Conditions: Rheumatoid Arthritis
Keywords: Phase 2a multiple ascending dose, Anti-Very Late Antigen-1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
A Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Escalating Doses of SAN-300 in Patients with Active Rheumatoid Arthritis with Inadequate Response to Disease-Modifying Anti-rheumatic Drug(s).

Detailed description:

Arms:
arm 1: SAN-300 0.5 mg/kg subcutaneous once weekly for six weeks arm 2: SAN-300 1.0 mg/kg subcutaneous once weekly for six weeks arm 3: SAN-300 2.0 mg/kg subcutaneous every other week for six weeks arm 4: SAN-300 4.0 mg/kg subcutaneous every other week for six weeks arm 5: SAN-300 4.0 mg/kg subcutaneous every other week for six weeks arm 6: Placebo dosing

Interventions: intervention 1: SAN-300 0.5 mg/kg QW intervention 2: SAN-300 1.0 mg/kg QW intervention 3: SAN-300 2.0 mg/kg QOW intervention 4: SAN-300 4.0 mg/kg QOW intervention 5: SAN-300 4.0 mg/kg QW intervention 6: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None

Protocol document:
Prot_000.pdf: 
 
 
 
 
Study Title: 
 
 
Study Number: 
Study Phase: 
Product Name: 
IND Number: 
Indication: 
Investigators: 
Sponsor: 
Sponsor's Medical 
Monitor: 
 
 
Study Contact: 
NCT02047604 
Clinical Trial Protocol:  C2013-0302 
A Randomized, Double-blind, Placebo-Controlled, Multiple Ascending Dose Study to 
Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Escalating 
Doses of SAN-300 in Patients with Active Rheumatoid Arthritis with Inadequate 
Response to Disease-Modifying Anti-rheumatic Drug(s) 
C2013-0302 
2a 
SAN-300 
118,321 
Rheumatoid Arthritis 
Multicenter 
Santarus, Inc. 
Santarus, Inc., a wholly owned subsidiary of Valeant Pharmaceuticals International 
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
 
Salix Pharmaceuticals, Inc. 
8510 Colonnade Center Drive 
Raleigh, NC 27615 
 
Date 
 
Original Protocol: 
13 August 2013 
 
Amendment 1: 
04 February 2014 
 
Amendment 2: 
24 February 2014 
 
Amendment 3: 
05 June 2014 
 
Amendment 4: 
15 September 2014 
 
Amendment 5: 
28 March 2016 
 
 
Confidentiality Statement 
The confidential information in the following document is provided to you as an investigator, potential 
investigator, or consultant for review by you, your staff, and applicable Institutional Review Board. By 
accepting this document, you agree that the information contained herein will not be disclosed to 
others, without written authorization from Santarus, Inc. except to the extent necessary to obtain 
informed consent from those persons to whom the drug will be administered and for implementation of 
the trial. 
 
 
 
 
Vice President, Clinical and Medical Affairs 
'. 
cas
l ,  Inc. on behaW of its Affiliate Santarus, 
 
\ 
Binu 
Senior Director, Clinical Operations 
Valeant Pharmaceuticals, Inc. on behalf of its Affiliate Santarus, 
Inc. 
Date 
' 
 
 
 
 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
SYNOPSIS 
Sponsor: 
Santarus, Inc. 
 
Name of Finished Product: 
SAN-300 
 
Name of Active Ingredient: 
SAN-300 
Study Title: 
A Randomized, Double-blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of Escalating Doses of SAN-300 in Patients with Active 
Rheumatoid Arthritis with Inadequate Response to Disease-Modifying Anti-rheumatic Drug(s) 
 
Study Number: 
C2013-0302 
 
Study Phase: 2a 
 
Primary Objective: 
To evaluate the safety and tolerability of repeat doses of SAN-300 in patients with active rheumatoid arthritis (RA) 
 
Secondary Objectives: 
• 
To evaluate the pharmacokinetics and pharmacodynamics of repeat doses of SAN-300 in patients with active 
RA 
• 
To evaluate the preliminary efficacy of repeat doses of SAN-300 in patients with active RA 
• 
To evaluate the immunogenicity of repeat doses of SAN-300 in patients with active RA 
Study Design: 
This is a multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose study to evaluate the 
safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and immunogenicity of 
subcutaneous (SC) administration of SAN-300 in five cohorts of patients with active RA with inadequate response 
to disease-modifying anti-rheumatic drug(s) (DMARDs). Planned dose cohorts for Study C2013-0302 are as 
follows: 
   Number of Patients to be Dosed  
 
 
once weekly 
once weekly 
every other week 
every other week 
once weekly 
once weekly 
Cohort 
SAN-300 
Placebo 
SAN-300 Dose 
A 
6 
2 
0.5 mg/kg SC 
B 
6 
2 
1.0 mg/kg SC 
C 
6 
2 
2.0 mg/kg SC 
D 
6 
2 
4.0 mg/kg SC 
E 
6 
2 
4.0 mg/kg SC 
F 
6 
2 
2.0 mg/kg SC 
Abbreviations: SC = subcutaneous 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
This is a multiple ascending dose study that will enroll patients sequentially into Cohorts A through F. All patients 
from each cohort will receive a total of 6 weeks of exposure to SAN-300 or placebo at their assigned dose and 
administration frequency. For the purposes of this protocol, the term “study drug” will include both SAN-300 and 
placebo. 
Safety and tolerability findings will be reviewed in a blinded manner, after each Cohort is fully enrolled and 
subjects have completed the 6-week Treatment Period (defined as completion of the Week 7 visit) to assess the 
study drug safety profile and determine whether enrollment will begin in the next cohort. Any subject who 
withdraws prior to the end of the 6-week Treatment Period will not be replaced and the Study Safety Committee 
will review the data from all subjects regardless of duration of participation in the study. The safety review will 
include, at minimum, the following information: adverse events (AEs); safety laboratory results; vital sign 
measurements; and reasons for premature study withdrawal. 
The decision to begin enrollment in the next cohorts will be based upon the results of the safety review. In 
addition, based on the findings from the safety review, the Sponsor may elect to modify the dose in the next 
cohort to a lower dose or terminate any further dose escalation. 
Individual patient dosing will be stopped if the patient experiences any of the following: a confirmed reduction in 
absolute neutrophil count (ANC) to < 1.0 x 103/µL; a clinically significant atypical or opportunistic infection 
(including those listed in Appendix 1); or a clinically significant adverse event related to study participation, in the 
opinion of the investigator. Study enrollment will be temporarily halted if any of the following occur: two or more 
patients in the study experience a confirmed reduction in ANC to < 1.0 x 103/µL, any one patient experiences a 
clinically significant atypical or opportunistic infection (including those listed in Appendix 1), or any other 
significant safety risk occurs, as noted by the Sponsor.  Resumption of study enrollment will be contingent upon 
further safety review. 
All patients will attend a minimum of 10 study visits: one Screening Visit, seven visits during the Treatment Period, 
and two follow-up visits. Additionally, all enrolled patients will be required to visit the clinic between certain study 
drug administrations for blood draws for the assessment of PK/PD endpoints. Patients are expected to remain on 
their existing, background RA regimen for at least the duration of the Follow-up Period. For a more detailed list of 
individual assessments, refer to the Schedule of Assessments in Appendix 2 and the Specialty PK and PD 
Laboratory Testing Schedule in Appendix 3. 
Screening: Between Days -21 and -1. Informed consent will be obtained before any study specific procedures are 
performed.  Eligibility assessments will be performed. 
Treatment Period: Days 1 to 43. Baseline assessments and measurements will be made before dosing with 
study drug.  Patients will receive SC injections of study drug as follows: 
• 
For all cohorts, patients randomized to receive placebo will be administered a total of six once-weekly 
injections of placebo on Days 1, 8, 15, 22, 29, and 36. 
• 
In Cohorts A, B, E and F, patients randomized to receive SAN-300 will be administered a total of six 
once-weekly injections of study drug on Days 1, 8, 15, 22, 29, and 36. 
• 
In Cohorts C and D, patients randomized to receive SAN-300 will be administered a total of three 
every-other-week injections of SAN-300 on Days 1, 15, and 29 and will be administered a total of three 
every-other-week injections of placebo on Days 8, 22, and 36. 
 
Study assessments and measurements will be performed on Days 1, 8, 15, 22, 29, 36, and 43. Patients will also 
visit the clinic between study drug administration visits for the assessment of PK/PD endpoints. The primary and 
secondary efficacy endpoints will be assessed at the End-of-Treatment Visit on Day 43. 
Follow-up Period: Days 43 to 71. Study patients will return for follow-up visits on Days 57 and 71 for safety and 
efficacy assessments. The Exit Visit will occur on Day 71. Patients who withdraw early from the study must 
return to the clinic to complete the Exit Visit assessments. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
Study Population: 
It is planned that approximately 40 patients (approximately 8 per cohort) with active RA will be enrolled into this 
study. 
Inclusion Criteria: 
1. Written informed consent 
2. Diagnosed with RA for ≥ 6 months according to American College of Rheumatology (ACR)/European League 
Against Rheumatism (EULAR) Classification Criteria 2010 (Appendix 4) 
3. 18 to 75 years of age, inclusive, at the time of informed consent 
4. Swollen joint count of ≥ 6 (66-joint count) and tender joint count of ≥ 6 (68-joint count) at Screening and 
randomization 
5. This criterion was removed in Amendment #3 
6. Inadequate response to therapy or discontinuation of therapy because of unacceptable toxicity from at least 
one prior traditional or biologic disease-modifying anti-rheumatic drug (DMARD). 
7. Stable dose of methotrexate (≥ 15 mg/week and ≤ 25 mg/week) for ≥ 6 weeks before randomization; a lower 
dosage of methotrexate (≥ 10 mg/week) is allowed if there is documented intolerance to dosages of ≥ 
15 mg/week; folic acid ≥ 5 mg/week (or an equivalent dose of folinic acid) is required for all patients. If taking 
hydroxychloroquine in combination with methotrexate, the patient must remain on a dose of ≤ 400 mg/day 
hydroxychloroquine that has been stable for ≥ 6 weeks before randomization. (Note: If discontinued from 
hydroxychloroquine, the patient must remain on this revised treatment regimen for at least 4 weeks before 
randomization.) 
All other DMARDs must have been discontinued for at least the following periods of time: 
• 
Oral DMARDs and etanercept at least 4 weeks before randomization 
• 
Rituximab and any other B-cell/lymphocyte-depleting therapy at least 1 year before randomization 
• 
All other biologic DMARDS (including infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, 
and tocilizumab) at least 8 weeks before randomization 
• 
Patients who have been on leflunomide must have not received leflunomide for at least 4 weeks before 
randomization and must undergo treatment to facilitate drug elimination with 8 g cholestyramine three 
times daily for 3 days to be eligible for participation 
8. Male or Female 
Females of childbearing (reproductive) potential must have a negative serum pregnancy test at screening and 
agree to use an acceptable method of contraception throughout their participation in the study. Acceptable 
methods of contraception include double barrier methods (condom with spermicidal jelly or a diaphragm with 
spermicide), hormonal methods (e.g., oral contraceptives, patches or medroxyprogesterone acetate), or an 
intrauterine device (IUD) with a documented failure rate of less than 1% per year. Abstinence or partner(s) 
with a vasectomy may be considered an acceptable method of contraception at the discretion of the 
investigator.  Men of reproductive potential must also agree to use an acceptable method of contraception. 
 
Note: Females who have been surgically sterilized (e.g., hysterectomy or bilateral tubal ligation) or who are 
postmenopausal (total cessation of menses for > 1 year) will not be considered “females of childbearing 
potential”. 
 
Exclusion Criteria 
Medical History 
1. Functional Class IV as defined by ACR classification of functional status in RA (Appendix 5) 
2. History of significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty’s 
syndrome) 
3. History of malignancy or carcinoma in situ within the 5 years before Screening or any history of melanoma. 
Patients with history of excised or adequately treated non-melanoma skin cancer are eligible 
4. Evidence of clinically significant uncontrolled concurrent diseases such as cardiovascular, endocrinologic, 
hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, 
renal, and/or other major diseases 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
5. History of recurrent clinically significant infections 
6. Current active infection or serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., 
pneumonia, septicemia) within 3 months before randomization 
7. Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 14 days before 
randomization 
8. History of drug or alcohol abuse (as defined by the Investigator) within the 1 year before Screening 
9. History of severe allergic or anaphylactic reactions to other biologic agents 
10. History of allergies to murine protein 
11. Surgery within 3 months before randomization (other than minor cosmetic surgery or minor dental 
procedures) or plans for a surgical procedure during the Treatment Period or Follow-up Period 
12. History of malaria; patients with a history of travel to a malaria-endemic region within 4 months before 
randomization may be considered for enrollment upon consultation with the Sponsor regarding confirmation of 
no active disease via a polymerase chain reaction (PCR).  Patients should not plan to travel to a 
malaria-endemic region throughout the duration of the study, including Screening and the 4-week Follow-up 
Period. 
13. History of tuberculosis or latent infection currently undergoing treatment 
Treatment History 
14. This criterion was removed in Amendment #3 
15. Treatment with another investigational agent, investigational device, or approved therapy for investigational 
use within the 4 weeks before randomization or within five half-lives of the investigational agent (longer of the 
two) 
16. Treatment regimen with prednisone that is either over 10 mg/day (or equivalent dose of another 
corticosteroid) or is not taken at a stable dose of ≤ 10 mg/day for at least 4 weeks before randomization 
17. Intra-articular corticosteroid injection(s) within 4 weeks before randomization 
18. Current use of opioids or other narcotics.  Note:  Patients receiving NSAIDS or the following opioids 
(tramadol, codeine and oral acetaminophen/codeine combination) at stable doses for at least 2 weeks prior to 
randomization will be eligible for inclusion 
19. Any live immunization/vaccination, including against Herpes zoster, within 4 weeks before randomization. 
Live vaccinations must also be avoided throughout the study. 
Laboratory Values 
20. Abnormal laboratory value at Screening or Day -1 considered clinically significant (as determined by the 
Investigator), or: 
• 
Serum creatinine > 1.6 mg/dL 
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN 
• 
Platelet count < 100,000/μL 
• 
Hemoglobin < 8.5 g/dL 
• 
Absolute neutrophil count (ANC) < 2.0 × 103/μL 
21. Women of childbearing potential who test positive for a serum pregnancy test at Screening or a urine 
pregnancy test within 12 hours before randomization. 
22. Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg) (Note: patients with 
positive HCV antibody who have previously received a curative treatment regimen may be considered for 
enrollment upon consultation with the Sponsor regarding confirmation of no active disease via a PCR test) 
23. Positive for human immunodeficiency virus (HIV) antibody 
24. Positive QuantiFERON®-TB Gold test (QFT) (Note: If the QFT result is indeterminate and the chest X-ray is 
without clinically significant findings, a second QFT may be performed. If the second QFT result is negative, 
the patient may be considered for enrollment. If the second QFT is positive or indeterminate, the patient is 
ineligible). 
25. Current enrollment in any other study with an investigational agent, investigational device, or approved 
therapy for investigational use 
26. Previous exposure to SAN-300 
27. Unwillingness or inability to comply with the requirements of this protocol, including the presence of any 
condition (physical, mental, or social) that is likely to affect the patient’s returning for follow-up visits on 
schedule 
NOTE:  Patients who cannot tolerate the magnetic resonance imaging (MRI) procedures due to physical or 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
other limitations may be enrolled in the study. 
28. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the patient unsuitable 
for enrollment 
29. Blood donation (450mL or more) within 1 month before Screening 
30. Nursing mothers or women who are planning to become pregnant during the study 
 
Test Product, Dose, and Mode of Administration: 
SAN-300 is a humanized anti-very late antigen-1 (VLA-1) monoclonal antibody (mAb). A total of six cohorts 
(Cohorts A, B, C, D, E and F) will be administered the appropriate weight-based volume dose of SAN-300 or 
matching volume of placebo in SC injections. 
 
Duration of Treatment: 
The total duration of study participation will be up to approximately 13 weeks. Patients will be screened for 
participation within 3 weeks of dosing (Days -21 to -1). The Treatment Period will consist of injections of SAN-300 
or placebo over a period of 6 weeks, concluding with the End-of-Treatment Visit (Days 1 to 43). The Follow-up 
Period will consist of an additional 4 weeks (Days 43 to 71). 
 
Safety Assessments: 
Safety assessments will consist of the following: physical examinations, vital sign measurements, 12-lead 
electrocardiograms (ECGs), laboratory parameters, AEs, and concomitant therapy use. 
 
Pharmacokinetic Assessments: 
Pharmacokinetic parameters for SAN-300 will be estimated using a population based approach with nonlinear 
mixed-effect modeling, in accordance with the FDA Draft Guidance on Population Pharmacokinetics (1999). In 
addition, exploratory assessments of linearity across doses/regimens, accumulation after repeated dosing and 
pharmacokinetic/pharmacodynamic relationships will be performed. 
 
Pharmacodynamic Assessments: 
PD parameters will consist of VLA-1 receptor occupancy (VLA-1 saturation assay); an immunophenotyping panel 
(CD3, CD4, CD8, CD14, CD19, CD45, CD45RO, and CD49α); CRP; and cytokines (interferon-gamma [IFNγ], 
tumor necrosis factor-alpha [TNFα], interleukin-6 [IL-6]). 
 
Efficacy Assessments: 
Efficacy evaluations will consist of changes from baseline in the Disease Activity Score with 28-joint count using 
CRP (DAS28-CRP), ACR Core Set Measurements, the Health Assessment Questionnaire – Disability Index 
(HAQ-DI), and magnetic resonance imaging (MRI) of the hand and wrist most clinically affected by RA. Each 
MRI will be scored using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI scoring 
(RAMRIS) system. 
Primary Efficacy Endpoint: 
DAS28-CRP mean change from baseline to the End-of-Treatment Visit 
Secondary Efficacy Endpoints: 
• 
American College of Rheumatology 20 (ACR20) responder rate at the End-of-Treatment Visit 
• 
DAS28-CRP ≤ 3.2 and < 2.6 responder rates at the End-of-Treatment Visit 
• 
ACR50 and ACR70 responder rates at the End-of-Treatment Visit 
• 
Change in HAQ-DI at the End-of-Treatment Visit 
• 
MRI findings of the hand and wrist most clinically affected by RA at the End-of-Treatment Visit 
Other Laboratory Assessments: 
Other laboratory parameters include anti-SAN-300 antibody levels, rheumatoid factor (RF), antinuclear antibody 
(ANA), and anti-citrunillated peptide antibodies (ACPA). 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
Statistical Methods: 
All endpoints in this study will be summarized by descriptive statistics. Descriptive statistics for continuous 
variables will include the mean, standard deviation, median, first and third quartiles, minimum, and maximum; 
categorical variables will be presented as counts and percentages. All statistical tests will be conducted at the 
two-sided α = 0.05 level of significance. All tests of binomial proportions will be conducted using the chi-square 
test unless more than one cell in a 2 x 2 table has an expected value of < 5, in which case the Fisher’s Exact Test 
will be used. All tests of continuous variables will be conducted using the Wilcoxon Rank-Sum Test. For all 
efficacy endpoints, patients will be analyzed according to the treatment to which they were randomized. For all 
safety endpoints, patients will be analyzed according to the treatment they received. Parameters presented by 
“treatment group” will compare the 6 patients on SAN-300 from each cohort with the 10 pooled patients on 
placebo. 
Safety: 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and 
percentages of patients reporting at least one occurrence of each AE will be tabulated by system organ class and 
preferred term. The number and percentages of patients reporting at least one occurrence of each AE by system 
organ class and preferred term will also be tabulated by severity and by the relationship to study drug.  For 
multiple occurrences of the same AE in a patient that differ in severity, the AE with the highest level of severity will 
be tabulated. For multiple occurrences of the same AE in a patient that differ in relationship to study drug (e.g., 
related and not related), the AE will be tabulated as related. All AEs for all patients will be presented in a data 
listing. 
All other safety parameters will be summarized using descriptive statistics and presented by time point and 
treatment group (6 active patients from each cohort and 10 pooled patients on placebo). All other safety 
parameters will be presented for individual patients in data listings. 
Pharmacokinetics: 
Population pharmacokinetic parameter estimates for SAN-300 will be presented by treatment groups in a tabular 
format as described in the Population Pharmacokinetic/Pharmacodynamic Analysis Plan, which will be finalized 
prior to data analysis. 
Pharmacodynamics 
PD parameters will be summarized using descriptive statistics and presented by time point and treatment group in 
tabular format. PD parameters for individual patients will be presented in data listings. Time-dependent PD 
parameters will be presented in figure format. PK/PD modeling will be conducted as described in the Population 
Pharmacokinetic/Pharmacodynamic Analysis Plan. 
Efficacy: 
Efficacy will be compared for the SAN-300 dose groups (0.5, 1.0, 2.0 and 4.0mg/kg once-weekly and 2.0 and 
4.0 mg/kg every other week) and the pooled placebo group. 
The DAS28-CRP and HAQ-DI will be calculated and presented by time point and treatment group. The mean 
change from baseline to the End-of-Treatment Visit for DAS28-CRP will be compared across treatment groups 
using the Wilcoxon Rank-Sum Test. The percentages of patients achieving a DAS28-CRP ≤ 3.2 and < 2.6 will be 
compared across treatment groups using the chi-square test. 
All components of the ACR Core Set will be summarized using descriptive statistics and presented by time point 
and treatment group. The percentages of patients achieving ACR20, ACR50, or ACR70 responses will be 
compared across treatment groups using the chi-square test. 
MRI data will be summarized across the treatment groups for each time point. All MRI data will be presented for 
individual patients in data listings. 
All efficacy assessments will be presented for individual patients in data listings. 
Additional analyses may be performed, as needed, to fully evaluate potential efficacy signals and evidence of 
clinical benefit. 
Other Laboratory Values: 
All other laboratory parameters will be summarized using descriptive statistics and presented by time point and 
treatment group.  All other laboratory parameters will be presented for individual patients in data listings. 
Laboratory parameters will be presented in figure format. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................................ 12 
1 
INTRODUCTION .......................................................................................................................................... 15 
1.1 
Role of VLA-1 in Inflammation ......................................................................................................... 15 
1.2 
Nonclinical Studies of Anti-VLA-1 Antibodies ................................................................................ 15 
1.2.1 
Pharmacology.......................................................................................................................... 15 
1.2.2 
Pharmacokinetics .................................................................................................................... 15 
1.2.3 
Preclinical Toxicology ............................................................................................................. 16 
1.3 
Clinical Experience with SAN-300 ................................................................................................... 16 
2 
STUDY OBJECTIVES ................................................................................................................................. 18 
2.1 
Primary Objective .............................................................................................................................. 18 
2.2 
Secondary Objectives ....................................................................................................................... 18 
3 
INVESTIGATIONAL PLAN .......................................................................................................................... 19 
3.1 
Overall Study Design and Plan ........................................................................................................ 19 
3.2 
Rationale for Study Design and Control Group ............................................................................. 22 
3.2.1 
Rationale for Dosing Regimen .............................................................................................. 22 
3.2.2 
Rationale for Control Group .................................................................................................. 22 
3.2.3 
Rationale for Study Population ............................................................................................. 22 
3.3 
Study Duration.................................................................................................................................... 23 
3.4 
Stopping Rules for Individual Patient Dosing and for Study Enrollment ................................... 23 
3.4.1 
Stopping Rules for Individual Patient Dosing ..................................................................... 23 
3.4.2 
Stopping Rules for Study Enrollment ................................................................................... 23 
3.4.3 
Resumption of Study Enrollment ......................................................................................... 24 
3.5 
Study Safety Committee ................................................................................................................... 24 
4 
STUDY POPULATION SELECTION ......................................................................................................... 25 
4.1 
Study Population ................................................................................................................................ 25 
4.2 
Inclusion Criteria ................................................................................................................................ 25 
4.3 
Exclusion Criteria ............................................................................................................................... 26 
5 
TREATMENTS TO BE ADMINISTERED ................................................................................................. 28 
5.1 
Planned Dose Cohorts ...................................................................................................................... 28 
5.2 
Method of Assigning Patients to Treatment Groups .................................................................... 28 
5.3 
Blinding ................................................................................................................................................ 29 
5.4 
Breaking the Blind .............................................................................................................................. 29 
5.5 
Treatment Compliance ...................................................................................................................... 29 
5.6 
Description of Treatments ................................................................................................................ 29 
5.6.1 
SAN-300 for Subcutaneous Injection ................................................................................... 29 
5.6.2 
Placebo for Subcutaneous Injection .................................................................................... 30 
5.7 
Packaging and Labeling ................................................................................................................... 30 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
5.8 
Storage and Accountability............................................................................................................... 30 
5.8.1 
Receipt of Supplies ................................................................................................................. 30 
5.8.2 
Storage of Supplies ................................................................................................................ 30 
5.8.3 
Control of Supplies ................................................................................................................. 30 
5.9 
Investigational Product Retention ................................................................................................... 31 
6 
CONCOMITANT THERAPY ....................................................................................................................... 32 
7 
PATIENT WITHDRAWAL AND STUDY TERMINATION ....................................................................... 33 
7.1 
Reasons for Withdrawal .................................................................................................................... 33 
7.2 
Procedures for Early Withdrawal ..................................................................................................... 33 
7.3 
Sponsor’s Termination of Study ...................................................................................................... 34 
8 
STUDY ASSESSMENTS ............................................................................................................................ 34 
8.1 
Demographic Data/Medical History ................................................................................................ 34 
8.2 
Physical Examination ........................................................................................................................ 34 
8.3 
Vital Signs ........................................................................................................................................... 34 
8.4 
12-Lead ECG...................................................................................................................................... 34 
8.5 
Clinical Laboratory Tests .................................................................................................................. 35 
8.5.1 
Laboratory Parameters .......................................................................................................... 35 
8.6 
Pharmacokinetic Assessments ........................................................................................................ 37 
8.7 
Pharmacodynamic Assessments .................................................................................................... 37 
8.8 
Efficacy Assessments ....................................................................................................................... 37 
8.8.1 
DAS28-CRP Assessment ...................................................................................................... 37 
8.8.2 
ACR Core Data Set ................................................................................................................ 38 
8.8.2.1 
Physician’s Global Assessment of Disease Activity ............................................... 38 
8.8.2.2 
Patient Assessment of Pain ....................................................................................... 38 
8.8.2.3 
Patient’s Global Assessment of Disease Activity .................................................... 38 
8.8.3 
HAQ-DI Quality of Life Assessments ................................................................................... 39 
8.8.4 
Magnetic Resonance Imaging of Hand and Wrist ............................................................. 39 
8.9 
Other Laboratory Assessments ....................................................................................................... 39 
8.10 
Assessing Hypersensitivity ............................................................................................................... 39 
8.11 
Appropriateness of Measurements ................................................................................................. 40 
9 
SAFETY REPORTING ................................................................................................................................ 41 
9.1 
Operating Definitions for Assessing Safety ................................................................................... 41 
9.1.1 
Adverse Event ......................................................................................................................... 41 
9.1.2 
Serious Adverse Event .......................................................................................................... 42 
9.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs...... 43 
9.3 
Method, Frequency, and Time Period for Detecting AEs and SAEs ......................................... 43 
9.3.1 Time Period for Detecting and Reporting of AEs and SAEs .................................................. 43 
9.3.2 Post-Study SAEs ........................................................................................................................... 43 
9.4 
Documenting AEs and SAEs ........................................................................................................... 43 
9.5 
Follow-up of AEs and SAEs ............................................................................................................. 44 
9.6 
Assessment of Causality .................................................................................................................. 44 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
9.7 
Prompt Reporting of SAEs to Product Safety ............................................................................... 45 
9.8 
Pregnancy Reporting ........................................................................................................................ 45 
9.9 
Transmission of SAE Report Forms and Pregnancy Notification Forms .................................. 45 
9.10 
Regulatory Reporting Requirements for SAEs.............................................................................. 46 
10 STUDY ACTIVITIES .................................................................................................................................... 47 
10.1 
Visit 1: Screening (Days  -21 to -1) ................................................................................................. 47 
10.2 
Treatment Period (Days 1 to 43) ..................................................................................................... 47 
10.2.1 
Visit 2 (Day 1) Procedures..................................................................................................... 48 
10.2.2 
Visit 2A (between Days 2 to 4) and Visit 2B (between Days 5 to 7) ............................... 49 
10.2.3 
Visits 3, 4, and 5 (Days 8, 15, and 22) Procedures ........................................................... 49 
10.2.4 
Visit 3A (between Days 9 to 11) ........................................................................................... 49 
10.2.5 
Visits 6 and 7 (Days 29 and 36) Procedures ...................................................................... 50 
10.2.6 
Visit 6A (between Days 30 to 32), Visit 7A (between Days 37 to 39), and Visit 7B 
(between Days 40 to 42) ........................................................................................................ 50 
10.2.7 
Visit 8: End-of-Treatment Visit (Day 43) or Early Withdrawal Visit (Treatment 
Period) ...................................................................................................................................... 50 
10.3 
Follow-up Period (Days 43 to 71) .................................................................................................... 51 
10.3.1 
Visit 8A (Day 50) and Visit 9A (Day 64) .............................................................................. 51 
10.3.2 
Visit 9 (Day 57) and Visit 10 (Day 71) or Early Withdrawal Visit (Follow-up Period) .. 51 
11 PLANNED STATISTICAL METHODS....................................................................................................... 53 
11.1 
General Considerations .................................................................................................................... 53 
11.2 
Determination of Sample Size ......................................................................................................... 53 
11.3 
Analysis Populations ......................................................................................................................... 53 
11.3.1 
Intent-to-Treat Population ...................................................................................................... 53 
11.3.2 
Safety Population .................................................................................................................... 53 
11.3.3 
Per Protocol Population ......................................................................................................... 53 
11.4 
Demographics and Baseline Characteristics ................................................................................. 53 
11.5 
Safety Analysis ................................................................................................................................... 54 
11.6 
Pharmacokinetic Analysis ................................................................................................................ 54 
11.7 
Pharmacodynamic Analysis ............................................................................................................. 54 
11.8 
Efficacy Analysis ................................................................................................................................ 54 
11.9 
Other Laboratory Values .................................................................................................................. 55 
11.10 Interim Analysis .................................................................................................................................. 55 
12 DATA HANDLING AND QUALITY ASSURANCE ................................................................................... 56 
12.1 
Case Report Forms ........................................................................................................................... 56 
12.2 
Monitoring of the Study ..................................................................................................................... 56 
12.3 
Inspection of Records ....................................................................................................................... 56 
12.4 
Study Record Retention .................................................................................................................... 57 
13 ADMINISTRATIVE CONSIDERATIONS .................................................................................................. 58 
13.1 
Confidentiality ..................................................................................................................................... 58 
13.2 
Independent Ethics Committee/Institutional Review Board Approval........................................ 58 


