Subjects who become pregnant during the 
study will be asked to discontinue the study drug if this can be done safely.  
SAEs that result in death or are life threatening should be reported expeditedly. The 
expedited reporting will occur not later than 7 Days after the responsible investigator has first 
knowledge of the adverse event. This is for a preliminary report with another 8 Days for 
completion of the report. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an IMP related to any dose 
administered. 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in: 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
55 of 71 
- Summary of Product Characteristics (SPC) for an authorised medicinal 
product; 
- Investigator’s Brochure for an unauthorised medicinal product. 
The time frame for submitting suspected, unexpected serious adverse drug reaction or other 
information which qualifies for reporting to European Medicines Agency (EMA) and all 
participating investigators is no later than 15 calendar days after initial receipt of the 
information by Accelovance PV. 
Suspected and Unexpected fatal or life-threatening adverse reactions represent especially 
important safety information and, therefore, must be reported more rapidly to EMA. The 
requirement for reporting any Suspected and Unexpected fatal or life-threatening adverse 
reaction to EMA is no later than 7 calendar days after initial receipt of the information by 
Accelovance PV. If the safety report submitted within 7 calendar days is complete, an 
additional submission within 15 days from day zero is not required. 
Accelovance PV will report any suspected unexpected serious adverse reactions (SUSARs) 
on behalf of the Sponsor to the IEC/CA according to local requirements. 
The IRB/IEC should receive the following SUSARs expeditedly: 
 SUSARs that have arisen in the clinical trial that was assessed by the IEC 
 SUSARs that have arisen in other clinical trials of the same Sponsor and with the 
same medicinal product, and that could have consequences for the safety of the 
subjects involved in the clinical trial that was assessed by the IEC 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once every half year to the IEC. This line-listing provides an overview of all SUSARs from the 
study medicine, accompanied by a brief report highlighting the main points of concern.  
Premature unblinding of study drug may occur to reveal whether a subject has been treated 
with Nanocort or Depo-Medrol®, Unblinding should occur only in an emergency and if the 
information is considered by the Investigator (or other treating physician) as medically 
necessary. If unblinding occurs prior to notification of the Medical Monitor the circumstances 
leading to the unblinding must be clearly documented and promptly reported by telephone or 
in writing to the Medical Monitor. 
Development Safety Update Report  


CLR_15_05  
  
 
V3.1 25 September 2017 
 
56 of 71 
In addition to the expedited reporting of SUSARs, Accelovance Pharmacovigilance will 
submit, once a year throughout the clinical trial, a safety report to the accredited ethical 
committee competent authority, and competent authorities of the concerned Member States. 
This safety report consists of: 
 a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
 a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
9.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study.  
9.4 Data Safety Monitoring Board (DSMB) / Safety Committee 
DSMB is not planned for this study. Nanocort contains prednisolone. Prednisolone is in 
clinical use for years. The reference product, Depo-Medrol, which contains 
methy
lprednisolone, is also clinically used in current practice for the treatment of a variety of 
diseases. Considering the known safety profile of prednisolone or methylprednisolone in 
clinical use, DSMB is not planned.  
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
57 of 71 
10. STATISTICAL ANALYSIS 
10.1 General 
Descriptive statistics, including the number and percentage for categorical variables, and the 
number, mean, standard deviation (SD), median, minimum and max
imum for continuous 
variables will be provided. Listings of individual subjects’ data will be produced. Where 
appropriate time trends will be shown by graphically displays. 
For continuous data, one-way Analysis of variance (ANOVA) (in case of normally distributed 
variables) or the non-parametric Kruskal-Wallis test will be used; for categorical data and 
binary data the Chi-square test or Fisher’s exact test will be used. 
A detailed Statistical Analysis Plan (SAP) will be written and finalized in advance of database 
lock. All the details necessary to complete the statistical analyses will be provided in the 
SAP. This SAP should be approved by the Sponsor and MM (or designee) prior to un-
blinding.  
The statistical package SAS® v9.3 or higher will be used to produce all summary tables and 
data listings and to perform the hypotheses testing.  
10.2 Primary study parameter 
EULAR responders (good and moderate combined) at Day 8 
EULAR responders (good and moderate combined) at Day 8 will be summarized by 
treatment group and pair-wise compared between both Nanocort arms and the Depo-Medrol 
arm using the Cochrane-Mantel-Haenszel test stratified by study site.  
As sensitivity analysis a logistic regression model will be fitted on the EULAR responders 
with the stratification factor study site and additional baseline variables as covariates.. 
Proportional odds ratios will be presented. The SAP will specify the planned additional 
covariates .  
10.3  Key Secondary parameters 
EULAR good responder at Day 8,  
EULAR responder (good and moderate combined) at Day 15 
EULAR good responder at Day 15. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
58 of 71 
The key secondary parameters will be analyzed as the primary study parameter EULAR 
responder at Day 8. 
10.4 Secondary study parameters  
10.4.1 EULAR Response 
 EULAR response (good, moderate, no response) at Week 1, 2, 3, 4, 6, 8, and 12  
EULAR responses will be summarized by treatment group and the treatment groups will be 
compared by using the non-parametric Wilcoxon-Mann-Whitney test. . 
10.4.2 DAS28 mean and % change  
Absolute and % change from Baseline in DAS28 scores at 1, 2, 3, 4, 6, 8 and 12 Weeks will 
be submitted to an analysis of covariance, including baseline scores and study site as 
covariates or to an appropriate non-parametric alternative (e.g., Kruskal Wallis test). The time 
course of DAS28 scores will be submitted to a repeated measures analysis of variance.  
10.4.3 Time to first EULAR response (moderate or good) 
Time to first EULAR response, will be analyzed using the Kaplan-Meier method; comparison 
between treatment groups will be performed using the log-rank test. 
10.4.4 ACR 20/50/70 response scores 
The comparison of ACR20, ACR50 and ACR70 response rates among treatment groups will 
be analyzed using a stratified Cochrane-Mantel-Haenszel test,  .  
10.4.5 Tender and swollen joint counts 
The DAS28 score and the EULAR Response incorporate the tender and swollen joint counts. 
For this reason, no formal testing will be done between the three treatment groups. 
Descriptive statistics will be presented for the tender and swollen joint counts by treatment 
group.    
10.4.6 Visual Analog Score (VAS) 
 Patient VAS value for experience of pain and patient VAS value for General  
Health   
 Patient and Investigator VAS value for RA activity 
Changes from Baseline in VAS scores at 1, 2, 3, 4, 6, 8 and 12 Weeks, will be submitted to 
an analysis of covariance, including Baseline VAS scores and study site as covariates or to 
an appropriate non-parametric alternative (e.g., Kruskal Wallis test). 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
59 of 71 
10.4.7 Quality of Life and RA activity questionnaires 
Short Form 36 (SF-36) to assess physical and mental component at Baseline and Week 1, 2, 
4, 6, and 12. Pair-wise comparisons of absolute changes from Baseline at Weeks 4, 6 and 12 
will be performed using Analysis of covariance (ANCOVA), with study site, SF-36 score at 
Baseline DAS28 level, age and gender as covariates.  
The Health Assessment Questionnaire (HAQ) at every visit (except Screening visit). Pair-
wise group comparisons of HAQ score changes from Baseline at Weeks 3, 6 and 12 will be 
analyzed by ANCOVA, with study site, Baseline DAS28 level and HAQ score at baseline as 
covariates. 
The Functional Assessment of Chronic Illness Therapy (FACIT) at Baseline, Week 4 and 6. 
The pair-wise comparisons between treatment groups of the changes from Baseline in 
FACIT-Fatigue scores will be performed by using ANCOVA with study site, Baseline DAS28 
level and Baseline FACIT score as covariates. 
For the ANCOVA analyses, least squares means and the pairwise comparisons between 
treatment groups in adjusted least-squares means with their Tukey 95% CIs will be 
presented. 
Descriptive statistics for the surveys /questionnaires will be presented. 
10.4.8 Maintenance of Improvement at 12 Weeks   
Maintenance of Improvement at 12 Weeks will be compared between treatment groups using 
a stratified Cochrane-Mantel-Haenszel test. 
10.4.9 Safety assessments 
Safety results (AEs, vital signs, physical examinations, laboratory, ECG) will be compared 
between the Nanocort arms and the Depo-Medrol arm. Shift tables and shift plots will be 
used to evaluate changes in clinical laboratory test results at different time points compared 
to Baseline values. Proportion of patients whose test values are outside specific ranges will 
also be presented. 
All abnormalities in physical examination, ECG and vital signs will be presented. 
10.5 PK analysis 
The PK subset of the study is exploratory and only descriptive PK parameters will be derived. 
PK analytes including free prednisolone and prednisolone phosphate will be assessed. 
Statistical comparison for PK parameters will not be done. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
60 of 71 
10.6 Other study parameters 
No formal hypothesis testing of safety data will be undertaken; however, the data summaries 
will be examined for any trends amongst the dose levels. 
10.7 Interim analysis  
There will not be an interim analysis for this study. 
10.8 Analysis Populations 
The following analysis populations will be defined: 
Intent to treat (ITT) population 
All subjects randomized will be included in the ITT population, if: 
 At least one dose of study medication was administered  
Subjects will be assigned to treatment groups as randomized for analysis purposes. 
Per protocol (PP) population 
The per-protocol population will be defined as the subset of the ITT population without the 
following exclusions: 
 Major violation of inclusion or exclusion criteria 
 
Withdrawal from the study before week 2 
 Other major protocol violations, such as use of prohibited medication  
Details will be described in the data review plan. Subjects will be assigned to treatment 
groups as treated for analysis purposes. 
Safety (SAF) population 
All subjects randomized will be included in the SAF population, if: 
 At least one dose of study medication was administered and 
 At least one post randomization safety assessment was performed. 
Subjects will be assigned to treatment groups as treated for analysis purposes. 
 
