Clinical trial NCT02353780
Conditions: Rheumatoid Arthritis (RA)
Keywords: Rheumatoid arthritis TNF inhibitors
Sponsor: Dr. Larry W. Moreland
Start date: 2015-03-01; Completion date: 2018-11-30
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An Agency for Healthcare Research and Quality executive summary indicated that better comparative effectiveness trial designs are needed to determine the relative merits of existing versus new and expensive biologic drug therapies for rheumatoid arthritis (RA). There are now 9 biologic therapies approved for treating RA. Four classes of biologics (TNF antagonists, B-cell inhibitors, T-cell co-stimulator blocker, and Interleukin-6 receptor blocker) are approved for use in RA patients with moderate or severe disease activity. Several critical questions have arisen, such as 1) what therapy should be prescribed after failure of methotrexate and/or other oral disease modifying antirheumatic drugs (DMARDs) to adequately control disease activity; 2) what is the level of efficacy of the various biologic therapies when compared in head-to-head trials; and 3) what are the mechanisms associated with failure of methotrexate and/or other oral DMARD therapy and responsiveness to biologic therapies. The MAZERATI study will provide the foundation for answering these questions and determining the mechanisms associated with these biologic therapies.

Detailed description:
Single center, randomized, assessor-blinded, observational longitudinal assessment. Subjects will be randomized to treatment with an anti-TNF therapy, tocilizumab or abatacept and evaluated at baseline, and after 1, 3 and 6 months of therapy. All biologics will be administered subcutaneously (SQ). A blinded assessor will perform clinical disease activity assessments and blood samples will be obtained for mechanistic studies.

After randomization, patients must take at least one dose of the assigned medication and must maintain their baseline prednisone and oral disease modifying anti-rheumatic drug (DMARD) medications until they have received their first dose of assigned medication to be considered per protocol participants. During the first 3 months of therapy, patients and their physicians will be permitted to taper but not increase corticosteroids. Adjustments of study medication or oral DMARDs will not be permitted during the first 3 months of the study except as outlined in the protocol. Adjustments or additions of analgesics will be permitted throughout the study period.

Following randomization and treatment initiation, study participants will be seen in the clinic at 1 month (3-5 weeks), 3 months (10-14 weeks), and 6 months (22-30 weeks) after the initiation of therapy; at each time point, a blinded clinical disease activity assessment will occur and blood samples will be obtained for mechanistic studies. The occurrence and severity of unanticipated problems will be recorded continuously throughout the study.

Arms: arm 1: The participant will be prescribed any TNF antagonist in this arm. The treating rheumatologist selects the TNF antagonist and the appropriate options for that therapy. arm 2: The participant will be prescribed abatacept in this arm. The treating rheumatologist selects the appropriate options for that therapy. arm 3: The participant will be prescribed tocilizumab. The treating rheumatologist selects the appropriate options for that therapy.
Interventions: intervention 1: TNF Antagonist (enbrel, humire, remicade, cimzia, symponi) intervention 2: Abatacept intervention 3: Tocilizumab
Intervention descriptions: intervention 1: TNF Antagonist; treating rheumatologist selects specifics for the therapy chosen. intervention 2: Abatacept; SQ; specifics to be determined by the treating rheumatologist. intervention 3: Tocilizumab; SQ; specifics determined by the treating rheumatologist.

Protocol documents:
Prot_SAP_000.pdf: 
MAZERATI Clinical Protocol 
Version 3.0 
 
20 April 2015 
 
 
 ____________________________________________________________________________________________ 
 
MECHANISTIC STUDIES OF B- AND T-CELL FUNCTION IN 
RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TNF 
ANTAGONISTS, TOCILIZUMAB, OR ABATACEPT 
(MAZERATI) 
 
PREFACE 
 
An Agency for Healthcare Research and Quality executive summary indicated that better 
comparative effectiveness trial designs are needed to determine the relative merits of existing 
versus new and expensive biologic drug therapies for rheumatoid arthritis (RA). There are now 
9 biologic therapies approved for treating RA.  Four classes of biologics (TNF antagonists, B-
cell inhibitors, T-cell co-stimulator blocker, and Interleukin-6 receptor blocker) are approved for 
use in RA patients with moderate or severe disease activity.  Several critical questions have 
arisen, such as 1) what therapy should be prescribed after failure of methotrexate and/or other 
oral disease modifying antirheumatic drugs (DMARDs) to adequately control disease activity; 2) 
what is the level of efficacy of the various biologic therapies when compared in head-to-head 
trials; and 3) what are the mechanisms associated with failure of methotrexate and/or other oral 
DMARD therapy and responsiveness to biologic therapies.  The MAZERATI study will provide 
the foundation for answering these questions and determining the mechanisms associated with 
these biologic therapies. 
 
 


MAZERATI Clinical Protocol 
Version 3.0 
 
20 April 2015 
 
 
 ____________________________________________________________________________________________ 
 
 
MECHANISTIC STUDIES OF B- AND T-CELL FUNCTION IN 
RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TNF 
ANTAGONISTS, TOCILIZUMAB, OR ABATACEPT (MAZERATI) 
 
 
Sponsored by:  
National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) 
(Pending) and Genentech, Inc. 
 
Co-PI:  Larry W. Moreland, MD 
Co-PI:  Mandy McGeachy, PhD 
Investigator: Anthony Fabio, PhD, MPH 
Investigator:  Yong Hwang, MD 
 
Draft or Version Number: 3.0 
 
Day Month Year 
20 Apr 2015 
 
NCT02353780  
 
 
 
Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential investigators, 
consultants, study staff, and applicable independent ethics committees or institutional review boards.  The 
contents of this document shall not be disclosed to others without written authorization from Dr. Larry W. 
Moreland (or others, as applicable), unless it is necessary to obtain informed consent from potential study 
participants. 
 


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Statement of Compliance 
This trial will be conducted in compliance with the protocol, current GCPs recommended 
by the International Conference on Harmonization (ICH) and the applicable regulatory 
requirements for University of Pittsburgh. These include the tenets of the Declaration of 
Helsinki and review and approval by the IRB. 


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Signature Page 1 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator:  _______________________________________________ 
                                                                    Print/Type 
 
Signed: 
 
Date: 
 
 
Name/Title 
 
 
 


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Signature Page 2 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Investigator(s) of Record:  ______________________________________________ 
                                                                         Print/Type 
 
Signed: 
 
Date: 
 
 
Name/Title 
 
 
 
Additional Investigators: ______________________________________________ 
                                                                         Print/Type 
 
Signed: 
 
Date: 
 
 
Name/Title 
 
 
 
Additional Investigators: ______________________________________________ 
                                                                         Print/Type 
 
Signed: 
 
Date: 
 
 
Name/Title 
 
 
 


MAZERATI Clinical Protocol 
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Table of Contents 
 
 
 ____________________________________________________________________________________________ 
iv 
 
Statement of Compliance 
i 
 
Signature Page 1 
ii 
 
Signature Page 2 
iii 
 
List of Abbreviations 
viii 
 
Protocol Summary 
1 
1. 
Key Roles 
5 
1.1 
Background Information 
7 
1.1.1 
Description of the Study Agents 
7 
1.1.2 
Summary of Previous Pre-Clinical Studies 
8 
1.1.3 
Summary of Relevant Clinical Studies 
8 
1.1.4 
Summary of Epidemiological Data 
9 
1.2 
Rationale 
9 
1.3 
Potential Risks and Benefits 
10 
1.3.1 
Potential Risks 
10 
1.3.2 
Potential Benefits 
10 
2. 
Study Objectives 
11 
2.1 
Primary Objective 
11 
2.2 
Secondary Objectives 
13 
2.3 
Exploratory Objectives 
13 
3. 
Study Design 
13 
3.1 
Description of the Study Design 
13 
3.2 
Study Endpoints 
14 
3.2.1 
Primary Endpoint 
14 
3.2.2 
Secondary Endpoints 
15 
3.2.3 
Exploratory Endpoints 
15 
3.2.4 
Substudy Endpoints 
15 
4. 
Study Population 
15 
4.1 
Description of the Study Population 
15 
4.1.1 
Participant Inclusion Criteria 
15 
4.1.2 
Participant Exclusion Criteria 
16 
4.2 
Strategies for Recruitment and Retention 
17 
5 
Study Agents 
17 
5.1 
Study Agent Acquisition 
17 
5.1.1 
Etanercept (Enbrel) 
18 
5.1.1.1 
Etanercept Formulation, Packaging, and Labeling  
18 
5.1.1.2 
Preparation, Administration, Storage, and Dosage of Etanercept 
19 
5.1.1.3 
Study Agent Accountability Procedures 
20 
5.1.2 
Adalimumab (Humira) 
20 
5.1.2.1 
Formulation, Packaging, and Labeling 
20 
5.1.2.2 
Preparation, Administration, Storage, and Dosage of Adalimumab 
21 
5.1.2.3 
Study Agent Accountability Procedures 
23 
5.1.3 
Golimumab (Simponi) 
23 
5.1.3.1 
Formulation, Packaging, and Labeling 
23 
5.1.3.2 
Preparation, Administration, Storage, and Dosage of Golimumab 
24 
5.1.3.3 
Study Agent Accountability Procedures 
26 
5.1.4 
Certolizumab Pegol (Cimzia) 
26 