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13.3 
Modification of the Protocol .............................................................................................................. 58 
13.4 
Informed Consent .............................................................................................................................. 58 
13.5 
Protocol Violations and Deviations ................................................................................................. 59 
13.6 
Study Reporting Requirements ....................................................................................................... 59 
13.7 
Financial Disclosure and Obligations ............................................................................................. 59 
13.8 
Investigator Documentation ............................................................................................................. 60 
13.9 
Study Conduct .................................................................................................................................... 60 
13.10 Publications ........................................................................................................................................ 60 
14 REFERENCE LIST ....................................................................................................................................... 61 
 
 
LIST OF IN-TEXT TABLES 
Table 1. Overall Study Drug Exposure by Cohort ...................................................................................... 22 
Table 2. Dose Cohorts for Study C2013-0302 ........................................................................................... 28 
Table 3. List of Laboratory Tests .................................................................................................................. 36 
Table 4. Clinical Criteria for Diagnosing Anaphylaxis ............................................................................... 40 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Design for Study C2013-0302 .......................................................................................... 20 
Figure 2. Study Design for Individual Cohorts ............................................................................................ 21 
 
 
LIST OF APPENDICES 
Appendix 1 
Atypical or Opportunistic Infections ........................................................................... 62 
Appendix 2 
Schedule of Assessments for Study C2013-0302 .................................................. 63 
Appendix 3 
Specialty PK and PD Laboratory Testing Schedule ............................................... 66 
Appendix 4 
ACR / EULAR RA Classification Criteria .................................................................. 67 
Appendix 5 
ACR Revised Criteria for Classification of Global Functional Class in RA .......... 69 
Appendix 6 
Swollen and Tender Joint Assessment .................................................................... 70 
Appendix 7 
HAQ-DI Total Score and Individual Dimensions ..................................................... 71 
Appendix 8 
Scoring the Magnetic Resonance Imaging Scans .................................................. 72 
Appendix 9 
Investigator’s Signature .............................................................................................. 74 
Appendix 10 
Amendment 1 Summary of Changes ........................................................................ 75 
Appendix 11 
Amendment 2 Summary of Changes ...................................................................... 102 
Appendix 12 
Amendment 3 Summary of Changes ...................................................................... 103 
Appendix 13 
Amendment 4 Summary of Changes ...................................................................... 106 
Appendix 14 
Amendment 5 Summary of Changes ...................................................................... 114 


Santarus, Inc. 
SAN-300 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ACPA 
anti-citrunillated peptide antibodies 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANA 
antinuclear antibody 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC(0 – t) 
area under the concentration-time curve from time 0 to the last time point evaluated 
AUC(0 – inf) 
area under the concentration-time curve from time 0 and extrapolated to infinity 
CBC 
complete blood count with differential and platelet count 
CL/F 
apparent clearance 
Cmax 
peak serum concentration 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
Ct 
last measurable serum concentration 
CV 
curriculum vitae 
DAS28-CRP 
Disease Activity Score with 28-joint count using C-reactive protein 
DMARD 
disease-modifying anti-rheumatic drug 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESR 
erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FAAN 
Food Allergy and Anaphylaxis Network 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HAQ-DI 
Health Assessment Questionnaire - Disease Index 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 


Santarus, Inc. 
SAN-300 
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Clinical Trial Protocol: C2013-0302 
 
 
 
 
Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
HREC 
Human Research Ethics Committee 
CRP 
C-reactive protein 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL-6 
interleukin-6 
IND 
Investigational New Drug 
IFNγ 
interferon-gamma 
IM 
intramuscular(ly) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous(ly) 
IVRS/IWRS 
Interactive Voice/Web Response System 
JC virus 
John Cunningham virus 
kel 
terminal elimination rate constant 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCP 
metacarpophalangeal 
MRI 
magnetic resonance imaging 
NIAID 
National Institute of Allergy and Infectious Disease 
NOAEL 
no observed adverse effect level 
NSAID 
nonsteroidal anti-inflammatory drugs 
OMERACT 
Outcome Measures in Rheumatology Clinical Trials 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PGA 
Physician’s global assessment 
PK 
pharmacokinetic(s) 
PML 
progressive multifocal leukoencephalopathy 
PP 
Per Protocol 
PT 
prothrombin time 
QFT 
QuantiFERON®-TB Gold test 


Santarus, Inc. 
SAN-300 
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Abbreviation 
Definition 
RA 
rheumatoid arthritis 
RAMRIS 
Rheumatoid Arthritis Magnetic Resonance Imaging Score 
RF 
rheumatoid factor 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
T½ 
elimination half-life 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
Tmax 
time to peak serum concentration 
TNFα 
tumor necrosis factor-alpha 
UA 
urinalysis 
US 
United States 
VAS 
visual analogue scale 
Vd/F 
apparent volume of distribution 
VLA-1 
very late antigen-1 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
1 
INTRODUCTION 
Santarus is developing SAN-300 (previously known as BG00004) as a potential new therapy for the 
treatment of rheumatoid arthritis (RA). SAN-300 is a recombinant humanized murine antibody directed 
against very late antigen 1 (VLA-1; also known as α1β1 integrin). 
 
1.1 
Role of VLA-1 in Inflammation 
 
Inhibition of the human VLA-1 pathway using a specific monoclonal antibody such as SAN-300 is 
expected to interfere with VLA-1-dependent cellular functions, which are thought to be critical in the 
pathogenesis of RA. VLA-1 is expressed on activated cells, including T cells (specifically the subset of 
activated peripheral effector memory T cells), monocytes, macrophages, and natural killer cells. 
Elevated numbers of VLA-1+ cells have been observed in the synovial fluid taken from RA patients. 
Data suggest that VLA-1 function is critical to the migration, retention, and proliferation of these cells at 
sites of inflammation, thereby resulting in secretion of pro-inflammatory cytokines including tumor 
necrosis factor-α (TNFα) and interferon-γ (IFNγ). VLA-1-mediated adhesion has also been 
demonstrated to inhibit macrophage exit from inflammatory lesions (Becker, 2013). 
 
Consistent with a role for VLA-1 in the pathogenesis of RA, complete or partial loss of VLA-1 function is 
associated with a decrease in disease severity in models of acute and chronic inflammation. 
 
SAN-300 prevents the VLA-1 molecules on the surface of activated effector memory T cells and 
activated monocytes/macrophages from binding to their ligands in the extracellular matrix, primarily 
collagens and laminin. Thus, in RA patients, it is anticipated that blocking VLA-1/collagen interactions 
with a VLA-1–specific monoclonal antibody (SAN-300) will decrease the presence of VLA-1-expressing 
cells in chronically inflamed joints by inhibiting the migration, retention, proliferation, and survival of 
these cells at areas of inflammation. There is also evidence to specifically suggest that blockade of 
VLA-1 may be a useful treatment for those patients whose disease is inadequately controlled by 
anti-TNF therapies, which is an area of high unmet medical need (Ben-Horin, 2007). 
 
1.2 
Nonclinical Studies of Anti-VLA-1 Antibodies 
 
1.2.1 
Pharmacology 
 
SAN-300 binds to the I domain of the human α1 integrin subunit with high affinity at low SAN-300 
concentrations. This binding gives SAN-300 specificity for α1β1 integrin (VLA-1), as α1 integrin only 
associates with β1 integrin and no other β subunits (Pribila, 2004). 
 
Anti-mouse VLA-1 antibodies have been shown to be effective in murine models of arthritis, including 
murine anti-collagen II mAb arthritis, murine collagen-induced arthritis, and rat adjuvant arthritis. 
Anti-VLA-1 antibodies have also been shown to be effective in a variety of other inflammatory disease 
models including colitis, psoriasis, corneal transplant rejection, asthma, and atherosclerosis. The 
efficacy demonstrated in these studies is thought to be mediated through blockade of T-cell and/or 
monocyte/macrophage migration into and retention and proliferation at sites of inflammation. 
 
1.2.2 
Pharmacokinetics 
 
The in vivo pharmacokinetic (PK) profiles of SAN-300 and the anti-murine VLA-1 antibodies Ha31/8 
(hamster anti-murine VLA-1 mAb) and mHa31/8 (murinized Ha31/8) have been examined in the 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
cynomolgus monkey and the mouse, respectively. The metabolism and elimination of SAN-300 is 
expected to be similar to that of endogenous human antibodies. Both SAN-300 and the anti-murine 
VLA-1 antibodies (mHa31/8 or Ha31/8) exhibited dose-dependent PK characteristics. In cynomolgus 
monkeys, SAN-300 half-life (T1/2) increased with dose, ranging from 38.4 hours at 5 mg/kg to 154 hours 
at 50 mg/kg. SAN-300 showed bioavailability of approximately 50% to 60% by subcutaneous (SC) or 
intramuscular (IM) administration in the monkey, indicating SC and IM are viable alternative dosing 
routes for clinical use. Monkey anti-SAN-300 antibodies were observed upon repeat dosing in 
cynomolgus monkeys. 
 
1.2.3 
Preclinical Toxicology 
 
The in vivo toxicologic assessments were performed in the cynomolgus monkey as the most suitable 
species. SAN-300 has similar affinity for human and non-human primate VLA-1, and thus it is 
reasonable to expect the toxicity of SAN-300 in the cynomolgus monkey to be predictive for humans. 
 
In single-dose toxicity studies, SAN-300 was well tolerated at doses of up to 50 mg/kg via intravenous 
(IV) infusion. In a subsequent 3-month study, repeated twice-weekly administration of SAN-300 at 
doses up to 20 mg/kg IV or SC had no direct effects on mortality, clinical signs, physical examinations, 
cytokine levels, body weights, food consumption, ophthalmologic examinations, electrocardiography, 
clinical chemistry results, urine chemistry results, organ weights, macroscopic or microscopic 
observations, or the generation of antibody responses to foreign antigens. However, recrudescence of 
Plasmodium infection was observed in 6/60 animals, and Trichomonas parasites were observed in the 
gastrointestinal tract of 2/60 animals. As a result of these findings, a no observed adverse effect level 
(NOAEL) was not established in this study, and further studies were initiated. 
 
A second repeat-dose primate toxicology study was performed, this time using animals that had been 
pre-screened by PCR analysis for Plasmodium and excluding those animals that had a positive test 
result. There was no toxicity related to the test article at any dose level used in this study. Based on 
these results, the NOAEL for SAN-300 in male and female cynomolgus monkeys under the conditions 
of this study was considered to be ≤ 5 mg/kg. 
 
In addition, a set of host-resistance, immune-challenge studies were performed in mice. These studies 
indicated that exposure to treatment with the anti-murine VLA-1 antibody mHa31/8 had no specific 
inhibitory effects on the clearance of the bacterial and viral infections tested. 
 
1.3 
Clinical Experience with SAN-300 
 
A total of 66 healthy volunteer subjects and two patients with active RA participated in Phase 1 Study 
C2011-0301 (301), in which 45 healthy subjects and one patient with active RA received single doses 
of SAN-300 via IV infusion or SC injection. Detectable serum SAN-300 concentrations were not 
observed in the majority of subjects receiving SAN-300 0.03 mg/kg to 0.3 mg/kg IV. In subjects 
receiving SAN-300 0.6 to 2.0 mg/kg, there was a trend towards increasing serum SAN-300 
concentrations with increasing dose. Receptor occupancy was essentially complete (≥ 90%) over a 
wide range of doses tested for both the IV and SC formulations (by 72 hours postdose for > 0.8 mg/kg 
IV and by 24 hours postdose for 2.0 to 6.0 mg/kg SC). Receptor occupancy was also durable, with 
median occupancy remaining at approximately ≥ 70% at Day 8 for all dose groups administered 
SAN-300 SC. 


Santarus, Inc. 
SAN-300 
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Clinical Trial Protocol: C2013-0302 
 
 
 
 
SAN-300 was generally well tolerated in this study. Mild to moderate infusion reactions occurred upon 
IV administration of SAN-300 doses from 0.8 to 2.0 mg/kg; all events improved with or without 
treatment by 72 hours and none led to withdrawal from the study.  Among subjects receiving SC 
SAN-300 at doses ranging from 2.0 to 6.0 mg/kg, headaches and mild injection-site reactions were 
most common. No severe or serious infections were reported in any group. No clinically meaningful 
changes from baseline were observed after SAN-300 dosing for biochemistry parameters and for the 
majority of hematologic parameters tested. Transient, Grade I/II reductions from baseline in absolute 
neutrophil count (ANC) were observed in 12 subjects who received SAN-300. None of these cases 
were associated with concurrent infections, and all resolved. Two subjects tested positive for 
treatment-emergent anti-SAN-300 antibodies; no immunogenicity-related adverse events were 
observed in these subjects. The safety findings from this Phase 1 study support further development 
with the proposed multiple ascending dosing regimen in patients with RA. 
 
The primary objective of the Phase 1 study was to evaluate the safety and tolerability of single 
ascending doses of SAN-300, and the study mainly enrolled healthy subjects. In addition, efficacy 
parameters were collected and analyzed in two RA patients. These RA patients received either a 
single dose of 2.0 mg/kg SAN-300 or placebo IV over 4 hours and were evaluated in the clinic for 
24 hours and at follow-up assessments on Days 3, 8, 15, 22, and 29.  The RA patient who received 
SAN-300 experienced a reduction in DAS28-CRP from 3.97 at baseline to 2.31 (-1.66) at Day 15 and to 
3.05 (-0.92) at Day 29 and met the American College of Rheumatology (ACR) criteria for ACR50 at 
these time points. The RA patient who received placebo started with a baseline DAS28-CRP of 3.47, 
experienced a reduction to 3.24 (-0.24) at Day 15, followed by an increase to 3.77 (+0.30) at Day 29, 
and did not meet criteria for ACR20 any time point. However, any conclusions regarding efficacy drawn 
from this small sample of RA patients must necessarily be limited. 


Santarus, Inc. 
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Clinical Trial Protocol: C2013-0302 
 
 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 
The primary objective of this study is: 
• To evaluate the safety and tolerability of repeat doses of SAN-300 in patients with active RA 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are: 
• To evaluate the PK and pharmacodynamics (PD) of repeat doses of SAN-300 in patients with active 
RA 
• To evaluate the preliminary efficacy of repeat doses of SAN-300 in patients with active RA 
• To evaluate the immunogenicity of repeat doses of SAN-300 in patients with active RA 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
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Clinical Trial Protocol: C2013-0302 
 
 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
 
This is a multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose study to 
evaluate the safety, tolerability, PK, PD, preliminary efficacy, and immunogenicity of SC administration 
of SAN-300 in five cohorts of patients with active RA. The study will recruit approximately 40 patients 
(30 SAN-300; 10 placebo) with active RA to evaluate repeat doses of SAN-300 compared with placebo. 
The study will be conducted at multiple study centers in the United States. 
 
A study design schematic describing the progression of cohorts in this ascending-dose study is 
provided in Figure 1.  Refer to Section 5.2 for the method of treatment group assignment. 
 
The study will initially enroll patients in Cohort A, in which patients will receive six once-weekly SC 
administrations of 0.5 mg/kg SAN-300 or placebo. After Cohort A has completed the 6-week Treatment 
Period (defined as completion of the Week 7 visit), a Study Safety Committee will conduct a blinded 
Safety Committee Review (including, but not limited to; adverse events (AEs), safety laboratory 
assessments, vital sign assessments, and reasons for premature study withdrawal) for all patients.  If 
the Study Safety Committee determines that the safety profile is acceptable, then Cohort B can begin 
enrollment. Subsequent Safety Committee Reviews will take place following each dosing cohort. If the 
Study Safety Committee determines that the safety profile continues to be acceptable, then enrollment 
can begin into the next cohort. 
 
Any subject who withdraws prior to the end of the 6-week Treatment Period will not be replaced and the 
Study Safety Committee will review the data from all subjects regardless of duration of participation in 
the study. 
 
Based on the findings of the Study Safety Committee, the Sponsor may elect to modify the dose in the 
next cohort to a lower dose or terminate any further dose escalation. 
 
For the purposes of this protocol, the term “study drug” will include both SAN-300 and placebo. 
 
Figure 2 provides a study schematic indicating visit structure for each individual cohort. After initial 
Screening, eligible patients will return to the study site at weekly intervals throughout the Treatment 
Period for study drug administration and safety, PK, PD, efficacy, and other assessments. Enrolled 
patients will also return to the study site between study drug administration visits for the assessment of 
PK/PD endpoints. Primary and secondary efficacy endpoints will be assessed at the End-of-Treatment 
Visit on Day 43. During the 4-week Follow-up Period, patients will return to the study site at 2 weeks 
and 4 weeks after the end of the Treatment Period for additional assessments. 


Santarus, Inc. 
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Amendment 5:  28 Mar 2016 
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Clinical Trial Protocol: C2013-0302 
 
 
 
 
Figure 1. Study Design for Study C2013-0302 
 
 
Abbreviation: PBO = placebo; QW = every week; QOW = every other week. 
Notes: Patients will be randomized to each cohort in a 3:1 ratio of SAN-300 to placebo. A Safety Committee 
Review will occur after patients have completed the 6-week Treatment Period of each cohort. Any subject who 
withdraws prior to the end of the 6-week Treatment Period will not be replaced and the Study Safety Committee 
will review the data from all subjects regardless of duration of participation in the study. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
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Clinical Trial Protocol: C2013-0302 
 
 
 
 
Figure 2. Study Design for Individual Cohorts 
 
Abbreviation:  SC = subcutaneously. 
Screening: Between Days -21 and -1. Informed consent will be obtained before any study specific 
procedures are performed.  Eligibility assessments will be performed. 
 
Treatment Period: Days 1 to 43. Baseline assessments and measurements will be performed before 
dosing with study drug.  Patients will receive SC injections of study drug as follows: 
• For all cohorts, patients randomized to receive placebo will be administered a total of six 
once-weekly injections of placebo on Days 1, 8, 15, 22, 29, and 36. 
• In Cohorts A, B, E and F, patients randomized to receive SAN-300 will be administered a total of six 
weekly injections of SAN-300 on Days 1, 8, 15, 22, 29, and 36. 
• In Cohorts C and D, patients randomized to receive SAN-300 will be administered a total of three 
every-other-week injections of SAN-300 on Days 1, 15, and 29 and will be administered a total of 
three every-other-week injections of placebo on Days 8, 22, and 36. 
 
Study assessments and measurements will be performed on Days 1, 8, 15, 22, 29, 36, and 43. 
Patients will also visit the clinic between study drug administration visits for the assessment of PK/PD 
endpoints. The primary and secondary efficacy endpoints will be assessed at the End-of-Treatment 
Visit on Day 43. 
 
Follow-up Period: Days 43 to 71. Study patients will return for follow-up visits on Days 57 and 71 for 
safety and efficacy assessments. The Exit Visit will occur on Day 71. Patients who withdraw early from 
the study must return to the clinic to complete the Exit Visit assessments. 
 
Study procedures at each visit are described in the Schedule of Assessments, provided as Appendix 2. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
3.2 
Rationale for Study Design and Control Group 
 
3.2.1 
Rationale for Dosing Regimen 
 
The planned doses (0.5 mg/kg once weekly through 4.0 mg/kg every week) and duration of study 
treatment are based on the observed safety, PK, and PD profile of SAN-300 (including VLA-1 receptor 
occupancy) in Phase 1 single-dose Study 301 and data from up to 3 months of dosing in non-human 
primate studies (Section 1.2.3). Based on receptor occupancy data, SAN-300 2.0 mg/kg SC resulted in 
durable VLA-1 receptor occupancy through Day 8 and the 4.0 mg/kg SC dose extended this receptor 
occupancy through approximately Day 15. These results suggest that weekly or every-other-week 
dosing may be sufficient to maintain a therapeutic effect. 
 
In Study 301, single doses of SAN-300 up to 6.0 mg/kg SC were tolerated in a healthy volunteer 
population. To ensure patient safety, the design of the current multiple ascending dose study stipulates 
a Safety Review to occur after each dosing Cohort. The overall drug exposure in each cohort is as 
follows: 
 
Table 1  Overall Study Drug Exposure by Cohort 
 
Cohort 
SAN-300 Dose Regimen 
Overall Exposure 
A 
0.5 mg/kg QW 
3.0 mg/kg 
B 
1.0 mg/kg QW 
6.0 mg/kg 
C 
2.0 mg/kg QOW 
6.0 mg/kg 
D 
4.0 mg/kg QOW 
12.0 mg/kg 
E 
4.0 mg/kg QW 
24.0 mg/kg 
F 
2.0 mg/kg QW 
12.0 mg/kg 
Abbreviations:  QOW = every other week; QW = every week 
 
 
Both weekly and every-other-week dosing will be explored to investigate appropriate dosing parameters 
for SAN-300. Should every-other-week dosing be a viable option for treatment of patients with RA, this 
dosing regimen would decrease patient burden. 
 