Since the primary endpoint is EULAR response on Day 8, those subjects who had received 
the first dose on Day1 and EULAR response is assessed will be considered for primary 
endpoint analysis as these patients are fulfilling the requirement for primary endpoint 
assessment. Secondary endpoints are also assessed depending on the dataset available by 
which the particular endpoint can be calculated.  


CLR_15_05  
  
 
V3.1 25 September 2017 
 
61 of 71 
A list of protocol violations leading to exclusion from the PP population will be finalized before 
database lock. During the blind data review before database lock the PP population will be 
defined.  
10.9  Missing Data 
The handling of missing data for the clinical endpoints will be discussed in detail in the SAP. 
For the primary endpoint EULAR response on Day 8, subjects who withdraw from the study 
before Day 8, because of insufficient efficacy will be considered as non-responders. 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
62 of 71 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study is to be conducted in compliance with the protocol and in accordance with 
International Conference of Harmonisation (ICH) guidances, Good Clinical Practice (GCP) 
standards, the Declaration of Helsinki, the European Clinical Trial Directive 2001/20/EC of 4 
Apr 2001 and European Clinical Trial Directive 2005/28/EC of 8 Apr 2005 and local ethical 
and legal requirements. 
11.2 Recruitment and consent 
Subjects will be recruited from the investigational sites based on the eligibility criteria 
provided in the protocol.  
Voluntary written Informed Consent Form (ICF) must be obtained from each subject prior to 
performing any study related procedures in compliance with the recommendations of the 
Declaration of Helsinki. Subject should not be screened or study drug administered until the 
subject has signed an approved ICF written in a language that is understandable to the 
subject. 
Each subject should be given both verbal and written information describing the nature and 
duration of the clinical study. The ICF should be signed and personally dated in two originals 
by the subject and the person who conducted the informed consent discussion. The 
Investigator, or the attending health care professional, will explain the nature, purpose and 
risks of the study. The subject will be informed that he/she has the right to withdraw at any 
time from the study, without giving reasons. In this condition, the subject will also be informed 
that he/she will not receive any indemnity. The informed consent process should take place 
under conditions where the subject has adequate time to consider the risks and benefits 
associated with his/her participation in the study.  
Each subject should receive one original of the signed and dated written ICF and any other 
information provided to the subject. The second original of the signed and dated ICF should 
be retained in the Investigator’s file. The Investigator should maintain a log of all subjects 
who sign the ICF.  
11.3 Objection by minors or incapacitated subjects (if applicable) 
No minors or incompetent adults will be enrolled in this study. 
 
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
63 of 71 
11.4 Compensation for injury 
The Sponsor has a liability insurance which is in accordance with relevant legislation.  
In the event of any suffering, deterioration in health or well-being or any harmful susceptibility 
or tox
icity caused to subjects’ participation in the trial, the subject will receive appropriate 
compensation irrespective of the question of legal liability.  
The Sponsor has an insurance which is in accordance with the legal requirements in the 
participating countries. This insurance provides cover for damage to research subjects 
through injury or death caused by the study. The insurance applies to the damage that 
becomes apparent during the study or within 4 years after the end of the study. 
11.5 Incentives 
In addition to compensation for travel costs, a financial compensation will be provided to the 
subjects completing Baseline and Week 2 visits as compensation for the additional burden as 
per local regulations.  


CLR_15_05  
  
 
V3.1 25 September 2017 
 
64 of 71 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
12.1.1 
Data Handling 
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited.  With the subject’s permission, medical 
information may be given to his personal physician or other appropriate medical personnel 
responsible for his/her welfare. Data generated by this study must be available for inspection 
by representatives of, other national and local health authorities, the Sponsor, and the 
IRB/IEC for each study site, if appropriate. 
Subjects will be identified on CRFs and other documents submitted to the Sponsor or 
organisations working on behalf of the Sponsor by their subject number, or birth date, not by 
name or initials.  Documents not to be submitted to the Sponsor or organisations working on 
behalf of the Sponsor that identify the subject (e.g., the signed informed consent) must be 
maintained in confidence by the Investigator.  
12.1.2  Data Coding 
All subjects who sign a study informed consent will be assigned a unique subject 
identification number at the time of their Screening visit (after consent).  Subjects will be 
identified by this unique subject identification number for the duration of their participation in 
the study.  
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and subject names to enable records to be found at a later date. 
Subjects will be assigned identification numbers automatically via the eCRF. 
12.1.3  Data Confidentiality 
The Investigator is required to ensure that any documents or data given to the Sponsor or its 
representatives do not contain information that would affect the anonymity of the subjects. 
The Investigator will obtain permission for direct access to subject data from the subject as 
part of the written informed consent procedure. This gives permission to examine, analyze, 
verify, and reproduce any records and reports that are important to the evaluation of the trial. 
Any party (e.g., domestic and foreign regulatory authorities, Sponsor personnel or its 
representatives, and auditors) with direct access must take all reasonable precautions, within 
the constraints of the applicable regulatory requirement(s), to maintain the confidentiality of 
the subject’s identity and Sponsor’s proprietary information. 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
65 of 71 
12.1.4  Data Storage 
Each research site will retain copies/originals of the approved trial or study protocol, subjects
' 
participation agreements, relevant source documents and all other supporting documentation 
related to the trial or study for a period of fifteen (15) years. These documents should be 
retained for a longer (or shorter) period however if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. 
The Sponsor will provide each Investigator with information concerning the current status of 
the investigational drug as this may relate to the above stated obligation for the retention of 
study records. The Sponsor will inform each study site as to when these documents no 
longer need to be retained. Study sites should contact the Sponsor prior to disposing of or 
archiving any such records. 
12.2 Monitoring and Quality Assurance  
The Sponsor has ethical, legal and scientific obligations to conduct this study in accordance 
with established research principles and the ICH/GCP guidelines. The Sponsor’s 
representative has been delegated the responsibility for monitoring the conduct of the study 
in accordance with ICH/GCP. The Investigator must provide the monitor with full access to all 
source, medical and study documents as required for the study.  
The monitor assigned to each research site is responsible for establishing the schedule and 
procedures to be followed for monitoring this study. The major function of the clinical monitor 
is consistent with the ICH GCP Guidelines to ensure; the rights and well-being of human 
subjects are protected, the reported trial data are accurate, complete and verifiable from 
source documents and that the conduct of the trial is in compliance with the currently 
approved protocol, and local regulations.  The monitoring organization will be provided with 
appropriate training regarding the study IMP under investigation and will operate under 
written procedures to ensure compliance with the protocol. 
On-site monitoring visits include a pre-study visit, periodic visits, and a final visit at the close 
of the study. The pre-study visit is intended to review the Investigational Plan with the 
investigator and to ensure that the investigator: 
 has appropriate training, facilities, patient load, time, and willingness to comply 
with study requirements; 
 has the approval of the supervising Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) for the Investigational Plan;  
 has all study documentation and required records on site;  


CLR_15_05  
  
 
V3.1 25 September 2017 
 
66 of 71 
 and assumes responsibility for the investigation at her/his center. 
Periodic visits are intended to assess investigator
's adherence to the Investigational Plan, 
maintenance of records, reports and investigational products, and review of source 
documents for accuracy, completeness, and legibility. During these periodic visits, the 
monitor is required to assess the progress of the study toward meeting study objectives, and 
to identify any concerns that stem from observations of the review of the Investigator
's patient 
records, study management documents, and informed consent documents, and to ensure 
accountability of all patients that have been tested under the study. The monitor’s final on-
site visit at completion of the study is intended to assure that all of the data have been 
properly completed, and to conduct a closing meeting with the investigator and her/his staff 
members. 
Reports of the on-site visits will be made by the monitor and should include resolution of 
concerns, completion of appropriate follow-up activities, completion of assigned tasks, and 
any necessary corrective actions. At the close of the study, a final monitoring report will be 
prepared by the monitor. 
Communications by telephone, facsimile (fax) or mail (or email) may be used as needed to 
supplement site visits. Prior to the beginning of this study, each Investigator will be informed 
as to the anticipated frequency of the monitoring visits. In addition, the research site will 
receive reasonable notification prior to each monitoring visit during the course of the study. 
Principles of Risk-based monitoring will be employed for this study.  
At each visit, the Investigator will be expected to cooperate with Sponsor representative(s) 
for the review and verification of all CRFs, the drug supply and inventory records and any 
additional records as may have been previously arranged. 
12.3 Amendments  
The Investigator and research team must comply with ICH E6 principles and all applicable 
local regulatory laws and regulations. This protocol is to be followed exactly. To alter the 
protocol, amendments must be written, be agreed to by both the Sponsor and the 
Investigator, and receive IRB/IEC/Competent Authority approval prior to implementation (if 
appropriate).  
The IRB/IEC/Competent Authorities which granted original approval for the study must be 
notified of all changes in the protocol and must provide documented approval for any change 
or deviation which may increase the risk to the subject and/or which may adversely affect the 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
67 of 71 
rights of the subject or validity of the investigation. This stipulation does not apply to those 
changes made to reduce discomfort of or risk to subjects. 
A ‘substantial amendment’ is defined as an amendment to the terms of the IEC application, 
or to the protocol or any other supporting documentation, that is likely to affect to a significant 
degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
All substantial amendments will be notified to the IEC and to the Competent Authority. 
Non-substantial amendments will not be notified to the accredited IEC and the Competent 
Authority, but will be recorded and filed by the Sponsor. Examples of non-substantial 
amendments are typing errors and administrative changes like changes in names, telephone 
numbers and other contact details of involved persons mentioned in the submitted study 
documentation. 
All amendments will be distributed to all protocol recipients, with appropriate instructions. 
12.4 Annual progress report 
The Sponsor/Investigator will submit a summary of the progress of the trial to the accredited 
IRB/IEC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
12.5 End of study report 
The Sponsor will notify the accredited IRB/IEC and the Competent Authority of the end of the 
study within a period of 90 Days. The end of the study is defined as the last patient’s last 
visit.  
In case the study is ended prematurely, the Sponsor will notify the accredited IEC and the 
Competent Authority within 15 Days, including the reasons for the premature termination.  
  