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5.1.4.1 
Formulation, Packaging, and Labeling 
26 
5.1.4.2 
Preparation, Administration, Storage, and Dosage of Certolizumab Pegol 
27 
5.1.4.3 
Study Agent Accountability Procedures 
28 
5.1.5 
Tocilizumab (Actemra) 
29 
5.1.5.1 
Formulation, Packaging, and Labeling 
29 
5.1.5.2 
Preparation, Administration, Storage, and Dosage of Tocilizumab 
29 
5.1.5.3 
Study Agent Accountability Procedures 
30 
5.1.5.4 
Dose Modification & Toxicity Management 
30 
5.1.6 
Abatacept (Orencia) 
35 
5.1.6.1 
Formulation, Packaging, and Labeling 
35 
5.1.6.2 
Preparation, Administration, Storage, and Dosage of Abatacept 
35 
5.1.6.3 
Study Agent Accountability Procedures 
36 
5.2 
Assessment of Participant Compliance With Study Agents 
36 
5.3 
Concomitant Medications and Procedures 
36 
5.3.1 
Permitted Concurrent Medications 
36 
5.3.2 
Medication Changes and Monitoring for Toxicity for DMARDs and Steroids 
37 
5.4 
Precautionary and Prohibited Medications and Procedures 
38 
5.4.1 
Prohibited Medications and Procedures 
38 
5.4.2 
Precautionary Medications and Procedures 
38 
5.5 
Prophylactic Medications and Procedures 
39 
5.6 
Rescue Medications 
39 
6. 
Study Procedures/Evaluations 
39 
6.1 
Clinical Evaluations 
39 
6.2 
Laboratory Evaluations 
40 
6.2.1 
Clinical and Research Laboratory Evaluations and Specimen Collection 
40 
6.2.2 
Specimen Preparation, Handling and Shipping 
41 
6.3 
Substudies 
41 
7. 
Study Schedule 
42 
7.1 
Screening 
42 
7.1.1 
Evaluations and Procedures 
42 
7.1.2 
Instructions for Completing the Screening Visit 
42 
7.2 
Enrollment/Baseline 
43 
7.3 
Follow-Up 
44 
7.4 
Final Study Visit 
45 
7.5 
Early Termination Visit 
45 
7.6 
Pregnancy Visit 
45 
7.7 
Unscheduled Visits 
46 
8. 
Assessment of Safety 
46 
8.1 
Specification of Safety Parameters 
46 
8.2 
Definition of An Adverse Event (AE) 
46 
8.3 
Definition of a Serious Adverse Event (SAE) 
47 
8.4 
Methods and Timing for Assessing, Recording, and Analyzing, Managing 
Safety Parameters 
47 
8.4.1 
Methods and Timing for Assessment 
47 
8.4.1.1 
Adverse Event Reporting Period 
47 
8.4.2 
Assessment of Adverse Events 
48 


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8.5 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
48 
8.5.1 
Eliciting Adverse Events 
49 
8.5.2 
Specific Instructions for Recording Adverse Events 
49 
8.6 
Reporting of Serious Adverse Events 
50 
8.6.1 
Reporting of Serious Adverse Events Associated with Tocilizumab (Arm 2 
only) 
50 
8.6.2 
Reporting of Serious Adverse Events Associated with Abatacept (Arm 3 
only) 
52 
8.7 
AEs of Special Interest (AESIs) 
52 
8.7.1 
AESIs for Tocilizumab (Arm 2) only 
53 
8.7.2 
AESIs for Abatacept (Arm 3) only 
53 
8.8 
Modification of Study Agent(s)/Intervention(s) for a Participant 
53 
8.8.1 
Dose/Schedule Modifications for a Participant 
54 
8.9 
Halting Rules for the Protocol 
54 
8.10 
Stopping Rules for An Individual Participant/Cohort 
54 
8.11 
Premature Withdrawal of a Participant 
55 
9. 
Clinical Monitoring Structure 
55 
9.1 
Site Monitoring Plan 
55 
9.2 
Safety Monitoring Plan 
55 
10. 
Statistical Considerations 
56 
10.1 
Overview and Study Objectives 
56 
10.2 
Study Population 
56 
10.3 
Description of the Analyses 
57 
10.4 
Measures To Minimize Bias 
59 
10.5 
Appropriate Methods and Timing for Analyzing Outcome Measures. 
59 
10.6 
Study Hypotheses 
60 
10.7 
Sample Size Considerations 
60 
10.8 
Maintenance of Trial Treatment Randomization Codes 
60 
10.9 
Participant Enrollment and Follow-Up 
60 
10.10 
Planned Interim Analyses 
61 
10.11 
Safety Review 
61 
10.12 
Immunogenicity or Efficacy Review 
61 
10.13 
Final Analysis Plan 
61 
11. 
Quality Control and Quality Assurance 
62 
12. 
Ethics/Protection of Human Subjects 
62 
12.1 
Institutional Review Board/Ethics Committee 
62 
12.2 
Informed Consent Process 
63 
12.2.1 
Assent or Informed Consent Process (in Case of a Minor) 
63 
12.3 
Exclusion of Women, Minorities, and Children (Special Populations) 
64 
12.4 
Participant Confidentiality 
64 
12.5 
Study Discontinuation 
64 
13. 
Data Handling and Record Keeping 
64 
13.1 
Data Management Responsibilities 
64 
13.2 
Data Capture Methods 
65 
13.3 
Types of Data 
65 
13.4 
Source Documents and Access to Source Data/Documents 
65 


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13.5 
Timing/Reports 
66 
13.6 
Study Records Retention 
66 
13.7 
Protocol Deviations 
66 
14. 
Publication Policy 
67 
15. 
Scientific References 
67 
Appendix A 
Study Visits Schedule 
74 
Appendix B 
Genentech Safety Reporting Fax Cover Sheet 
75 


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List of Abbreviations 
AE 
Adverse Event/Adverse Experience 
CCP 
Cyclic Citrullinated Peptide 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
FDA 
Food and Drug Administration 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MedDRA © 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NCI 
National Cancer Institute, NIH 
NDA 
New Drug Application 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
RF 
Rheumatoid Factor 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
WHO 
World Health Organization 


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Protocol Summary 
Full Title 
MECHANISTIC STUDIES OF B- AND T-CELL FUNCTION IN 
RHEUMATOID ARTHRITIS PATIENTS TREATED WITH TNF 
ANTAGONISTS, TOCILIZUMAB, OR ABATACEPT (MAZERATI) 
Short Title 
MAZERATI 
Clinical Trial 
Phase 
Phase 4, investigator initiated 
IND Sponsor (if 
applicable) 
Not applicable 
Conducted By 
Investigator initiated and conducted at the University of Pittsburgh 
Medical Center  
Co-Principal 
Investigators 
Larry W. Moreland, MD 
Mandy McGeachy, PhD 
Sample Size 
90 subjects (30 subjects per treatment arm) 
Study Population 
Rheumatoid arthritis patients with an inadequate response to 
methotrexate and/or other oral DMARDs. Patients who are naïve to 
biological therapies 
Accrual Period 
July 1, 2014 to July 1, 2017 
Study Design 
One center, randomized, assessor-blinded, observational longitudinal 
assessment.  Subjects will be randomized to treatment with an anti-TNF 
therapy, tocilizumab or abatacept and evaluated at baseline, and after 1, 
3 and 6 months of therapy.  All biologics will be administered 
subcutaneously (SQ). A blinded assessor will perform clinical disease 
activity assessments and blood samples will be obtained for mechanistic 
studies. 
 
After randomization, patients must take at least one dose of the assigned 
medication and must maintain their baseline prednisone and oral DMARD 
medications until they have received their first dose of assigned 
medication to be considered per protocol participants.  Adjustments of 
study medication or oral DMARDs will not be permitted during the first 3 
months of the study except as outlined in the protocol.  Adjustments or 
additions of analgesics will be permitted throughout the study period. 
 
Following randomization and treatment initiation, study participants will be 
seen in the clinic at 1 month (3-5 weeks), 3 months (10-14 weeks), and 6 
months (22-30 weeks) after the initiation of therapy; at each time point, a 
blinded clinical disease activity assessment will occur and blood samples 
will be obtained for mechanistic studies.   


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The occurrence and severity of unanticipated problems and events will be 
recorded continuously throughout the study. 
 
Inclusion Criteria: 
• Must provide (sign) written informed consent to participate 
• Diagnosis of RA by a physician as defined by the 1987 and/or 2010 
ACR criteria. 
• 18 years of age or older at the time of diagnosis of RA. 
• Patient age is greater than or equal to 18 yrs and less than or equal to 
64 yrs. 
• RA Disease Activity CDAI > 10 
• If using oral corticosteroids, must have been on stable dose (≤ 10 
mg/day) for at least 2 weeks prior to study drug initiation. 
• PPD and/or Quantiferon TB-Gold negative or if PPD and/or 
Quantiferon TB-Gold positive documentation of therapy with INH for at 
least 1 month prior to study initiation and negative chest x-ray. 
• Must have been treated within the past year with methotrexate (MTX), 
leflunomide (LEF), hydroxychloroquine (HCQ) and/or sulfasalazine 
(SSZ) for ≥ 3 months. 
• Prior or concurrent use of other oral DMARD therapy, including LEF, 
SSZ, and HCQ, is permitted. Patients taking oral DMARDs must be on 
stable doses of DMARDs for at least 4 weeks prior to study drug 
initiation.  Subjects are not required to be taking an oral DMARD. 
• Be seropositive for rheumatoid factor (RF) and/or anti-citrullinated 
cyclic (anti-CCP) antibody 
 
Exclusion Criteria: 
• Use of cyclophosphamide, penicillamine, cyclosporine A, tacrolimus or 
gold therapy is not permitted in the 6 months prior to enrollment. 
• Patients who are using or have used biologic agents or tofacitinib 
concomitantly or prior to this study. 
• History of active and/or chronic infection such as hepatitis, pneumonia, 
pyelonephritis, herpetic infections, or chronic skin infections and any 
active opportunistic infection, including but not limited to evidence of 
active cytomegalovirus, active Pneumocystis carinii, aspergillosis, 
histoplasmosis or atypical mycobacterium infection. 
• Active TB or evidence of latent TB (positive PPD skin test, positive 
Quantiferon TB-Gold test or a history of old or latent TB on chest x-ray) 
without adequate therapy for TB. 
• Pregnant or lactating women. 
• Patients with current signs or symptoms of uncontrolled renal, 
gastrointestinal, endocrine, pulmonary, cardiovascular, neurologic or 
cerebral disease. 
• Diagnosis of liver disease or elevated hepatic enzymes, as defined by 
ALT, AST or both > 1.5 x the upper limit of normal (ULN) or total 
bilirubin > ULN. 


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• Any of the following hematologic abnormalities, confirmed by repeat 
tests: 
a) White blood count < 3,000/µL or > 14,000/µL 
b) Lymphocyte count <500/µL 
c) Platelet count < 100,000/µL 
d) Hemoglobin < 8.0 g/dL 
e) Neutrophil count < 2,000 cells/µL 
• 
Major surgery (including joint surgery) within 8 weeks prior to 
screening or planned major surgery within 6 months following 
randomization. 
• 
Immunization with a live/attenuated vaccine within 2 months prior to 
baseline or 3 months of last study visit. 
• 
History of severe allergic or anaphylactic reactions to human, 
humanized, or murine monoclonal antibodies 
• 
History of other malignancy within 5 years prior to screening, except 
for appropriately treated carcinoma in situ of the cervix, non-
melanoma skin carcinoma, or Stage I uterine cancer 
• 
Patients with reproductive potential not willing to use an effective 
method of contraception 
• 
History of alcohol, drug or chemical abuse with 1 year prior to 
screening 
Study Duration 
5 years 
Study 
Agent/Intervention 
Description 
Anti-TNF biologics (SQ) will be supplied by the subject’s pharmacy. 
Tocilizumab and abatacept will be provided by the study; abatacept by 
Bristol-Myers Squibb and tocilizumab by Genentech. 
 