3.2.2 
Rationale for Control Group 
 
In every cohort, 6 patients will be randomized to receive SAN-300 and 2 patients will be randomized to 
receive placebo. Placebo injections will be the best control for potential injection-site AEs, which were 
observed in the Phase 1 Study 301. Regardless of the cohort, all patients randomized to receive 
placebo will be administered a total of six once-weekly injections of placebo. In Cohorts C and D, 
patients randomized to receive SAN-300 will be administered three every-other-week injections of SAN- 
300 and three every-other-week injections of placebo on alternating weeks. In this way, cohorts with 
patients receiving every-other-week study drug injections will have matched placebo controls while, at 
the same time, patients on placebo from all six cohorts (totaling N = 10) can be pooled for safety and 
efficacy analyses. 
 
3.2.3 
Rationale for Study Population 
 
The proposed population for this study includes patients between 18 and 75 years of age who have 
been diagnosed with RA for at least 6 months, have a minimum of six swollen and six tender joints, and 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
have previously demonstrated an inadequate response or unacceptable toxicity from at least one 
traditional or biologic disease-modifying anti-rheumatic drug (DMARD). Patients will be required to 
remain on a stable background dose of methotrexate for ≥ 6 weeks before randomization and during 
the study. These criteria are intended to identify an appropriate study population for this initial multiple- 
dose experience with SAN-300, are consistent with ACR recommendations for the use of biologic 
DMARDs in patients with RA (Singh, 2012), and are aligned with the draft FDA industry guidance for 
the clinical development of new therapies for RA (FDA, 2013). The proposed patient population is also 
similar to that described in the published literature for several recent biologic DMARD programs 
(Keystone, 2009; Fleishmann, 2012; Weinblatt, 2010). Recent clinical studies for biologic DMARD 
agents for RA have enrolled patients with similar inclusion criteria, including established diagnosis of 
RA for at least 3 to 6 months, background therapy with methotrexate at comparable doses as those 
proposed in this study, similar numbers of affected joints (usually six or more tender and swollen joints), 
and previous intolerance and/or inadequate response to a limited number of DMARDs. Methotrexate 
was also selected as a required background medication because of its widespread use in RA and the 
high likelihood that SAN-300, if eventually approved for commercial use, would be frequently used in 
combination with methotrexate. 
 
There is no sample-size calculation, as this study is not intended to be powered to demonstrate 
efficacy.  Results from this study will be used to guide the design of future efficacy and safety studies. 
 
3.3 
Study Duration 
 
The total duration of study participation will be up to approximately 13 weeks. Patients will be screened 
for participation within 3 weeks of dosing (Days -21 to -1). The Treatment Period will consist of 
injections of study drug over a period of 6 weeks and conclude with the End-of-Treatment Visit (Days 1 
to 43).  The Follow-up Period will consist of an additional 4 weeks (Days 43 to 71). 
 
3.4 
Stopping Rules for Individual Patient Dosing and for Study Enrollment 
 
The investigator must notify the Clinical Project Manager immediately (via telephone or email) if a 
patient experiences any of the events listed in the individual patient dosing or study enrollment stopping 
rules. 
 
3.4.1 
Stopping Rules for Individual Patient Dosing 
 
The dosing of an individual patient will be stopped under the following circumstances: 
• The patient experiences a confirmed reduction in ANC to < 1.0 × 103/μL. 
• The patient experiences a clinically significant atypical or opportunistic infection (including those 
listed in Appendix 1). 
• The patient experiences a clinically significant adverse event related to study participation, in the 
opinion of the investigator or Sponsor. 
 
3.4.2 
Stopping Rules for Study Enrollment 
 
New patient enrollment into the study will be temporarily halted, pending review by the Study Safety 
Committee, under the following circumstances: 
• Two or more patients in the study experience a confirmed reduction in ANC to < 1.0 × 103/μL. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
• Any one patient experiences a clinically significant atypical or opportunistic infection (including 
those listed in  Appendix 1). 
• Any other significant safety risk occurs, as noted by the Sponsor. 
3.4.3 
Resumption of  Study Enrollment 
 
Resumption of study enrollment will be contingent upon review and approval by the Study Safety 
Committee. 
 
3.5 
Study Safety Committee 
 
The Study Safety Committee will be composed of, at a minimum, a Sponsor representative and two 
independent expert physicians. This committee will review ongoing blinded study safety data, decide 
whether dose escalation is appropriate (see Section 3.1 for the role of safety reviews in dose 
escalation), recommend any modifications in dosing, and evaluate whether resumption of individual 
patient dosing or study enrollment is permissible after any interruption triggered by the stopping rules 
for patient dosing and for study enrollment (see Section 3.4). 


Santarus, Inc. 
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Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
 
It is planned that approximately 40 patients (approximately 8 per cohort) with active RA will be enrolled 
into this study. 
 
4.2 
Inclusion Criteria 
 
Each patient must meet the following criteria to be enrolled in this study: 
 
1. Written informed consent 
2. Diagnosed with RA for ≥ 6 months according to ACR/European League Against Rheumatism 
(EULAR) Classification Criteria 2010 (Appendix 4) 
3. 18 to 75 years of age, inclusive, at the time of informed consent 
4. Swollen joint count of ≥ 6 (66-joint count) and tender joint count of ≥ 6 (68-joint count) at Screening 
and randomization 
5. This criterion was removed in Amendment #3 
6. Inadequate response to therapy or discontinuation of therapy because of unacceptable toxicity from 
at least one prior traditional or biologic DMARD 
7. Remain on a stable dose of methotrexate (≥ 15 mg/week and ≤ 25 mg/week) for ≥ 6 weeks before 
randomization; a lower dosage of methotrexate (≥ 10 mg/week) is allowed if there is documented 
intolerance to dosages of ≥ 15 mg/week; folic acid ≥ 5 mg/week (or an equivalent dose of folinic 
acid) is required for all patients. If taking hydroxychloroquine in combination with methotrexate, the 
patient must remain on a dose of ≤ 400 mg/day hydroxychloroquine that has been stable for 
≥ 6 weeks before randomization. (Note: If discontinued from hydroxychloroquine, the patient must 
remain on this revised treatment regimen for at least 4 weeks before randomization.) 
All other DMARDs must have been discontinued for at least the following periods of time: 
• Oral DMARDs and etanercept at least 4 weeks before randomization 
• Rituximab and any other lymphocyte/B-cell-depleting therapy at least 1 year before 
randomization 
• All other biologic DMARDs, including infliximab, adalimumab, golimumab, certolizumab pegol, 
abatacept, and tocilizumab, at least 8 weeks before randomization 
• Patients who have been on leflunomide must have not received leflunomide for at least 4 weeks 
before randomization and must undergo treatment to facilitate drug elimination with 8 g 
cholestyramine three times daily for 3 days to be eligible for participation. 
 
8. Male or Female 
Females of childbearing (reproductive) potential must have a negative serum pregnancy test at 
screening and agree to use an acceptable method of contraception throughout their participation in 
the study. Acceptable methods of contraception include double barrier methods (condom with 
spermicidal jelly or a diaphragm with spermicide), hormonal methods (eg, oral contraceptives, 
patches or medroxyprogesterone acetate), or an intrauterine device (IUD) with a documented 
failure rate of less than 1% per year. Abstinence or partner(s) with a vasectomy may be considered 
an acceptable method of contraception at the discretion of the investigator. Men of reproductive 
potential must also agree to use an acceptable method of contraception. 


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Clinical Trial Protocol: C2013-0302 
 
 
 
 
 
Note: Females who have been surgically sterilized (eg, hysterectomy or bilateral tubal ligation) or 
who are postmenopausal (total cessation of menses for > 1 year) will not be considered “females of 
childbearing potential”. 
 
4.3 
Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from the study. 
 
Medical History 
 
1. Functional Class IV as defined by ACR classification of functional status in RA (Appendix 5) 
2. History of significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or 
Felty’s syndrome) 
3. History of malignancy or carcinoma in situ within the 5 years before Screening or a history of 
melanoma. Patients with history of excised or adequately treated non-melanoma skin cancer are 
eligible 
4. Evidence of clinically significant uncontrolled concurrent diseases such as cardiovascular, 
endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, 
dermatologic, psychiatric, renal, and/or other major diseases 
5. History of recurrent clinically significant infections 
6. Current active infection or serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., 
pneumonia, septicemia) within 3 months before randomization 
7. Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 14 days before 
randomization 
8. History of drug or alcohol abuse (as defined by the Investigator) within the 1 year before Screening 
9. History of severe allergic or anaphylactic reactions to other biologic agents 
10. History of allergies to murine protein 
11. Surgery within 3 months before randomization (other than minor cosmetic surgery or minor dental 
procedures) or plans for a surgical procedure during the Treatment Period or Follow-up Period 
12. History of malaria; patients with a history of travel to a malaria-endemic region within 4 months 
before randomization may be considered for enrollment upon consultation with the Sponsor 
regarding confirmation of no active disease via a polymerase chain reaction (PCR). Patients should 
not plan to travel to a malaria-endemic region throughout the duration of the study, including 
Screening and the 4-week Follow-up Period. 
13. History of tuberculosis or latent infection currently undergoing treatment 
Treatment History 
14. This criterion was removed in Amendment #3. 
15. Treatment with another investigational agent, investigational device, or approved therapy for 
investigational use within the 4 weeks before randomization or within 5 half-lives of the 
investigational agent (longer of the two). 
16. Treatment regimen with prednisone that is either over 10 mg/day (or equivalent dose of another 
corticosteroid) or is not taken at a stable dose of ≤ 10 mg/day for at least 4 weeks before 
randomization. 
17. Intra-articular corticosteroid injection(s) within 4 weeks before randomization 
18. Current use of opioids or other narcotics. Note: Patients receiving NSAIDS or the following opioids 
(tramadol, codeine and oral acetaminophen/codeine combination) at stable doses for at least 2 
weeks prior to randomization will be eligible for inclusion. 


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19. Any live immunization/vaccination, including against Herpes zoster, within 4 weeks before 
randomization.  Live vaccinations must also be avoided throughout the study. 
Laboratory Values 
20. Abnormal laboratory value at Screening or Day -1 considered clinically significant (as determined by 
the Investigator), or: 
• Serum creatinine > 1.6 mg/dL 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN 
• Platelet count < 100,000/μL 
• Hemoglobin < 8.5 g/dL 
• ANC < 2.0 × 103/μL 
21. Women of childbearing potential who test positive for a serum pregnancy test at Screening or a 
urine pregnancy test within 12 hours before randomization. 
22. Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg) (Note: patients 
with positive HCV antibody may be considered for enrollment upon consultation with the Sponsor 
regarding confirmation of no active disease via a PCR test). 
23. Positive for human immunodeficiency virus (HIV) antibody. 
24. Positive QuantiFERON®-TB Gold test (QFT) (Note: If the QFT result is indeterminate and the chest 
X-ray is without clinically significant findings, a second QFT may be performed. If the second QFT 
result is negative, the patient may be considered for enrollment. If the second QFT is positive or 
indeterminate, the patient is ineligible.) 
25. Current enrollment in any other study with an investigational agent, investigational device, or 
approved therapy for investigational use 
26. Previous  exposure to SAN-300 
27. Unwillingness or inability to comply with the requirements of this Protocol, including the presence of 
any condition (physical, mental, or social) that is likely to affect the patient’s returning for follow-up 
visits on schedule 
NOTE: Patients who cannot tolerate the magnetic resonance imaging (MRI) procedures due to 
physical or other limitations may be enrolled in the study. 
28. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the patient 
unsuitable for enrollment 
29. Blood donation (450 mL or more) within 1 month before Screening 
30. Nursing mothers or women who are planning to become pregnant during the study 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
5 
TREATMENTS TO BE ADMINISTERED 
5.1 
Planned Dose Cohorts 
 
Eligible patients will be enrolled into a dose cohort and randomized (3:1) to receive either SAN-300 via 
SC injection over 6 weeks or a matching volume of placebo. More than one SC injection may be 
required (maximum volume of 1.2 mL per SC injection) depending on the total dose administered and 
the weight of the individual patient.  Dosing by cohort is provided in Table 2. 
 
Table 2. Dose Cohorts for Study C2013-0302 
Number of Patients to be Dosed 
 
Cohort 
SAN-300 
Placebo 
SAN-300 Dose 
A 
6 
2 
0.5 mg/kg SC once weekly 
B 
6 
2 
1.0 mg/kg SC once weekly 
C 
6 
2 
2.0 mg/kg SC every other week 
D 
6 
2 
4.0 mg/kg SC every other week 
E 
6 
2 
4.0 mg/kg SC once weekly 
F 
6 
2 
2.0 mg/kg SC once weekly 
Abbreviations:  SC = subcutaneous 
 
Safety and tolerability findings will be reviewed in a blinded manner for all patients in a cohort after the 
6-week Treatment Period to determine whether or not enrollment will begin in the next cohort. Any 
subject who withdraws prior to the end of the 6-week Treatment Period will not be replaced and the 
Study Safety Committee will review the data from all subjects regardless of duration of participation in 
the study. The safety review will include, at minimum, the following information: AEs; safety laboratory 
results; vital sign measurements; and reasons for premature study withdrawal. 
 
The decision to begin enrollment in the next cohort will be based upon the results of the safety review. 
In addition, based on the findings of the Study Safety Committee, the Sponsor may elect to modify the 
dose in the next cohort to a lower dose or terminate any further dose escalation. 
 
Refer to Section 3.4 for patient and study stopping rules. 
 
5.2 
Method of Assigning Patients to Treatment Groups 
 
Fixed allocation will be used to randomize patients in a ratio of three on SAN-300 to one on placebo 
within each cohort of approximately 8 total patients. 
 
Cohort A will be enrolled first, with 6 patients randomly assigned to receive SAN-300 and 2 patients 
randomly assigned to receive matching placebo in two blocks of four patients (three on SAN-300, one 
on placebo). After Cohort A has completed the 6-week Treatment Period, a Study Safety Committee 
will conduct a blinded safety review. If the Study Safety Committee determines that the safety profile is 
acceptable, then Cohort B can begin enrollment. Additional Safety Committee reviews will occur 
following completion of the 6-week Treatment Period for each of the subsequently enrolled cohorts. 


Santarus, Inc. 
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Amendment 5:  28 Mar 2016 
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Clinical Trial Protocol: C2013-0302 
 
 
 
 
Randomization will be central and occur after a patient has been deemed eligible. Randomization will 
be performed by Interactive Voice/Web Response System (IVRS/IWRS). The unblinded pharmacist or 
designated study center personnel assigned to this role will be responsible for obtaining the treatment 
assigned to each patient in each cohort by contacting the IVRS/IWRS system by phone or Web site. 
This unblinded person will then prepare the study drug and provide it to the Investigator. The study 
drug will then be administered by qualified, blinded study personnel on the day of or within 24 hours 
after randomization. 
 
5.3 
Blinding 
 
Study drug will be prepared by unblinded pharmacy staff or designated study center personnel. 
 
The randomization code that assigns treatments to patients will be available in confidence only to 
personnel responsible for preparation of the study drug for administration. Except in circumstances of 
immediate threat to patient safety (e.g., medical emergencies) detailed in Section 5.4, the code will not 
be broken until after all data entry is completed, the validity of the data is checked, all queries are 
resolved, the statistical analyses are defined, and the database is locked. 
 
5.4 
Breaking the Blind 
 
Only in the case of an emergency, when knowledge of the study drug is essential for the clinical 
management or welfare of the subject, will the investigator be allowed to unblind a subject’s treatment 
assignment. To discuss breaking of the blind please contact the Clinical Project Manager at Santarus, 
Inc. by using the following contact information: 
 
Protocol C2013-0302 Medical Monitor 
Jason Vittitow, PhD 
Santarus, Inc., a wholly owned subsidiary of Valeant Pharmaceuticals International 
400 Somerset Corporate Boulevard 
Bridgewater, NJ 08807 
Phone:  + 1 908-541-3060 
 
If the investigator breaks the blind for an individual subject, the reason must be recorded in the  
subject’s source documents and the subject will be removed from the study. 
 
5.5 
Treatment Compliance 
 
The Investigational Product will be administered to study patients by the study staff. Therefore, no 
patient compliance measures with regard to the Investigational Product are necessary. 
 
All used and unused Investigational Product will be retained for verification by the Study Monitor. 
 
5.6 
Description of Treatments 
 
5.6.1 
SAN-300 for Subcutaneous Injection 
 
The Investigational Product for SC injection (SAN-300-F02) is manufactured by IntegrityBio, Inc of 
Camarillo, CA, USA under Good Manufacturing Practice (GMP). The SAN-300-F02 drug product is 
formulated with 180 mg/mL anti-VLA-1 mAb, 30 mM histidine, 250 mM sorbitol, and 0.01% polysorbate 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
20 at pH 6. The drug product is filled to a total volume of 1 mL in a 2-mL USP type I glass vial with a 
13-mm chlorobutyl stopper and a 13-mm aluminum seal. The storage temperature for the drug product 
is 2 °C to 8 °C, protected from light. 
 
For SC administration, the appropriate volumetric dose of SAN-300 will be injected with a 27-gauge, 
½ inch syringe needle on a weight-based calculation. More than one SC injection may be required 
(maximum volume of 1.2 mL per injection) depending on the total dose administered and the weight of 
the individual patient. 
 
5.6.2 
Placebo for Subcutaneous Injection 
 
For SC administration, placebo is 30 mM histidine, 250 mM sorbitol, 0.01% polysorbate 20, and 
3 µg/mL riboflavin at pH 6, with a 1-mL fill in the same container closure system as the drug product. 
This was also manufactured by IntegrityBio, Inc of Camarillo, CA, USA under GMP. The appropriate 
volumetric dose of placebo will be injected with a 27-gauge, ½ inch syringe needle via SC injection. 
The volume of placebo administered SC will match the volume according to the weight-based 
calculations as if SAN-300 were to be administered. More than one SC injection may be required 
(maximum volume of 1.2 mL per injection) depending on the total dose administered and the weight of 
the individual patient. The intended storage temperature for the placebo product is 2 °C to 8 °C, 
protected from light. 
 
5.7 
Packaging and Labeling 
 
Packaging, labeling, and shipping of study drug will be done by Catalent Pharma Solutions, LLC, 
located in Kansas City, MO, USA. Contracted regional drug distribution facilities will provide drug 
supplies to the investigational study centers. 
 
5.8 
Storage and Accountability 
 
5.8.1 
Receipt of Supplies 
 
When supplies of study materials are received by the unblinded study personnel, he/she will 
acknowledge receipt by signing and dating documentation enclosed with the shipment, and returning it 
as instructed on the documentation.  A copy will be retained for the Investigator File. 
 
5.8.2 
Storage of Supplies 
 
Study materials will be stored by the study personnel according to the documentation provided with the 
study materials. The Sponsor reserves the right to inspect the Investigational Product storage area 
before and during the study. A written record will be made of the storage condition of the study 
materials and retained for the Investigator File. 
 
5.8.3 
Control of Supplies 
 
Dispensing of the Investigational Product will be carefully recorded on appropriate Investigational 
Product accountability forms and will be verified periodically by an unblinded Study Monitor. 
 
The accountability logs should include dates, quantities, batch numbers, expiration dates (if applicable), 
and any unique numbers assigned to the patient.  The accountability logs will also include general 


Santarus, Inc. 
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Amendment 5:  28 Mar 2016 
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Clinical Trial Protocol: C2013-0302 
 
 
 
 
details related to the study, including the Protocol/Amendment number, Sponsor, indication, and the 
Investigator. 
 
5.9 
Investigational Product Retention 
 
The Investigator must maintain accurate records demonstrating dates and amount of Investigational 
Product received and dispensed and accounts of any Investigational Product accidentally or 
deliberately destroyed. Sufficient quantities of study drug will be kept by the Sponsor to reconfirm 
specifications if the need arises. These samples should be retained until the analyses of study data are 
complete or as required by the applicable regulatory requirement. 
 
An unblinded Study Monitor will review the Investigational Product accountability logs and check all 
Investigational Product returns (both unused and used) before authorizing the destruction of used 
Investigational Product by the study site. 


Santarus, Inc. 
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Clinical Trial Protocol: C2013-0302 
 
 
 
6 
CONCOMITANT THERAPY 
The efficacy and safety of immunization during periods of SAN-300 therapy have not been adequately 
studied. It is recommended that a patient’s vaccination record and possible vaccination requirements 
be reviewed and, if necessary, the patient be administered any required vaccination or booster at least 
4 weeks before randomization. Review of the patient’s immunization status and their need for the 
following vaccinations is recommended: tetanus; diphtheria; influenza; pneumoccocal polysaccharide; 
varicella; measles, mumps, and rubella; and hepatitis B vaccines. Immunization with a live vaccine is 
specifically prohibited within 4 weeks before randomization and throughout the study. 
Folic acid ≥ 5 mg/week (or an equivalent dose of folinic acid) is required for all patients. 
Patients must remain on a stable dose of methotrexate (≥ 15 mg/week and ≤ 25 mg/week) for 
≥ 6 weeks before randomization; a lower dosage of methotrexate (≥ 10 mg/week) is allowed if there is 
documented intolerance to dosages of ≥ 15 mg/week. If taking hydroxychloroquine in combination with 
methotrexate, the patient must remain on a dose of ≤ 400 mg/day hydroxychloroquine that has been 
stable for ≥ 6 weeks before randomization. Note: If discontinued from hydroxychloroquine, the patient 
must remain on the revised treatment regimen for at least 4 weeks before randomization. 
 
All other DMARDs are to be discontinued for at least the following periods of time: 
 
• Oral DMARDs and etanercept at least 4 weeks before randomization 
• Rituximab and any other B-cell/lymphocyte-depleting therapy at least 1 year before randomization 
• All other biologic DMARDs, including infliximab, adalimumab, golimumab, certolizumab pegol, 
abatacept, and tocilizumab, at least 8 weeks before randomization 
• Patients who have been on leflunomide must have leflunomide withdrawn for at least 4 weeks 
before randomization and must undergo treatment to facilitate drug elimination with 8 g 
cholestyramine three times daily for 3 days to be eligible for participation 
 
Patients receiving treatment with prednisone (or equivalent dose of another corticosteroid) that is either 
over 10.0 mg/day or is not stable for at least 4 weeks before randomization are to be excluded. 
Intra-articular corticosteroid injection(s) are not permitted within 4 weeks of randomization and should 
not be given during the course of the study. 
 
Patients receiving treatment with opioids or other narcotics are to be excluded.  Note:  Patients 
receiving NSAIDS or the following opioids (tramadol, codeine and oral acetaminophen/codeine 
combination) at stable doses for at least 2 weeks prior to randomization will be eligible for inclusion. 
 
Patients are to remain on their stable RA treatment regimen (i.e., the RA treatment they are receiving at 
the time of randomization) throughout the course of the study, including the Follow-up Period. 
Concomitant use of other anti-arthritic treatments, including approved or experimental agents, 
therapies, or devices is not permitted. 
 
All patients should be instructed not to start taking any new medications or therapies, including 
non-prescribed drugs, unless they have received permission from the Investigator. Any medication and 
any non-drug therapy or procedure used starting from signing of the Informed Consent Form (ICF) until 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
the completion of the study must be recorded in the patient’s CRF according to the instructions for CRF 
completion. 
 
7 
PATIENT WITHDRAWAL AND STUDY TERMINATION 
7.1 
Reasons for Withdrawal 
 
Participation in the study is strictly voluntary. A patient has the right to withdraw from the study at any 
time for any reason.  If he/she chooses to withdraw, the patient must inform the Investigator 
immediately and will be asked to make an Early Withdrawal Visit. If feasible, it is also highly 
recommended that the patient schedule a Follow-up Visit for a safety evaluation 4 weeks after their last 
dose of study drug.  The Investigator has the right to terminate participation of any patient at any time if 
it is deemed to be in the patient’s best interest. The reason and circumstances for premature 
discontinuation will be documented in the patient’s electronic case report form (eCRF). Possible 
examples for reasons of premature study withdrawal include: 
• Withdrawal of consent 
• Intolerable AE 
• Intake of non-permitted concomitant medication 
• Significant non-compliance with the protocol 
• Positive pregnancy test in a female patient 
• Clinical or administrative reason consistent with the requirements of the protocol at the 
Investigator’s discretion 
• Clinically significant worsening of RA that, in the opinion of the Investigator, requires immediate, 
specific medical treatment 
 
7.2 
Procedures for Early Withdrawal 
 
When it is determined that a patient should withdraw from the study, the reason(s) must be recorded, 
final assessments must be scheduled, and provisions for the continued treatment of RA within the 
standards of care must be discussed with the patient. Safety and study endpoint evaluations for the 
Early Withdrawal Visit (see Sections 10.2.6 and 10.3.1) will be performed as soon as possible after the 
decision is made to withdraw the patient. 
 
Additional interventions (concomitant medications or therapies) may be prescribed as needed by the 
patient. The patient’s history and preferences should be considered and discussed when prescribing a 
new medication for RA. 
 
Appropriate medical follow-up with the patient should be conducted as clinically indicated after the Early 
Withdrawal Visit. Telephone contacts between the patient and the study staff should be conducted as 
frequently as needed. 
 