Within one year after the end of the study, the Investigator/Sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited IEC and the Competent Authority.  
 


CLR_15_05  
  
 
V3.1 25 September 2017 
 
68 of 71 
12.6 Public disclosure and publication policy 
The final report will be written in English in a Word format and its structure will follow a 
template based upon the ICH E3
(i) guidelines unless otherwise specified by the Sponsor 
during financial agreement. 
Suggested inclusions in the report are: study objectives, materials and methods (including 
any deviations from the study protocol), evaluation of the study results, observations by the 
Investigator as to the value of the study drug per se, and a discussion of all adverse 
experiences with interpretation by the Investigator as to the study drug involvement. 
All information concerning the tested drug and the Sponsor
's operation, such as patent 
applications, formulae, manufacturing processes, basic scientific data and formulation 
information supplied by the Sponsor and not previously published are considered confidential 
and shall remain the sole property of the Sponsor. The Investigator agrees to use this 
information only in accomplishing this study and will not use it for other purposes without 
written consent from the Sponsor.  
It is understood by the Investigator that the information from the clinical study will be used by 
the Sponsor in connection with the development of the tested drug and, therefore, may be 
disclosed as required to other clinical Investigators or to government agencies. In order to 
allow for the use of the information derived from the clinical studies, it is understood that 
there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study. 
The trial drug and the information in this document and in any future information supplied 
contain trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by law or regulations.  
In any event, persons to whom the information is disclosed must be informed that the 
information is privileged or confidential and may not be further disclosed by them. 
Publication rules will be consistent with local regulation and will be addressed in the study 
contract and should not be in contradiction with the text in the protocol. 
 


CLR_15_05  
  
 
V3.0 10 February 2017 
 
69 of 71 
 
13. REFERENCES 
 
1. Bodman KB, Roitt IM. The pathophysiology of rheumatoid arthritis. Fund Am Clin 
Immunol 1994; 2:73–81. 
2. Guidelines for the management of rheumatoid arthritis: American College of 
Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 
39:713–22. 
3. Saag KG. Glucocorticoid use in rheumatoid arthritis. Curr Rheumatol Rep 2002; 
4:218–25 
4. Snell ES. The pharmacological properties of corticosteroids in relation to clinical 
efficacy. Br J Dermatol 1976; 94 SupPEG-lip PLP 12:15–23. 
5. Nanocort Development Safety Update Report (DSUR) #4, 25 March 2015. 
6. Aletaha, D., et al., 2010 rheumatoid arthritis classification criteria: an American 
College of Rheumatology/European League Against Rheumatism collaborative 
initiative. Arthritis & Rheumatism, 2010. 62(9): p. 2569-2581. 
7. Sokka, T., M. Envalds, and T. Pincus, Treatment of rheumatoid arthritis: a global 
perspective on the use of antirheumatic drugs. Mod Rheumatol, 2008. 18(3): p. 
228-39. 
8. Singh, J.A., et al., 2012 Update of the 2008 American College of Rheumatology 
recommendations for the use of disease‐modify
ing antirheumatic drugs and 
biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 
(Hoboken), 2012. 64(5): p. 625-639. 
9. Smolen, J.S., et al., EULAR recommendations for the management of rheumatoid 
arthritis with synthetic and biological disease-modify
ing antirheumatic drugs. Ann 
Rheum Dis, 2010. 69(6): p. 964-75. 
10. http://www.ema.europa.eu/docs/en GB/documentlibrary/Scientificguideline/2015/
06/WC500187583. 
11. Duru, N., et al., EULAR evidence-based and consensus-based recommendations 
on the management of medium to high-dose glucocorticoid therapy in rheumatic 
diseases. Ann Rheum Dis, 2013. 72(12): p. 1905-13. 
12. Hoes, J.N., et al., EULAR evidence-based recommendations on the management 
of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis, 2007. 
66(12): p. 1560-7. 
13. Dams ET, Oyen WJ, Boerman OC, Storm G, Laverman P, Kok PJ, Buijs WC, 
Bakker H, van der Meer JW, Corstens FH. 99mTc-PEG liposomes for the 
scintigraphic detection of infection and inflammation: clinical evaluation. J Nucl Med 
2000; 41:622-630. 
15. Metselaar, J.M., et al., Complete remission of experimental arthritis by joint 
targeting of glucocorticoids w
ith long-circulating liposomes. Arthritis Rheum, 2003. 
48(7): p. 2059-66. 
16. Metselaar, J.M., et al., Liposomal targeting of glucocorticoids to synovial lining cells 
strongly increases therapeutic benefit in collagen type II arthritis. Ann Rheum Dis, 
2004. 63(4): p. 348-53. 


CLR_15_05  
  
 
V3.0 10 February 2017 
 
70 of 71 
17. Nanocort Investigator’s Brochure (IB) Edition 5.0, Release Date 17 July 2015.   
18. http://www.rx
list.com/depo-medrol-drug.htm. 
19. http://emupdates.com/wp-content/uploads/2009/11/ICUPocketGuide.pdf. 
20. Wo
lfe F1, Michaud K, Pincus T., Development and validation of the health 
assessment questionnaire II: a revised version of the health assessment 
questionnaire.  Arthritis Rheum. 2004 Oct;50(10):3296-305. 
21. Ware JE Jr1, Sherbourne CD, The MOS 36-item short-form health survey (SF-36). 
I. Conceptual framework and item selection. Med Care. 1992 Jun; 30(6):473-83. 
22. http://www.facit.org/FACITOrg/Questionnaires. 
23. Felson DT1, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, 
Lightfoot R Jr, Paulus H, Strand V, et al., American College of Rheumatology. 
Preliminary definition of improvement in rheumatoid arthritis Arthritis Rheum. 1995 
Jun; 38(6):727-35. 
 
14 APPENDICES 
 
14.1 
SF-36 
14.2  
HAQ 
14.3  
FACIT 
14.4  
Health Economics Questionnaire 
 
Note: Appendices are samples only; current versions will be used as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CLR_15_05  
  
 
V3.0 10 February 2017 
 
71 of 71 
 
 