Arm #1 (n=30): anti-TNF biologic (either etanercept, 
adalimumab,certolizumab or golimumab; selection based on discretion of 
treating physician and subject) 
Arm #2 (n=30): SQ tocilizumab  
Arm #3 (n=30): SQ abatacept  
 
1.)  Etanercept: 50 mg SQ qweek 
2.)  Adalimumab: 40 mg SQ q 2 weeks; increased to 40 mg SQ q 7 days 
at 3 months if CDAI > 2.8 and approved by primary rheumatologist 
3.)  Certolizumab: 400 mg SQ at baseline and at weeks 2 and 4 followed 
by either 200 mg SQ q 2 weeks or 400 mg SQ q 4 weeks; the dosing 
regimen for maintenance is at the discretion of the treating physician 
4.)  Golimumab: 50 mg SQ q month  
5.)  Tocilizumab: 162 mg SQ q 2 weeks for patients < 100 kg, increased 
to q week based on clinical response; or 162 mg SQ q week for 
patients ≥ 100 kg 


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6.)  Abatacept: SQ route: 125 mg SQ q week 
Objectives 
 
1.) To use a randomized observation study design as a means to 
evaluate the correlation between changes in disease activity and changes 
in B and T cell mechanistic studies following institution of a TNF 
antagonist, tocilizumab or abatacept. 
2.)  To use a randomized observation study design as a means to 
evaluate differences in the mechanisms of action of three clinically 
relevant treatment options (TNF antagonist vs. tocilizumab vs. abatacept) 
for rheumatoid arthritis patients with a moderate or high disease activity 
score (CDAI > 10), and an inadequate response to methotrexate and/or 
other oral DMARDs. 
 
Endpoints 
1.) Completion of at least 3 months of follow-up on stable doses of study 
medications. 
2.) Comparisons of mechanistic study results a.) with changes in disease 
activity, b.) before initiation of therapy and following therapy and c.) 
between groups based on study drugs. 
 
 
 
MAZERATI Study Design Schematic: 
 
The MAZERATI study will occur according to the schematic below.   
 
 


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1. KEY ROLES 
 
This is a single-site clinical trial occurring at the University of Pittsburgh within the University of 
Pittsburgh Medical Center (UPMC) Rheumatology Network.   
 
A.  Institutions: 
University of Pittsburgh 
123 University Drive 
Pittsburgh, PA 15260 
Allan DiPalma, Director 
Office of Research 
Phone:  412-624-7400 
Fax:  412-624-7409 
Email:  offres@offres.pitt.edu 
 
University of Pittsburgh Medical Center (UPMC) Rheumatology Network 
3500 Terrace Street 
Pittsburgh, PA 15261 
Larry W. Moreland, MD 
Chief, Division of Rheumatology and Clinical Immunology 
Phone:  412-383-8000 
Fax:  412-383-8864 
E-mail: lwm5@pitt.edu 
 
B.  Sponsors:   
 
UPMC/University of Pittsburgh Division of Rheumatology  
Genetech (funding of RACER and supply of tocilizumab) 
Bristol Myers Squibb (supply of abatacept) 
 
C.  Investigators:   
 
Co-Principal Investigator: 
 
Larry W. Moreland, MD 
Chief, Professor of Medicine 
Division of Rheumatology & Clinical Immunology 
Department of Medicine 
University of Pittsburgh School of Medicine 
200 Lothrop Street 
S711 Biomedical Science Tower-South 
Pittsburgh, PA 15261 
Phone:  412-648-0148 
Fax:  412-648-8894 
E-mail: lwm5@pitt.edu 
 
 
 
 
 


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Co-Principal Investigator: 
 
Mandy McGeachy, PhD 
Assistant Professor of Medicine 
Division of Rheumatology & Clinical Immunology 
Department of Medicine 
University of Pittsburgh School of Medicine 
200 Lothrop Street 
S719 Biomedical Science Tower-South 
Pittsburgh, PA 15261 
Phone:  412-648-1587 
Fax:  412-383-8864 
E-mail:  mmcgeach@pitt.edu 
 
Investigators: 
 
 
Anthony Fabio, PhD, MPH 
Director, CIRCA (Consortium for Injury Research and Community Action)  
Assistant Professor, Epidemiology Data Center, Department Of Epidemiology  
University of Pittsburgh, Graduate School of Public Health 
Phone:  412-624-4612 | 
Fax:  412-624-3120 
E-mail: afabio@pitt.edu 
 
Yong Gil Hwang, MD 
Assistant Professor of Medicine 
Division of Rheumatology and Clinical Immunology 
S703 Thomas E. Starzl Biomedical Science Tower 
3500 Terrace Street 
Pittsburgh, PA 15261 
Phone: 412-648-8440 
Fax: 412-648-8894 
E-mail: hwangyg@upmc.edu 
 
Data Manager (EDC): 
 
Heather Eng 
Associate Director of Data Management 
Epidemiology Data Center, Graduate School of Public Health 
University of Pittsburgh 
130 DeSoto Street 
127 Parran Hall 
Pittsburgh, PA 15261 
Phone:  412-624-5177 
Fax: 412-624-3775 
E-mail:  heng@pitt.edu 
 


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Background Information and Scientific Rationale 
 
1.1 
Background Information 
 
 
1.1.1 Description of the Study Agents 
 
The medications to be evaluated are all approved by the FDA at the doses and in the 
combination(s) outlined in this protocol. 
 
Overview of Anti-TNFα Biologics 
 
There are currently five FDA-approved biologics that target tumor necrosis factor alpha (TNF), 
and all have a similar safety profile.  Published post-marketing experience has drawn attention 
to TNF inhibitor associated infectious complications (e.g., tuberculosis and other opportunistic 
infections) [1-6]; demyelination [7], vasculitis [8], lymphoma [6, 9-13], drug-induced systemic 
lupus erythematosus (SLE) [14, 15], and congestive heart failure [16].  Although there continues 
to be active research to determine the real relationships and severity of these reported adverse 
events and TNF inhibitors [17, 18], the U.S. Food and Drug Administration issued a black-box 
warning to doctors appearing in the product labeling of the anti-TNF drugs instructing them to 
screen and monitor potential patients carefully. All five of these agents inhibit TNF, but there are 
different mechanisms of action of these TNF antagonists. 
 
Etanercept (Enbrel) was approved by the FDA in 1998 for treatment of RA.  Etanercept is a 
fusion protein created by linking the human soluble TNF receptor 2 to the Fc domain of human 
IgG1.  Acting as a decoy receptor, etanercept effectively neutralizes a fraction of TNFα in the 
body, thereby reducing the inflammatory response.  The typical dose of etanercept is 50 mg 
administered subcutaneously every week. 
 
Adalimumab (Humira) was the first fully human monoclonal antibody approved by the FDA in 
2002 for the treatment of RA.  Like infliximab and etanercept, adalimumab binds to TNFα, 
preventing it from activating TNF receptors [19].  The typical starting dose of adalimumab is 40 
mg every 2 weeks administered subcutaneously, with an increase to 40 mg every week if 
adalimumab is ineffective at the 2 week dosing interval. 
 
Certolizumab pegol (Cimzia) was approved by the FDA for treating RA in 2009 and approved 
for treating Crohn’s disease in April 2008. The current approved dose for RA is 400 mg 
subcutaneously once monthly or 200 mg twice monthly.  Certolizumab pegol is a recombinant, 
humanized Fab antibody fragment with specificity for human TNFα.  It is conjugated to a ~40 
kDa polyethylene glycol (PEG) to enhance plasma half-life.  In contrast to infliximab and 
adalimumab, certolizumab pegol does not fix complement or cause antibody-dependent cell-
mediated cytoxicity in vitro, as it does not contain an Fc region. 
 
Golimumab (Simponi) is a fully human monoclonal antibody and was approved in 2009 for the 
treatment of RA.  Golimumab is administered once-monthly subcutaneously at a dose of 50 mg.   
 
 
Infliximab (Remicade) will not be used in this study due the need to adjust dose to achieve 
maximal efficacy. 
 


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Other Biologics 
 
Tocilizumab (Actemra), delivered intravenously and subcutaneously, was approved in 2009 for 
the treatment of RA.  Tocilizumab is a humanized monoclonal antibody targeting the interleukin-
6 (IL-6) receptor and thereby blocking the activity of IL-6. Tocilizumab is typically administered 
initially at a monthly dose of 4 mg/kg and then increased to 8 mg/kg if not effective and no side-
effects occur.  A SQ route of tocilizumab administration has been approved for treatment of RA 
at 162 mg every other week for patients < 100 kg, increased to every week based on clinical 
response; or 162 mg per week for patients ≥ 100 kg. We will only use the subcutaneous 
administration for this study. 
 
Abatacept (Orencia) modulates the immune response by inhibiting the costimulation of T cells 
via CD28.  Abatacept is a fusion protein composed of the extracellular domain of CTLA-4 and 
an immunoglobulin Fc domain.  Abatacept binds to the B7 protein on antigen presenting cells, 
thus preventing B7 from binding and activating CD28-mediated costimulation of T cells.  The 
typical intravenous monthly dose of abatacept is 500-1000 mg depending on body weight.  
Abatacept is also approved for subcutaneous administration at a dose of 125 mg every week. 
We will only use the subcutaneous administration for this study. 
 
 
1.1.2 Summary of Previous Pre-clinical Studies 
 
The MAZERATI trial is a phase IV clinical trial.  All of the therapies in the MAZERATI trial are 
FDA-approved and will be used for FDA-approved indications.  The objective of the MAZERATI 
trial is to determine how best to utilize these therapies in humans, and no pre-clinical studies 
support that objective. 
 