If the patient is found to have an AE or clinically significant laboratory abnormality, the patient will be 
followed until the event/abnormality is resolved, or until the Investigator determines that further 
follow-up is no longer medically indicated. The responsible IEC/IRB should be notified of any AEs 
and/or circumstances leading to early withdrawal. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
If a patient is withdrawn from study participation because of pregnancy, Product Safety and IEC/IRB 
should be informed by the site within 24 hours of awareness. All pregnancies occurring in female 
patients must be reported. The pregnancy will be reported according to the procedures provided in 
Section 9.8. Should the patient have a spontaneous abortion or complications during the pregnancy, 
then the event must be captured as an SAE. Sites are obligated to follow the patient until the outcome 
of the pregnancy is known. The patient and/or her treating physician should be encouraged to report 
any future medical problems the child develops of which they become aware that are considered 
related to the study drug. 
 
Patients who are randomized and who subsequently withdraw from the study will not be replaced. 
 
7.3 
Sponsor’s Termination of Study 
 
Santarus reserves the right to discontinue the study at any time for clinical or administrative reasons. 
 
If the study is prematurely terminated or suspended for any reason, the Investigator must inform all 
study patients currently receiving study drug and assure appropriate follow-up. Santarus should 
promptly inform the Investigators/institutions and the regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension in accordance with applicable 
regulations. The IEC/IRB should also be informed promptly and provided with the reason(s) for the 
termination or suspension by Santarus or by the Investigator/institution, as specified by the applicable 
regulatory requirement(s). 
 
8 
STUDY ASSESSMENTS 
8.1 
Demographic Data/Medical History 
 
Demographic data, current medications (including existing RA therapy), and medical history will be 
recorded at Screening. In addition, a separate detailed RA history including date of diagnosis and all 
prior treatments will be recorded. 
 
8.2 
Physical Examination 
 
The physical examination will be conducted according to the Schedule of Assessments provided in 
Appendix 2 and will include the following: examination of general appearance, skin, head, neck 
(including thyroid), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, extremities, and 
nervous system.  Height will be recorded at Screening only. 
 
8.3 
Vital Signs 
 
Vital signs will include the following: body temperature (°C), pulse, respiratory rate, blood pressure, and 
weight. Vital signs will be assessed at all study site visits. On visits when study drug is to be 
administered vital signs will be assessed before dosing and blood pressure and pulse will be assessed 
at the end of the 1 hour observation period.   Vital signs should be assessed prior to any blood draws. 
 
8.4 
12-Lead ECG 
 
A 12-lead electrocardiogram (ECG) will be collected according to the Schedule of Assessments 
provided in Appendix 2.  Patients should be in a resting, supine position for 10 minutes before ECG 


Santarus, Inc. 
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Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
collection. The Investigator (or a designated, qualified observer at the investigational site) will interpret 
the ECG using one of the following categories: within normal limits, abnormal but not clinically 
significant, or abnormal and clinically significant. 
 
8.5 
Clinical Laboratory Tests 
 
8.5.1 
Laboratory Parameters 
 
Blood samples for clinical laboratory assessments will be collected according to the Schedule of 
Assessments provided in Appendix 2. Patients will be in a seated or in a supine position during blood 
collection. Safety and Screening laboratory tests will include those listed in Table 3 and will be 
performed at a central laboratory. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
Table 3. List of Laboratory Tests 
Hematology: 
• 
Hematocrit (Hct) 
• 
Hemoglobin (Hgb) 
• 
Mean corpuscular hemoglobin (MCH) 
• 
Mean corpuscular hemoglobin concentration 
(MCHC) 
• 
Mean corpuscular volume (MCV) 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
White blood cell (WBC) count with differential 
(neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils) 
 
 
Urinalysis: 
• 
Appearance 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Microscopic examination of sediment 
• 
Nitrite 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
• 
Urine human chorionic gonadotropin (hCG) 
(only for females of childbearing potential) 
 
Additional Assessments: 
• 
Serum Immunoglobulin 
• 
Serum tryptase 
• 
Histamine 
• 
C-reactive protein (CRP) 
• 
Erythrocyte sedimentation rate (ESR) 
(conducted at site) 
 
 
Serum Chemistry: 
• 
Albumin (ALB) 
• 
Alkaline phosphatase (ALK-P) 
• 
Alanine aminotransferase (ALT; SGPT) 
• 
Aspartate aminotransferase (AST; SGOT) 
• 
Blood urea nitrogen (BUN) 
• 
Calcium (Ca) 
• 
Carbon dioxide (CO2) 
• 
Chloride (Cl) 
• 
Creatinine 
• 
Creatine kinase 
• 
Gamma-glutamyl transferase (GGT) 
• 
Globulin 
• 
Glucose 
• 
Lactate dehydrogenase (LDH) 
• 
Phosphorus 
• 
Potassium (K) 
• 
Sodium (Na) 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Total cholesterol 
• 
Total protein 
• 
Triglycerides 
• 
Uric acid 
• 
Serum hCG (only for females of childbearing 
potential) 
 
Coagulation: 
• 
Prothrombin time (PT) 
• 
Activated partial thromboplastin time (aPTT) 
• 
International normalized ratio (INR) 
Serology: 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis C virus (HCV) antibodies 
• 
Human immunodeficiency virus (HIV) antibodies 
• 
QuantiFERON®-TB Gold test (QFT) 
 
 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
 
 
 
 
 
8.6 
Pharmacokinetic Assessments 
 
For patients in each cohort, serum SAN-300 concentrations will be determined from blood samples 
collected according to the Schedule of Assessments provided in Appendix 2 and the Specialty PK and 
PD Laboratory Testing Schedule provided in Appendix 3. Pharmacokinetic parameters for SAN-300 
will be estimated using a population based approach with nonlinear mixed-effect modeling, in 
accordance with the FDA Draft Guidance on Population Pharmacokinetics (1999). Population PK 
methods will be used to estimate the relevant PK parameters for the population as well as for each 
patient who received SAN-300 and had sufficient blood samples in which SAN-300 was quantifiable. 
The details of the analysis will be documented in a Population Pharmacokinetic/Pharmacodynamic 
Analysis Plan. 
 
8.7 
Pharmacodynamic Assessments 
 
The following PD parameters will be determined for all patients from blood samples collected at the 
same time as PK blood samples according to the Schedule of Assessments provided in Appendix 2 
and the Specialty PK and PD Laboratory Testing Schedule provided in Appendix 3: 
• VLA-1 receptor occupancy 
• An immunophenotyping panel (CD3, CD4, CD8, CD14, CD19, CD45, CD45RO, and CD49α) 
• Cytokines: IFNγ, TNFα, interleukin-6 (IL-6) 
• CRP 
Exploratory PK/PD modeling will be conducted as described in the Population 
Pharmacokinetic/Pharmacodynamic Analysis Plan. 
 
8.8 
Efficacy Assessments 
 
Efficacy assessments will be conducted according to the Schedule of Assessments provided in 
Appendix 2 and will consist of Disease Activity Score for 28-joint count using C-reactive protein 
(DAS28-CRP), ACR Core Set Measurements, Health Assessment Questionnaire Disease Index 
(HAQ-DI), and MRI of the hand and wrist most clinically affected by RA. 
 
8.8.1 
DAS28-CRP Assessment 
 
The DAS28 assessment is a standardized measure of improvement made using four components, two 
made by an assessor, one made by the patient, and one laboratory value (CRP), as shown below: 
• Swollen and tender joint assessment (assessor – refer to Appendix 6) 
• Patient’s global assessment of disease activity (patient) 
• CRP (laboratory test) 
The assessor will be an experienced rheumatology clinical assessor. 


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8.8.2 
ACR Core Data Set 
 
The ACR Core Data Set is a standardized measure of arthritis activity consisting of seven measures, 
three made by an assessor, three made by the patient, and one laboratory value (CRP or ESR), as 
shown below: 
• Swollen and tender joint assessment (assessor – refer to Appendix 6) 
• Physician’s global assessment of disease activity (assessor) 
• Patient assessment of pain (patient) 
• Patient’s global assessment of disease activity (patient) 
• Patient’s assessment of physical function as measured by Health Assessment Questionnaire (HAQ) 
(patient – Refer to Appendix 7) 
• CRP or ESR (laboratory test) 
The assessor will be an experienced rheumatology clinical assessor. 
 
8.8.2.1 
Physician’s Global Assessment of Disease Activity 
 
The physician’s global disease assessment will be documented on a visual analogue scale (VAS) of 
0 to 100 mm, ranging from 0 mm no disease activity to 100 mm (worst disease activity).  The distance 
between the single vertical line marked by the physician will be measured in millimeters (mm) from the 
left end of the scale using a 100 mm ruler that will be provided. To standardize measurements, the 
same person should take the measurement wherever possible throughout the study. 
 
8.8.2.2 
Patient Assessment of Pain 
 
Patients will be asked to rate their current pain intensity on a VAS. The VAS consists of a 100 mm-long 
scale ranging from 0 mm (no pain) to 100 mm (severe pain). The distance between the single vertical 
line marked by the patient will be measured in mm from the left end of the scale by the study staff, 
using the ruler provided. 
 
8.8.2.3 
Patient’s Global Assessment of Disease Activity 
 
Patient’s global disease assessment will be documented on a VAS of 0 mm (no disease activity) to 100 
mm (worst disease activity). The distance between the single vertical line marked by the patient will be 
measured in mm from the left end of the scale by the study staff, using the ruler provided. 
 
A patient is considered to have an ACR20/50/70 response if there is an improvement of 20%/50%/70% 
in all of the following: 
• Swollen joint count (66 joints) 
• Tender joint count (68 joints) and 
• At least three of the following five assessments: 
- 
Patient’s assessment of pain 
- 
Patient’s global assessment of disease activity 
- 
Physician’s global assessment of disease activity 
- 
Patient’s assessment of physical function, as measured by the HAQ-DI 
- 
CRP 


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8.8.3 
HAQ-DI Quality of Life Assessments 
 
Quality of life will be assessed according to the Schedule of Assessments provided in Appendix 2 using 
the HAQ-DI (Appendix 7). 
 
8.8.4 
Magnetic Resonance Imaging of Hand and Wrist 
 
The requirements for the Magnetic Resonance Imaging (MRI) scans are as follows: 
• Magnet strength: 1.5 Tesla 
• The same MRI scanner should be used for all scans of any individual patient throughout the study 
• Region imaged: The hand with the most clinically affected metacarpophalangeal (MCP) joints and 
wrist at screening. Image will include the distal radioulnar joint. The same hand and wrist will be 
assessed for the follow up scan. 
• Sequences will include T1-weighted 3D gradient echo (GRE) coronal scans pre- and 
post-gadolinium contrast, axial T1-weighted GRE scans post-contrast, and coronal STIR 
sequences. 
• Exam time should  last approximately 1 hour, including all patient setup and positioning 
Using a central reader, all MRI scans will be assessed by two experienced rheumatology clinical 
assessors (see Appendix 8 for MRI scoring criteria) and their readings will be averaged to minimize any 
error due to the inherent variability of the MRI scoring process. 
 
8.9 
Other Laboratory Assessments 
 
Additional laboratory parameters will be assessed according to the Schedule of Assessments provided 
in Appendix 2 and will include the following: 
• Anti-SAN-300 antibody 
• Rheumatoid factor (RF), antinuclear antibody (ANA), and anti-citrunillated peptide antibodies 
(ACPA) 
 
8.10 
Assessing Hypersensitivity 
 
For suspected cases of anaphylaxis or hypersensitivity reactions, blood samples will be obtained for 
laboratory assessment of tryptase and histamine concentrations. In addition, Investigators should 
apply the criteria outlined in the National Institute of Allergy and Infectious Disease (NIAID) and the 
Food Allergy and Anaphylaxis Network (FAAN) second symposium on the definition of anaphylaxis 
report (Sampson, 2006), as outlined in Table 4, to assess patients for potential anaphylactic reactions. 


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Table 4. Clinical Criteria for Diagnosing Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both 
(e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, 
incontinence) 
 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to 
several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP* 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline 
 
PEF = peak expiratory flow; BP = blood pressure. 
*Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year, less than 
(70 mm Hg + [2 x age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years. 
Source:  Sampson, 2006 
 
8.11 
Appropriateness of Measurements 
 
All procedures used to measure the safety, tolerability, and PK profile of SAN-300 in this study were 
considered by the Sponsor and Investigators to be appropriate and necessary to obtain the required 
safety, tolerability, and PK data for the investigational product. The safety assessments used in this 
study, such as vital signs, ECG, and clinical chemistry and hematology monitoring, are widely used and 
are considered appropriate for monitoring patient health and well-being in this type of study. 
 
The efficacy measures were selected to be generally comparable to published clinical studies in RA. 
The Investigators consider the measures to be standard assessments and endpoints for this disease. 
CRP and ESR measurements reflect the general inflammatory state of a patient and are components of 
the ACR Core Set Measurements. 
 
The PD markers were chosen to allow assessment of the immunological effects of SAN-300. These 
assessments are designed to provide information relevant to their usefulness as biomarkers and 
measures of potential safety and efficacy. Changes in VLA-1 on lymphocytes and monocytes as well 
as changes in the levels of the pro-inflammatory cytokines IFNγ, TNFα, and IL-6 will be useful as 
potential biomarkers and indications of potential efficacy. VLA-1+ leukocytes, TNFα, and IL-6 are 
thought to be important drivers of inflammation in RA; IFNγ is a cytokine secreted by VLA-1+ T cells. 
Changes (specifically, any potential increases) in the levels of IFNγ, TNFα, and IL-6 will also be 
important safety markers. 


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9 
SAFETY REPORTING 
Santarus maintains a robust pharmacovigilance system comprised of a governance framework and 
standard operating procedures supporting a systematic process for review, evaluation, and 
management of accumulating safety data from clinical trials and other sources to: 
 
• 
Identify a potential new safety signal; 
• 
Ensure that an investigational product’s risks are adequately assessed and communicated to 
investigators, IRBs/ECs, and regulatory bodies during clinical development. 
 
For this study, safety monitoring activities will include but are not limited to: 
 
• 
Review and evaluation of single SAE occurrences in real-time as reported through the SAE 
reporting process as outlined in this section of the protocol; 
 
• 
Review and evaluation, in real-time, of one or more occurrences of an uncommon SAE that is not 
commonly associated with product exposure; 
 
• 
Findings and/or safety data obtained during this study will provide information for the overall review 
of safety that is conducted by Santarus on a routine basis. Santarus will report expeditiously any 
findings from clinical trials (ongoing or completed), epidemiological studies, pooled analysis of 
multiple studies, and findings from animal or in vitro testing that suggest a significant risk in humans 
exposed to the study product. 
Safety data collection for this study begins at the time of the subject’s signing of the informed consent 
according to the operating definitions defined in this section of the protocol. 
 
The Investigator is responsible for reporting all AEs that occur during the study, regardless of their 
relationship to study drug or their clinical significance. 
 
9.1 
Operating Definitions for Assessing Safety 
 
9.1.1 
Adverse Event 
 
An AE is any untoward medical occurrence in a patient or clinical investigation patient administered a 
study product and which does not necessarily have a causal relationship with the treatment. 
 
An AE can therefore be any unfavorable and unintended sign (that could include a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a study 
product, without any judgment about causality (i.e., whether or not considered related to the study 
product). 
 
Additionally, an event that is associated with study participation (regardless of administration of or 
relationship to study drug) should be treated as a reportable adverse event for this protocol (e.g., 
complications resulting from the taking of a blood sample or performance of a protocol required 
procedure). 


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An AE does include the following: 
 
• 
Exacerbation or worsening of a pre-existing illness. 
• 
NOTE: if the pre-existing illness is the disease under study, then “exacerbation” refers to 
an unexpected worsening from the condition at baseline. 
• 
Increase in frequency or intensity of a pre-existing episodic event or condition. 
• 
Condition detected or diagnosed after study product administration even though it may have been 
present prior to the start of the study. 
• 
Symptom associated with disease not previously reported by the patient 
 
An AE does not include the following: 
 
• 
Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) as event 
terms; the condition that led to the procedure is the AE if it meets the definition of an AE. 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
cosmetic elective surgery; and social and/or convenience admissions). 
• 
Overdose of either study product or concurrent medication without any signs or symptoms. 
• 
Symptoms associated with disease, which are consistent with the patient’s usual clinical course; 
unless the subject experiences worsening of their symptom(s) or the symptom(s) meet the criteria 
for an SAE. Any medical condition present at the time of screening but does not worsen during the 
course of the study should be recorded as medical history. 
 
9.1.2 
Serious Adverse Event 
 
A serious adverse event (SAE) is any AE that fulfills any of the following criteria: 
• Results in death 
• Is life-threatening 
NOTE: the term “life-threatening” refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which could hypothetically have caused death had it 
been more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. “In-patient” hospitalization 
means the subject has been formally admitted to a hospital for medical reasons. This may or may 
not be overnight.  It does not include presentation at a casualty or emergency room. 
• Results in persistent or significant disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental 


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trauma (e.g., sprained ankle) that may interfere or prevent everyday life functions but do not 
constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Is medically significant or requires intervention to prevent one of the outcomes listed above. 
NOTE: For example, allergic bronchospasm requiring intensive treatment in an emergency room or 
at home [see Section 8.10 on Assessing Hypersensitivity], blood dyscrasias, or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
9.2 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and 
SAEs 
 
Abnormal laboratory findings (e.g., clinical chemistry, hematology) or other abnormal assessments 
(e.g., abnormal findings during examinations or ECG monitoring) that are judged by the investigator as 
clinically significant must be recorded as AEs or SAEs if they meet the definition of an AE or SAE. 
The investigator should exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment (including ECG monitoring) is clinically 
significant. 
 
9.3 
Method, Frequency, and Time Period for Detecting AEs and SAEs 
 
At each visit, after the patient has had an opportunity to spontaneously mention any problems, the 
investigator should inquire about AEs by asking the following standard questions: 
 
1. "Have you had any (other) medical problems since your last visit/assessment?" 
 
2. "Have you taken any new medicines, other than those given to you in this study, since your last 
visit/assessment?" 
9.3.1 Time Period for Detecting and Reporting of AEs and SAEs 
 
From the time of informed consent through study completion/withdrawal, including the follow-up period. 
9.3.2 Post-Study SAEs 
 
Investigators are not obligated to actively seek SAE information in former study participants, but 
investigators are encouraged to notify the sponsor of any SAEs, of which they become aware 
occurring at any time after a patient has completed, discontinued or terminated study participation that 
they judge may reasonably be related to study treatment or study participation. 
9.4 
Documenting AEs and SAEs 
 
All AEs that occur after the patient has signed the ICF and during the course of the study, regardless of 
causality or seriousness, will be assessed and recorded in the patient’s medical records and in the 
CRF.  In addition, SAEs must be documented on the paper SAE Report Form. 
 
A separate paper SAE Report Form should be used for each SAE. However, if at the time of initial 
reporting, multiple SAEs are present that are temporally and/or clinically related, they may be reported 
on the same SAE Report Form. 


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The investigator should attempt to establish a diagnosis for the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE and 
SAE and not the individual signs/symptoms. 
 
For clinically significant abnormal laboratory findings or other abnormal assessments meeting the 
definition of an AE or SAE, a diagnosis, if known (or clinical signs and symptoms if diagnosis is 
unknown), should be recorded by the investigator. If a diagnosis is unknown and clinical signs and 
symptoms are not present, then the abnormal finding should be recorded. When documenting as an 
SAE on the SAE Report Form, relevant laboratory data should either be recorded in the ‘Details of 
Relevant Assessments’ section of the SAE Report Form (including the reference range and units) or 
copies of the laboratory report (with reference ranges and units) should be sent with the SAE Report 
Form. 
 
The SAE Report Form should be completed as thoroughly as possible and signed by the investigator or 
his/her designee before transmittal to Product Safety. It is very important that the investigator provide 
his/her assessment of causality to study product at the time of initial SAE reporting. 
 
9.5 
Follow-up of AEs and SAEs 
 
All AEs, regardless of seriousness, must be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or the subject is lost to follow-up. The investigator is responsible to 
ensure that follow-up includes any supplemental investigations as may be indicated to elucidate as 
completely as practical the nature and/or causality of the AE. This may include additional laboratory 
tests or investigations, histopathological examinations, relevant hospital records (i.e. discharge 
summary), or consultation with other health care professionals. 
 
Product Safety may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations. If a patient dies during participation in the study or during a 
recognized follow-up period, Product Safety should be provided with a copy of any postmortem 
findings, including histopathology. 
 
For SAEs, new or updated information should be recorded on the originally completed paper SAE 
Report Form and all changes signed and dated by the Investigator or designee. By signing the SAE 
Report Form, the investigator or designee attests to the accuracy and completeness of the data and 
that he/she has reviewed and approved the report being submitted. The investigational sites IRB/IEC 
must be notified about SAEs in accordance with the requirements of the governing IRB/IEC. 
 
9.6 
Assessment of Causality 
 
The Investigator’s assessment of the relationship to study drug of an AE is part of the documentation 
process but is not a factor in determining whether or not it is reported. All AEs, regardless of causality, 
must be reported. The blind should not be broken for the purpose of making this assessment.  If there 
is uncertainty as to whether a clinical observation is an AE, the event should be reported. 
 
The relationship of the event to the study drug should be determined by the Investigator according to 
the following criteria: 
 
Not related 
An event for which sufficient data exist to indicate that the etiology is unrelated to the 
drug. 


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Unlikely related 
An event that does not follow a reasonable temporal sequence relative to administration 
of the drug.  However, causality from the drug cannot be ruled out. 
 
Possibly related 
An event that follows a reasonable temporal sequence relative to administration of the 
drug; that follows a known or expected pattern of response to the drug; but that could 
readily have been produced by other factors. 
 
Probably related 
An event that follows a reasonable temporal sequence relative to administration of the 
drug; that follows a known or expected pattern of response to the suspected drug; and 
that could not be reasonably explained by the known characteristics of that patient’s 
clinical state. 
 
9.7 
Prompt Reporting of SAEs to Product Safety 
 
SAEs must be reported promptly to Product Safety once the investigator determines that the event 
meets the protocol definition of a SAE. 
 
Prompt reporting of a SAE requires: 
 
• 
Completion and transmission of the SAE Report Form to Product Safety via fax within 24 hours of 
the investigator’s knowledge of the event. In parallel, a corresponding AE with the SAE details 
should be entered into the AE CRF within 48 hours of submitting the paper SAE Report Form. 
• 
Prompt reporting of additional information for previously reported SAEs should follow the same 
reporting timeframe as initial reports. In addition, the corresponding AE in the AE CRF (as 
applicable) should be updated to ensure all data points documented in the AE CRF are aligned with 
the matching data points on the paper SAE Report Form. 
9.8 
Pregnancy Reporting 
 
Pregnancies detected in subjects assigned to study drug should be promptly reported to Product Safety 
within 24 hours of awareness via fax, using the Pregnancy Notification Form. If a female patient 
becomes pregnant following assignment to study treatment, the study product will be immediately 
discontinued and the patient will be followed until the outcome of the pregnancy is known. 
 
Product Safety should be notified promptly via fax of any updates on the status of the pregnancy by 
update and/or amendment of the initial pregnancy notification form. 
 
Although pregnancy occurring in a clinical study is not considered to be an AE or SAE, any pregnancy 
complication (i.e. spontaneous abortion) or elective termination of a pregnancy, for medical reasons, 
will be recorded as an AE or SAE and followed as such. 
 
9.9 
Transmission of SAE Report Forms and Pregnancy Notification Forms 
 
Completed SAE Report Forms and completed pregnancy notification forms should be transmitted to 
Product Safety via the fax number provided below: 
 
US sites: Product Safety Fax: 888-314-5934 


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For questions regarding SAE and/or Pregnancy reports, contact Product Safety via the phone number 
provided below: 
 
US sites: Product Safety SAE Hotline: 888-314-1963 
 
9.10 Regulatory Reporting Requirements for SAEs 
 
The investigator, or responsible person per local requirements, must comply with the applicable local 
regulatory requirements related to the reporting of SAEs and IND safety reports to regulatory authorities 
and their IRB/EC. 


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10 STUDY ACTIVITIES 
The study Schedule of Assessments is provided as Appendix 2, and the Specialty PK and PD 
Laboratory Testing Schedule is provided as Appendix 3. 
 
10.1 
Visit 1: Screening (Days  -21 to -1) 
 
Study specific screening procedures will begin only after the informed consent form (ICF) has been 
signed and the consent process conducted with the patient has been briefly described in the patient’s 
source documents. The Screening Period will be scheduled to conduct procedures that confirm the 
patient is fully eligible for the study. Screening for the inclusion/exclusion criteria will occur within 3 
weeks before study drug administration. 
 
The following procedures will be performed during Screening: 
• Obtain informed consent 
• Evaluate inclusion and exclusion criteria 
• Record patient demographics, medical history, and vital signs 
• Record medication history (prescription and over the counter [OTC]) during the 8 weeks before 
Screening 
• Record RA history and prior RA treatment(s) 
• Perform a 12-lead ECG 
• Perform a chest X-ray (Note: a chest X-ray is not required if a chest X-ray with no clinically 
significant findings was performed within 1 month of randomization) 
• Perform a physical examination 
• Perform a serum pregnancy test for all females of childbearing potential 
• Collect blood samples on a day during Screening when the patient has fasted for 4 to 6 hours for: 
- 
Complete blood count with differential and platelet count (CBC) and chemistry 
- 
CRP 
- 
HCV antibody, HIV antibody, HBsAg, and QFT 
- 
RF and ACPA 
- 
ESR (done at site with the kit provided) 
• Collect urine sample for urinalysis 
• Inform patients of the study restrictions outlined in the inclusion/exclusion criteria 
• Conduct the DAS28-CRP and ACR Core Set Measurements 
• Complete the HAQ-DI 
10.2 
Treatment Period (Days 1 to 43) 
 
The once-weekly visits during the Treatment and Follow-up Periods can be scheduled for ±2 days 
around each of the designated Days in this schedule, but the designated Days themselves will not be 
shifted relative to Day 1. 