CLR_15_05 SAP 
V5.2 June 7, 2018 
 
3 of 40 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................... 5 
1. 
INTRODUCTION .......................................................................................................... 7 
1.1 
STUDY POPULATION ................................................................................................................... 7 
1.2 
STUDY DESIGN .......................................................................................................................... 7 
1.3 
PRIMARY AND SECONDARY STUDY OBJECTIVES .......................................................................... 11 
1.3.1 
Primary Objectives ......................................................................................................... 11 
1.3.2 
Secondary Objectives .................................................................................................... 11 
1.4 
PRIMARY, KEY SECONDARY AND SECONDARY ENDPOINTS ......................................................... 11 
1.4.1 
Primary Endpoint ........................................................................................................... 11 
1.4.2 
Key Secondary Endpoints ............................................................................................. 11 
1.4.3 
Secondary Endpoints ..................................................................................................... 11 
2. 
ANALYSIS POPULATIONS ........................................................................................... 12 
2.1 
INTENT-TO-TREAT POPULATION ................................................................................................ 12 
2.2 
PER-PROTOCOL POPULATION ................................................................................................... 13 
2.3 
PHARMACOKINETIC EVALUABLE POPULATION ............................................................................ 13 
2.4 
SAFETY POPULATION ............................................................................................................... 13 
3. 
BLINDED REVIEW OF THE DATA ................................................................................. 14 
4. 
STATISTICAL AND ANALYTICAL METHODS .................................................................. 14 
4.1 
GENERAL STATISTICAL CONSIDERATIONS.................................................................................. 14 
4.2 
MISSING DATA HANDLING ......................................................................................................... 15 
4.3 
BASELINE DEFINITION ............................................................................................................... 15 
4.4 
DEFINITION OF STUDY DAY AND VISIT WINDOW ......................................................................... 15 
4.4.1 
Study Day ............................................................................................................................ 15 
4.4.2 
Visit Window ........................................................................................................................ 16 
4.5 
PATIENT DISPOSITION .............................................................................................................. 16 
4.6 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS.................................................................... 16 
4.7 
MEDICAL AND SURGICAL HISTORY ............................................................................................ 17 
4.8 
EFFICACY ANALYSIS ................................................................................................................. 17 
4.8.1 
Original Analyses ........................................................................................................... 17 
4.8.2 
Simplified Analyses ........................................................................................................ 20 
4.8.3 
Other Secondary Analyses ............................................................................................ 20 
4.9 
SAFETY ANALYSES ................................................................................................................... 23 
4.9.1 
Laboratory Results ................................................................................................................ 23 
4.9.2 
Vital Signs ............................................................................................................................ 24 
4.9.3 
Physical Examinations ........................................................................................................... 24 
4.9.4 
ECG ..................................................................................................................................... 24 
4.9.5 
Concomitant Medications ..................................................................................................... 24 
4.9.6 
Adverse Events ..................................................................................................................... 24 
4.10 
PK ANALYSIS ........................................................................................................................... 25 
4.11 
MODIFICATIONS FROM THE STATISTICAL SECTION IN THE PROTOCOL ........................................... 25 
5. 
INTERIM ANALYSES ................................................................................................... 26 
6. 
SAMPLE SIZE AND POWER CALCULATIONS ................................................................ 26 
7. 
TABLES, LISTINGS AND FIGURES ................................................................................ 28 
8. 
STATISTICAL SOFTWARE ............................................................................................ 31 
9. 
REFERENCES .............................................................................................................. 31 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
4 of 40 
10. 
APPENDIX A – SCORING AND CODING FOR SF-36 – SHORT FORM 36 ...................... 32 
11. 
APPENDIX B – SCORING AND CODING FOR EULAR .................................................. 35 
12. 
APPENDIX C – SCORING AND CODING FOR DAS28 .................................................. 36 
13. 
APPENDIX D – SCORING AND CODING FOR ACR 20/50/70 ...................................... 37 
14. 
APPENDIX E – SCORING AND CODING FOR HAQ ..................................................... 38 
15. 
APPENDIX F – SCORING AND CODING FOR FACIT .................................................... 39 
 
 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
5 of 40 
List of abbreviations 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CA 
Competent Authority 
CK 
Creatine kinase 
Ca++ 
Calcium 
CRF 
Case report form 
CRP 
C-reactive protein 
DAS28 
Disease Activity Score in 28 Joints 
DMARDs 
Disease-modifying antirheumatic drugs 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of study 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FACIT 
The Functional Assessment of Chronic Illness Therapy 
FWER 
Family wise error rate 
HAQ 
Health Assessment Questionnaire 
HEQ 
Health Economics Questionnaire 
HbA1c 
Hemoglobin A1c 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
Hgb 
Hemoglobin 
ICF 
Informed Consent Form 
ITT 
Intent To Treat 
IV 
Intravenous 
IWRS 
Interactive Web-based Randomization System 
K+ 
Potassium 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MTX 
Methotrexate 
Na+ 
Sodium 
PE 
Physical examination 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
Per protocol  
QoL 
Quality of Life 
RA 
Rheumatoid Arthritis 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
6 of 40 
RBC 
Red blood cells 
RF 
Rheumatoid Factor 
SAE 
Serious Adverse Event  
SAF 
Safety 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SF-36 
Short Form 36 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SPC 
Summary of Product Characteristics 
VAS 
Visual Analogue Scale 
WBC 
White blood cells 
 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
7 of 40 
1. 
 Introduction 
 
This analysis plan gives a detailed description of the statistical methodologies, data 
listings, and summary tables planned in the analysis of the data in the CLR_15_05 study. 
The statistical data analysis, described in this document, is intended to provide unbiased and 
valid conclusions concerning the objectives of the study.  
1.1 Study Population 
The study has been conducted at 21 sites in the Netherlands and Belgium. Sites were 
selected based on previous study experience in RA and accessibility to study required 
populations. The study population will consist of male and female subjects (≥ 18 years old) 
with active RA who are experiencing a flare / exacerbation defined as a recent increase in 
symptoms and a measured increase in DAS28 > 1.2 or > 0.6 if DAS28 ≥ 3.2 despite disease-
modifying anti-rheumatic drugs (DMARDs) therapy or treatment naïve patients compared to 
last DAS28 measurement (maximum 6 months before screening).  
1.2 Study Design  
The study is a randomized, double- blind, double dummy, active controlled, parallel, 
multi-center study in which IV Pegylated Liposomal Prednisolone Sodium Phosphate 
(Nanocort) will be compared with IM injection of methylprednisolone acetate (Depo-
Medrol®) to evaluate efficacy and safety.  Each patient will receive an infusion and an IM 
injection containing either an active treatment or a dummy treatment. Opaque IV lines, 
sleeved bags and opaque syringes will be used to maintain blinding of either liposomal 
product or reference product. The total duration of the trial is 14 weeks maximum for each 
subject (up to 2 weeks of screening period and 12 weeks of treatment with follow up). 
During this 14 weeks study, the dosage of any DMARDs should not be changed (in case 
the subject is receiving such treatment at screening).  All subjects will be provided an 
informed consent form (ICF) containing information about the study. After fully 
understanding of the ICF, subjects will voluntarily sign the ICF. Subjects will enter a screening 
period for up to 14 Days to assess laboratory values and other inclusion/exclusion criteria. 
Medical history and serious medical conditions as determined by the Principal Investigator 
(PI) will be reviewed during screening. In addition, the screening period will include a 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
8 of 40 
physical examination, blood and urine collection for laboratory assessments, vital signs, 
electrocardiogram (ECG) and confirmation of RA diagnosis (flare criteria).  
Subjects with active RA who meet all eligibility criteria will undergo Baseline visit (Day 
1) assessments. At this visit, prior to receiving treatments, subjects will be assessed for 
baseline parameters and then will be randomized. A total of up to 330 subjects will be 
enrolled and randomized into 3 groups indicated below: 
 Nanocort 75 mg IV infusion and IM saline injection 
 Nanocort 150 mg IV infusion and IM saline injection 
 Depo-Medrol® 120 mg IM injection and IV saline infusion 
Dosing will occur on Baseline (Day 1) and Week 2 (Day 15). Study visits will occur at Week 1, 
Week 2, Week 3, Week 4, Week 6, Week 8 and Week 12 / End of Study (EOS) to assess 
efficacy and safety evaluations as indicated in the Schedule of Assessments. Subjects 
receiving any treatment dose will be followed till Week 12 for safety if possible. 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
9 of 40 


CLR_15_05 SAP 
V5.2 June 7, 2018 
 
10 of 40 
 
 
 
 
 
 
 
 
 
    
 
  
  
 
 
    
 
 
    


CLR_15_05 SAP 
V5.0 June 2, 2018 
11 of 40 
 
1.3 Primary and secondary study objectives 
1.3.1 Primary Objectives 
To assess efficacy and safety (treatment of signs and symptoms) of Nanocort 
in comparison to a standard of care medication (Depo-Medrol) in subjects with 
active rheumatoid arthritis who are experiencing a flare/exacerbation. 
1.3.2 Secondary Objectives 
 To evaluate patient-reported outcomes in subjects with Active Rheumatoid 
Arthritis who are experiencing a flare/exacerbation receiving IV Nanocort as 
compared with subjects receiving IM injections of Depo-Medrol. 
 To assess PK parameters, in a subset population from each treatment group.   
1.4 Primary, Key Secondary and Secondary Endpoints 
1.4.1 Primary Endpoint 
 The EULAR responder (moderate and good combined) rate at Week 1 (Day 
8) 
1.4.2 Key Secondary Endpoints 
 The EULAR good responder (only good) rate at Week 1 (Day 8) 
 The EULAR responder (moderate and good combined) rate at Week 2 (Day 
15) 
 The EULAR good responder (only good) rate at Week 2 (Day 15) 
1.4.3 Secondary Endpoints 
 EULAR response at Week 1 (Day 8), Week 2 (Day 15), Week 3, 4, 6, 8 and 12  
 DAS28 mean and % change from baseline at Week 1, 2, 3, 4, 6, 8 and 12 
 Time to first EULAR responder (moderate/good)  
 ACR 20/50/70 response scores at Week 1, 2, 3, 4, 6, 8 and 12 
 Tender joint counts at Week 1, 2, 3, 4, 6, 8 and 12 
 Swollen joint counts at Week 1, 2, 3, 4, 6, 8 and 12 
 Patient pain and Global Visual Analog Score (VAS) score at Week 1, 2, 3, 4, 6, 
8 and 12 
 Investigator Global Visual Analog Score (VAS) score at Week 1, 2, 3, 4, 6, 8 
and 12 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
12 of 40 
 
 
 
 
 
 
 
 
 
 
 
 Short Form 36 (SF-36) to assess physical and mental component at Week 1, 
2, 4, 6 and 12 
 Health Assessment Questionnaire (HAQ) at Week 1, 2, 3, 4, 6, 8 and 12.  
 The Functional Assessment of Chronic Illness Therapy (FACIT) at Baseline, 
Week 4 and 6  
 Health Economics Questionnaire at Week 12 
 Maintenance of Improvement at 12 Weeks assessed during a blinded review 
by the Medical Monitor and PI at the end of the study, before database lock 
 Pharmacokinetics (PK) assessment in subset of patient population at 
Baseline, Week 1, 2, 3, 4 and 6 
 AEs (including glucocorticoid related AEs), AEs leading to withdrawal, AEs 
leading to discontinuation of medication, and AEs due to infusion reactions) 
 Vital signs 
 Physical examinations 
 Laboratory 
 ECG 
 Assessment by monitoring cortisol levels at Screening, Baseline 6 and 12 -
weeks  
2. 
Analysis Populations 
 