1.1.3 Summary of Relevant Clinical Studies 
 
Although therapy with methotrexate is the current standard-of-care for RA patients initiating 
DMARD therapy, there is no clear consensus about how RA patients should be treated if there 
is an inadequate response to methotrexate.  Many rheumatologists initiate therapy with a TNF 
antagonist in RA patients with an inadequate response to methotrexate but only about 50% of 
patients treated with a TNF antagonist or another biologic will respond to therapy [20] and there 
is currently no way to predict which patients will respond.  Furthermore, there are two classes of 
biologic therapies (abatacept and tocilizumab) besides TNF antagonists approved for use in 
methotrexate inadequate responders.  In addition, triple oral therapy with methotrexate, 
sulfasalazine and hydroxychloroquine may be equally effective at reducing disease activity in 
RA patients with an inadequate response to methotrexate [21, 22], but biologic therapies as 
opposed to triple oral therapy reduce the likelihood of developing bone erosions [21] and 
treatment with a biologic is perceived to work faster than oral therapy.  The choice of a TNF 
antagonist, as opposed to abatacept or tocilizumab, for methotrexate inadequate responders 
likely occurs because TNF antagonists were first to market and occurs despite the fact that 
abatacept and tocilizumab appear to be at least as safe and effective as TNF antagonists [23-
26].  In a head-to-head study of RA patients with an inadequate response to methotrexate 
treated with either the TNF antagonist adalimumab or subcutaneously administered abatacept, 
both biologics were equally efficacious and abatacept patients had fewer drug discontinuations 
due to adverse events [24, 25].  Likewise, a systematic review suggested that tocilizumab may 
be more efficacious than other biologics [27], and in a head-to-head comparison of 
monotherapy with adalimumab versus tocilizumab in RA patients intolerant or with an 


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inadequate response to methotrexate, tocilizumab therapy was more efficacious and had an 
equivalent number of side-effects [26].  Therefore, it remains unclear which biologic therapy is 
most efficacious and safe in RA patients with an inadequate response to methotrexate and 
more importantly what is needed is a way to predict which RA patients will respond to a 
particular biologic therapy. 
 
1.1.4 Summary of Epidemiological Data 
 
There are no published epidemiological data that bear on the question of which biologic therapy 
to select for the treatment of RA patients that have had an inadequate clinical response to 
methotrexate and/or other oral DMARDs. 
 
1.2 
Rationale 
 
RA is a complex inflammatory disorder causing synovitis and joint destruction [28]. Biologics 
including TNF inhibitors (adalimumab, infliximab, certolizumab, golimumab, etanercept), anti-
IL6R blocking drugs (tocilizumab), anti B cell (rituximab) and the T cell costimulation blocker 
CTLA4Ig (abatacept) have improved outcomes for many RA patients. However, around 40-50% 
of patients fail to respond to a given biologic therapy, and there are currently no biomarkers that 
predict response to aid clinicians in their treatment choices [20]. Therefore, there remains a 
great clinical need to understand the mechanisms by which different biologics target 
pathological immune responses in RA, and to develop simple bioassays to measure these 
responses. Autoreactive memory B cells and Th17 cells contribute to the pathogenesis of RA 
through production of  antibodies and cytokines that activate monocytes and joint stromal cells 
[29]. Memory B cells and Th17 cells react to similar citrullinated joint proteins, and both 
populations have been shown to decrease in response to therapy with TNF inhibitors. However, 
interactions between these cells have not been interrogated in the same RA patients, and 
whether they are similarly affected by different biologic therapies is unknown. The objective of 
this proposal is to determine the impact of different biologic therapies (tocilizumab, abatacept, 
and TNF inhibitors) on the frequency and function of autoreactive Th17 cells and autoreactive 
memory B cells in RA.  
 
Memory CD4+ T cells bearing markers of both TfH (CXCR5) and Th17 (CCR6) cells have been 
suggested to contribute to inflammation in other autoimmune diseases including juvenile 
dermatomyositis [30] and Sjögren’s syndrome [31]. The combined properties of TfH and Th17 
cells position CXCR5+Th17 cells to be superior mediators of both B cell activation and tissue 
inflammation, and our preliminary data indicate that both CXCR5+Th17 cells and memory B 
cells are increased in the peripheral blood of patients with RA and decreased by TNF inhibitors. 
Our central hypothesis is that the activities of autoimmune CXCR5+Th17 and memory B cells 
are linked in driving RA pathogenesis, and therefore successful therapies must directly or 
indirectly alter both of these populations. We have the unique opportunity to test this hypothesis 
by performing longitudinal analysis of peripheral blood mononuclear cells (PBMC) from RA 
patients with active disease initiating one of three biologic therapies with distinct targets: 
tocilizumab, abatacept or TNF inhibitor.  
 


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To date, we have a surprisingly poor mechanistic understanding of how IL-6, TNF and co-
stimulation blockade ameliorate aberrant immune responses in RA [20, 32], and the reasons for 
variation in drug efficacy among patients remains unclear. There are no diagnostic or predictive 
parameters to guide informed decisions on the most appropriate therapy for each patient. This 
proposal will compare the mechanisms of action of tocilizumab, abatacept and TNF inhibitors on 
T and B cell populations in RA, and will test the predictive value of PBMC gene expression for 
these changes. This contribution will inform our understanding of how different therapies work in 
individual patients and will ultimately lead to better decisions about how to best use these drugs 
in clinical practice. These data will also advance our understanding of the complex immune 
mechanisms that mediate RA, since Th17 cells and B cells have typically been studied only in 
isolation or in animal models. Th17 cells and autoreactive B cells are common co-features of 
other autoimmune diseases including multiple sclerosis, systemic lupus erythematosus and 
Sjögren’s syndrome, therefore the insights provided by this study will be broadly applicable.  
 
1.3 
Potential Risks and Benefits 
 
1.3.1 Potential Risks 
 
Known and Potential Risks of TNF antagonists 
The most common side-effects associated with treatment with TNF antagonists are injection site 
reactions, including pain and rash; infections, headaches, and nausea.  The major serious side-
effects of treatment with TNF antagonists are serious infections, leucopenia, and lymphoma.  It 
is recommended that all patients initiating TNF antagonist therapy be tested for PPD reactivity 
and/or with a Quantiferon TB-Gold test to assess for the presence of latent TB.  We will follow 
the ACR recommendations for monitoring for toxicity during treatment with TNF antagonists [33, 
34]. 
 
Known and Potential Risks of Tocilizumab 
The most common adverse reactions associated with treatment with tocilizumab are upper 
respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, and 
injection site reactions.  The major serious side-effect of treatment with tocilizumab is serious 
infections.  We will follow the manufacturer’s and ACR recommendations for monitoring for 
toxicity during treatment with tocilizumab [33, 34]. 
 
Known and Potential Risks of Abatacept 
The most common side-effects associated with treatment with abatacept are headaches, upper 
respiratory tract infections, nasopharyngitis, and nausea. We will follow the ACR 
recommendations for monitoring for toxicity during treatment with abatacept [33, 34]. 
 
1.3.2 Potential Benefits 
 
The therapies that are being offered to patients in this study are therapies that would typically be 
offered to RA patients as standard-of-care for patients at this stage of their disease.  As such, it 
is expected that for many patients enrolled in this study that the therapies being offered to these 
patients will lower RA disease activity. 
 
 


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2. STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
To use a randomized observation study design as a means to evaluate the correlation 
between changes in disease activity and changes in B and T cell mechanistic studies following 
institution of a subcutaneously administered TNF antagonist, tocilizumab or abatacept. 
 
To use a randomized observation study design as a means to evaluate differences in the 
mechanisms of action of three clinically relevant treatment options (TNF antagonist vs. 
tocilizumab vs. abatacept) for rheumatoid arthritis patients with a moderate or high disease 
activity score (CDAI > 10), and an inadequate response to methotrexate and/or other oral 
DMARDs. 
 
The study agents are reviewed in Section 1.1.1.  Details of dosing and administration of study 
agents are provided in Section 5. 
 
The primary objectives of the MAZERATI study are covered in the following mechanistic specific 
aims: 
 
AIM 1: Determine the longitudinal effects of blocking TNF, IL-6R and T cell costimulation 
on CXCR5+Th17 cells in RA: Hypothesis: CXCR5+Th17 cell frequency and function (cytokine 
production) are altered differently by each therapy correlating with clinical response and 
changes in autoantibody. In Aim 1a, we will analyze freshly obtained PBMC by flow cytometry 
using well-established surface markers and intracellular cytokine staining to identify changes in 
T cell and B cell subsets over course of therapy in each individual. We will complement these ex 
vivo assays with in vitro stimulation assays in Aim 1b, to fully define cytokine responses in 
active RA and changes that occur with each therapy. These data will be correlated with serum 
autoantibody levels, as well as clinical disease activity over the 6-month trial period. In Aim 1c, 
we will use the highly sensitive and unbiased RNA-Seq approach to confirm observed T cell 
changes at the molecular level, and define novel gene expression signatures that correlate with 
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AIM 2: Define the pathogenic functions of CXCR5+Th17 cells on B cells and synovial 
fibroblasts in RA, and effect of different biologic therapies on these functions. 
Hypothesis: CXCR5+Th17 cells are the most potent T activators of autoreactive B cells and 
synovial fibroblasts in RA. CXCR5+Th17 cells have been shown to strongly induce antibody 
production in healthy donors, but their ability to activate autoantibody production in RA is 
unknown. Therefore, in Aim 2a we will compare the capacity of CXCR5+ and CXCR5- T cell 
subsets from RA patients to promote antibody production and to direct isotype switching by B 
cells, and delineate the role of T cell produced cytokines in this process, using blocking 
antibodies. We will also assess the impact of biologic therapy on B cell activation over the 
course of therapy, and correlate these findings with serum antibody levels. Synovial fibroblasts 
are thought to drive cartilage and bone erosion in RA, and are a major downstream target of 
Th17 cytokines, including IL-17. In Aim 2b we will therefore perform parallel proof-of-concept 
experiments to assess the capacity of RA CXCR5+Th17 cells to activate RA synovial fibroblasts 
(as measured by cytokine and chemokine expression), and roles of IL-6, TNF and CD28 
costimulation. 
 


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These data will for the first time determine the effects of tocilizumab, abatacept, and TNF 
inhibitors head-to-head in the same patient cohort, with a focus on the newly identified subset of 
CXCR5+Th17 cells, and its relationship to memory B cells in the same patients. By analyzing 
longitudinal effects of these drugs in the same study, we have the unique opportunity to reveal 
therapy-specific differences in mechanisms of action and drug resistance, that will inspire future 
development of predictive biomarkers and ultimately lead to informed decisions on therapy 
choice. 
 