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10.2.1 
Visit 2 (Day 1) Procedures 
 
Eligible patients will return to the study site for enrollment, randomization, and administration of the first 
dose of study drug.  Patients should arrive at the study site having fasted for 4 to 6 hours.  The 
following procedures will be performed at Visit 2: 
 
Before Randomization: 
• Review inclusion and exclusion criteria and medical history 
• Record all AEs since previous visit 
• Record all medications (prescription and OTC) taken by the patient since Screening 
• Record RA history and prior RA treatment(s) 
• Record vital signs 
• Perform a urine pregnancy test for all females of childbearing potential 
• Collect urine for urinalysis 
• MRI of the hand and wrist most clinically affected by RA (to occur within 5 days before or at Visit 2) 
should be performed on patients able to tolerate the MRI procedure. 
 
Randomize  the  patient  via  the  IVRS/IWRS  system. 
After Randomization but before Study Drug Administration: 
• Collect blood samples for: 
- 
CBC and chemistry 
- 
ESR (done at site with the kit provided) 
- 
International normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time 
(aPTT) 
- 
Tryptase and histamine 
- 
Complement (C3, C4, and CH50) 
- 
CRP concentration 
- 
Serum immunoglobulins 
- 
ANA 
- 
Anti-SAN-300 antibodies 
- 
Serum SAN-300 concentration 
- 
Cytokine assessments (IFNγ, TNFα, IL-6) 
- 
Immunophenotyping panel (CD3/CD14/CD45RO/CD49a/CD45/CD4/CD19/CD8) 
- 
VLA-1 receptor occupancy 
• Conduct the DAS28-CRP and ACR Core Set Measurements 
• Complete the HAQ-DI 
Administer study drug according to the randomization of the patient. Day 1 study drug administration 
should occur on the day of or within 24 hours after randomization. 
 
After Study Drug Administration: 
• Observe subject at minimum 1 hour post dose. Longer observation allowed if deemed necessary by 
investigator or designee. 


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• Record blood pressure and pulse at the end of the 1 hour observation period prior to the blood 
sample collection 
• Collect blood sample at 1 hour post dose for serum SAN-300 concentration 
• Collect AEs since study drug administration 
10.2.2 
Visit 2A (between Days 2 to 4) and Visit 2B (between Days 5 to 7) 
 
Patients will come to the study site at a random, scheduled time within each of these intervals to have 
blood samples collected for serum SAN-300 concentration and VLA-1 receptor occupancy. 
 
Record all AEs and medications taken since previous visit 
 
10.2.3 
Visits 3, 4, and 5 (Days 8, 15, and 22) Procedures 
 
Patients should arrive at the study site having fasted for 4 to 6 hours. The following procedures will be 
performed at Visits 3 to 5: 
• Record all medications (prescription and OTC) taken by the patient since previous visit 
• Record all AEs since previous visit 
• Record vital signs 
• Perform a urine pregnancy test for all females of childbearing potential (Visit 5 only) 
• Collect blood samples for: 
- 
CBC and chemistry 
- 
ESR (done at site with the kit provided) 
- 
CRP concentration 
- 
Anti-SAN-300 antibodies (Visit 3 only) 
- 
Serum SAN-300 concentration 
- 
Cytokine assessments (IFNγ, TNFα, IL-6) (Visit 3 only) 
- 
Immunophenotyping panel (CD3/CD14/CD45RO/CD49a/CD45/CD4/CD19/CD8) (Visits 3 and 4 
only) 
- 
VLA-1 receptor occupancy (Visits 3 and 4 only) 
• Conduct the DAS28-CRP and ACR Core Set Measurements 
• Administer the study drug appropriate to the randomization of the patient 
• Complete the HAQ-DI 
• Observe subject at minimum 1 hour post dose. Longer observation allowed if deemed necessary by 
investigator or designee 
• Record blood pressure  and pulse at the end of the 1 hour observation period 
• Collect AEs since study drug administration 
10.2.4 
Visit 3A (between Days 9 to 11) 
 
Patients will come to the study site at a random, scheduled time within this interval to have a blood 
sample collected for serum SAN-300 concentration. 
 
Record all AEs and medications taken since previous visit 


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10.2.5 
Visits 6 and 7 (Days 29 and 36) Procedures 
 
Patients should arrive at the study site having fasted for 4 to 6 hours. The following procedures will be 
performed at Visits 6 and 7: 
 
Before Study Drug Administration during Visits 6 and 7: 
• Record all medications (prescription and OTC) taken by the patient since previous visit 
• Record all AEs since previous visit 
• Record vital signs 
• Perform a urine pregnancy test for all females of childbearing potential (Visit 7 only) 
• Collect blood samples for: 
- 
CBC and chemistry 
- 
ESR (done at site with the kit provided) 
- 
CRP concentration 
- 
Serum SAN-300 concentration 
- 
Cytokine assessments (IFNγ, TNFα, IL-6) 
- 
Immunophenotyping panel (CD3/CD14/CD45RO/CD49a/CD45/CD4/CD19/CD8) 
- 
VLA-1 receptor occupancy 
• Conduct DAS28-CRP and ACR Core Set Measurements 
• Complete HAQ-DI 
Administer the study drug appropriate to the randomization of the patient. 
 
After Study Drug Administration during Visits 6 and 7: 
• Observe subject at minimum 1 hour post dose. Longer observation allowed if deemed necessary by 
investigator or designee 
• Record blood pressure and pulse prior to the blood sample collection 
• Collect blood samples at 1 hour post dose (Visit 7 only) for: 
- 
Serum SAN-300 concentration 
- 
Cytokine assessments (IFNγ, TNFα, IL-6) 
• Collect AEs since study drug administration 
10.2.6 
Visit 6A (between Days 30 to 32), Visit 7A (between Days 37 to 39), and Visit 7B 
(between Days 40 to 42) 
 
Patients will come to the study site at a random, scheduled time within each of these intervals to have 
blood samples collected for serum SAN-300 concentration and VLA-1 receptor occupancy. 
 
Record all AEs and medications taken since previous visit. 
 
10.2.7 
Visit 8: End-of-Treatment Visit (Day 43) or Early Withdrawal Visit (Treatment Period) 
 
Patients should arrive at the study site having fasted for 4 to 6 hours. The following procedures will be 
performed at the End-of-Treatment Visit (Visit 8) or at an Early Termination Visit for patients who 
discontinue study participation during the Treatment Period: 


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• Record all medications (prescription and OTC) taken by the patient since Visit 7 
• Record all AEs since previous visit 
• Perform a 12-lead ECG 
• Perform a physical examination 
• Record vital signs 
• Collect urine for urinalysis 
• Perform a serum pregnancy test for all females of childbearing potential 
• Collect blood samples for: 
- 
CBC and chemistry 
- 
ESR (done at site with the kit provided) 
- 
INR, PT, aPTT 
- 
Complement (C3, C4, and CH50) 
- 
CRP concentration 
- 
Serum immunoglobulins 
- 
Anti-SAN-300 antibodies 
- 
Serum SAN-300 concentration 
- 
Cytokine assessments (IFNγ, TNFα, IL-6) 
- 
Immunophenotyping panel (CD3/CD14/CD45RO/CD49a/CD45/CD4/CD19/CD8) 
- 
VLA-1 receptor occupancy 
- 
RF, ANA, and ACPA 
• Conduct DAS28-CRP and ACR Core Set Measurements 
• HAQ-DI 
• MRI of the hand and wrist most clinically affected by RA (same as screening) should be performed 
on patients who are able to tolerate the MRI procedure. 
 
10.3 
Follow-up Period (Days 43 to 71) 
 
10.3.1 
Visit 8A (Day 50) and Visit 9A (Day 64) 
 
Patients will come to the study site to have blood samples collected for: 
• Serum SAN-300 concentration 
• VLA-1 receptor occupancy 
• Immunophenotyping panel 
• Anti-SAN antibodies (Visit 9A only) 
• Record all AEs and medications taken since previous visit 
 
10.3.2 
Visit 9 (Day 57) and Visit 10 (Day 71) or Early Withdrawal Visit (Follow-up Period) 
 
Patients should arrive at the study site having fasted for 4 to 6 hours. The following procedures will be 
performed at Visits 9 and 10 or at the Early Termination Visit for patients who discontinue study 
participation during the Follow-up Period: 
• Record all medications (prescription and OTC) taken by the patient since previous visit 


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• Record all AEs since previous visit 
• Perform a physical examination (Visit 10 and Early Termination only) 
• Record vital signs 
• Collect urine for urinalysis (Visit 10 and Early Termination only) 
• Collect blood samples for: 
- 
CBC and chemistry 
- 
ESR (done at site with the kit provided) 
- 
INR, PT, aPTT (Visit 10 and Early Termination only) 
- 
Complement (C3, C4, and CH50) (Visit 10 and Early Termination only) 
- 
CRP concentration 
- 
Serum immunoglobulins (Visit 10 and Early Termination only) 
• Conduct DAS28-CRP and ACR Core Set Measurements 
• Complete the HAQ-DI 


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11 PLANNED STATISTICAL METHODS 
11.1 
General Considerations 
 
All endpoints in this study will be summarized by descriptive statistics. Descriptive statistics for 
continuous variables will include the mean, standard deviation, median, first and third quartiles, 
minimum, and maximum value; categorical variables will be presented as counts and percentages. 
All statistical tests will be conducted at the two-sided α = 0.05 level of significance. All tests of binomial 
proportions will be conducted using the chi-square test unless more than one cell in a 2 x 2 table has 
an expected value of < 5, in which case the Fisher’s Exact Test will be used. All tests of continuous 
variables will be conducted using the Wilcoxon Rank-Sum Test. For all efficacy endpoints, patients will 
be analyzed according to the treatment to which they were randomized. For all safety endpoints, 
patients will be analyzed according to the treatment they received.  Parameters presented by 
“treatment group” will compare the 6 patients on SAN-300 from each cohort with the 10 pooled patients 
on placebo. 
 
11.2 
Determination of Sample Size 
 
There is no sample size calculation, as this study is not intended to be powered to demonstrate 
efficacy.  Results from this study will be used to design future efficacy studies. 
 
11.3 
Analysis Populations 
 
11.3.1 
Intent-to-Treat Population 
 
The Intent-to-Treat (ITT) Population is defined as all randomized patients who received at least one 
dose of a study drug. Patients in the ITT Population will be analyzed according to the treatment to 
which they were randomized. 
 
The ITT Population is the primary population for the analysis of all efficacy endpoints. 
 
11.3.2 
Safety Population 
 
The Safety Population is defined as all patients who received at least one dose of a study drug; this 
population will be used for the safety analysis. Patients in the Safety Population will be analyzed 
according to the treatment they received. 
 
11.3.3 
Per Protocol Population 
 
The Per Protocol (PP) Population is defined as all patients in the ITT Population with the exception of 
those who failed to meet Inclusion Criterion 4; or met Exclusion Criteria 1 and 2. 
 
11.4 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized by treatment group and will be presented 
for individual patients in data listings. 


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11.5 
Safety Analysis 
 
All AEs will be coded using MedDRA. The number and percentages of patients reporting at least one 
occurrence of each AE will be tabulated by system organ class and preferred term. The number and 
percentages of patients reporting at least one occurrence of each AE by system organ class and 
preferred term will also be tabulated by severity and by the relationship to study drug. For multiple 
occurrences of the same AE in a patient that differ in severity, the AE with the highest level of severity 
will be tabulated.  For multiple occurrences of the same AE in a patient that differ in relationship to 
study drug (e.g., related and not related), the AE will be tabulated as related. All AEs for all patients will 
be presented in a data listing. 
 
All other safety parameters will be summarized using descriptive statistics and presented by time point 
and treatment group. All other safety parameters will be presented for individual patients in data 
listings. 
 
11.6 
Pharmacokinetic Analysis 
 
Population PK methods will be employed to estimate the relevant PK parameters for the population as 
well as for each individual patient who received SAN-300 and had at least one blood sample in which 
SAN-300 was quantifiable. The details of the population PK analysis will be documented in a 
Population Pharmacokinetic/Pharmacodynamic Analysis Plan. 
 
PK parameters will be summarized using descriptive statistics and presented by time point and 
treatment group in tabular format. PK parameters for individual patients will be presented in data 
listings.  Time-dependent SAN-300 concentrations will be presented in figure format. 
 
11.7 
Pharmacodynamic Analysis 
 
PD parameters will be summarized using descriptive statistics and presented by time point and 
treatment group in tabular format. PD parameters will be summarized from baseline to each time point 
by treatment group.  PD parameters for individual patients will be presented in data listings. 
Time-dependent PD parameters will be presented in figure format. 
 
11.8 
Efficacy Analysis 
 
Efficacy will be compared for the SAN-300 dose groups (0.5, 1.0, 2.0 and 4.0 mg/kg once-weekly and 
2.0 and 4.0 mg/kg every other week) and the pooled placebo group. 
 
The DAS28-CRP and HAQ-DI will be calculated and presented by time point and treatment group. The 
mean change from baseline to the End-of-Treatment Visit for DAS28-CRP will be compared across 
treatment groups using the Wilcoxon Rank-Sum Test.  The percentages of patients achieving a 
DAS28-CRP ≤ 3.2 and < 2.6 will be compared across treatment groups using the chi-square test. 
 
All components of the ACR Core Set will be summarized using descriptive statistics and presented by 
time point and treatment group. The percentages of patients achieving ACR20, ACR50, or ACR70 
responses will be compared across treatment groups using the chi-square test. 
 
MRI data will be summarized across the treatment groups for each time point. All MRI data will be 
presented for individual patients in data listings. 


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All efficacy assessments will be presented for individual patients in data listings. 
 
Additional analyses may be performed, as needed, to fully evaluate potential efficacy signals and 
evidence of clinical benefit. 
 
11.9 
Other Laboratory Values 
 
All other laboratory parameters will be summarized using descriptive statistics and presented by time 
point and treatment group. All other laboratory parameters will be presented for individual patients in 
data listings.  Laboratory parameters will be presented in figure format. 
 
11.10 Interim Analysis 
 
There will be no formal interim analysis during the course of the study. 


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12 DATA HANDLING AND QUALITY ASSURANCE 
12.1 
Case Report Forms 
 
As part of the responsibilities assumed by participating in the study, the Principal Investigator or 
Sub-investigators agree to maintain adequate case histories for the patients treated as part of the 
research under this protocol. The case histories include accurate eCRFs and source documentation. 
The primary source documents for this study will be the patients’ medical records and research records 
maintained by the Investigators. 
 
The Principal Investigator or Sub-investigator is responsible for ensuring that the clinical data required 
by the study protocol are carefully entered in the eCRFs.  They are also responsible for checking that 
the data reported in the eCRFs correspond to those in the source files. To ensure legibility, the eCRFs 
will be entered in English. Data changes are documented and saved in an audit trail in the clinical trial 
database, and there is no deletion of entered data. In the interests of completeness of data acquisition, 
the questions which are repeated in each section of the eCRF should be answered in full, even if there 
are no changes from a previous examination. A reasonable explanation must be given by the 
Investigator for all missing data. 
 
After data have been entered, reviewed, and edited and source data verification has been performed, 
completed eCRFs must be electronically signed by the Principal Investigator or Sub-investigator. 
 
12.2 
Monitoring of the Study 
 
The study will be supervised by regional clinical research associates (CRAs). The CRAs will visit the 
Principal Investigator or Sub-investigator at each study facility at periodic intervals to review and 
discuss study progress. In addition, CRAs will maintain regular telephone, email, and letter contact with 
each study facility.  The CRAs will maintain current personal knowledge of the study through 
observation, review of study records and direct access to source documentation, and discussion of the 
conduct of the study with the Principal Investigator and/or Sub-investigator and staff. 
 
All aspects of the study will be carefully monitored by the CRO and Santarus for compliance with 
applicable government regulation with respect to current Good Clinical Practice (GCP) and current 
Standard Operating Procedures. 
 
The eCRFs will be checked for completeness, plausibility, and consistency with source documents and 
any queries will be resolved by the Investigator. 
 
12.3 
Inspection of Records 
 
Principal or Sub-investigators and institutions involved in the study will permit trial-related monitoring, 
audits, IEC/IRB review, and regulatory inspection(s).  In the event of an audit, the Principal or 
Sub-investigator agrees to allow the Sponsor, representatives of the Sponsor, FDA, or other regulatory 
authorities access to all study records and source documentation. 
 
The Principal Investigator or Sub-investigator should promptly notify the Sponsor and the CRO of any 
audits scheduled by any regulatory authorities and promptly forward copies of any audit reports 
received to the Sponsor. 


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12.4 
Study Record Retention 
 
Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an International Conference on Harmonisation (ICH) region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. It is the responsibility of the Sponsor to inform the Principal 
Investigator or Sub-investigator/institution as to when these documents no longer need to be retained. 


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13 ADMINISTRATIVE CONSIDERATIONS 
The following administrative items are meant to guide the Principal Investigator and Sub-investigator in 
the conduct of the trial but may be subject to change based on industry and government Standard 
Operating Procedures or Working Practice Documents or Guidelines. 
 
13.1 
Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a manner 
designed to maintain patient confidentiality. All records will be kept in a secure storage area with 
limited access. Clinical information will not be released without the written permission of the patient, 
except as necessary for monitoring and auditing by the Sponsor, its designee, Regulatory Authorities, 
or the IEC/IRB. 
 
The Principal Investigator or Sub-investigator and all employees and co-workers involved with this 
study may not disclose or use for any purpose other than performance of the study, any data, record, or 
other unpublished, confidential information disclosed to those individuals for the purpose of the study. 
Prior written agreement from the Sponsor or its designee must be obtained for the disclosure of any 
said confidential information to other parties. 
 
13.2 
Independent Ethics Committee/Institutional Review Board Approval 
 
ICH guidelines require that approval be obtained from an IEC/IRB before the participation of human 
patients in research studies.  Before the study starts, the protocol, the ICF, advertisements to be used 
for patient recruitment, and any other written information regarding this study to be provided to the 
patient (or the patient’s legal guardian) must be approved by the IEC/IRB.  Documentation of all 
IEC/IRB approvals and of the IEC/IRB compliance with ICH Guideline E6 will be maintained by the site 
and will be available for review by the Sponsor or its designee. All IEC/IRB approvals should be signed 
by the IEC/IRB Chairman or designee and must identify the IEC/IRB name and address, the clinical 
protocol by title and/or protocol number and the date approval and/or favorable opinion was granted. 
 
The Principal Investigator or Sub-investigator is responsible for obtaining notification of continued 
review of the clinical research at intervals not exceeding one year or otherwise specified by the 
IEC/IRB. The Principal Investigator or Sub-investigator must supply the Sponsor or its designee with 
written documentation of annual IEC/IRB review and approval of the clinical research. 
 
13.3 
Modification of the Protocol 
 
Any changes in this research activity, except those necessary to remove an apparent, immediate 
hazard to the patient, must be reviewed and approved by the Sponsor or its designee. Amendments to 
the protocol must be submitted in writing to the Principal Investigator’s IEC/IRB for approval before 
patients are enrolled into an amended protocol. 
 
13.4 
Informed Consent 
 
Written informed consent will be obtained from each patient before entering the study or before 
performing any unusual or non-routine procedure that involves risk to the patient. An agreed ICF, 
reviewed by the Sponsor and/or its designee, will be submitted by the Principal Investigator or 


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Sub-investigator to his or her IEC/IRB for review and approval before the start of the study. If the ICF is 
revised during the study, all active participating patients must sign the revised ICF. 
 
Before recruitment and enrollment, each prospective patient will be given a full explanation of the study 
and allowed to read the IEC/IRB-approved ICF. Once the Principal Investigator or Sub-investigator is 
assured that the patient understands the implications of participating in the study, the patient will be 
asked to give consent to participate in the study by signing the ICF. The informed consent process will 
be briefly described in the source documents for each patient. 
The original and any amended signed 
and dated informed consent documents must be retained at the study site; and a copy must be given to 
the patient or the patient’s legally authorized representative(s). Note: The ICF for this study will be 
provided as a separate document. 
 
13.5 
Protocol Violations and Deviations 
 
The Principal Investigator or Sub-investigator or designee must document and explain in the patient’s 
source documentation any deviation from the approved protocol.  The Principal Investigator or 
Sub-investigator may implement a deviation from, or a change of, the protocol to eliminate an 
immediate hazard to trial patients without prior IEC/IRB approval. As soon as possible after such an 
occurrence, the implemented deviation or change, the reasons for it, and any proposed protocol 
amendment(s) should be submitted to the IEC/IRB for review and approval, to the Sponsor for 
agreement, and to the regulatory authorities, if required. 
 
A deviation from the protocol can be an unintended and/or unanticipated departure from the procedures 
and/or processes approved by the Sponsor and the IEC/IRB and agreed to by the Principal Investigator 
or Sub-investigator.  Deviations usually have an impact on individual patients or a small group of 
patients and do not involve inclusion/exclusion or primary endpoint criteria. A protocol violation occurs 
when there is non-adherence to the protocol that results in a significant, additional risk to the patient, 
when the patient or Principal Investigator or Sub-investigator has failed to adhere to significant protocol 
requirements (e.g., an inclusion/exclusion criterion) and the patient was enrolled without prior Sponsor 
approval, or when there is non-adherence to ICH-GCP guidelines. 
 
Protocol violations and deviations will be documented by the Principal Investigators or 
Sub-investigators. The IEC/IRB should be notified of protocol violations and substantial deviations that 
impact on the safety and integrity of the study in a timely manner. Other deviations from the protocol 
must also be reported to the IEC/IRB according to their requirements. 
 
13.6 
Study Reporting Requirements 
 
By participating in this study the Principal Investigator or Sub-investigator agrees to submit reports of 
SAEs and pregnancies according to the timeline and method outlined in the protocol. In addition, the 
Principal Investigator or Sub-investigator agrees to submit annual reports to his/her IEC/IRB as 
appropriate. The Principal Investigator or Sub-investigator also agrees to provide the Sponsor with an 
adequate report of the Principal Investigator’s or Sub-investigator’s participation in the study. 
 
13.7 
Financial Disclosure and Obligations 
 
Principal Investigators and Sub-investigators are required to provide financial disclosure information to 
allow the Sponsor to submit the complete and accurate certification or disclosure statements required 
under Part 54 of Title 21 of the CFR.  Note: this study may be used as part of a US submission 


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package and hence the appropriate CFRs need to apply to all study sites. In addition, the Principal 
Investigator and Sub-investigators must provide to the Sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 1 year after the 
completion of the study 
 
Neither the Sponsor nor study CROs are financially responsible for further testing/treatment of any 
medical condition that may be detected during the screening process. In addition, in the absence of 
specific arrangements, neither the Sponsor nor the study CROs are financially responsible for further 
treatment of the patient’s disease. 
 
13.8 
Investigator Documentation 
 
Before beginning the study, the Principal Investigator will be asked to comply with ICH E6 8.2 
guidelines and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• An original signed Investigator’s Statement page of the protocol (Appendix 9) 
• An IEC/IRB-approved ICF, samples of site advertisements for recruitment for this study, and any 
other written information regarding this study that is to be provided to the patient 
• IEC/IRB approval 
• FDA 1572 form 
• Curriculum vitae (CV) for the Principal Investigator and each Sub-investigator. Current licensure 
must be noted on the CV. They will be signed and dated by the Principal Investigators and Sub- 
investigators at study start-up, indicating that they are accurate and current 
• Financial disclosure information to allow the Sponsor to submit complete and accurate certification 
or disclosure statements required under Part 54 of Title 21 of the CFR. In addition, the 
Investigators must provide to the Sponsor a commitment to promptly update this information if any 
relevant changes occur during the course of the investigation and for 1 year after the completion of 
the study 
 
13.9 
Study Conduct 
 
The Principal Investigator agrees that the study will be conducted according to the principles of the ICH 
E6 Guideline on GCP and the ethical principles that have their origins in the WMA Declaration of 
Helsinki. The Principal Investigator will conduct all aspects of this study in accordance with all national 
and local laws or regulations. 
 
13.10 Publications 
 
After completion of the study, the data may be considered for reporting at a scientific meeting or for 
publication in a scientific journal.  In these cases, the Sponsor will be responsible for these activities 
and will work with Investigators to determine how the manuscript is written and edited, the number and 
order of authors, the publishing journal/newsletter to which it will be submitted, and other related issues. 
Data are the property of the Sponsor and cannot be published without prior authorization from the 
Sponsor, but data and publication thereof will not be unduly withheld. 


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14 REFERENCE LIST 
Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham C, et al. 2010 Rheumatoid arthritis 
classification criterion. Arthritis & Rheumatism. 2010;62(9):2569-2581. 
 
Ben-Horin S, Goldstein I, Koltakov A, Langevitz P, Ehrenfeld M, et al. The effect of blockade of tumor 
necrosis factor alpha on VLA-1+ T-cells in rheumatoid arthritis patients. J Clin Immunol. 
2007;27(6):580-588. 
 
Becker HM, Rullo J, Chen M, Ghazarian M, Bak S, Xiao H. α1β1 integrin-mediated adhesion inhibits 
macrophage exit from peripheral inflammatory lesion. J Immunol. 2013;190:4305-4314. 
 
Fleishmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD. Placebo-controlled trial of 
tofacitinib monotherapy in rheumatoid arthritis. New Eng J Med. 2012;367:495-507. 
 
Food and Drug Administration. Guidance for industry. Clinical development programs for drugs, 
devices, and biological products for the treatment of rheumatoid arthritis (RA). 1999. 
 
Hochberg M, Chang R, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 
1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis & 
Rheumatism. 1992;35(5):498-502. 
 
Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall ST, Miranda PC. Golimumab, a human 
antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid 
arthritis despite methotrexate therapy: the GO-FORWARD study. Ann Rheum Dis. 2009;68:789-796. 
 