Analysis of safety data will be based on the safety population (SAF). The 
primary analysis population for efficacy will be the Intent-to-Treat (ITT) population. 
Analysis of primary efficacy endpoint and key secondary endpoints will also be 
performed on the Per-Protocol (PP) population to confirm the findings from the ITT 
population. 
2.1 Intent-to-Treat Population 
All patients randomized into the study will be included in the ITT population, if 
at least one dose or a part of Nanocort IV/Placebo infusion or Depo-Medrol/placebo 
IM injection was administered and at least one post-baseline efficacy measurement 
was performed. 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
13 of 40 
 
 
 
 
 
 
 
 
 
 
 
Patients will be analyzed within the original treatment group they were 
randomized to. All analyses will be completed for the ITT population. The main 
analyses for assessment of study success will be analysis of the primary endpoint on 
the ITT population (see section 4.8). 
2.2 Per-Protocol Population 
The PP population is defined as a subset of the ITT population excluding major 
protocol violators. The following is a list of some of the conditions which, if met, 
would likely exclude the patient from the PP population: 
 Violation of inclusion or exclusion criteria 
 Breaking the blind 
 Randomization irregularities 
 Withdrawal from the study before week 12 
 Current use of prohibited DMARDs or biological RA treatments per protocol  
 Any other relevant violations observed during the conduct of the trial 
Final specification of the criteria, definitions and processes are detailed in the 
‘Blinded Review Report of Deviations Leading to Exclusion from the Per-Protocol 
Analysis’ document. 
Patients will be analyzed based on the treatment received.  Analyses on the 
PP population will be seen as supportive analyses. The primary and secondary 
efficacy endpoints will be analyzed for the PP population.  
The list of protocol deviations leading to exclusion from the PP population will 
be finalized before database lock. During the blind data review before database lock 
the PP population will be defined by determining subjects not eligible for the PP 
population and the reason they cannot be included. 
2.3 Pharmacokinetic Evaluable Population 
This SAP describes only the analyses for the study objectives not involving the 
PK objectives. The PK objectives will be described in a separate analysis plan. 
2.4 Safety Population 
The safety population (SAF) will include all patients who receive at least one 
infusion or part of infusion with Nanocort/placebo or at least one IM injection or 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
14 of 40 
 
 
 
 
 
 
 
 
 
 
 
part of IM injection with Depo-Medrol/placebo and had at least one post baseline 
safety assessment.  
Patients will be assigned to treatment groups as treated for analysis.  
3. 
Blinded Review of the Data 
A blinded data review will be held before breaking the blind. The blinded 
data review will be performed by at least the Principal Investigator, the Medical 
Monitor, the Study Lead and the Trial Statistician. The goal of the blinded data 
review is to determine for each subject the maintenance of improvement at 12 
Weeks, the protocol violations and to evaluate the impact of these protocol 
violations on the EULAR response. 
The decisions taken during the blinded data review will be finalized and 
signed by participants on the blinded data review report before unblinding. 
4. 
Statistical and Analytical Methods 
This analysis plan gives a detailed description of the statistical 
methodologies, data listings, and summary tables planned in the analysis of the 
data in the CLR-15-05 study.  This section describes the statistical analyses of the 
study 
based 
on 
the 
statistical 
section 
of 
the 
protocol 
(CLR15_05_Prot_V3.1_Amend_25Sep2017.pdf). Any difference with the protocol 
will be identified and documented.  The statistical data analysis, described in this 
document, is intended to provide unbiased and valid conclusions concerning the 
objectives of the study.   
This SAP describes only the analyses for the study objectives not involving the 
PK objectives. The PK objectives will be described in a separate analysis plan. 
4.1 General Statistical Considerations 
Individual data listings will be provided for all subjects enrolled, sorted by 
treatment group, site, subject and time point. Summary tables will be presented for 
the safety population by treatment group.  
Descriptive statistics for continuous variables will be number of subjects (N), 
mean (Mean), standard deviation (SD), median (Median), minimum (Min) and 
maximum (Max). For categorical variables, the absolute (N) and relative frequency 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
15 of 40 
 
 
 
 
 
 
 
 
 
 
 
(%) will be tabulated. Confidence intervals (CI) for mean values will be added if 
appropriate. 
The analyses of the primary and key secondary efficacy endpoint are 
described in sections 4.8.1 and 4.8.2.  
Due to early termination of the study, the sample size will be much less than 
planned.  As a result, the statistical power can be inadequate for the planned 
gatekeeping methodology.  Therefore, standard hypothesis testing methods may be 
used instead to analyze the data. 
4.2 Missing Data Handling 
Imputation will be implemented for partial start/end dates of adverse events 
dates.  If the start day is missing, impute the 1st of the month, unless month and 
year are the same as month and year of the first dose of study drug then impute the 
first dose date. If start day and start month are both missing, impute 1st January but 
if year is the same as year of the first dose date, then impute first dose date.  If the 
end day is missing, impute the last day of the month. If end day and end month are 
both missing impute 31st December.  No other imputation of missing data will be 
performed, and only available data will be presented.  
4.3 Baseline Definition 
For all variables, baseline will be considered to be the last value obtained 
prior to first start of treatment, and may be on Screening or on Day 1, dependent on 
parameter. Change from baseline will be the difference between the value at a 
given time point and the baseline value. 
4.4 Definition of Study Day and Visit Window  
4.4.1 Study Day 
For each patient, the day of first dose of study medication 
(Nanocort/placebo 
IV 
infusion 
and 
Depo-Medrol/placebo 
IM 
injection) 
administered on or after the day of randomization will be considered study day 1.  
Each assessment will be assigned a study day. The calculation for study day is 
dependent on whether the actual date of assessment is before or after the date of 
study day 1 and is calculated as follows: 




CLR_15_05 SAP 
 
V5.2 June 7, 2018 
17 of 40 
 
 
 
 
 
 
 
 
 
 
 
4.7 Medical and Surgical History 
Numbers and percentages of subjects with any known history of relevant 
abnormalities, disease or surgery will be summarized by treatment group and 
overall. Reported term, preferred term, body system code, date of onset/procedure 
and date of resolution or ongoing will be listed.  
Medical history will be coded by the MedDRA coding dictionary, version 19. 
4.8 Efficacy Analysis 
The primary and key secondary analyses will be completed for the ITT and PP 
populations. 
Due to early termination of the study, the sample size will be much less than 
planned.  As a result, the statistical power can be inadequate for the planned 
gatekeeping methodology.  Therefore, standard hypothesis testing methods may be 
used instead to analyze the data. 
To account for these possibilities and to facilitate better understanding of the 
data, the data will be analyzed ‘as planned’ in the protocol AND using more simple, 
unadjusted alpha analyses with basic chi-square tests.  Therefore the data (Table 8A 
and 8B) will be analyzed two ways: 
- 
Original Primary and Key Secondary Analyses using Hochberg’s 
procedure and gatekeeping methods  
- 
Modified Primary and Key Secondary Analyses using simple chi-square 
tests. 
4.8.1 Original Analyses 
4.8.1.1 Primary Analyses 
The primary endpoint is EULAR response (good and moderate combined) 
rate at Day 8.  The primary analysis involves two comparisons: 1) Nanocort 150 mg 
vs. Depo-Medrol®, 2) Nanocort 75 mg vs. Depo-Medrol®. 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
18 of 40 
 
 
 
 
 
 
 
 
 
 
 
H0,1 : EULAR response (good and moderate combined) rate at Day 8 for Nanocort 
150 mg - EULAR responder rate at Day 8 for Depo-Medrol® = 0 
vs 
H1,1 : EULAR response (good and moderate combined) rate at Day 8 for Nanocort 
150 mg - EULAR responder rate at Day 8 for Depo-Medrol® ≠ 0 
and 
H0,2 : EULAR response (good and moderate combined) rate at Day 8 for Nanocort 
75 mg - EULAR responder rate at Day 8 for Depo-Medrol®  = 0 
vs 
H1,2 : EULAR response (good and moderate combined) rate at Day 8 for Nanocort 
75 mg - EULAR responder rate at Day 8 for Depo-Medrol® ≠ 0 
The primary analyses will be completed for the ITT and PP populations. 
4.8.1.2 Key Secondary Analyses 
The three key secondary endpoints are:  1) EULAR response (good) rate at 
Day 8, 2) EULAR response (good and moderate combined) rate at Day 15, and 3) 
EULAR response (good) rate at Day 15.  Both comparisons (Nanocort 150 mg vs. 
Depo-Medrol®, and Nanocort 75 mg vs. Depo-Medrol®) will be completed for each 
of the three key secondary endpoints (i.e., up to 6 key secondary analyses). 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
19 of 40 
 
 
 
 
 
 
 
 
 
 
 
The key secondary hypotheses will only be tested if at least one primary 
analysis is significant. If for one of the dosages the primary analyses is not 
significant, then the corresponding key secondary hypotheses will not be tested. 
The key secondary hypotheses will be tested with a two-sided confidence level, αs. 
The calculation of αs depends on the maximum p-value from the primary 
hypotheses, the significance of the primary hypotheses and αp.  
Step 1: The primary hypotheses are tested using Hochberg procedure at αp = 0.045 
< α (0.05). If at least one of the primary null hypotheses is rejected then go to Step 
2. The significance value for Step 2 (αs) is a function of largest primary p-value. 
Step 2:  Test the secondary null hypotheses using Hochberg procedure at αs. 
                    