2.2 
Secondary Objectives 
 
To use a randomized observation study design to evaluate the relative efficacy of three clinically 
relevant treatment options (anti-TNF vs. tocilizumab vs. abatacept) for RA in patients who have 
an inadequate response to methotrexate and/or other oral DMARDs.  For these analyses, we 
will compare the change in CDAI before and after therapy between each of the three different 
treatment arms. Given the small number of patients, this study is not powered for efficacy and 
we will not perform inferential statistics with regard to efficacy. 
 
2.3 
Exploratory Objectives 
 
To determine the effect of disease duration on the results of mechanistic studies and to 
determine the effect of clinical response on the results of the mechanistic studies.  We will also 
establish the feasibility of a novel, low-cost trial design (randomized observation) for conducting 
comparative effectiveness studies in RA patients that mirrors real-world clinical practice, but 
includes randomization, blinded assessments, and fixed time points for assessment. 
 
3. STUDY DESIGN 
 
3.1 
Description of the Study Design 
 
Summary:  MAZERATI is an open-label, assessor-blinded, randomized, observational study of 
90 subjects to determine the mechanisms associated with treatment with a TNF inhibitor or non-
TNF inhibitor biologic therapies (tocilizumab or abatacept) in the setting of an inadequate clinical 
response to methotrexate and/or other oral DMARDs in patients with RA.  A summary of key 
study characteristics is provided in Table 1. 
 
Table 1.  Summary of the Key Characteristics of the MAZERATI trial.   
Phase: 
IV 
Study Arms: 
3 arms, with 30 participants in each arm 
Sites: 
Single site; UPMC Rheumatology RACER Network 
Population: 
Participants will be diagnosed with rheumatoid arthritis and have 
a moderate to severe level of disease activity (CDAI > 10) 
Clinic Location: 
Out-patient rheumatology offices 
Total Enrollment Time: 
30 participants enrolled per year; total of 3 years for enrollment of 
90 participants 
Participation Duration: 
6 months per participant 
Study Agents: 
See also Section 1.1.1; etanercept, adalimumab, certolizumab, 
golimumab, tocilizumab, and abatacept (all administered 


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subcutaneously) 
 
Randomization:  90 eligible subjects will be randomized in a 1:1:1 ratio to receive either a TNF 
antagonist, tocilizumab, or abatacept.  Following screening, participants eligible for the study will 
be randomized to a TNF antagonist (specific one to be selected by the treating physician), 
tocilizumab, or abatacept.  Subjects will be randomized on a password-protected web-based 
program on a computer.  The costs for an anti-TNF drug will be the subject’s responsibility.  If 
insurance authorization is not obtained or available for the study drug, then we will work with the 
clinic staff to help the subject apply for assistance to pay for the medication from one of several 
foundations.  If foundation financial assistance is not available, the subject will be referred to 
UPMC Social Services and/or a UPMC financial counselor to review their options for covering 
the cost of the drug.  Finally, after every effort has been made to minimize costs to the subject, 
the subject may choose to pay out of pocket for the remaining expenses associated with the 
study drug,,If a patient chooses not to pay out-of-pocket,  they  may be prescribed  another 
rheumatoid arthritis medication that their insurance will cover or continue on their current 
medications per the recommendation of their rheumatologist. In these cases, patients will be 
followed to study completion and included in analysis under the intent to treat principle. 
 
 
Third party payors at this time feel that a TNF antagonist is the next line of treatment in RA 
patients who have failed MTX. Thus, they will not approve payment for abatacept or tocilizumab 
in this setting. This is despite current FDA approval for these two agents for this indication. 
Thus, the only way around this roadblock for this study was to seek free abatacept and 
tocilizumab from Bristol Myers Squibb and Genentech, respectively. We now have written 
approval for these agents from these two pharmaceutical companies. 
 
Table 2.  List of Specific Contraindications for the Use of MAZERATI Treatments 
Study Drug 
Contraindications Specific to Given Study Drug* 
TNF antagonist 
Class III or IV congestive heart failure 
Past or current history of demyelinating neurological disorder 
Past or current history of lymphoma 
Past or current history of malignancy besides lymphoma within the past 5 
years 
Tocilizumab 
Known hypersensitivity to tocilizumab 
 
Abatacept 
Severe chronic obstructive pulmonary disease (COPD) 
 
* Additional contraindications related to all study drug treatments, such as a history of active or 
recurrent infection, are listed in the exclusion criteria for the study. If patients have any of these 
contraindications as part of screening they will not be eligible for this study. 
 
Blinding:  This study will utilize a partial blinding plan. The participant, the participant’s 
physician, and the study coordinator will not be blinded to the participant’s treatment 
assignment. Only the blinded assessor, who will perform a joint examination at fixed intervals, 
will be blinded to each participant’s treatment. 
 
 
3.2 
Study Endpoints 
 


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3.2.1 Primary Endpoint 
 
There will be no primary efficacy endpoints for the study.  The primary endpoint of the study will 
be mechanistic comparisons within, between and including all the different treatment groups.  
The mechanistic comparisons will compare results from studies of samples 1.) within groups, 
before initiation of therapy and following therapy, between responders and non-responders 
within each group, and as a correlation between mechanistic results and disease activity, 2.) 
between groups, where groups are based on different study drugs, and 3.) including all 
treatment groups as a correlation between mechanistic results and disease activity. 
 
3.2.2 Secondary Endpoints 
 
Efficacy as measured by CDAI remission < 2.8; 
Efficacy as measured by DAS remission with a DAS28-CRP < 2.6; 
Efficacy as measured by ACR20, 50, and 70 response; 
Adherence to drug regimen; 
Reason for discontinuation of treatment (side effects, lack of efficacy, cost, patient compliance, 
etc.) 
 
3.2.3 Exploratory Endpoints 
 
None 
 
3.2.4 Substudy Endpoints 
 
None 
 
4. STUDY POPULATION 
 
Selection of Subjects 
 
We will enroll RACER participants and other RA patients evaluated in UPMC rheumatology 
clinics with an inadequate response to methotrexate and/or other oral DMARDs.  We will obtain 
a final sample of 90 (30 per treatment arm) participants that complete the 3-month study visit.  
“Inadequate response to methotrexate and/or other oral DMARDs” will be defined as RA 
patients having a Clinical Disease Activity Index (CDAI) > 10 after at least 3 months of treatment 
with methotrexate and/or other oral DMARDs.  Treatment with methotrexate and/or other oral 
DMARDs must have occurred within the 1-year period prior to enrollment.  If an RA patient is 
identified as an oral DMARD inadequate responder, s/he will be prescreened to confirm 
eligibility according to the inclusion and exclusion criteria. 
 
4.1 
Description of the Study Population 
 
4.1.1 Participant Inclusion Criteria 
 
To be eligible, patients must meet all of the following criteria: 
 
• Must provide (sign) written informed consent to participate 
• Diagnosis of RA by a physician as defined by the 1987 and/or 2010 ACR criteria. 


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• 18 years of age or older at the time of diagnosis of RA. 
• RA Disease Activity CDAI > 10 
• Patient age is greater than or equal to 18 yrs and less than or equal to 64 yrs. 
 
• If using oral corticosteroids, must have been on stable dose (≤ 10 mg/day) for at least 2 
weeks prior to study drug initiation. 
• PPD and/or Quantiferon TB-Gold negative or if PPD and/or Quantiferon TB-Gold positive 
documentation of therapy with INH for at least 1 month prior to study initiation and negative 
chest x-ray. 
• Must have been treated within the past year with methotrexate (MTX), leflunomide (LEF), 
hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ) for ≥ 3 months. 
• Prior or concurrent use of other oral DMARD therapy, including LEF, SSZ, and HCQ, is 
permitted. Patients taking oral DMARDs must be on stable doses of DMARDs for at least 4 
weeks prior to study drug initiation.  Subjects are not required to be taking an oral DMARD. 
• Be seropositive for rheumatoid factor (RF) and/or anti-citrullinated cyclic (anti-CCP) antibody 
 
4.1.2 Participant Exclusion Criteria 
 
Patients meeting any of the exclusion criteria at baseline will be excluded from the study. 
 
• Use of cyclophosphamide, penicillamine, cyclosporine A, tacrolimus or gold therapy is not 
permitted in the 6 months prior to enrollment. 
• Patients who are using or have used biologic agents or tofacitinib concomitantly or prior to 
this study. 
• History of active and/or chronic infection such as hepatitis, pneumonia, pyelonephritis, 
herpetic infections, or chronic skin infections and any active opportunistic infection, including 
but not limited to evidence of active cytomegalovirus, active Pneumocystis carinii, 
aspergillosis, histoplasmosis or atypical mycobacterium infection. 
• Active TB or evidence of latent TB (positive PPD skin test, positive Quantiferon TB-Gold test 
or a history of old or latent TB on chest x-ray) without adequate therapy for TB. 
• Pregnant or lactating women. 
• Patients with current signs or symptoms of uncontrolled renal, gastrointestinal, endocrine, 
pulmonary, cardiovascular, neurologic or cerebral disease. 
• Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST or both > 
1.5 x the upper limit of normal (ULN) or total bilirubin > ULN. 
• Any of the following hematologic abnormalities, confirmed by repeat tests: 
a) White blood count < 3,000/µL or > 14,000/µL 
b) Lymphocyte count <500/µL 
c) Platelet count < 100,000/µL 
d) Hemoglobin < 8.0 g/dL 
e) Neutrophil count < 2,000 cells/µL 
• 
Major surgery (including joint surgery) within 8 weeks prior to screening or planned major 
surgery within 6 months following randomization. 
• 
Immunization with a live/attenuated vaccine within 2 months prior to baseline or 3 months of 
last study visit. 
• 
History of severe allergic or anaphylactic reactions to human, humanized, or murine 
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• 
History of other malignancy within 5 years prior to screening, except for appropriately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer 
• 
Patients with reproductive potential not willing to use an effective method of contraception 
• 
History of alcohol, drug or chemical abuse with 1 year prior to screening 
 
4.2 
Strategies for Recruitment and Retention 
 
Enrollment 
 
Subjects that are prescreened and meet the eligibility criteria for the study will be asked to 
consider participation in the study by her/his primary rheumatologist, and if the patient agrees, 
then written, informed consent will be sought and obtained by a clinical research coordinator. 
Two of the medications under investigation will be provided by the study. Tocilizumab and 
abatacept will be provided by Genentech and BMS, respectively. If patients are randomized to a 
TNF inhibitor, it will be paid for by the patient’s insurance. Thus, for those randomized to a TNF 
inhibitor, screening will consist of obtaining preauthorization from the patient’s insurance 
provider to ensure coverage of whatever TNF inhibitor the patient’s attending physician orders.  
Based on the step-wise process described in Section 3.1, participants will be randomized to 
one arm of the study.  The mechanism used for randomization will allow for even, unbiased 
distribution of patients into each arm of the study.  A patient must take at least one dose of the 
assigned medication to be considered a study participant.  Enrollment will continue until 90 
participants have completed the 3-month study visit while receiving their originally randomized 
therapy and have not violated the protocol. 
 