Østergaard M, Peterfy C, Conaghan P, McQueen F, Bird P, Ejbjerg B, et al. OMERACT Rheumatoid 
Arthritis Magnetic Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, 
and the OMERACT RA-MRI scoring system. J Rheumatol. 2003;30(6):1385-1386. 
 
Peterfy CG, DiCarlo JC, Olech E, Bagnard MA, Gabriele A, Gaylis N. Evaluating joint-space narrowing 
and cartilage loss in rheumatoid arthritis by using MRI. Arthritis Res Ther. 2012;14(3):R131. 
 
Pribila JT, Quale AC, Mueller KL, Shimizu Y. Integrins and T cell-mediated immunity. Ann Rev 
Immunol. 2004.22:157-180. 
 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. Second 
symposium on the definition and management of anaphylaxis: summary report-second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaplylaxis Network symposium. J Allergy 
Clin Immunol. 2006;117:391-397. 
 
Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM et al. 2012 update of the 2008 
American College of Rheumatology recommendations for the use of disease-modifying antirheumatic 
drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care & Research. 
2012;64:625-639. 
 
Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral spleen 
tyrosine kinase (syk) inhibitor for rheumatoid arthritis. New Eng J Med. 2010;363:1303-1312. 


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Appendix 1 
Atypical or Opportunistic Infections 
 
1. Mycobacterial infections: tuberculosis (TB), nontuberculosis mycobacteria 
2. Viral infections: progressive multifocal leukoencephalopathy (PML) (JC [John Cunningham] virus), 
hepatitis B virus, Cytomegalovirus, and disseminated Herpes zoster 
3. Systemic/invasive fungal infections: coccidioidomycosis, aspergillosis, cryptococcosis, 
histoplasmosis, blastomycosis, Pneumocystis jirovecii, and invasive or systemic candidiasis 
4. Protozoal infections: malaria (Plasmodium) 
5. Other infections: nocardiosis 


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Page 63 of 118 
 
 
 
Appendix 2 
Schedule of Assessments for Study C2013-0302 
 
Screening 
(21 days) 
Double-blind Treatment Period (42 days [3 to 6 doses]) 
Follow-up Period 
(28 days) 
Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 9 
Week 11 
Visit: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Day: 
Day -21 to -1 
Day 1a 
Day 8a 
Day 15a 
Day 22a 
Day 29a 
Day 36a 
Day 43a 
Day 57a 
Day 71a 
Timing 
(where applicable): 
Pre-dose 
Post- 
dose 
Pre- 
dose 
Post-dose 
Pre- 
dose 
Post- 
dose 
End-of- 
Treatment 
Visit 
Exit Visit 
Eligibility Assessments 
Informed Consent 
X 
Inclusions/Exclusions 
X 
X 
Demographics 
X 
Medical History 
X 
X 
Medication History 
X 
X 
RA History and Prior RA 
Treatment 
X 
X 
HCV Antibody, HBsAg, HIV 
Antibody 
X 
Chest X-rayb 
X 
QuantiFERON-GOLD 
X 
Dosing 
Randomization 
X 
Administration of SAN-300 
or Placeboc 
Xd 
Xc 
X 
Xc 
X 
Xc 
Safety Assessments 
Vital Sign Measurements 
X 
X 
Xg 
Xg 
Xg 
Xg 
X 
Xg 
X 
Xg 
X 
X 
X 
Physical Examination 
X 
X 
X 
CBC, Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UA 
X 
X 
X 
X 
INR, PT, aPTT, 
Complement 
X 
X 
X 


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Screening 
(21 days) 
Double-blind Treatment Period (42 days [3 to 6 doses]) 
Follow-up Period 
(28 days) 
Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 9 
Week 11 
Visit: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Day: 
Day -21 to -1 
Day 1a 
Day 8a 
Day 15a 
Day 22a 
Day 29a 
Day 36a 
Day 43a 
Day 57a 
Day 71a 
Timing 
(where applicable): 
Pre-dose 
Post- 
dose 
Pre- 
dose 
Post-dose 
Pre- 
dose 
Post- 
dose 
End-of- 
Treatment 
Visit 
Exit Visit 
Tryptase, histaminee 
X 
Serum Immunoglobulins 
X 
X 
X 
12-Lead ECG 
X 
X 
Pregnancy Test 
Serum 
Urine 
Urine 
Urine 
Serum 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
ACR Core Set 
Assessments, DAS28-CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAQ-DI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI of Hand and Wristf 
X 
X 
Other Assessments 
RF, ACPA 
X 
X 
ANA 
X 
X 
Abbreviations: ACPA = anti-citrunillated peptide antibodies; ACR = American College of Rheumatology; ANA = antinuclear antibody; aPTT = activated partial 
thromboplastin time; CBC = complete blood count with differential and platelet count; CCP = cyclic citrullinated peptide; DAS28-CRP = Disease Activity Score with 
28-joint count C-reactive protein; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; HAQ-DI = Health Assessment Questionnaire – Disease Index; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; CRP = C reactive protein; INR = international normalized 
ratio; MRI = magnetic resonance imaging; PT = prothrombin time; QFT = QuantiFERON®-TB Gold test; RA = rheumatoid arthritis; RF = rheumatoid factor; UA = 
urinalysis. 
a 
Weekly visits during the Treatment and Follow-up Periods can be scheduled for ±2 days around each of the designated Days in this schedule, but the 
designated Days themselves will not be shifted relative to Day 1. 
b 
If a chest X-ray was performed with no clinically significant findings within 1 month of randomization, another chest X-ray is not required at Screening. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 65 of 118 
 
 
c 
For all cohorts, patients randomized to receive placebo will be administered a total of 6 once-weekly SC injections of placebo on Days 1, 8, 15, 22, 29, and 36. 
In Cohorts A, B, and D, patients randomized to receive SAN-300 will be administered a total of 6 once-weekly SC injections of SAN-300 on Days 1, 8, 15, 22, 
29, and 36. In Cohorts C and E, patients randomized to receive SAN-300 will be administered a total of three every-other-week SC injections of SAN-300 on 
Days 1, 15, and 29 and will be administered a total of three every-other-week SC injections of placebo on Days 8, 22, and 36.  Note:  Subject to be observed 
at minimum 1 hour post- dose. Longer observation allowed if deemed necessary by investigator or designee. 
d 
Day 1 dosing will occur on the day of or within 24 hours after randomization. 
e 
After baseline assessment, additional assessments of tryptase and histamine to occur only in suspected cases of anaphylaxis or hypersensitivity reactions. 
f 
In patients who are able to tolerate the MRI,  it should be performed within 5 days prior to or at Visit 2 (Day 1, prior to dosing).  MRI of hand and wrist most 
clinically affected by RA will be imaged at Baseline, the same wrist will be imaged at End of Treatment. 
g 
Blood pressure and pulse will be collected at the end of the observation period; prior to the subject leaving the clinic. When a post-dose blood sample is 
collected, the blood pressure and pulse should be assessed prior to the sample collection. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 66 of 118 
 
 
 
Appendix 3 
Specialty PK and PD Laboratory Testing Schedule 
 
For all cohorts, blood samples for PK and PD analysis will be collected at the specified times predose and postdose, at random times intermittently 
scheduled between dosing visits, and at visits within the Follow-up Period. A predose sample will be collected before every study drug 
administration. A postdose sample will be collected at 1 h after the first study drug administration on Day 1 and at 1 h after the last study drug 
administration on Day 36. In addition, all patients will return to the study site at random times within the specified intervals between certain study 
drug administration visits for additional sample collection. Finally, samples will be collected for all cohorts after the end of all drug dosing, on Days 
43, 50, and 64. 
 
SC 
Dose #: 
SC 
#1 
SC 
#2 
SC 
#3 
SC 
#4 
SC 
#5 
SC 
#6 
End-of- 
Treat- 
ment 
Visit 
Follow-up 
Period 
Week: 
Wk 1 
Wk 2 
Wk 3 
Wk 4 
Wk 5 
Wk 6 
Wk 7 
Wk 8 Wk 10 
Visit: 
Visit 2 
Visit 2A Visit 2B Visit 3 Visit 3A Visit 4 Visit 5 Visit 6 Visit 6A 
Visit 7 
Visit 7A Visit 7B Visit 8 Visit 
8A 
Visit 
9A 
Day: 
Day 1 
Day 1 
Day 2-4 Day 5-7 
Day 
8 
Day 9-11 Day 15 Day 22 Day 29 
Day 
30-32 
Day 
36 
Day 
36 
Day 
37-39 
Day 
40-42 
Day 
43 
Day 
50 
Day 
64 
Timing: 
Pre- 
Dose 
1 h Post- 
Dose 
Random Random 
Pre- 
Dose Random 
Pre- 
Dose 
Pre- 
Dose 
Pre- 
Dose Random Pre- 
Dose 
1 h 
Post- 
Dose 
Random Random 
PK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cyto 
X 
X 
X 
X 
X 
X 
RO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IPT 
X 
X 
X 
X 
X 
X 
X 
X 
ADA 
X 
X 
X 
X 
Abbreviations: ADA = anti-drug (SAN-300) antibody; Cyto = cytokines (IFNγ, TNFα, IL-6); IPT = immunophenotyping panel (CD3, CD4, CD8, CD45, CD45RO, 
CD14, CD19, and CD49α); PK = pharmacokinetics; RO = receptor occupancy (VLA-1); SC = subcutaneous. Note: At each visit, AEs and medications taken 
should be recorded. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 67 of 118 
 
 
 
Appendix 4 
ACR / EULAR RA Classification Criteria 
 
ACR / EULAR RA Classification Criteria (2010) 
 
Target population (Who should be tested?): 
1. Patients who have at least one joint with definite clinical synovitis (swelling)1 
2. Patients whose synovitis is not better explained by another disease2 
Classification criteria for RA (score-based algorithm: add score of categories A–D; a score of ≥ 6/10 is 
needed for classification of a patient as having definite RA)3 
A. Joint involvement4 
1 large joint5 
0 
2-10 large joints 
1 
1-3 small joints (with or without involvement of large joints)6 
2 
4-10 small joints (with or without involvement of large joints) 
3 
> 10 joints (at least 1 small joint)7 
5 
B. Serology (at least 1 test result is needed for classification)8 
Negative RF and negative ACPA 
0 
Low-positive RF or low-positive ACPA 
2 
High-positive RF or high-positive ACPA 
3 
C. Acute-phase reactants (at least 1 test result is needed for classification)9 
Normal CRP and normal ESR 
0 
Abnormal CRP or abnormal ESR 
1 
D. Duration of symptoms10 
< 6 weeks 
0 
≥ 6 weeks 
1 
Abbreviations: ACPA = anti-citrunillated peptide antibody; CRP = C-reactive protein; ESR = erythrocyte 
sedimentation rate; RA = rheumatoid arthritis; RF = rheumatoid factor. 
1 
The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease 
typical of RA with a history compatible with prior fulfillment of the 2010 criteria should be classified as having 
RA. Patients with longstanding disease, including those whose disease is inactive (with or without treatment) 
who, based on retrospectively available data, have previously fulfilled the 2010 criteria, should be classified 
as having RA. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 68 of 118 
 
 
2 
Differential diagnoses vary among patients with different presentations but may include conditions such as 
systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear which of the relevant differential 
diagnoses to consider, an expert rheumatologist should be consulted. 
3 
Although patients with a score of < 6/10 are not classifiable as having RA, their status can be reassessed, 
and the criteria might be fulfilled cumulatively over time. 
4 
Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging 
evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal 
joints are excluded from assessment. Categories of joint distribution are classified according to the location 
and number of involved joints, with placement into the highest category possible based on the pattern of joint 
involvement. 
5 
"Large joints" refers to shoulders, elbows, hips, knees, and ankles. 
6 
"Small joints" refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth 
metatarsophalangeal joints, thumb interphalangeal joints, and wrists. 
7 
In this category, at least one of the involved joints must be a small joint; the other joints can include any 
combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., 
temporomandibular, acromioclavicular, sternoclavicular, etc.). 
8 
Negative refers to International Unit (IU) values that are less than or equal to the upper limit of normal (ULN) 
for the laboratory and assay; low-positive refers to IU values that are higher than the ULN but ≤ 3 times the 
ULN for the laboratory and assay; high-positive refers to IU values that are > 3 times the ULN for the 
laboratory and assay. Where RF information is only available as positive or negative, a positive result should 
be scored as low-positive for RF. 
9 
Normal/abnormal is determined by local laboratory standards. 
10 
Duration of symptoms refers to patient self-report of the duration of signs or symptoms of synovitis (e.g., pain, 
swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment 
status. 
 
Source: Aletaha, 2010 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 69 of 118 
 
 
 
Appendix 5 
ACR Revised Criteria for Classification of Global Functional Class in 
RA 
 
ACR Revised Criteria for Classification of Global Functional Class in RA (1991) 
Class 
Definition 
 
Class I: 
Completely able to perform usual activities of daily living (self-care, vocational, and avocational)1 
Class II: 
Able to perform usual self-care and vocational activities, but limited in avocational activities. 
Class III: 
Able to perform usual self-care activities, but limited in vocational and avocational activities. 
Class IV: 
Limited in ability to perform usual self-care, vocational and avocational activities. 
1 
Usual self-care activities include dressing, feeding, bathing, grooming, and toileting. Vocational (school, work, 
homemaking) and avocational (recreational and/or leisure) activities are patient-desired and age- and sex- 
specific. 
Source: Hochberg, 1992 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 70 of 118 
 
 
 
Appendix 6 
Swollen and Tender Joint Assessment 
 
An experienced assessor will evaluate joint counts. 
 
Joints to be Assessed for Swelling and Tenderness 
 
The joints to be assessed for tenderness (68 joints) and swelling (66 joints) consist of the following: 
• Temporomandibular joint 
• Sternoclavicular joint 
• Acromioclavicular joint 
• Shoulders* 
• Elbows* 
• Wrists* 
• Interphalangeal on digit 1* 
• Distal interphalangeal joints on digits 2 – 5 
• Proximal interphalangeal joints on digits 2 – 5* 
• Metacarpophalangeal joints on digits 1 – 5* 
• Hips (tenderness only) 
• Knees* 
• Ankles 
• Metatarsals 
• Interphalangeal joints on toes 1 – 5 
• Metatarsophalangeal joints on toes 1 – 5 
Joints assessed for swelling are the same, with the exception of the hips, which are excluded. 
 
* The 28 joints used to calculate the DAS28. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 71 of 118 
 
 
 
Appendix 7 
HAQ-DI Total Score and Individual Dimensions 
 
The physical functional status of the patient will be assessed using the HAQ. This is a widely used 
patient self-report tool which assesses the degree of difficulty a person has had in accomplishing tasks 
in eight functional areas, over the previous week. 
 
The eight categories assessed by the HAQ are 
 
(1) dressing and grooming, 
 
(2) rising, 
 
(3) eating, 
 
(4) walking, 
 
(5) hygiene, 
 
(6) reach, 
 
(7) grip, 
 
(8) common daily activities. 
 
For each of these categories, patients report the amount of difficulty they have in performing two or 
three specific activities. There are four possible responses for the HAQ questions: without ANY difficulty 
(0), with SOME difficulty (1), with MUCH difficulty (2) and UNABLE to do (3).  The scores for each of 
the eight categories are calculated. The HAQ is then derived by adjusting the score for each of these 
categories, if necessary, based upon the patient’s use of an aid, device, or assistance for that category, 
totaling the sum of the category scores and dividing by the number of categories answered. The HAQ 
score can range between 0 and 3. 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 72 of 118 
 
 
 
Appendix 8 
Scoring the Magnetic Resonance Imaging Scans 
 
Each MRI will be scored using the published OMERACT RA MRI Score (RAMRIS) (Østergaard, 2003) 
and cartilage loss scoring (Peterfy, 2012). 
 
Scoring of Bone Erosion: 
Erosion will be scored at the following 25 locations: the distal radius and ulna, the eight carpal bones, 
including the trapezium, trapezoid, capitate, hamate, pisiform, scaphoid, lunate, and triquetrum, as well 
as the five metacarpal bases, the five metacarpal heads, and the five proximal phalangeal bases. 
Bone erosion is scored 0-10, according to the proportion (in increments of 10%) of erosion of articular 
bone:  0: 0%, 1: 1%-10%, 2: 11%-20%, ……..10: 91%-100% 
 
Scoring of Osteitis: 
Osteitis will be scored at the same 25 bone locations as erosion: the distal radius and ulna, the eight 
carpal bones, including the trapezium, trapezoid, capitate, hamate, pisiform, scaphoid, lunate, and 
triquetrum, as well as the five metacarpal bases, the five metacarpal heads, and the five proximal 
phalangeal bases. 
Osteitis is scored 0-3 according to the proportion (in increments of 33%) of involvement of original 
articular bone:  0: 0%, 1: 1%-33%, 2: 34%-66%, 3: 67%-100% 
 
Scoring of Synovitis: 
Synovitis will be scored at the following eight joint locations: the distal radioulnar joint, the radiocarpal 
joint, the intercarpal and carpometacarpal joints together, and the five metacarpophalangeal (MCP) 
joints. 
Synovitis is scored 0-3 according to the proportion of volume enhancement: 
0: 0%, 1: 1%-33%, 2: 34%-66%, 3: 67%-100% 
 
Scoring of Cartilage Loss: 
Cartilage loss will be assessed in the MRI images of the hand with the most clinically significant 
synovitis (25 joints). Joints that will be assessed include MCP joints 1-5, proximal inter-phalangeal 
joints (1-5), as well as the following joints of the wrist: 
• Four carpometacarpal (CMC) joints 2-5 
• Scaphotrapezoid joint 
• Scaphotrapezium joint 
• Trapezoid-trapezium joint 
• Radioscaphoid joint 
• Radiolunate joint 
• Lunate-triquetrum joint 
• Hamate-triquetrum joint 
• Capitate-hamate joint 
• Capitate-lunate joint 
• Scaphocapitate joint 
• Capitate-trapezoid joint 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 73 of 118 
 
 
 
The following joints are not scored: CMC joint 1, scapholunate joint, triquitropisiform joint, and the 
radioulnar joint. 
 
Cartilage loss is scored 0-4 according to the following scale: 
 
Score 
Definition 
0 
Normal 
0.5 
Equivocal 
1.0 
Mild (definitive narrowing) 
1.5 
Mild-moderate 
2.0 
Moderate 
2.5 
Moderate-severe, including partial bone-on-bone narrowing 
3.0 
Severe, complete bone-on-bone narrowing (bilateral cartilage denuding) 
3.5 
Partial ankylosis 
4.0 
Complete ankylosis 


Santarus, Inc. 
SAN-300 
Amendment 5:  28 Mar 2016 
CONFIDENTIAL 
Clinical Trial Protocol: C2013-0302 
Page 75 of 118 
 
 
 
Appendix 9 
Investigator’s Signature 
 
Study Title: 
A Randomized, Double-blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, Pharmacokinetics, 
Pharmacodynamics, and Efficacy of Escalating Doses of SAN-300 in Patients with Active Rheumatoid Arthritis with Inadequate Response to 
Disease-Modifying Anti-rheumatic Drug(s) 
Study Number: 
C2013-0302 
Final Date: 
15 Sep 2014 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to conduct the study as described in the protocol. 
 
 
 
 
 
Signed:  
 
Date:  
 
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
 
<enter address> 
 
<enter phone number> 
 
 
 

SAP_001.pdf: 
Study C2013-0302 – Clinical Study Report 
16.1.9 Documentation of Statistical Methods 
Statistical Analysis Plan, Version 2.0, 20Mar2017 
NCT02047604


Salix Pharmaceuticals, Inc. 
 Statistical Analysis Plan 
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
STATISTICAL ANALYSIS PLAN 
Study Protocol Number: C2013-0302 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTIPLE 
ASCENDING DOSE STUDY TO EVALUATE SAFETY, PHARMACOKINETICS, 
PHARMACODYNAMICS AND EFFICACY OF ESCALATING DOSES OF SAN-300 IN 
PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS WITH INADEQUATE 
RESPONSE TO DISEASE MODIFYING ANTI-RHEUMATIC DRGUG(S) 
Date of Original Protocol: 13 August 2013 
Amendment 5: 28 March 2016 
Prepared by: 
Edetek, Inc.
101 College Road East, 2nd Floor 
Princeton, NJ 08540 USA 
Reviewed by: 
Edetek, Inc.
101 College Road East, 2nd Floor 
Princeton, NJ 08540 USA 
Final: 10 March 2017 
Confidential 


Salix Pharmaceuticals, Inc. 
Protocol: C2013-0302 
Approval 
Statistical Analysis Plan 
Version 2.0 - March 20, 2017 
The undersigned have reviewed and approved the statistical analysis plan and find the document 
to be consistent with the requirements of the Protocol. 
2 


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
3
REVISION HISTORY ................................................................................................................... 5 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
1 
INTRODUCTION ......................................................................................................... 8 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 8 
2.1 
Study objectives ......................................................................................................................... 8 
2.2 
Endpoints .................................................................................................................................... 9 
2.2.1 
Efficacy Endpoints ................................................................................................................................. 9 
2.2.2 
Safety Endpoints .................................................................................................................................... 9 
3 
INVESTIGATIONAL PLAN ...................................................................................... 10 
3.1 
Overall Study Design and Plan ............................................................................................... 10 
3.2 
Selection of Subjects ................................................................................................................ 13 
3.2.1 
Inclusion Criteria ................................................................................................................................. 13 
3.2.2 
Exclusion Criteria ................................................................................................................................ 15 
3.3 
Treatments ............................................................................................................................... 18 
3.4 
Randomization and Unblinding ............................................................................................. 19 
3.5 
Sample Size ............................................................................................................................... 19 
4 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ...................................... 19 
4.1 
Analysis Populations ............................................................................................................... 20 
4.2 
Protocol Deviation ................................................................................................................... 21 
5 
SUBJECT DISPOSITION .......................................................................................... 21 
6 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS ................ 21 
6.1 
Demographics .......................................................................................................................... 21 
6.2 
Baseline Characteristics .......................................................................................................... 22 
6.3 
Medical History ....................................................................................................................... 23 
7 
EFFICACY ANALYSIS .............................................................................................. 23 
7.1 
Primary Efficacy Analysis ...................................................................................................... 23 
7.2 
Secondary Efficacy Analysis ................................................................................................... 24 
7.2.1 
Pharmacokinetics of SAN-300 ............................................................................................................ 25 
7.3 
Exploratory Efficacy Analysis ................................................................................................ 25 
8 
SAFETY PRESENTATION ....................................................................................... 26 
8.1 
Extent of Exposure .................................................................................................................. 26 
8.2 
Adverse Events ......................................................................................................................... 26 
8.2.1 
Treatment-Emergent Adverse Events .................................................................................................. 26 
8.2.2 
Treatment-Emergent Adverse Events by Intensity .............................................................................. 27 
8.2.3 
Treatment-Emergent Adverse Events Related to Study Drug ............................................................. 27 
8.2.4 
Treatment-Emergent Serious Adverse Events ..................................................................................... 27 


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
4
8.2.5 
Treatment-Emergent AEs that Led to Premature Discontinuation of Study ........................................ 27 
8.2.6 
Treatment-Emergent SAEs that Led to Premature Discontinuation of Study ...................................... 27 
8.2.7 
Deaths .................................................................................................................................................. 28 
8.3 
Clinical Laboratory Evaluations ............................................................................................ 28 
8.4 
Other Laboratory Evaluations ............................................................................................... 28 
8.5 
Prior and Concomitant Medications ...................................................................................... 28 
8.5.1 
Prior Medications ................................................................................................................................. 29 
8.5.2 
Concomitant and Newly Initiated Medications.................................................................................... 29 
8.6 
Vital Sign Measurements ........................................................................................................ 29 
8.7 
Physical Exam .......................................................................................................................... 29 
8.8 
Electrocardiogram (ECG) ...................................................................................................... 29 
9 
STATISTICAL AND ANALYTICAL ISSUES ........................................................... 31 
9.1 
Handling of dropouts or missing data ................................................................................... 31 
10 
INTERIM ANALYSES AND DATA MONITORING ............................................... 32 
11 
REFERENCES ............................................................................................................ 32 
APPENDIX 1 
 OVERALL TIME AND EVENTS SCHEDULE ........................................... 33 
APPENDIX 2 
 LIST OF TABLES, FIGURES AND LISTINGS .......................................... 36 


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
5
REVISION HISTORY  
Version 
Number 
Version Date 
Description of Significant Changes from Previous Approved 
Version 
1.0 
10March2017 
Not Applicable – Original 
Version 
2.0
20March2017

Appendix 2 “List of Table, Figures and Listings” was
update for tables to appear in consecutive order.