αs = min( λ α*/(p*)2, αp)         
 
if p* > αp  and  
αs = α  
 
  
 
 
if p* <= αp  
 Where p* is the largest primary p-value, λ is chosen to control the global FWER at 
the alpha level. 
                     
α* = αp(1-sqrt(2- αp/(k1- 1) – α / αp)2   
if  α’ <= α 
                          =    αp (α - αp)/ (k1 -1 - αp)    
 
 
if   α’ >   α    
Where α’ = αp + αp
2/(k1 – 1) - αp
3 /(k1 – 1)2 
           K1 = Number of primary endpoints (in this case k1 = 2) 
The significance level carried over to αs depends on the magnitude of the primary p-
values rather than the number of significant primary p-values. This method assumes 
a full parametric model.  The joint distribution of the hypotheses in primary and 
secondary endpoints is considered to calculate λ. If the joint distribution of the test 
statistic is not specified, the λ parameter is chosen under the worst-case scenario. 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
20 of 40 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The key secondary analyses will be completed for the ITT and PP 
populations. 
4.8.2 Simplified Analyses 
The primary and key secondary analyses will be completed using the 
Hochberg and gatekeeping methodology described above but will also be analyzed 
using simple chi-square tests. 
The simplified analyses will be completed for the ITT and PP populations. 
4.8.3 Other Secondary Analyses 
All other secondary analyses will be completed for both the ITT and PP 
populations.  EULAR response (good, moderate, no response) at Week 1, 2, 3, 4, 6, 8 
and 12 will be summarized by treatment group and the treatment groups will be 
compared by using the non-parametric Wilcoxon-Mann-Whitney test. 
DAS28 will be summarized and analyzed at Week 1, 2, 3, 4, 6, 8 and 12.  The 
DAS28 score is calculated as follows: 





GH
ESR
SJC
TJC
DAS
e








0142
.0
log
7.0
284
.0
555
.0
28
 
where TJC = tender joint counts on 28 joints, SJC = swollen joint counts on 28 joints, 
GH = general health, i.e. patient’s global assessment of disease activity (100 mm 
VAS) and ESR = erythrocyte sedimentation rate (mm/hr). If ESR was not available, 
then CRP may be used instead. See Appendix C for details on scoring and coding. At 
a particular timepoint, if one or more of the four components used in calculating 
DAS28 are missing, then the DAS28 will be considered missing at that timepoint. 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
21 of 40 
 
 
 
 
 
 
 
 
 
 
 
If DAS28 scores are approximately normally distributed via visual inspection, 
then DAS28 scores at 1, 2, 3, 4, 6, 8 and 12 weeks will be analyzed using analysis of 
covariance (ANCOVA), including baseline scores and study site as covariates.  If 
DAS28 scores are markedly non-normally distributed via visual inspection, then the 
Kruskal-Wallis test will be used to compare the groups at each time point. In 
addition to the group comparison, the time course of DAS28 scores will be 
submitted to a repeated measures analysis of variance, with treatment group, time 
and the interaction of treatment group and time in the model. 
If the percentage change in DAS28 scores is approximately normally 
distributed via visual inspection, then % change at 1, 2, 3, 4, 6, 8 and 12 weeks will 
be analyzed using ANCOVA, including baseline scores and study site as covariates.  If 
% change is markedly non-normally distributed via visual inspection, then the 
Kruskal-Wallis test will be used to compare the groups at each time point. In 
addition to the group comparison, the time course of % change will be submitted to 
a repeated measures analysis of variance, with treatment group, time and the 
interaction of treatment group and time in the model. 
Time to first EULAR response (moderate or good) will be analyzed using the 
Kaplan-Meier method; comparison between the treatment groups will be 
performed using the log-rank test. 
American College of Rheumatology (ACR) 20/50/70 response at week 1, 2, 
3, 4, 6, 8 and 12 will be summarized and analyzed.  See Appendix D for details on 
scoring and coding. ACR score is a scale to measure change in rheumatoid arthritis 
symptoms. It is named after the American College of Rheumatology. Different 
degrees of improvement are referred to as ACR20, ACR50, ACR70. The following 
definition of improvement was selected: 20% improvement in tender and 
swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set 
measures: patient and physician global assessments, pain, disability, and an 
acute-phase reactant [23]. ACR 50 and ACR 70 criteria are defined in a manner 
similar to that for ACR 20, but with improvement of at least 50 percent and 70 
percent in the individual measures, respectively.  The comparison of ACR20, 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
22 of 40 
 
 
 
 
 
 
 
 
 
 
 
ACR50 and ACR70 response rates among treatment groups will be analyzed using 
a stratified Cochrane-Mantel-Haenszel test. 
Tender and swollen joint counts at week 1, 2, 3, 4, 6, 8 and 12 will be 
summarized.  The DAS28 score and the EULAR Response incorporate the tender and 
swollen joint counts. For this reason, no formal testing will be done between the 
three treatment groups.  
 
Four Visual Analog Scores (VAS) will be summarized and analyzed at week 
1, 2, 3, 4, 6, 8 and 12 including:  1) patient VAS value for experience of pain, 2) 
patient VAS value for General Health, 3) patient VAS value for RA activity, and 4) 
investigator VAS value for RA activity. 
If the change from baseline in VAS is approximately normally distributed via 
visual inspection, then the change from baseline in VAS at 1, 2, 3, 4, 6, 8 and 12 
weeks will be analyzed using ANCOVA, including baseline scores and study site as 
covariates.  If the change from baseline in VAS is markedly non-normally distributed 
via visual inspection, then the Kruskal-Wallis test will be used to compare the 
groups at each time point.  
Short Form 36 (SF-36) to assess physical and mental component at baseline, 
week 1, 2, 4, 6, and 12 will be summarized and analyzed.  See Appendix A for details 
on scoring and coding. If the change from baseline is approximately normally 
distributed via visual inspection, then the change from baseline at 1, 2, 3, 4, 6, 8 and 
12 weeks will be analyzed using ANCOVA, including baseline scores, age and gender 
as covariates.  If the change from baseline is markedly non-normally distributed via 
visual inspection, then the Kruskal-Wallis test will be used to compare the groups at 
each time point. 
Health Assessment Questionnaire (HAQ) at baseline, week 1, 2, 3, 4, 6, 8 and 
12 will be summarized and analyzed.  See Appendix E for details on scoring and 
coding. If the change from baseline is approximately normally distributed via visual 
inspection, then the change from baseline at 1, 2, 3, 4, 6, 8 and 12 weeks will be 
analyzed using ANCOVA, including baseline HAQ, baseline DAS28 and study site as 
covariates.  If the change from baseline is markedly non-normally distributed via 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
23 of 40 
 
 
 
 
 
 
 
 
 
 
 
visual inspection, then the Kruskal-Wallis test will be used to compare the groups at 
each time point. 
FACIT Fatigue Scale at baseline, week 4 and 6 will be summarized and 
analyzed.  See Appendix F for details on scoring and coding.  If the change from 
baseline is approximately normally distributed via visual inspection, then the 
change from baseline at 1, 2, 3, 4, 6, 8 and 12 weeks will be analyzed using 
ANCOVA, including baseline FACIT, baseline DAS28 and study site as covariates.  If 
the change from baseline is markedly non-normally distributed via visual inspection, 
then the Kruskal-Wallis test will be used to compare the groups at each time point. 
Maintenance of Improvement at 12 Weeks assessed during a blinded review 
by the Medical Monitor (MM) and Principal Investigator (PI) at the end of the study 
will be compared between treatment groups using a stratified Cochrane-Mantel-
Haenszel test, stratified by study site. 
The Health Economics Questionnaire (HEQ) at week 12 will be summarized in 
a table of the responses for each treatment group as recorded on the 
questionnaire. 
4.9 Safety Analyses 
Safety results (AEs, vital signs, physical examinations, laboratory, ECG) will be 
compared between the Nanocort arms and the Depo-Medrol arm. Shift tables and 
shift plots will be used to evaluate changes in clinical laboratory test results at 
different time points compared to Baseline values. Proportion of patients whose 
test values are outside specific ranges will also be presented.  All abnormalities in 
physical examination, ECG and vital signs will be presented. 
No formal hypothesis testing of safety data will be undertaken; however, the 
data summaries will be examined for any trends amongst the dose levels. 
4.9.1 Laboratory Results 
Hematology, chemistry and urinalysis analysis test results in SI units will be 
summarized by lab test, treatment group and time point. For hematology, 
chemistry and urinalysis tests, changes from baseline will be included in these 
tables. 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
24 of 40 
 
 
 
 
 
 
 
 
 
 
 