 
5. STUDY AGENTS 
 
5.1 
Study Agent Acquisition 
 
General Statement on Study Agent Acquisition:  The MAZERATI study is a blinded-
assessor, randomized-observational study.  Participants will be randomized to different RA 
therapies.  Clinicians will provide a prescription for TNF inhibitors, within the guidelines of the 
MAZERATI protocol.  For TNF inhibitors, participants will fill the prescription at their chosen 
pharmacy, and the pharmacist will use the labeling and provide materials as directed by their 
institution.   Abatacept and tocilizumab prescriptions and orders will be handled by Dr. Moreland 
and the UPMC Investigational Drug Service (IDS).  No placebo is utilized in this study.  All study 
agents will be utilized in an open-label manner, within the guidelines of the MAZERATI clinical 
protocol, supplied in their standard form.  The MAZERATI study utilizes board-certified, 
unblinded rheumatologists and open-label therapies administered with standard-of-care 
procedures; these study investigators are very familiar with the clinical management of these 
products.  Descriptions of these study agents are provided below. 
 
Dose regimen for biologic therapies 
 
1.)  Etanercept (50 mg SQ q week) 
2.)  Adalimumab (40 mg SQ q 2 weeks; increased to 40 mg SQ q 7 days at 3 months if CDAI > 
2.8 and if acceptable with primary rheumatologist) 


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3.)  Certolizumab (400 mg SQ at baseline and at weeks 2 and 4 followed by either 200 mg SQ q 
2 weeks or 400 mg SQ q 4 weeks; the dosing regimen for maintenance is at the discretion of 
the treating physician) 
4.)  Golimumab (50 mg SQ q month)  
5.)  Tocilizumab (162 mg SQ q 2 weeks for patients < 100 kg, increased to q week based on 
clinical response; or 162 mg SQ q week for patients ≥ 100 kg) 
6.)  Abatacept (SQ route:  125 mg SQ q week)  
5.1.1 
Etanercept (Enbrel) 
 
6.1.1.1 Formulation, Packaging, and Labeling 
 
As stated in the General Statement on Study Agent 
Acquisition at the beginning of Section 5.1, etanercept 
(Enbrel) will be supplied by the participant’s chosen 
pharmacy.  Cost is the responsibility of the participant or 
the participant’s third-party payer.  No special labels or 
formulation are required in the MAZERATI study.   
 
Enbrel® (etanercept) is supplied in prefilled syringes as a 
preservative-free, sterile solution for subcutaneous 
administration. The following packaging configurations 
are available. 
 
Enbrel Single-use Prefilled SureClick Autoinjector:  
Enbrel is dispensed in a carton containing four prefilled 
SureClick Autoinjectors. Each prefilled SureClick 
Autoinjector is a single dose and contains a 1 mL 
prefilled syringe with a fixed 27 gauge ½ inch needle, 
providing 50 mg (1 mL) of Enbrel. The NDC number is 
58406-445-04.  See Figure 1.   
 
Enbrel Single-use Prefilled Syringe:  Enbrel is 
dispensed in a carton containing four prefilled syringes. 
Each prefilled syringe is a single dose and contains a 1 
mL prefilled syringe with a fixed 27 gauge ½ inch needle, 
providing 50 mg (1 mL) of Enbrel. The NDC number is 
58406-435-04.  See Figure 1.   
 
Storage and Stability:  Do not use beyond the expiration date on the container. Enbrel must be 
refrigerated at 2 to 8° C (36 to 46° F). Do not freeze. Protect the prefilled syringe from exposure 
to light. Store in original carton until time of administration.  Do not shake Enbrel at any time.   
 
Summary for:  Etanercept (Enbrel) 
Formulation: 
Solution for subcutaneous injection 
Labeling: 
Routine labeling from participant’s chosen pharmacy 
Figure 1.  Packaging Configurations 
for Etanercept.   


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Manufacturer Name: 
Amgen and Pfizer, Inc. 
Stability: 
Enbrel must be refrigerated at 2 to 8° C (36 to 46° F); it 
should not be frozen. Enbrel is light-sensitive and should 
not be exposed to direct light. 
Expiration Time: 
Enbrel is supplied as a single-dose autoinjector or a single-
dose prefilled syringe.  It should not be used after the 
expiration date.   
 
 
 
5.1.1.2  Preparation, Administration, Storage, and Dosage of Etanercept 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, etanercept will be supplied by a participant’s chosen pharmacy.  Etanercept is supplied in 
prefilled, ready-to-use syringes as a preservative-free, sterile solution for subcutaneous 
administration.  The recommended dose of etanercept for adult patients with rheumatoid 
arthritis is 50 mg in 1 mL administered every week.  Participants will be encouraged to continue 
with etanercept for the full 6 months of randomization.  Clinicians will monitor their patients and 
change study medications if desired by either the clinician or the participant, as this is a real-
world study.   
The prescribing physicians are board-certified rheumatologists, with experience prescribing and 
monitoring patients taking etanercept.  In addition to counseling at the outpatient clinic and 
possibly at their pharmacy, patients will be instructed to read the full medication guide before 
taking etanercept.  All participants will be tested for latent TB and hepatitis B and C prior to 
enrollment in the study, and all participants will be advised to consult their rheumatologist if they 
develop any signs of infection, including TB and hepatitis reactivation.  Etanercept will be 
discontinued if a patient develops a serious infection or sepsis during treatment.  Participants 
will be advised to seek immediate medical attention if they experience any symptoms of severe 
allergic reactions. Latex-sensitive participants will be advised that the needle cap of the prefilled 
syringe contains latex.  Participants will also be advised to report any signs of new or worsening 
medical conditions such as heart disease, neurological disease, autoimmune disorders, or 
symptoms suggestive of any cytopenia.   
Etanercept can be supplied as either a single-dose autoinjector or single-dose syringe.  There is 
no need for participants to thaw, dilute, mix, reconstitute, or prepare the solution.  Participants 
will be counseled in the outpatient clinic on the proper way to administer the injection.  The first 
injection will be performed under the supervision of a qualified health care professional. A 
puncture-resistant container for disposal of needles and syringes will be provided. Participants 
will be cautioned against reuse of these items.  Specific, detailed instructions will be provided to 
participants by both their pharmacy and the nurse coordinators.  The following are abridged 
instructions for administration of etanercept.   
 
• 
Check and make sure the name ENBREL appears on the box and syringe/autoinjector 
label. 
• 
Check the expiration date on the syringe/autoinjector label to make sure the date has not 
passed. Do not use a syringe/autoinjector if the date has passed. 
• 
Have a special sharps (puncture proof) container nearby for disposing of the used 
syringe/autoinjector. 


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• 
Choose a site on the front of your thighs or your stomach area (abdomen) for 
administration.  
• 
Wipe the site where etanercept (Enbrel) is to be injected with an alcohol prep (swab), 
using a circular motion. Do not touch this area again until you are ready to inject. 
• 
Check the solution through the windows on the side of the syringe/autoinjector to make 
sure the liquid is clear and colorless. Do not use a syringe/autoinjector if the liquid is 
cloudy or discolored or has large particles in it. Do not use if frozen or if it was ever 
previously frozen. 
• 
Check to make sure that the amount of liquid in the syringe/autoinjector is the same or 
close to the fill line seen through the window. If the syringe/autoinjector does not have 
the full amount of liquid, do not use that syringe/autoinjector.  
• 
Inject the etanercept (Enbrel).   
 
Participants should store etanercept in a refrigerator at 36 to 46ºF (2 to 8ºC) in the original 
container until it is used. It should be protected from light. Do not freeze etanercept or use 
previously frozen etanercept. Refrigerated etanercept remains stable to use until the expiration 
date printed on the prefilled syringe or autoinjector. If a participant will need to take etanercept 
outside of the home, such as when traveling, it must be stored in a cool carrier with an ice pack 
and protected from light. If etanercept freezes, do not use it, even after it has thawed. Do not 
use a autoinjector or prefilled syringe if the liquid is cloudy, discolored, or has large particles in 
it. Do not drop or crush etanerecept. For additional information or questions, coordinators or 
participants can call 1-888-4Enbrel (1-888-436-2735). 
 
Summary for:  Etanercept (Enbrel) 
Route: 
Subcutaneous injection by trained participant 
Dosing: 
50mg 
Duration: 
Full 6 months of MAZERATI study 
Frequency: 
Every week 
Expiration Time: 
Follow expiration date on the packaging 
 
5.1.1.3  Study Agent Accountability Procedures 
 If a participant is randomized to the anti-TNF arm of the study, then their treating 
rheumatologist can order any anti-TNF from the study agent list of anti-TNF therapies, provided 
that the patient has not had previous experience with any anti-TNF agent.  As stated in the 
General Statement on Study Agent Acquisition at the beginning of Section 5.1, etanercept 
will be supplied by a participant’s chosen pharmacy when a prescription is presented.  These 
therapies will be used in an open-label manner, so frequency of product distribution and amount 
of product dispensed will be within open-label guidelines for each specific therapy (see specific 
dosing regimens in Section 6.1).   
Participants will be provided with a sharps container for their spent etanercept syringes or 
autoinjectors. Participants will bring the sharps container to each study visit with a list of their 
unused etanercept syringes or autoinjectors.  Coordinators will log the number of spent syringes 
or pens in the container to verify proper drug dosing. Used syringes or pens, expired etanercept, 
and unused etanercept will be returned to the study coordinators, who will dispose of it 
according to the appropriate regulations.   
 


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5.1.2 Adalimumab (Humira) 
5.1.2.1 Formulation, Packaging, and Labeling 
 
 
 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, adalimumab (Humira) will be supplied by a participant’s chosen pharmacy.  Cost is the 
responsibility of the participant or the participant’s third-party payer.  No special labels or 
formulation is required in the MAZERATI study.   
 
Humira® (adalimumab) is supplied in prefilled syringes as a 
preservative-free, sterile solution for subcutaneous 
administration. The following packaging configurations are 
available. 
 