Tables 14.2.2.7 and 14.2.2.8 ”ANCOVA Analysis of The
Mean Change from Baseline to the End-of-Treatment Visit
for HAQ-DI” for ITT and PP populations were added

Tables 14.2.3.9 and 14.2.3.10 titles were changed to clarify
analysis performed in these tables

Listing 16.2.9.4 ”Abnormal ECG Measurement” for All
Randomized Subjects was added


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
6
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACPA 
Anti-Citrunillated Peptide Antibodies 
ACR 
American College of Rheumatology 
ACR20 
American College of Rheumatology 20 responder rate 
ACR50 
American College of Rheumatology 50 responder rate 
ACR70 
American College of Rheumatology 70 responder rate 
AE
Adverse event
ALT
Alanine Aminotransferase
ANA
Antinuclear Antibody
ANCOVA 
Analysis of Covariance 
ANC 
Absolute Neutrophil Count 
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC0-τ 
Area under the concentration-time curve from time 0 to the last time 
point evaluated 
CBC 
Complete Blood Count with Differential and Platelet Count 
Cmax
Peak serum concentration
CRF  
Case report form 
CTCAE 
Common terminology criteria for adverse events 
DAS28-CRP 
Disease Activity Score with 28-joint count using C-reactive protein 
DMARD 
Disease-Modifying Anti-Rheumatic Drug 
ECG
Electrocardiogram
EOT 
End of treatment 
ESR
Erythrocyte Sedimentation Rate
FDA  
Food and Drug Administration 
GMP 
Good Manufacturing Practice 
HAQ-DI 
Health Assessment Questionnaire - Disease Index 
HAV
Hepatitis A virus
HAQ 
Health Assessment Questionnaire 
HBsAg 
Hepatitis B surface antigen 
HCV
Hepatitis C Virus
Hep B 
Hepatitis B virus 


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
7
Abbreviation 
Definition 
HIV 
Human Immunodeficiency Virus 
ITT
Intent-to-treat
IV
Intravenous(ly)
IUD
Intrauterine device
IWRS 
Interactive Web Response System 
mAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic Resonance Imaging
NSAID 
Nonsteroidal Anti-Inflammatory Drugs 
OMERACT
Outcome Measures in Rheumatology Clinical Trials 
OTC
Over-The- Counter
PCR 
Polymerase Chain Reaction 
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PP
Per protocol
PSAP 
Pharmacokinetics statistical analysis plan  
QFT 
QuantiFERON®-TB Gold test 
RA
Rheumatoid Arthritis
RAMRIS 
Rheumatoid Arthritis Magnetic Resonance Imaging Score 
RF
Rheumatoid Factor
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SC
Subcutaneous(ly)
SD
Standard deviation
TEAE 
Treatment-emergent adverse event 
UA
Urinalysis
VAS 
Visual Analogue Scale 
VLA-1 
Very Late Antigen-1 
WHODRUG 
World Health Organization Drug  


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
8
1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the details of the statistical 
analyses to be performed, and the rules and conventions to be used in the presentation of the 
results and analyses in the evaluation of safety, preliminary efficacy, and immunogenicity of 
subcutaneous (SC) administration of SAN-300 in  six treatment cohorts (A ,B, C, D, E, and F, 
with cohort F being optional) of patients with active RA with inadequate response to disease-
modifying anti-rheumatic drug(s) (DMARDs). Lists of summary tables, figures and by subject 
data listings are included at the end of this SAP (see Appendix 2). Analyses of pharmacokinetic 
data will be described separately in the Pharmacokinetics Statistical Analysis Plan (PSAP).  
2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study objectives 
2.1.1.1 Primary Objective 

To evaluate the safety and tolerability of repeat doses of SAN-300 in patients with active
rheumatoid arthritis (RA).
2.1.1.2 Secondary Objectives 

To evaluate the pharmacokinetics and pharmacodynamics of repeat doses of SAN-300 in
patients with active RA

To evaluate the preliminary efficacy of repeat doses of SAN-300 in patients with active
RA

To evaluate the immunogenicity of repeat doses of SAN-300 in patients with active RA.


Salix Pharmaceuticals, Inc. 
Statistical Analysis Plan  
Protocol: C2013-0302 
Version 2.0 - March 20, 2017 
 
 
9
2.2 
Endpoints  
2.2.1 Efficacy Endpoints 
2.2.1.1 Primary Efficacy Endpoint 

Disease Activity Score with 28-joint count using C-reactive protein (DAS28-CRP) mean
change from baseline to the End-of-Treatment Visit
2.2.1.2 Secondary Endpoints 
The secondary endpoints for this study are:  

Pharmacodynamic (PD) analysis of SAN-300

Maximum plasma concentration (Cmax) of SAN-300 by dose group

Area under the plasma concentration-time curve over the dosing interval (AUC0-τ) of
SAN-300 by dose group

The immunogenicity of repeat doses of SAN-300

American College of Rheumatology 20 (ACR20) responder rate at the End-of-Treatment
Visit

DAS28-CRP ≤ 3.2 and < 2.6 responder rates at the End-of-Treatment Visit

ACR50 and ACR70 responder rates at the End-of-Treatment Visit

Change in Health Assessment Questionnaire - Disease Index (HAQ-DI) at the End-of-
Treatment Visit

Magnetic Resonance Imaging (MRI) findings of the hand and wrist most clinically
affected by RA at the End-of-Treatment Visit
The details of the statistical analyses on pharmacokinetic (PK) data for the definition of related 
to PK analyses endpoints will be documented in a Population 
Pharmacokinetic/Pharmacodynamic Statistical Analysis Plan (PSAP). 
2.2.2 Safety Endpoints 
The safety and tolerability will be assessed by the following endpoints:  

Incidence of treatment-emergent adverse events (TEAEs).

Changes from baseline in clinical laboratory parameters.


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
Changes from baseline in vital sign measurements.

Changes from baseline in electrocardiogram measurements.

Symptom driven physical examinations
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose 
study to evaluate the safety, tolerability, PK, pharmacodynamics (PD), preliminary efficacy, and 
immunogenicity of SC administration of SAN-300 in five cohorts of patients with active RA. 
Planned dose cohorts for Study C2013-0302 are as follows:  
Cohort 
Number of Patients to be Dosed 
SAN-300 Dose 
SAN-300 
Placebo 
A
6
2
0.5 mg/kg SC once weekly 
B
6
2
1.0 mg/kg SC once weekly 
C
6
2 
2.0 mg/kg SC every other week 
D
6
2 
4.0 mg/kg SC every other week 
E
6
2
4.0 mg/kg SC once weekly 
F
6
2
2.0 mg/kg SC once weekly 
Abbreviations: SC = subcutaneous 
The sponsor may elect to modify the dose in the next cohort to a lower dose or 
terminate any further dose escalation 
This is a multiple ascending dose study that was planned to enroll patients sequentially into 
Cohorts A through F, with cohort F as optional cohort. All patients from each cohort received a 
total of 6 weeks of exposure to SAN-300 or placebo at their assigned dose and administration 
frequency. The study was planned to recruit approximately 48 patients with active RA to 
evaluate repeat doses of SAN-300 compared with placebo.  


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A study design schematic describing the progression of cohorts in this ascending-dose study is 
provided in Figure 1. 
The study will initially enroll patients in Cohort A, in which patients will receive six once-
weekly SC administrations of 0.5 mg/kg SAN-300 or placebo. After Cohort A has completed the 
6-week Treatment Period (defined as completion of the Week 7 visit), a Study Safety Committee
will conduct a blinded Safety Committee Review (including, but not limited to; adverse events
(AEs), safety laboratory assessments, vital sign assessments, and reasons for premature study
withdrawal) for all patients. If the Study Safety Committee determines that the safety profile is
acceptable, then Cohort B can begin enrollment. Subsequent Safety Committee Reviews will
take place following each dosing cohort. If the Study Safety Committee determines that the
safety profile continues to be acceptable, then enrollment can begin into the next cohort.
Figure 1. 
Study Design
Abbreviation: PBO = placebo; QW = every week; QOW = every other week. 
Notes: Patients will be randomized to each cohort in a 3:1 ratio of SAN-300 to placebo. A Safety 
Committee Review will occur after patients have completed the 6-week Treatment Period of 


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each cohort. Any subject who withdraws prior to the end of the 6-week Treatment Period will 
not be replaced and the Study Safety Committee will review the data from all subjects regardless 
of duration of participation in the study. 
Figure 2 provides a study schematic indicating visit structure for each individual cohort. After 
initial Screening, eligible patients will return to the study site at weekly intervals throughout the 
Treatment Period for study drug administration and safety, PK, PD, efficacy, and other 
assessments. Enrolled patients will also return to the study site between study drug 
administration visits for the assessment of PK/PD endpoints. Primary and secondary efficacy 
endpoints will be assessed at the End-of-Treatment Visit on Day 43. During the 4-week Follow-
up Period, patients will return to the study site at 2 weeks and 4 weeks after the end of the 
Treatment Period for additional assessments. 
Figure 2. Study Design for Individual Cohorts 
Abbreviation: SC = subcutaneously. 
Screening: Between Days -21 and -1. Informed consent will be obtained before any study 
specific procedures are performed. Eligibility assessments will be performed. 
Treatment Period: Days 1 to 43. Baseline assessments and measurements will be performed 
before dosing with study drug. Patients will receive SC injections of study drug as follows: 

For all cohorts, patients randomized to receive placebo will be administered a total of six
once-weekly injections of placebo on Days 1, 8, 15, 22, 29, and 36.


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
In Cohorts A, B, E and F, patients randomized to receive SAN-300 will be administered a
total of six weekly injections of SAN-300 on Days 1, 8, 15, 22, 29, and 36.

In Cohorts C and D, patients randomized to receive SAN-300 will be administered a total
of three every-other-week injections of SAN-300 on Days 1, 15, and 29 and will be
administered a total of three every-other-week injections of placebo on Days 8, 22, and
36.
Study assessments and measurements will be performed on Days 1, 8, 15, 22, 29, 36, and 43. 
Patients will also visit the clinic between study drug administration visits for the assessment of 
PK/PD endpoints. The primary and secondary efficacy endpoints will be assessed at the End-of-
Treatment Visit on Day 43. 
Study procedures at each visit are described in the Schedule of Assessments, provided as 
Appendix 1. 
Follow-up Period: Days 43 to 71. Study patients will return for follow-up visits on Days 57 and 
71 for safety and efficacy assessments. The Exit Visit will occur on Day 71. Patients who 
withdraw early from the study must return to the clinic to complete the Exit Visit assessments. 
3.2 
Selection of Subjects 
3.2.1 Inclusion Criteria   
A subject will be eligible for inclusion in this study if he/she meets all of the following criteria: 
1. Written informed consent
2. Diagnosed with RA for ≥ 6 months according to American College of Rheumatology
(ACR)/European League Against Rheumatism
3. 18 to 75 years of age, inclusive, at the time of informed consent
4. Swollen joint count of ≥ 6 (66-joint count) and tender joint count of ≥ 6 (68-joint count) at
Screening
5. This criterion was removed in Amendment #3


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6. Inadequate response to therapy or discontinuation of therapy because of unacceptable
toxicity from at least one prior traditional or biologic DMARD.
7. Remain on a stable dose of methotrexate (≥ 15 mg/week and ≤ 25 mg/week) for ≥ 6 weeks
before randomization; a lower dosage of methotrexate (≥ 10 mg/week) is allowed if there is
documented intolerance to dosages of ≥ 15 mg/week; folic acid ≥ 5 mg/week (or an
equivalent dose of folic acid) is required for all patients. If taking hydroxychloroquine in
combination with methotrexate, the patient must remain on a dose of ≤ 400 mg/day
hydroxychloroquine that has been stable for ≥ 6 weeks before randomization. (Note: If
discontinued from hydroxychloroquine, the patient must remain on this revised treatment
regimen for at least 4 weeks before randomization.)
All other DMARDs must have been discontinued for at least the following periods of time: 

Oral DMARDs and etanercept at least 4 weeks before randomization

Rituximab and any other lymphocyte/B-cell-depleting therapy at least 1 year before
randomization

All other biologic DMARDs, including infliximab, adalimumab, golimumab, certolizumab
pegol, abatacept, and tocilizumab, at least 8 weeks before randomization

Patients who have been on leflunomide must have not received leflunomide for at least 4
weeks before randomization and must undergo treatment to facilitate drug elimination with
8gcholestyramine three times daily for 3 days to be eligible for participation.
8. Male or Female
Females of childbearing (reproductive) potential must have a negative serum pregnancy test at
screening and agree to use an acceptable method of contraception throughout their participation
in the study. Acceptable methods of contraception include double barrier methods (condom with
spermicidal jelly or a diaphragm with spermicide), hormonal methods (e.g., oral contraceptives,
patches or medroxyprogesterone acetate), or an intrauterine device (IUD) with a documented
failure rate of less than 1% per year. Abstinence or partner(s) with a vasectomy may be
considered an acceptable method of contraception at the discretion of the investigator. Men of
reproductive potential must also agree to use an acceptable method of contraception.


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3.2.2 Exclusion Criteria 
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
Current or Past Medical History 
1. Functional Class IV as defined by ACR classification of functional status in RA.
2. History of significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary
fibrosis, or Felty’s syndrome).
3.
History of malignancy or carcinoma in situ within the 5 years before Screening or a history
of melanoma. Patients with history of excised or adequately treated non-melanoma skin
cancer are eligible.
4. Evidence of clinically significant uncontrolled concurrent diseases such as cardiovascular,
endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic,
dermatologic, psychiatric, renal, and/or other major diseases.
5. History of recurrent clinically significant infections.
6. Current active infection or serious local infection (e.g., cellulitis, abscess) or systemic
infection (e.g., pneumonia, septicemia) within 3 months before randomization.
7. Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 14 days
before randomization.
8. History of drug or alcohol abuse (as defined by the Investigator) within the 1 year before
Screening.
9. History of severe allergic or anaphylactic reactions to other biologic agents.
10. History of allergies to murine protein.
11. Surgery within 3 months before randomization (other than minor cosmetic surgery or minor
dental procedures) or plans for a surgical procedure during the Treatment Period or Follow-
up Period.


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12. History of malaria; patients with a history of travel to a malaria-endemic region within 4
months before randomization may be considered for enrollment upon consultation with the
Sponsor regarding confirmation of no active disease via a polymerase chain reaction (PCR).
Patients should not plan to travel to a malaria-endemic region throughout the duration of the
study, including Screening and the 4-week Follow-up Period.
13. History of tuberculosis or latent infection currently undergoing treatment.
Treatment History 
14. This criterion was removed in Protocol Amendment #3.
15. Treatment with another investigational agent, investigational device, or approved therapy for
investigational use within the 4 weeks before randomization or within 5 half-lives of the
investigational agent (longer of the two).
16. Treatment regimen with prednisone that is either over 10 mg/day (or equivalent dose of
another corticosteroid) or is not taken at a stable dose of ≤ 10 mg/day for at least 4 weeks
before randomization.
17. Intra-articular corticosteroid injection(s) within 4 weeks before randomization.
18. Current use of opioids or other narcotics. Note: Patients receiving nonsteroidal anti-
inflammatory drugs (NSAIDS) or the following opioids (tramadol, codeine and oral
acetaminophen/codeine combination) at stable doses for at least 2 weeks prior to
randomization will be eligible for inclusion.
19. Any live immunization/vaccination, including against Herpes zoster, within 4 weeks before
randomization. Live vaccinations must also be avoided throughout the study.
Laboratory Values 
20. Abnormal laboratory value at Screening or Day -1 considered clinically significant (as
determined by the Investigator), or:

Serum creatinine > 1.6 mg/dL


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
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN

Platelet count < 100,000/μL

Hemoglobin < 8.5 g/dL

Absolute neutrophil count (ANC) < 2.0 × 103/μL
21. Women of childbearing potential who test positive for a serum pregnancy test at Screening or
a urine pregnancy test within 12 hours before randomization.
General/Compliance 
22. Positive for hepatitis C virus (HCV) antibody or hepatitis B surface antigen (HBsAg) (Note:
patients with positive HCV antibody may be considered for enrollment upon consultation
with the Sponsor regarding confirmation of no active disease via a PCR test).
23. Positive for human immunodeficiency virus (HIV) antibody.
24. Positive QuantiFERON®-TB Gold test (QFT) (Note: If the QFT result is indeterminate and
the chest X-ray is without clinically significant findings, a second QFT may be performed. If
the second QFT result is negative, the patient may be considered for enrollment. If the
second QFT is positive or indeterminate, the patient is ineligible.)
25. Current enrollment in any other study with an investigational agent, investigational device, or
approved therapy for investigational use).
26. Previous exposure to SAN-300
27. Unwillingness or inability to comply with the requirements of this Protocol, including the
presence of any condition (physical, mental, or social) that is likely to affect the patient’s
returning for follow-up visits on schedule
NOTE: Patients who cannot tolerate the magnetic resonance imaging (MRI) procedures due
to physical or other limitations may be enrolled in the study


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28. Other unspecified reasons that, in the opinion of the Investigator or the Sponsor, make the
patient unsuitable for enrollment
29. Blood donation (450 mL or more) within 1 month before Screening
30. Nursing mothers or women who are planning to become pregnant during the study
3.3 Treatments 
SAN-300 for Subcutaneous Injection 
The Investigational Product for SC injection (SAN-300-F02) is manufactured by IntegrityBio, 
Inc. of Camarillo, CA, USA under Good Manufacturing Practice (GMP). The SAN-300-F02 
drug product is formulated with 180 mg/mL anti-VLA-1 mAb, 30 mM histidine, 250 mM 
sorbitol, and 0.01% polysorbate 20 at pH 6. The drug product is filled to a total volume of 1 mL 
in a 2-mL USP type I glass vial with a 13-mm chlorobutyl stopper and a 13-mm aluminum seal. 
The storage temperature for the drug product is 2 ºC to 8 ºC, protected from light. 
For SC administration, the appropriate volumetric dose of SAN-300 will be injected with a 27-
gauge, ½ inch syringe needle on a weight-based calculation. More than one SC injection may be 
required (maximum volume of 1.2 mL per injection) depending on the total dose administered 
and the weight of the individual patient. 
Placebo for Subcutaneous Injection 
For SC administration, placebo is 30 mM histidine, 250 mM sorbitol, 0.01% polysorbate 20, and 
3 μg/mL riboflavin at pH 6, with a 1-mL fill in the same container closure system as the drug 
product. This was also manufactured by IntegrityBio, Inc. of Camarillo, CA, USA under GMP. 
The appropriate volumetric dose of placebo will be injected with a 27-gauge, ½ inch syringe 
needle via SC injection. The volume of placebo administered SC will match the volume 
according to the weight-based calculations as if SAN-300 were to be administered. More than 
one SC injection may be required (maximum volume of 1.2 mL per injection) depending on the 
total dose administered and the weight of the individual patient. The intended storage 
temperature for the placebo product is 2 ºC to 8 ºC, protected from light. 


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3.4 
Randomization and Unblinding 
Fixed allocation will be used to randomize subjects in a ratio of three on SAN-300 to one on 
placebo 3:1 within each cohort of approximately 8 total subjects using a randomization code 
generated by an Interactive Web Response System (IWRS).  Central randomization will be 
utilized for this study.   
Only in the case of an emergency, when knowledge of the study drug is essential for the clinical 
management or welfare of the subject, will the investigator be allowed to unblind a subject’s 
treatment assignment.  If the investigator breaks the blind for an individual subject, the reason 
must be in the subject’s source documents and the subject will be removed from the study. 
3.5 
Sample Size 
There is no sample size calculation, as this study is not intended to be powered to demonstrate 
efficacy. Results from this study will be used to design future efficacy studies. 
After safety review it was decided that no dose adjustment is needed for optional cohort F, and as 
a result 41 subjects were randomized into study. 
4 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS 
All statistical testing will be two-sided with an alpha level of 0.05. Any p-values displayed will 
be rounded to four decimal places, with p-values below 0.0001 displayed as ‘<.0001’, and p-
values above 0.9999 displayed as ‘>.9999’. 
Categorical variables will be summarized by frequency counts and percentages for subjects in 
each category.  Percentages will contain one decimal place.  In cases of zero frequency counts, 
the percentage will not be reported.   
Continuous variables will be summarized with the number of observations (n), mean, standard 
deviation (SD), median, minimum, and maximum. The mean and median will be presented to 
one decimal place more than the captured data.  The SD will be presented to two decimal places 


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more than the captured data. The minimum and maximum will be presented to the same 
precision as the captured data.  
Study day will be calculated as follows: 

Assessments/events prior to the first dose date, study day will be the assessment date
minus the first dose date.

Assessments/events on or after the first dose date, study day will be the assessment date
minus the first dose date plus one.
Baseline is defined to be the last non-missing assessment (including assessments measured at 
unscheduled visits) before receiving the first dose of the study medication. 
End of treatment (EOT) value is defined as last available post-baseline value during the 
treatment period. 
Subjects will be identified in listings by center number and subject number. Unless otherwise 
specified, all listings will be sorted by randomized treatment, subject identification number and 
visit (if applicable).  
Efficacy analysis will be performed on the Intent-to-Treat (ITT) population by treatment group 
to which subjects were randomized. Safety analysis will be performed on the Safety population 
by treatment received. 
Parameters presented by “treatment group” will display the patients on SAN-300 from each 
cohort and the pooled patients on placebo, unless otherwise indicated. 
4.1 
Analysis Populations 
The ITT population is defined as all randomized patients who received at least one dose of a 
study drug. Patients in the ITT Population will be analyzed according to the treatment to which 
they were randomized. 


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The Per Protocol (PP) Population is defined as all patients in the ITT Population except for 
those who failed to meet Inclusion Criterion 4; or met Exclusion Criteria 1 and 2. 
The Safety Population is defined as all patients who received at least one dose of a study drug; 
this population will be used for the safety analysis. Patients in the Safety Population will be 
analyzed according to the treatment they received. 
The summaries and analyses of baseline characteristics and efficacy will be performed for the 
ITT Population.  All efficacy analyses will also be performed on the PP Population as a 
sensitivity analysis.  All safety analyses will be performed on the Safety Population. 
4.2 
Protocol Deviation 
All protocol deviations will be listed. 
5 
 SUBJECT DISPOSITION 
Subject disposition will be summarized for all randomized subjects and will include the number 
of subjects randomized; number and percentage of subjects who completed or prematurely 
discontinued the study, classified by reasons for premature discontinuation; the number of 
subjects randomized at each study site; and the number and percentage of subjects who 
completed or discontinued the study at each study site. 
The number and percentages of subjects in each population and reason for exclusion from 
population will be summarized for all randomized subjects. 
6 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS 
6.1 
Demographics  
Demographics listed below will be summarized descriptively by treatment group and overall 
using the ITT population.  

Age (years);


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
Sex (male/female);

Ethnicity (Hispanic or Latino/not Hispanic or Latino);

Race (American Indian or Alaskan Native, Asian, Black or African-American, Native
Hawaiian or Pacific Islander, and White); where subjects who identified more than one race
will be categorized as “Multiple”;

Height (cm);

Weight (kg); and

Body mass index (kg/m2) = (Weight in kg)/ (Height in m)2.
6.2 
Baseline Characteristics  
Baseline characteristics listed below will be summarized descriptively by treatment group and 
overall using the ITT population.  

Disease Activity Score with 28-joint count using C-reactive protein (DAS28-CRP), ACR
Core Set Measurements, the Health Assessment Questionnaire – Disability Index (HAQ-
DI)

MRI score using the Outcome Measures in Rheumatology Clinical Trials (OMERACT)
RA MRI scoring (RAMRIS) system

Visual Analog Scale (VAS) score

Duration of RA disease from initial diagnosis

Use of Methotrexate, Chloroquine, NSAIDS, Corticosteroid


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6.3 
Medical History 
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 19.0 or later and will be listed. In addition, Medical history data will be 
summarized by system organ class and preferred term. A separate detailed RA history also be 
summarized descriptively by treatment group. 
7 
EFFICACY ANALYSIS 
Efficacy evaluations will consist of changes from baseline in the Disease Activity Score with 28-
joint count using C-reactive protein (DAS28-CRP), ACR Core Set Measurements, the Health 
Assessment Questionnaire – Disability Index (HAQ-DI), and magnetic resonance imaging (MRI) 
of the hand and wrist most clinically affected by RA. Each MRI will be scored using the 
OMERACT RAMRIS system. 
7.1 
Primary Efficacy Analysis 
Efficacy endpoints will be summarized and maybe compared by between the SAN-300 dose 
groups (0.5, 1.0, and 4.0 mg/kg once-weekly and 2.0 and 4.0 mg/kg every other week) and the 
pooled placebo group. 
The DAS28-CRP and HAQ-DI will be calculated and presented by time point and treatment 
group.  
The HAQ queries the ability to perform 20 activities of daily living with four response categories 
[without any difficulty (score 0), with some difficulty (score 1), with much difficulty (score 2), 
not being able to do (score 3)]. The 20 activities are classified into eight categories with two or 
three activities each. A score is then assigned to each of the eight categories based on the highest 
score of any activity within the category. Patients are also asked about the use of aids and 
devices, and if they need help from another person for activities in any of the eight categories. If 
the category score is lower than 2, it is increased to 2 in any category in which the patient uses a 
device or help from another person, so that underlying disability is more accurately represented.  
The DAS28 assessment is a standardized measure of improvement made using four components, 
two made by an assessor, one made by the patient, and one laboratory value (CRP), as shown 
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
Swollen and tender joint assessment (assessor – refer to Appendix 6 of Protocol
(Amendment 5))

Patient’s global assessment of disease activity (patient)

CRP (laboratory test)
DAS28-CRP= 0.56 x  sqrt(TJC28) x  sqrt(SJC28) + 0.36 x ln(CRP+1) +0.014 x VAS +0.96  
Where 
TJC28: The number of tender joints (0-28). 
SJC28: The number of swollen joints (0-28). 
CRP: The C-Reactive Protein level (in mg/l  
VAS General Health Assessment (from 0=best to 100=worst). 
The mean change from baseline to the End-of-Treatment Visit for DAS28-CRP will be 
compared across treatment groups using the Wilcoxon Rank-Sum Test.  
7.2 
Secondary Efficacy Analysis 
The percentages of patients achieving a DAS28-CRP ≤ 3.2 and < 2.6 will be compared across 
treatment groups using the chi-square test. 
The ACR Core Data Set is a standardized measure of arthritis activity consisting of seven 
measures, three made by an assessor, three made by the patient, and one laboratory value (CRP 
or erythrocyte sedimentation rate [ESR]), as shown below: 

Swollen and tender joint assessment (assessor – refer to Appendix 6 of Protocol
(Amendment 5))

Physician’s global assessment of disease activity (assessor)

Patient assessment of pain (patient)

Patient’s global assessment of disease activity (patient)

Patient’s assessment of physical function as measured by Health Assessment
Questionnaire (HAQ) (patient – refer to Appendix 7 of Protocol (Amendment 5))

CRP or ESR (laboratory test)
The assessor will be an experienced rheumatology clinical assessor. 