Abnormality findings i.e. normal, abnormal, not clinically significant (NCS) or 
abnormal, clinically significant (CS) will be summarized by lab test, treatment group 
and time point.  
Shift tables will be provided for each lab test with baseline value (low, 
normal, high) for each treatment group across the top and the time point value 
(low, normal, high) along the side. 
4.9.2 Vital Signs 
Vital sign results and absolute changes from baseline for systolic blood 
pressure, diastolic blood pressure, heart rate, respiration rate and body 
temperature will be summarized by treatment group and time points.  
4.9.3 Physical Examinations 
The complete and abbreviated physical examination results will be tabulated 
by treatment group and time points. The number and percentage of subjects with 
normal, abnormal, not clinically significant and abnormal, clinically significant 
results will be given. 
4.9.4 ECG 
The number and percentage of subjects with clinically significant results will 
be summarized by treatment group and time point. 
4.9.5 Concomitant Medications 
The number and percentage of subjects with at least one concomitant 
medication (CM) and one CM given for AE will be tabulated by treatment and 
overall.  Concomitant medication will be coded by the WHODD coding dictionary 
version June 2015. 
4.9.6 Adverse Events 
The number and percentages of subjects with different AEs will be tabulated 
with MedDRA System Organ Class (SOC) and Preferred Term (PT) by treatment and 
overall. If a subject had more than one AE for a particular SOC, he/she will be 
counted only once for that SOC. If a subject had more than one AE for a particular 
PT, he/she will be counted only once for that PT.  In addition, summary tables will 
include occurrence rates for:  


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
25 of 40 
 
 
 
 
 
 
 
 
 
 
 
- 
AE,  
- 
SAE 
- 
Severe AE 
- 
AE related to IM injection 
- 
SAE related to IM injection 
- 
AE related to IV infusion 
- 
SAE related to IV infusion 
- 
IM injection related AE leading to drug withdrawal 
- 
IV infusion related AE leading to drug withdrawal 
- 
AE leading to death 
- 
AE leading to concomitant medication 
- 
AE starting during IV infusion 
- 
AE starting within 24 hrs of end of IV infusion 
- 
AE requiring treatment given. 
Adverse events will be coded by the MedDRA coding dictionary, version 19. 
4.10  PK Analysis 
The pharmacokinetic blood sampling will be listed with the date and time of 
sampling.  This SAP describes only the analyses for the study objectives not 
involving the PK objectives. The PK objectives will be described in a separate 
analysis plan. 
4.11 Modifications from the statistical section in the protocol 
The protocol stated hypotheses with one-sided testing using less than and 
greater than symbols.  This is corrected in the SAP to two-sided hypotheses, as 
planned, using equal and not equal symbols. 
The protocol stated that Cochrane-Mantel-Haenszel test stratified by study 
site will be used for the primary analysis.  However, this conflicts with the primary 
and key secondary hypotheses planned in the protocol which are not stratified, so 
this is revised in the SAP to match with the planned hypotheses. 
Due to early termination of the study, the sample size will be much less than 
planned.  As a result, the statistical power can be inadequate for the planned 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
26 of 40 
 
 
 
 
 
 
 
 
 
 
 
gatekeeping methodology.  Therefore, standard hypothesis testing methods may be 
used instead to analyze the data (see section 4.8). 
5. 
Interim analyses 
No interim analyses were planned. 
6. 
Sample size and Power calculations 
A total of 330 subjects were to be enrolled and randomized into 3 groups 
(1:1:1).  
The EULAR response rate will be considered as primary parameter. See 
Appendix B for details on scoring and coding. There is a special interest in the 
percentage of subjects with an EULAR response category of good or moderate 
(good and moderate combined) and the percentage of subjects with an EULAR 
response category of only good. These subjects will be called EULAR responders and 
EULAR good-responders, respectively. 
 
 
 
 
 
 
Primary endpoint: 
 
The percentage of EULAR responders (good + moderate) at Day 8 
Key secondary endpoints: 
 
The percentage of EULAR good responders at Day 8 
 
The percentage of EULAR responders at Day 15 
 
The percentage of EULAR good responders at Day 15 




CLR_15_05 SAP 
 
V5.2 June 7, 2018 
28 of 40 
 
 
 
 
 
 
 
 
 
 
 
7. 
Tables, Listings and Figures 
Below are the titles for the planned study tables, listings and figures 
 
Table 1  
Subject Distribution  
Table 2.A 
Subject Distribution By Center (ITT) 
Table 2.B 
Subject Distribution By Center (PP) 
Table 3.A 
Demographics and Baseline Characteristics (ITT) 
Table 3.B 
Demographics and Baseline Characteristics (PP) 
 
Table 4  
Medical and Surgical History (ITT) 
Table 5.A 
Dose Administration (ITT) 
Table 5.B 
Dose Administration (PP) 
Table 6.A 
Dose Administration by Visit (ITT) 
Table 6.B 
Dose Administration by Visit (PP) 
Table 7.A 
Dose Administration by Center (ITT) 
Table 7.B 
Dose Administration by Center (PP) 
Table 8.A 
EULAR Good/Moderate Responders - Original and Simplified Analyses (ITT) 
Table 8.B 
EULAR Good/Moderate Responders - Original and Simplified Analyses (PP) 
Table 9.A 
EULAR Response by Visit (ITT) 
Table 9.B 
EULAR Response by Visit (PP) 
Table 10.A 
 
Time to First EULAR Good/Moderate Response (ITT) 
Table 10 .B 
Time to First EULAR Good/Moderate Response (PP) 
Table 11 .A 
DAS28 Scores (ITT) 
Table 11 .B 
DAS28 Scores (PP) 
Table 12 .A 
Tender and Swollen Joints (ITT) 
Table 12 .B 
Tender and Swollen Joints (PP) 
Table 13.1.A 
Visual Analog Scale (VAS) – Patient Pain (ITT) 
Table 13.1.B 
Visual Analog Scale (VAS) – Patient Pain (PP) 
Table 13.2.A 
Visual Analog Scale (VAS) – Patient RA Disease Activity (ITT) 
Table 13.2.B 
Visual Analog Scale (VAS) – Patient RA Disease Activity (PP) 
Table 13.3.A 
Visual Analog Scale (VAS) – Investigator RA Disease Activity (ITT) 
Table 13.3.B 
Visual Analog Scale (VAS) – Investigator RA Disease Activity (PP) 
Table 14 .A 
American College of Rheumatology (ACR) 20/50/70 Response (ITT) 
Table 14 .B 
American College of Rheumatology (ACR) 20/50/70 Response (PP) 
Table 15.1.A 
SF-36 Physical Component Score (ITT) 
Table 15.1.B 
SF-36 Physical Component Score (PP) 
Table 15.2.A 
SF-36 Mental Component Score (ITT) 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
29 of 40 
 
 
 
 
 
 
 
 
 
 
 
Table 15.2.B 
SF-36 Mental Component Score (PP) 
Table 16 .A 
Health Assessment Questionnaire (HAQ) (ITT) 
Table 16 .B 
Health Assessment Questionnaire (HAQ) (PP) 
Table 17 .A 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score (ITT) 
Table 17 .B 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Score (PP) 
Table 18 
Maintenance Improvement at Week 12 (Day 85) 
Table 19 .A 
Health Economics Questionnaire (HEQ) at Week (Day 85) (ITT) 
Table 19 .B 
Health Economics Questionnaire (HEQ) at Week (Day 85) (PP) 
Table 20.A 
Laboratory Results (SAF) 
Table 20.B 
Laboratory Abnormalities (SAF) 
Tabl3 20.C 
Laboratory Shift (SAF) 
Table 21 
Vital Signs (SAF) 
Table 22 
Physical Exam (SAF) 
Table 23 
12-Lead ECG (SAF) 
Table 24.A 
Concomitant Medications Summary (SAF) 
Table 24.B 
Concomitant Medications (SAF) 
Table 25.A 
Adverse Event Summary (SAF) 
Table 25.B 
Adverse Events 
 
Listing 1  
Subject Disposition  
Listing 2  
Subjects Excluded from the Analysis Populations (randomized subjects) 
Listing 3  
Protocol Violations (SAF) 
Listing 4  
Visit Windows (SAF) 
Listing 5  
Demographics and Baseline Characteristics (SAF) 
Listing 6.A 
Medical and Surgical History (SAF) 
Listing 6.B 
Medical and Surgical History with MedDRA Coding (SAF) 
Listing 7.A 
Dosing Administration (SAF) 
Listing 7.B 
Dosing Administration (cont’d) (SAF) 
Listing 7.C 
Doses Not Given According to Protocol – Interrupted (SAF) 
Listing 7.D 
Doses Not Given According to Protocol – Discontinued (SAF) 
Listing 7.E 
Doses Not Given According to Protocol – Adjusted Rate (SAF) 
Listing 8  
DAS28 Scores and EULAR Response (SAF) 
Listing 9  
Swollen and Tender Joints (SAF) 
Listing 10.A 
Visual Analog Scale (VAS) – Patient Assessment of General Health and Pain (SAF) 
Listing 10.B 
Visual Analog Scale (VAS) – Patient and Investigator Assessment of RA Disease 
Activity (SAF) 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
30 of 40 
 
 
 
 
 
 
 
 
 
 
 