Humira Pen Carton:  Humira is dispensed in a carton 
containing two alcohol preps and two dose trays. Each 
dose tray consists of a single-use pen, containing a 1 mL 
prefilled glass syringe with a fixed 27 gauge ½ inch 
needle, providing 40 mg (0.8 mL) of Humira. The NDC 
number is 0074-4339-02.  See Figure 2.   
 
Prefilled Syringe Carton – 40 mg:  Humira is dispensed 
in a carton containing two alcohol preps and two dose 
trays. Each dose tray consists of a single-dose, 1 mL 
prefilled glass syringe with a fixed 27 gauge ½ inch 
needle, providing 40 mg (0.8 mL) of Humira. The NDC 
number is 0074-3799-02.  See Figure 2.   
 
Storage and Stability:  Do not use beyond the expiration 
date on the container. Humira must be refrigerated at 2 to 
8° C (36 to 46° F). Do not freeze. Protect the prefilled 
syringe from exposure to light. Store in original carton until time of administration. 
 
Summary for:  Adalimumab (Humira) 
Formulation: 
Solution for subcutaneous injection 
Labeling: 
Routine labeling from participant’s chosen pharmacy 
Manufacturer Name: 
Abbott Laboratories 
Stability: 
Humira must be refrigerated at 2 to 8° C (36 to 46° F); it 
should not be frozen. Humira is light-sensitive and should 
not be exposed to direct light. 
Expiration Time: 
Humira is supplied as a single-dose pen or a single-dose 
syringe.  It should not be used after the expiration date.   
 
5.1.2.2  Preparation, Administration, Storage, and Dosage of Adalimumab 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, adalimumab will be supplied by a participant’s chosen pharmacy.  Adalimumab is supplied 
in prefilled, ready-to-use syringes as a preservative-free, sterile solution for subcutaneous 
administration.  The recommended dose of adalimumab for adult patients with rheumatoid 
Figure 2.  Packaging 
Configurations for Adalimumab. 
 
 


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22 
arthritis is 40 mg in 0.8 mL administered every other week. In rheumatoid arthritis, some 
patients not taking concomitant methotrexate may derive additional benefit from increasing the 
dosing frequency of adalimumab to 40 mg every week.  Clinicians will be permitted to order the 
appropriate dose and frequency for their patients.  Participants will be encouraged to continue 
with adalimumab for the full 6 months of randomization.  Clinicians will monitor their patients 
and change study medications if desired by either the clinician or the participant, as this is a 
real-world study.   
The prescribing physicians are board-certified rheumatologists, with experience prescribing and 
monitoring patients taking adalimumab.  In addition to counseling at the outpatient clinic and 
possibly at their pharmacy, patients will be instructed to read the full medication guide before 
taking adalimumab.  All participants will be tested for latent TB and hepatitis B and C prior to 
enrollment in the study, and all participants will be advised to consult their rheumatologist if they 
develop any signs of infection, including TB and hepatitis reactivation.  Adalimumab will be 
discontinued if a patient develops a serious infection or sepsis during treatment.  Participants 
will be advised to seek immediate medical attention if they experience any symptoms of severe 
allergic reactions. Latex-sensitive participants will be advised that the needle cap of the prefilled 
syringe contains latex.  Participants will also be advised to report any signs of new or worsening 
medical conditions such as heart disease, neurological disease, autoimmune disorders, or 
symptoms suggestive of any cytopenia.   
Adalimumab can be supplied as either a single-dose pen or single-dose syringe.  There is no 
need for participants to thaw, dilute, mix, reconstitute, or prepare the solution.  Participants will 
be counseled in the outpatient clinic on the proper way to administer the injection.  The first 
injection will be performed under the supervision of a qualified health care professional. A 
puncture-resistant container for disposal of needles and syringes will be provided. Participants 
will be cautioned against reuse of these items.  Specific, detailed instructions will be provided to 
participants by both their pharmacy and the nurse coordinators.  The following are abridged 
instructions for administration of adalimumab.   
 
• 
Check and make sure the name HUMIRA appears on the dose tray and syringe/pen 
label. 
• 
Check the expiration date on the dose tray label and the syringe/pen label to make sure 
the date has not passed. Do not use a syringe/pen if the date has passed. 
• 
Have a special sharps (puncture proof) container nearby for disposing of the used 
syringe/pen. 
• 
Choose a site on the front of your thighs or your stomach area (abdomen) for 
administration.  
• 
Wipe the site where adalimumab (Humira) is to be injected with an alcohol prep (swab), 
using a circular motion. Do not touch this area again until you are ready to inject. 
• 
Check the solution through the windows on the side of the syringe/pen to make sure the 
liquid is clear and colorless. Do not use a syringe/pen if the liquid is cloudy or discolored 
or has flakes or particles in it. Do not use if frozen or if it was ever previously frozen. 
• 
Check to make sure that the amount of liquid in the syringe/pen is the same or close to 
the fill line seen through the window. If the syringe/pen does not have the full amount of 
liquid, do not use that syringe/pen.  
• 
Inject the adalimumab (Humira).   
 


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Participants should store adalimumab in a refrigerator at 36 to 46ºF (2 to 8ºC) in the original 
container until it is used. It should be protected from light. Do not freeze adalimumab or use 
previously frozen adalimumab. Refrigerated adalimumab remains stable to use until the 
expiration date printed on the prefilled syringe or pen. If a participant will need to take 
adalimumab outside of the home, such as when traveling, it must be stored in a cool carrier with 
an ice pack and protected from light. If adalimumab freezes, do not use it, even after it has 
thawed. Do not use a pen or prefilled syringe if the liquid is cloudy, discolored, or has flakes or 
particles in it. Do not drop or crush HUMIRA. The prefilled syringe is glass.  For additional 
information or questions, coordinators or participants can call 1-800-4HUMIRA (448-6472). 
 
Summary for:  Adalimumab (Humira) 
Route: 
Subcutaneous injection by trained participant 
Dosing: 
40mg 
Duration: 
Full 6 months of MAZERATI study 
Frequency: 
Every week or every other week 
Expiration Time: 
Follow expiration date on the packaging 
 
5.1.2.3  Study Agent Accountability Procedures 
If a participant is randomized to the anti-TNF arm of the 
study, then their treating rheumatologist can order any 
anti-TNF from the study agent list of anti-TNF therapies, 
provided that the patient has not had previous experience 
with any anti-TNF agent.  As stated in the General 
Statement on Study Agent Acquisition at the beginning 
of Section 5.1, adalimumab will be supplied by a 
participant’s chosen pharmacy when a prescription is 
presented.  These therapies will be used in an open-label 
manner, so frequency of product distribution and amount 
of product dispensed will be within open-label guidelines 
for each specific therapy (see specific dosing regimens in 
Section 5.1).   
Participants will be provided with a sharps container for 
their spent adalimumab syringes or pens.  Participants will 
bring the sharps container to each study visit with a list of 
their unused adalimumab syringes or pens.  Coordinators 
will log the number of spent syringes or pens in the 
container to verify proper drug dosing. Used syringes or 
pens, expired adalimumab, and unused adalimumab will 
be returned to the study coordinators, who will dispose of 
it according to the appropriate regulations.   
 
5.1.3 Golimumab (Simponi) 
 
5.1.3.1 Formulation, Packaging, and Labeling 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, golimumab (Simponi) will be supplied by a participant’s chosen pharmacy.  Cost is the 
Figure 3.  Packaging 
Configurations for Golimumab.   


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24 
responsibility of the participant or the participant’s third-party payer.  No special labels or 
formulation is required in the MAZERATI study.   
 
Simponi (golimumab) is supplied in prefilled syringes as a sterile solution for subcutaneous 
administration.  The following packaging configurations are available.  Each golimumab 
(Simponi) prefilled autoinjector or prefilled syringe is packaged in a light-blocking, cardboard 
outer carton.  
 
 
Prefilled SmartJect Autoinjector:  Golimumab prefilled SmartJect Autoinjectors are dispensed 
with one autoinjector per box.  Each single dose SmartJect autoinjector contains a prefilled 
glass syringe (27 gauge, ½ inch) providing 50 mg of golimumab (Simponi) per 0.5 mL of 
solution.  The NDC number is 57894-070-02.  See Figure 3.   
 
Prefilled Syringe:  Golimumab prefilled syringes are dispensed with one syringe per box.  Each 
single dose prefilled glass syringe (27 gauge, ½ inch) contains 50 mg of golimumab (Simponi) 
per 0.5 mL of solution.  The NDC number is 57894-070-01.  See Figure 3.   
 
Storage and Stability:  Do not use beyond the expiration date on the container. Golimumab 
must be refrigerated at 2 to 8° C (36 to 46° F). Do not freeze. Do not shake golimumab.  Protect 
the prefilled syringe from exposure to light. Store in the original carton until the time of 
administration. 
 
Summary for:  Golimumab (Simponi) 
Formulation: 
Solution for subcutaneous injection 
Labeling: 
Routine labeling from participant’s chosen pharmacy 
Manufacturer 
Name: 
Centocor Ortho Biotech, Inc. 
Stability: 
Simponi must be refrigerated at 2 to 8° C (36 to 46° F); it should not be 
frozen. Simponi is light-sensitive and should not be exposed to direct 
light. 
Expiration Time: 
Simponi is supplied as a single-dose autoinjector or a single-dose 
prefilled syringe.  It should not be used after the expiration date.   
 
5.1.3.2  Preparation, Administration, Storage, and Dosage of Golimumab 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, golimumab will be supplied by a participant’s chosen pharmacy.  Golimumab is supplied in 
prefilled, ready-to-use syringes as a preservative-free, sterile solution for subcutaneous 
administration.  The recommended dose of golimumab for adult patients with rheumatoid 
arthritis is 50 mg in 0.5 mL administered every month.  Participants will be encouraged to 
continue with golimumab for the full 6 months of randomization.  Clinicians will monitor their 
patients and change study medications if desired by either the clinician or the participant, as this 
is a real-world study.   
The prescribing physicians are board-certified rheumatologists, with experience prescribing and 
monitoring patients taking golimumab.  In addition to counseling at the outpatient clinic and 
possibly at their pharmacy, patients will be instructed to read the full medication guide before 
taking golimumab.  All participants will be tested for latent TB and hepatitis B and C prior to 
enrollment in the study, and all participants will be advised to consult their rheumatologist if they 


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25 
develop any signs of infection, including TB and hepatitis reactivation.  Golimumab will be 
discontinued if a patient develops a serious infection or sepsis during treatment.  Participants 
will be advised to seek immediate medical attention if they experience any symptoms of severe 
allergic reactions. Latex-sensitive participants will be advised that the needle cap of the prefilled 
syringe contains latex.  Participants will also be advised to report any signs of new or worsening 
medical conditions such as heart disease, neurological disease, autoimmune disorders, or 
symptoms suggestive of any cytopenia.   
Golimumab can be supplied as either a single-dose autoinjector or single-dose syringe.  There 
is no need for participants to thaw, dilute, mix, reconstitute, or prepare the solution.  Participants 
will be counseled in the outpatient clinic on the proper way to administer the injection.  The first 
injection will be performed under the supervision of a qualified health care professional. A 
puncture-resistant container for disposal of needles and syringes will be provided. Participants 
will be cautioned against reuse of these items.  Specific, detailed instructions will be provided to 
participants by both their pharmacy and the nurse coordinators.  The following are abridged 
instructions for administration of golimumab. 
 