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All components of the ACR Core Set will be summarized using descriptive statistics and 
presented by time point and treatment group. The percentages of subjects achieving ACR20, 
ACR50, or ACR70 responses will be compared across treatment groups using the chi-square test. 
MRI data will be summarized across the treatment groups for each time point. All MRI data will 
be presented for individual patients in data listings. 
All efficacy assessments will be presented for individual patients in data listings. 
Additional analyses may be performed, as needed, to fully evaluate potential efficacy signals and 
evidence of clinical benefit. 
7.2.1 Pharmacokinetics of SAN-300 
Statistical analysis (including exploratory data analysis and population modeling) for 
pharmacokinetics of SAN-300 will be described in detail in the PSAP document. The PSAP will 
be finalized prior to database lock.  
7.3 
Exploratory Efficacy Analysis 
An exploratory analysis of the primary endpoint will be performed using analysis of covariance 
(ANCOVA) model with treatment as factor and baseline DAS28-CRP and HAQ-DI scores as 
covariates. Normality of the mean change from baseline of DAS28-CRP data will be tested and 
if necessary transformation such as but not limited to logarithmic transformation could be 
applied. 
The ratios of the least squares (LS) geometric means and 95% confidence intervals (CI) for mean 
change from baseline of to the EOT Visit for DAS28-CRP from the administration of SAN-300 
(“test”) relative to the administration of Placebo (“reference”), test/reference, will be calculated. 
 Comparison analysis for ACR20, ACR50, or ACR70 responses for pooled treatment group 
against placebo will be conducted using Fisher exact test. Bar chart will be plotted by SAN-300 
treatment regimen to show if there is linear relationship between ACR20, ACR50, and ACR70 
and SAN-300 dose level and frequency. 
 In addition, logistic regression model with treatment regimen as ordinal variable will be 
performed on to compare percentage of subjects achieved ACR20, ACR50, and ACR70 
responses at the EOT Visit.   Predictor variables may include swollen joint count at screening, 
tender joint count at screening, and methotrexate use (yes/no).      


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Statistical analyses will be performed and statistical tables will be generated using Statistical 
Analysis Software (SAS) version 9.3 or higher. Statistical significance will be assessed at the 
two-sided 5% level. 
8 
SAFETY PRESENTATION 
8.1 
Extent of Exposure  
The number of subjects administered study drug and the extent (duration) of exposure to study 
drug will be summarized descriptively by treatment group (n, mean, median, SD, minimum, and 
maximum values).  Extent of exposure is defined as last dose of study drug – first dose of study 
drug +1. Additionally, number and percent by duration category by week for the first 4 weeks 
and then by 2-week intervals thereafter will also be summarized by treatment group.   
8.2 
Adverse Events 
Adverse events will be coded using the MedDRA version 19.0 or later coding dictionary.   If an 
adverse event is not coded then the verbatim investigator text will be listed at the end of each 
applicable summary table. 
8.2.1 Treatment-Emergent Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as any AE started post-treatment. 
Summary tables will include number of subjects with treatment-emergent AEs and as percentage 
of number of subjects in the treatment group. The number of serious TEAEs will be summarized 
in the appropriate summary table. Summary tables will also be presented for the frequency of 
AEs by MedDRA-preferred term and severity of AE. Severity of AEs will be based on the scale 
as indicated in Section 8.2.2. 
The subset of AEs that are considered by the Investigator to have a possible or definite 
relationship to study medication will be considered as treatment-related AEs. If the Investigator 
does not specify the relationship of the AE to study medication, the AE will be considered as 
treatment-related. The incidence of AEs and TEAEs will be tabulated per treatment. AEs will 
also be summarized by severity, using the categories described in Section 8.2.2. 


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8.2.2 Treatment-Emergent Adverse Events by Intensity 
Adverse events are categorized for severity by the investigator as “Mild”, “Moderate” or 
“Severe”. The frequency of TEAEs by intensity will be summarized by body system, and 
preferred term, overall and by treatment group.  TEAEs with missing intensity will be considered 
‘Severe’ in the tabular summaries but data listings will show severity listed as missing.  In case 
of multiple TEAEs for the same body system and preferred term for the same subject, only the 
TEAE with the maximum intensity will be counted in the table.   
8.2.3 Treatment-Emergent Adverse Events Related to Study Drug 
Related AEs are the AEs with “Related” or “Possibly Related” for causality. TEAEs with 
missing relationship to study drug will be considered “related” in the tabular summaries but data 
listings will show relationship as missing.   
8.2.4  Treatment-Emergent Serious Adverse Events 
Any AE reported as serious in the Case Report Form (CRF) will be reported as a serious adverse 
event (SAE). The clinical database will be reconciled with the SAE database (from the Salix 
Safety department) before database lock.  
All treatment-emergent SAEs will be summarized by body system and preferred term, overall 
and by treatment group. 
8.2.5  Treatment-Emergent AEs that Led to Premature Discontinuation of Study 
All TEAEs that led to subject discontinuation from the study will be summarized and listed 
separately.  
8.2.6 Treatment-Emergent SAEs that Led to Premature Discontinuation of Study 
All treatment-emergent SAEs that led to subject discontinuation from the study will be 
summarized and listed separately.  


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8.2.7 Deaths 
Deaths will be listed. 
8.3  Clinical Laboratory Evaluations 
Hematology, blood chemistry, and urinalysis parameters will be summarized at baseline and at 
each time point.  Additionally, the change from baseline in each parameter will be summarized.  
Laboratory values and changes from baseline in laboratory values will be summarized 
descriptively by treatment group. 
A summary of shifts from baseline will be given for each treatment group for each parameter.  
The normal range for each parameter will be used to create categories of low, normal, or high.  
Any result higher than upper limit of normal or lower than lower limit of normal will be 
categorized as high or low respectively, and any result within the lower and upper limits of 
normal will be categorized as normal.  The number and percentage of subjects in each treatment 
group in each shift category from baseline to final evaluation will be shown for each parameter.   
Hepatitis Panel data (Hep B surface antibody, Hep B Surface antigen, Hep B core antibody total, 
HCV antibody and hepatitis A virus (HAV) total) collected will be listed. 
8.4 
Other Laboratory Evaluations 
Other laboratory parameters include anti-SAN-300 antibody levels, rheumatoid factor (RF), 
antinuclear antibody (ANA), and anti-citrunillated peptide antibodies (ACPA). All other 
laboratory parameters will be summarized using descriptive statistics and presented by time point 
and treatment group. All other laboratory parameters will be presented for individual patients in 
data listings. 
8.5 
Prior and Concomitant Medications 
All prior medications and concomitant medications captured in the Electronic Data Capture 
system will be coded to preferred term using World Health Organization Drug (WHODRUG) 
dictionary (September 2015). Concomitant medications will be summarized by Anatomical 
Therapeutic Chemical (ATC) Class term and preferred term for the Safety population.  


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Medication start and end dates will be used to determine whether a medication is prior, 
concomitant or newly initiated. When start and end dates are incomplete or missing and the 
medication category cannot be determined, the standard Salix estimation rule for concomitant 
medications will be followed.  
8.5.1 Prior Medications 
Prior medications are defined as any medication ended prior to the first study drug 
administration.  All prior medications captured in CRF will be summarized and listed. 
8.5.2 Concomitant and Newly Initiated Medications  
Concomitant medications (medications taken at any time after first dose date including those 
taken prior to and continued after first dose date) and newly initiated medications (medications 
taken after initiation of the study drug administration) will be listed by subject and tabulated 
overall and by treatment group. In this summary, the number and percentage of subjects who 
take at least one concomitant medication and the number and percent of subjects who take each 
specific concomitant medication will be presented by ATC class, preferred term, and treatment 
group.  
8.6 
Vital Sign Measurements 
Vital sign measurements and change from baseline including body temperature, heart rate, sitting 
blood pressures, and weight will be summarized at each scheduled visit descriptively by 
treatment group. 
8.7 
Physical Exam 
Physical examination data will be listed. 
8.8 
Electrocardiogram (ECG) 
Actual value and change from baseline of ECG parameters will be summarized by treatment 
group using descriptive statistics. In order to assess the QT interval data, corrected QT values as 


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suggested in the FDA QTc Guidance Document will be calculated based on the following three 
methods. 
1) Fridericia’s correction: QTc=QT/RR0.33,
2) Bazett’s Correction: QTc=QT/RR0.5 ,
And 
3) Correction based on linear regression techniques: Based on the data from baseline
study population, the intercept(a) and slope (b) will be estimated separately for males and
females using the equation QT=a+b(1-RR).  Those estimates will be used to calculate the
corrected QT values at post baseline time points.
A summary table will be presented of the number and percentage of subjects with worst QTc, 
QRS, PR, and ventricular rate abnormalities observed during the treatment period.  Specific 
criteria to be used include the following: 
ECG Parameter 
Definition 
QTcB interval 
Absolute QTcB interval prolongation values: 
> 450 to < 480 msec
> 480 to < 500 msec
> 500 msec;
Increase from baseline values: 
> 30 to < 60 msec
> 60 msec;
QTcF interval 
Absolute QTcF interval prolongation values: 
> 450 to < 480 msec
> 480 to < 500 msec
> 500 msec;


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ECG Parameter 
Definition 
Increase from baseline values: 
> 30 to < 60 msec
> 60 msec;
QRS duration 
Absolute values are abnormally low < 50 msec, normal > 50 to 
< 120 msec, and abnormally high > 120 msec; 
PR interval 
Absolute values are normal < 210 msec and abnormally high 
> 210 msec;
Ventricular rate 
Absolute values are abnormally low < 50 bpm, normal > 50 to      
< 120 bpm, and abnormally high > 120 bpm. 
9 
STATISTICAL AND ANALYTICAL ISSUES 
9.1 
Handling of dropouts or missing data 
Subjects who prematurely discontinue before the end of the treatment will be contacted via 
follow-up phone call as frequently as needed. If the patient is found to have an AE or clinically 
significant laboratory abnormality, the patient will be followed until the event/abnormality is 
resolved, or until the Investigator determines that further follow-up is no longer medically 
indicated. 
For subjects who discontinue prematurely, the last completed post-baseline assessment will be 
used as EOT.  
Missing data will not be imputed in other analyses unless specified otherwise. 
For subjects who terminate early from the study, if the study day of the EOT visit falls into a 
specific protocol defined scheduled visit window, the EOT visit will be reassigned to that 
specific scheduled visit for the analyses by protocol defined scheduled visit.   
For cases where the start date of an AE is not complete, the assumption is made that the AE is a 
treatment-emergent event unless there is evidence to the contrary. 


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For cases where the start or the stop date of medication is not complete, the assumption is made 
that the medication is a concomitant medication unless there is evidence to the contrary. 
10 INTERIM ANALYSES AND DATA MONITORING 
There will be no formal interim analysis during the course of the study.  
11 REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles for
Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and Content of
Clinical Study Reports (E3), 30 November 1995.
3. T. Uhlig,  E. A. Haavardsholm,  T. K. Kvien Comparison of the Health Assessment
Questionnaire (HAQ) and the modified HAQ (MHAQ) in patients with rheumatoid arthritis,
Rheumatology (Oxford) (2006) 45 (4): 454-458,  15 November 2005


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APPENDIX 1 
OVERALL TIME AND EVENTS SCHEDULE 
STUDY ASSESSMENTS 
Screening 
(21 days) 
Treatment Period 
Follow-up Period 
(28 days) 
Week: 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 9 
Week 11 
Visit: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Day 
-21 to -7
Day 1a 
Day 8a 
Day 15a 
Day 22a 
Day 29a 
Day 36a 
Day 43a 
Day 57a 
Day 71a 
Timing 
(where applicable): 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
EOT 
Exit Visit 
Eligibility Assessments 
Informed Consent 
X 
Inclusions/Exclusions 
X 
X 
Demographics 
X 
Medical History 
X 
X 
Medication History 
X 
X 
RA History and Prior RA 
Treatment 
X 
X 
HCV Antibody, HBsAg, HIV 
Antibody 
X 
Chest X-rayb 
X 
QuantiFERON-GOLD 
X 
Dosing 
Randomization 
X 
Administration of SAN-300 
or Placeboc 
Xd 
Xc 
X 
Xc 
X 
Xc 
Safety Assessments 
Vital Sign Measurements 
X 
X 
Xg 
Xg 
Xg 
Xg 
X 
Xg 
X 
Xg 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
CBC, Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UA 
X 
X 
X 
X 


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STUDY ASSESSMENTS 
Screening 
(21 days) 
Treatment Period 
Follow-up Period 
(28 days) 
Week: 
 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
Week 7 
Week 9 
Week 11 
Visit: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Day 
-21 to -7 
Day 1a 
Day 8a 
Day 15a 
Day 22a 
Day 29a 
Day 36a 
Day 43a 
Day 57a 
Day 71a 
Timing 
(where applicable): 
 
Pre-
dose 
Post-
dose 
 
 
 
Pre-
dose 
Post-
dose 
Pre-
dose 
Post-
dose 
EOT 
 
Exit Visit 
INR, PT, aPTT, Complement 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum Immunoglobulins 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy Test 
Serum 
Urine 
 
 
 
Urine 
 
 
Urine 
 
Serum 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
ACR Core Set Assessments, 
DAS28-CRP 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
HAQ-DI 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
ESR 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
CRP 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
MRI of Hand and Wristf 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Other Assessments 
RF, ACPA 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
ANA 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: ACPA = anti-citrunillated peptide antibodies; ACR = American College of Rheumatology; ANA = antinuclear antibody; aPTT = activated partial 
thromboplastin time; CBC = complete blood count with differential and platelet count; CCP = cyclic citrullinated peptide; DAS28-CRP = Disease Activity Score with 
28-joint count C-reactive protein; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; HAQ-DI = Health Assessment Questionnaire – Disease Index; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; CRP = C reactive protein; INR = international normalized 
ratio; MRI = magnetic resonance imaging; PT = prothrombin time; QFT = QuantiFERON®-TB Gold test; RA = rheumatoid arthritis; RF = rheumatoid factor; UA = 
urinalysis. 
a Weekly visits during the Treatment and Follow-up Periods can be scheduled for ±2 days around each of the designated Days in this schedule, but the 
designated Days themselves will not be shifted relative to Day 1. 


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b If a chest X-ray was performed with no clinically significant findings within 1 month of randomization, another chest X-ray is not required at Screening. 
c For all cohorts, patients randomized to receive placebo will be administered a total of 6 once-weekly SC injections of placebo on Days 1, 8, 15, 22, 29, and 36. 
In Cohorts A, B, and D, patients randomized to receive SAN-300 will be administered a total of 6 once-weekly SC injections of SAN-300 on Days 1, 8, 15, 22, 
29, and 36. In Cohorts C and E, patients randomized to receive SAN-300 will be administered a total of three every-other-week SC injections of SAN-300 on 
Days 1, 15, and 29 and will be administered a total of three every-other-week SC injections of placebo on Days 8, 22, and 36. Note: Subject to be observed at minimum 1 hour 
post- dose. Longer observation allowed if deemed necessary by investigator or designee. 
d Day 1 dosing will occur on the day of or within 24 hours after randomization. 
e After baseline assessment, additional assessments of tryptase and histamine to occur only in suspected cases of anaphylaxis or hypersensitivity reactions. 
f In patients who are able to tolerate the MRI, it should be performed within 5 days prior to or at Visit 2 (Day 1, prior to dosing). MRI of hand and wrist most clinically affected by 
RA will be imaged at Baseline, the same wrist will be imaged at End of Treatment. 
g Blood pressure and pulse will be collected at the end of the observation period; prior to the subject leaving the clinic. When a post-dose blood sample is collected, the blood 
pressure and pulse should be assessed prior to the sample collection 


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APPENDIX 2 
LIST OF TABLES, FIGURES AND LISTINGS 
Tables and Figures 
Number 
Title 
Subject Disposition 
14.1.1 
Subject Disposition by Treatment Group – All Randomized Subjects 
14.1.2  
Summary of Analysis Populations by Treatment Group – All Randomized 
Subjects  
Demographics and Baseline characteristics 
14.1.3.1 
Summary of Demographic Data by Treatment Group - ITT population 
14.1.3.2  
Summary of Baseline Characteristics by Treatment Group - ITT population 
Medical History  
14.1.4 
Summary of Medical History by Treatment Group - ITT population 
Study Drug Exposure 
14.1.5  
Summary of study drug exposure and treatment compliance by treatment group - 
Safety population 
Prior and Concomitant Medications 
14.1.6   
Summary of Prior Medications – ITT Population 
14.1.7 
Summary of Concomitant Medications – ITT Population 
14.1.8 
Summary of Newly Initiated Medications – ITT Population 
14.1.9 
Summary of Prior RA Related Medications by Treatment Group – ITT 


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Number 
Title 
Population 
14.1.10 
Summary Biologic Products Use by Treatment Group – ITT Population 
Efficacy Analysis 
14.2.1.1 
Summary of Primary Efficacy Endpoint: Change from Baseline in the DAS28-
CRP by Time Point and Treatment Group – ITT population 
14.2.1.2 
Summary of Primary Efficacy Endpoint: Change from Baseline in the DAS28-
CRP by Time Point and Treatment Group – PP population 
14.2.1.3 
Summary of Primary Efficacy Endpoint: Change from Baseline in HAQ-DI by 
Time Point and Treatment Group – ITT population 
14.2.1.4 
Summary of Primary Efficacy Endpoint: Change from Baseline in the DAS28-
CRP by Time Point and Treatment Group – PP population 
14.2.2.1 
Analysis of Primary Efficacy Endpoint: The Mean Change from Baseline to the 
End-of-Treatment Visit for DAS28-CRP – ITT population 
14.2.2.2 
Analysis of Primary Efficacy Endpoint: The Mean Change from Baseline to the 
End-of-Treatment Visit for DAS28-CRP – PP population 
14.2.2.3 
Analysis of Secondary Efficacy Endpoint: The Percentages of Subjects 
Achieving a DAS28-CRP ≤ 3.2 and < 2.6 – ITT population 
14.2.2.4 
Analysis of Secondary Efficacy Endpoint: The Percentages of Subjects 
Achieving a DAS28-CRP ≤ 3.2 and < 2.6 – PP population 
14.2.2.5 
ANCOVA Analysis of The Mean Change from Baseline to the End-of-
Treatment Visit for DAS28-CRP – ITT population 
14.2.2.6 
ANCOVA Analysis of The Mean Change from Baseline to the End-of-


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Number 
Title 
Treatment Visit for DAS28-CRP – PP population 
14.2.2.7 
ANCOVA Analysis of The Mean Change from Baseline to the End-of-
Treatment Visit for HAQ-DI – ITT population 
14.2.2.8 
ANCOVA Analysis of The Mean Change from Baseline to the End-of-
Treatment Visit for HAQ-DI – PP population 
14.2.3.1 
Summary of ACR Core Set by Time Point and Treatment Group – ITT 
population 
14.2.3.2 
Summary of ACR Core Set by Time Point and Treatment Group – PP population 
14.2.3.3 
Analysis of Secondary Endpoint: The Percentages of Subjects Achieving 
ACR20, ACR50, or ACR70 Responses– ITT population 
14.2.3.4 
Analysis of Secondary Endpoint: The Percentages of Subjects Achieving 
ACR20, ACR50, or ACR70 Responses – PP population 
14.2.3.5a 
Bar Chart of ACR20 by SAN300 Treatment Regimen – ITT population 
14.2.3.5b 
Bar Chart of ACR50 by SAN300 Treatment Regimen – ITT population 
14.2.3.5c 
Bar Chart of ACR70 by SAN300 Treatment Regimen – ITT population 
14.2.3.6a 
Bar Chart of ACR20 by SAN300 Treatment Regimen – PP population 
14.2.3.6b 
Bar Chart of ACR50 by SAN300 Treatment Regimen – PP population 
14.2.3.6c 
Bar Chart of ACR70 by SAN300 Treatment Regimen – PP population 
14.2.3.7 
Comparison Analysis for ACR20, ACR50, or ACR70 Responses for Pooled 
Treatment Group Against Placebo – ITT population 
14.2.3.8 
Comparison Analysis for ACR20, ACR50, or ACR70 Responses for Pooled 


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Number 
Title 
Treatment Group Against Placebo – PP population 
14.2.3.9 
The logistic regression analysis of percentages of subjects achieving ACR20, 
ACR50, or ACR70 responses – ITT population 
14.2.3.10 
The logistic regression analysis of percentages of subjects achieving ACR20, 
ACR50, or ACR70 responses – PP population 
14.2.4.1 
Summary of MRI Data by Time Point and Treatment Group – ITT population 
14.2.4.2 
Summary of MRI Data by Time Point and Treatment Group – PP population 
Safety Analysis 
14.3.1.1 
Summary of All Adverse Events by Treatment Group- Safety Population 
14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Treatment Group – Safety Population 
14.3.1.3 
Summary of Treatment-Emergent Serious Adverse Events by System Organ 
Class, Preferred Term and Treatment Group – Safety Population 
14.3.1.4 
Summary of Treatment-Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class, Preferred Term and Treatment Group – 
Safety Population 
14.3.1.5 
Summary of Treatment-Emergent Serious Adverse Events Leading to Study 
Discontinuation by System Organ Class, Preferred Term and Treatment Group – 
Safety Population 
14.3.1.6 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, Maximum Intensity and Treatment Group – Safety Population 
14.3.1.7 
Summary of Treatment-Emergent Adverse Events related to Study Drug, System 


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Number 
Title 
Organ Class, Preferred Term and Treatment Group – Safety Population 
14.3.1.8 
Listing of Deaths – Safety Population 
14.3.2.1 
Summary of Mean and Mean Change from Baseline in Hematology/Coagulation 
Results by Treatment Group – Safety Population 
14.3.2.2 
Summary of Mean and Mean Change from Baseline in Blood Chemistry Results 
by Treatment Group – Safety Population 
14.3.2.3 
Summary of Mean and Mean Change from Baseline in Urinalysis Results (pH 
and Specific Gravity) by Treatment Group – Safety Population 
14.3.2.4 
Summary of Urinalysis Results (Other Parameters) by Treatment Group – Safety 
Population 
14.3.2.5 
Summary of Shift from Baseline in Hematology/Coagulation Results by 
Treatment Group – Safety Population 
14.3.2.6 
Summary of Shift from Baseline in Chemistry Results by Treatment Group – 
Safety Population 
14.3.2.7 
Summary of Shift from Baseline in Urinalysis Results by Treatment Group – 
Safety Population 
14.3.2.8 
Summary of Post-Baseline CTC Grades Increase – Safety Population 
14.3.2.9 
Summary of Study Specific Laboratory Test Results by Treatment Group – 
Safety Population 
14.3.3 
Summary of Mean and Mean Change from Baseline in Vital Signs by Treatment 
Group – Safety Population 
14.3.4 
Summary of ECG parameters by Treatment Group – Safety Population 


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Listings 
Number 
Title 
16.2.1 
Subject Disposition – All Randomized Subjects 
16.2.2 
Analysis Population – All Randomized Subjects 
16.2.3.1 
Protocol Deviations – All Randomized Subjects 
16.2.3.2 
Inclusion and Exclusion Criteria – All Randomized Subjects 
16.2.4.1 
Demographic Characteristics and Informed Consent – All Randomized Subjects 
16.2.4.2 
Medical History – All Randomized Subjects 
16.2.5.1 
Drug Exposure Information – All Randomized Subjects  
16.2.5.2 
Methotrexate Initial Dosage - All Randomized Subjects 
16.2.5.3.1 
Prior and Concomitant Medications – All Randomized Subjects 
16.2.5.3.2 
Prior RA Treatments – All Randomized Subjects 
16.2.5.3.3 
History of Biologics – All Randomized Subjects 
16.2.6.1 
Disease Activity Score with 28-joint count using CRP (DAS28-CRP) Results – 
All Randomized Subjects 
16.2.6.2 
ACR Core Set Measurements Results – All Randomized Subjects 
16.2.6.3 
The Health Assessment Questionnaire – Disability Index (HAQ-DI) Results – All 
Randomized Subjects 
16.2.6.4 
Magnetic Resonance Imaging (MRI) Results – All Randomized Subjects 
16.2.7.1 
All Adverse Events – All Randomized Subjects 


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Number 
Title 
16.2.7.2 
Serious Adverse Events – All Randomized Subjects 
16.2.7.3 
Adverse Events Leading to Withdrawal from the Study – All Randomized 
Subjects 
16.2.8.1.1 
Hematology Results – All Randomized Subjects 
16.2.8.1.2 
Hematology Results with CTCAE Grade >= 1 – All Randomized Subjects 
16.2.8.2.1 
Chemistry Results – All Randomized Subjects – All Randomized Subjects 
16.2.8.2.2 
Chemistry Results with CTCAE Grade >= 1 – All Randomized Subjects 
16.2.8.3.1 
Urinalysis Results – All Randomized Subjects 
16.2.8.4 
Pregnancy Test Results – All Randomized Subjects 
16.2.8.5 
Hepatitis Panel Results – All Randomized Subjects 
16.2.8.6 
Laboratory Results with CTCAE Grade >= 3 or Shift >= 2 – All Randomized 
Subjects 
16.2.8.7 
Study Specific Laboratory Test Results – All Randomized Subjects 
16.2.9.1 
Vital Signs – All Randomized Subjects 
16.2.9.2 
Physical Exam – All Randomized Subjects 
16.2.9.3 
ECG Results – All Randomized Subjects 
16.2.9.4 
Abnormal ECG Measurement – All Randomized Subjects