Listing 11 
American College of Rheumatology (ACR) 20/50/70 Response (SAF) 
Listing 12.A 
SF-36 Physical and Mental Component Scores (SAF) 
Listing 12.B 
SF-36 Physical Functioning (SAF) 
Listing 12.C 
SF-36 Role Limitations Due to Physical Health (SAF) 
Listing 12.D 
SF-36 Role Limitations Due to Emotional Health (SAF) 
Listing 12.E 
SF-36 Social Functioning and Pain 
Listing 12.F 
SF-36 Energy/Fatigue 
Listing 12.G 
Emotional Well-Being 
Listing 12.H 
General Health 
Listing 13.A 
Health Assessment Questionnaire (HAQ) (SAF) 
Listing 13.B 
Health Assessment Questionnaire (HAQ) (cont’d) (SAF) 
Listing 13.C 
Health Assessment Questionnaire (HAQ) (cont’d) (SAF) 
Listing 13.D 
Health Assessment Questionnaire (HAQ) (cont’d) (SAF) 
Listing 13.E 
HAQ Scores (SAF) 
Listing 14 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale (SAF) 
Listing 15.A 
Health Economics Questionnaire (HEQ) – Use of Hospital Services (SAF) 
Listing 15.B 
HEQ – Use of Hospital Services (cont’d) (SAF) 
Listing 15.C 
HEQ – Use of Hospital Services (cont’d) (SAF) 
 
Listing 15.D 
HEQ – Use of Ambulatory Care Services (SAF) 
Listing 15.E 
HEQ – Use of Ambulatory Care Services (cont’d) (SAF) 
Listing 15.F 
HEQ – Other Expenses (SAF) 
Listing 15.G 
HEQ – Other Expenses (cont’d) (SAF) 
Listing 16.A 
Laboratory – Chemistry (SAF) 
Listing 16.B 
Laboratory – Hematology (SAF) 
Listing 16.C 
Laboratory – Urinalysis (SAF) 
Listing 16.D 
Laboratory – ESR (SAF) 
Listing 17 
Vital Signs (SAF) 
Listing 18 
Physical Exam (SAF) 
Listing 19 
12-Lead ECG (SAF) 
Listing 20 
Concomitant Medications (SAF) 
Listing 21.A 
Adverse Events (SAF) 
Listing 21.B 
Adverse Events (cont’d) (SAF) 
Listing 22 
PK Sampling (SAF) 
 
Figure 1  
Time to First EULAR Good/Moderate Response (ITT) 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
31 of 40 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
Statistical software 
SAS version 9.3 or higher will be used for all tables, listings and figures. 
 
9. 
References  
LI J., Mehrotra D.V. (2008). Gatekeeping testing via adaptive alpha allocation. 
Biometrical Journal. 50:708-714 
 






CLR_15_05 SAP 
 
V5.2 June 7, 2018 
34 of 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
35 of 40 
 
 
 
 
 
 
 
 
 
 
 
11. 
APPENDIX B – Scoring and Coding for EULAR 
 
Change in DAS28 from baseline 
DAS28 after xx weeks 
>1.2 
>0.6 and 1.2 
0.6 
3.2 (inactive) 
Good 
Moderate 
No response 
>3.2 and 5.1 (moderate) 
Moderate 
Moderate 
No response 
>5.1 (very active) 
Moderate 
No response 
No response 
 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
36 of 40 
 
 
 
 
 
 
 
 
 
 
 
12. 
APPENDIX C – Scoring and Coding for DAS28 
 
The DAS28 is a combined index for measuring disease activity in RA. The index 
includes the assessment of 28 joints for swelling and tenderness, acute phase 
response (ESR or CRP), and general health status. The index is calculated using the 
following formula: 
DAS28 = 0.56 × √(TJC28) + 0.28 × √(SJC28) + 0.70 × ln(ESR) + 0.014 × VAS 
where  
TJC28 = tender joint count on 28 joints  
SJC28 = swollen joint count on 28 joints  
ln = natural log  
ESR = erythrocyte sedimentation rate (mm/hr) 
VAS = visual analogue scale, i.e., patient’s global assessment of disease activity (100 
mm VAS) 
 
 
 
 
 
 
  
 
 
 
 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
37 of 40 
 
 
 
 
 
 
 
 
 
 
 
13. 
APPENDIX D – Scoring and Coding for ACR 20/50/70  
The ACR core set of outcome measures and their definition of improvement 
includes a 20% improvement (ACR20) compared to Baseline in both SJC and TJC as 
well as in three out of five additional parameters: Physician’s Global Assessment of 
disease activity VAS, patient’s Global Assessment of disease activity VAS, patient’s 
assessment of pain VAS, HAQ-DI, and acute phase reactant (either CRP or 
erythrocyte sedimentation rate [ESR]). 
Achievement of an ACR50 requires a 50% improvement in the same parameters 
and an ACR70 requires a 70% improvement. 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
38 of 40 
 
 
 
 
 
 
 
 
 
 
 
14. 
APPENDIX E – Scoring and Coding for HAQ  
The Stanford HAQ-DI is a patient-oriented outcome assessment questionnaire 
specific for RA. It consists of 20 questions referring to eight component sets: 
dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each 
question asks on a scale ranging from 0 to 3 if the categories can be performed 
without any difficulty (scale 0) up to cannot be done at all (scale 3). 
The patient must have a score for at least 6 of the 8 categories. If there are less than 
6 categories completed, a HAQ-DI cannot be computed, whether the missing 
categories are due to missing values or they do not apply to the respondent. 
In the event where there is a missing domain score but a corresponding aid or 
device is listed, then the score for that domain will reflect the use of the aid or 
device, i.e. it will be scored as 2.  
If a domain consists of two questions and one response is missing, then the domain 
score will be the non-missing response but if both responses are missing, the 
domain score will be missing. If a domain consists of three questions and one 
response is missing, the domain score will be highest of the non-missing responses, 
but if two or more responses are missing, then the domain score will be missing.  
The HAQ-DI will be set to missing if more than two of the domain scores are 
missing. In the event that one or two domain scores are missing the final HAQ-DI 
score will be derived by dividing the total of the remaining domain scores by the 
number of non-missing domains.  
 
 
The HAQ-DI is usually analyzed by calculating scores. In each dimension ("dressing & 
grooming", "arising", "eating", "walking", "hygiene", "reach", "grip", "activities") 
the raw score is calculated as Max (Dimension Score) and corrected if aids and 
devices were used or help from another person was needed. When aids or devices or 
help are indicated by the patient, the score for the category item is raised from a 0 
or a 1 to a 2, but if the patient's highest score for that sub-category is a 3, it stays a 
3. The available categories scores are summed and divided by the number of 
categories answered which yields the Standard Disability Index. 
 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
39 of 40 
 
 
 
 
 
 
 
 
 
 
 
15. 
APPENDIX F – Scoring and Coding for FACIT  
The symptom-specific measure FACIT-F (Functional Assessment of Chronic Illness 
Therapy - Fatigue) was developed to assess chronic illness therapy with special 
emphasis on fatigue in the past 7 days and consists of 5 dimensions: 
1. 
physical well-being (PWB: 7 items),  
2. 
social/family well-being (SWB: 7 items), 
3. 
emotional well-being (EWB: 6 items), 
4. 
functional well-being (FWB: 7 items), and 
5. 
additional concerns (FS: 13 items). 
 
Each of the questions is categorically answered using the scales 0=not at all, 1=a 
little bit, 2=somewhat, 3=quite a bit, and 4=very much. The values of some items 
are reversed during score calculations, so that higher score values indicate more 
favorable conditions: negatively stated items are reversed by subtracting the 
response from ‘4’. Apart from the single dimension scores, 3 composite scores can 
be derived based on the 5 dimensions:  
FACIT-F trial outcome index (TOI) with a potential range of 0 to 108,  
FACT-G total score with a potential range of 0 to 108, and  
FACIT-F total score with a potential range of 0 to 160. 
The 13 items included in the dimension "additional concerns" will be used to 
calculate the brief score for FACIT-F (fatigue) scale (potential score range: 0-52).  
When there are missing data, pro-rating subscale scores are acceptable as long as 
more than 50% of the items are answered in that subscale. Subscale scores can be 
prorated by multiplying the sum of the subscale by the number of items in the 
subscale, then dividing by the number of items actually answered:  
Prorated subscale score=[Sum of items scores] x [N of items in subscale]/[N of items 
answered] .  
The total score is then calculated as the sum of the unweighted subscale scores. The 
FACT scale is considered to be an acceptable indicator of patient quality of life as 
long as overall item response rate is greater than 80% (i.e., at least 22 of 27 FACT-G 
items completed: first 4 domains). 
To derive a FACIT-F Trial Outcome Index (TOI): 
  __________ + __________ + __________ =________=FACIT-F TOI 
  (PWBscore)    (FWBscore)       (FSscore)   
 
To Derive a FACT-G total score:   
 __________ + __________ + __________ + __________=________=FACT-G Total 
score 
 (PWBscore)     (SWBscore)     (EWBscore)    (FWBscore) 
 
To Derive a FACIT-F total score: 
________ + ________ + _________ + _________ + ________ =____=FACIT-F Total 
score 
(PWBscore) (SWBscore) (EWBscore) (FWBscore)   (FSscore) 
 


CLR_15_05 SAP 
 
V5.2 June 7, 2018 
40 of 40 
 
 
 
 
 
 
 
 
 
 
 
 
The Fatigue Subscale score is calculated as follows: the individual items scores are 
summed, multiplied by 13 and divided by number of items answered.