• 
Check and make sure the name SIMPONI appears on the box and syringe/autoinjector 
label.   
• 
Check the expiration date on the box label and the syringe/autoinjector label to make 
sure the date has not passed. Do not use a syringe/pen if the date has passed. 
• 
Allow golimumab to warm up for 30 minutes prior to use.  Do this by leaving the 
syringe/autoinjector sit out at room temperature for 30 minutes where children can’t 
reach it.  Never warm up golimumab any other way.   
• 
Have a special sharps (puncture proof) container nearby for disposing of the used 
syringe/pen. 
• 
Choose a site on the front of your thighs or your stomach area (abdomen) for 
administration.  
• 
Wipe the site where golimumab (Simponi) is to be injected with an alcohol prep (swab), 
using a circular motion. Do not touch this area again until you are ready to inject. 
• 
Check the solution through the windows on the side of the syringe/autoinjector to make 
sure the liquid is clear and colorless. Do not use a syringe/autoinjector if the liquid is 
cloudy or discolored or has large particles in it. Do not use if frozen or if it was ever 
previously frozen. 
• 
Check to make sure that the amount of liquid in the syringe/autoinjector is the same or 
close to the fill line seen through the window. If the syringe/autoinjector does not have 
the full amount of liquid, do not use that syringe/pen.  
• 
Inject the golimumab (Simponi).   
Participants should store golimumab in a refrigerator at 36 to 46ºF (2 to 8ºC) in the original 
container until it is used. It should be protected from light. Do not freeze golimumab or use 
previously frozen golimumab. Refrigerated golimumab remains stable to use until the expiration 
date printed on the prefilled syringe or pen. If a participant will need to take golimumab outside 
of the home, such as when traveling, it must be stored in a cool carrier with an ice pack and 
protected from light. If golimumab freezes, it should not be used, even after it has thawed. Do 
not use a autoinjector or prefilled syringe if the liquid is cloudy, discolored, or has large particles 
in it. Do not drop or crush Simponi. The prefilled syringe is glass.  For additional information or 
questions, coordinators or participants can call 1-800-457-6399. 
 
Summary for:  Golimumab (Simponi) 


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Route: 
Subcutaneous injection by trained participant 
Dosing: 
50mg 
Duration: 
Full 6 months of MAZERATI study 
Frequency: 
Every month 
Expiration Time: 
Follow expiration date on the packaging 
 
 
5.1.3.3    Study Agent Accountability Procedures 
If a participant is randomized to the anti-TNF arm of the study, then their treating rheumatologist 
can order any anti-TNF from the study agent list of anti-TNF therapies, provided that the patient 
has not had previous experience with any anti-TNF agent.  As stated in the General Statement 
on Study Agent Acquisition at the beginning of Section 5.1, golimumab will be supplied by a 
participant’s chosen pharmacy when a prescription is presented.  These therapies will be used 
in an open-label manner, so frequency of product distribution and amount of product dispensed 
will be within open-label guidelines for each specific therapy.  See Section 5.1 for detailed 
dosing information for each therapy.   
Participants will be provided with a sharps container for their spent golimumab syringes or 
autoinjectors.  Participants will bring the sharps container to each study visit with a list of their 
unused golimumab syringes or autoinjectors.  Coordinators will log the number of spent 
syringes or autoinjectors in the container to verify proper drug dosing. Used syringes or 
autoinjectors, expired golimumab, and unused golimumab will be returned to the study 
coordinators, who will dispose of it according to the appropriate regulations.   
 
5.1.4 Certolizumab pegol (Cimzia) 
Figure 4.  Packaging Configurations for 


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5.1.4.1  Formulation, Packaging, and Labeling 
 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, certolizumab pegol (Cimzia) will be supplied by a participant’s chosen pharmacy.  Cost is 
the responsibility of the participant or the participant’s third-party payer.  No special labels or 
formulation is required in the MAZERATI study.   
 
Cimzia (certolizumab) is supplied in prefilled glass syringes as a sterile solution for 
subcutaneous administration.  Only 1 packaging configuration is available.  Each certolizumab 
(Cimzia) prefilled syringe is packaged in a light-blocking, cardboard outer carton.  
Prefilled Syringe:  Certolizumab prefilled syringes are dispensed with two syringes per box.  
Each single dose prefilled glass syringe (25 gauge, ½ inch) contains 200 mg of certolizumab 
(Cimzia) per 1.0 mL of solution.  The NDC number is 50474-710-79.  See Figure 4.   
 
Storage and Stability:  Do not use beyond the expiration date on the container. Certolizumab 
must be refrigerated at 2 to 8° C (36 to 46° F). Do not freeze. Protect the prefilled syringe from 
exposure to light. Store in the original carton until the time of administration. 
5.1.4.2  Preparation, Administration, Storage, and Dosage of Certolizumab Pegol 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, certolizumab will be supplied by a participant’s chosen pharmacy.  Certolizumab is supplied 
in prefilled, ready-to-use syringes as a sterile solution for subcutaneous administration.  The 
recommended dose of certolizumab for adult patients with rheumatoid arthritis is 400 mg at 
baseline and at weeks 2 and 4, followed by either 200 mg every 2 weeks or 400 mg every 4 
weeks.  The dosing regimen for maintenance is at the discretion of the treating physician.  
Participants will be encouraged to continue with infliximab for the full 6 months of randomization. 
Clinicians will monitor their patients and change study medications if desired by either the 
clinician or the participant, as this is a real-world study.   
The prescribing physicians are board-certified rheumatologists, with experience prescribing and 
monitoring patients taking certolizumab.  In addition to counseling at the outpatient clinic and 
possibly at their pharmacy, patients will be instructed to read the full medication guide before 
taking certolizumab.  All participants will be tested for latent TB and hepatitis B and C prior to 
enrollment in the study, and all participants will be advised to consult their rheumatologist if they 
develop any signs of infection, including TB and hepatitis reactivation.  Certolizumab will be 
discontinued if a patient develops a serious infection or sepsis during treatment.  Participants 
will be advised to seek immediate medical attention if they experience any symptoms of severe 
allergic reactions. Participants will also be advised to report any signs of new or worsening 
medical conditions such as heart disease, neurological disease, autoimmune disorders, or 
symptoms suggestive of any cytopenia.   
Certolizumab is supplied as a single-dose syringe.  There is no need for participants to thaw, 
dilute, mix, reconstitute, or prepare the solution.  Participants will be counseled in the outpatient 
clinic on the proper way to administer the injection.  The first injection will be performed under 
the supervision of a qualified health care professional. A puncture-resistant container for 
disposal of needles and syringes will be provided. Participants will be cautioned against reuse of 
these items.  Specific, detailed instructions will be provided to participants by both their 
Certolizumab Pegol.   


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pharmacy and the nurse coordinators.  The following are abridged instructions for administration 
of certolizumab.   
 
• 
Check and make sure the name CIMZIA appears on the box and syringe label.   
• 
Check the expiration date on the box label and the syringe label to make sure the date 
has not passed. Do not use a syringe if the date has passed. 
• 
Allow certolizumab to warm up for 30 minutes prior to use.  Do this by leaving the 
syringe sit out at room temperature for 30 minutes where children can’t reach it.  Never 
warm up certolizumab any other way.   
• 
Have a special sharps (puncture proof) container nearby for disposing of the used 
syringe/pen. 
• 
Choose a site on the front of your thighs or your stomach area (abdomen) for 
administration.  
• 
Wipe the site where certolizumab (Cimzia) is to be injected with an alcohol prep (swab), 
using a circular motion. Do not touch this area again until you are ready to inject.  
Alcohol swabs are provided in the certolizumab injection kit.   
• 
Check the solution through the windows on the side of the syringe to make sure the 
liquid is clear and colorless. Do not use a syringe if the liquid is cloudy or discolored or 
has large particles in it. Do not use if frozen or if it was ever previously frozen. 
• 
Check to make sure that the amount of liquid in the syringe is the same or close to the fill 
line seen through the window. If the syringe does not have the full amount of liquid, do 
not use that syringe.  
• 
Inject the certolizumab (Cimzia).   
Participants should store certolizumab in a refrigerator at 36 to 46ºF (2 to 8ºC) in the original 
container until it is used. It should be protected from light. Do not freeze certolizumab or use 
previously frozen certolizumab. Refrigerated certolizumab remains stable to use until the 
expiration date printed on the prefilled syringe. If a participant will need to take certolizumab 
outside of the home, such as when traveling, it must be stored in a cool carrier with an ice pack 
and protected from light. If certolizumab freezes, it should not be used, even after it has thawed. 
Do not use a prefilled syringe if the liquid is cloudy, discolored, or has large particles in it. Do not 
drop or crush certolizumab. The prefilled syringe is glass.  For additional information or 
questions, coordinators or participants can call 1-866-489-1899. 
 
Summary for:  Certolizumab (Cimzia) 
Route: 
Subcutaneous injection by trained participant 
Dosing: 
400mg loading dose, then 200 or 400mg as warranted 
Duration: 
Full 6 months of MAZERATI study 
Frequency: 
Every month or twice monthly as warranted 
Expiration Time: 
Follow expiration date on the packaging 
 
5.1.4.3   Study Agent Accountability Procedures 
 Certolizumab pegol will be supplied by a participant’s chosen pharmacy when a prescription is 
presented for prefilled syringes or by a UPMC pharmacist at an outpatient rheumatology clinic 
when the rheumatologist or participant decide against self-injection of certolizumab pegol.  If a 
participant is randomized to the anti-TNF arm of the study, then their treating rheumatologist 
can order any anti-TNF from the study agent list of anti-TNF therapies provided that the patient 
has not had previous experience with any anti-TNF agent.  These therapies will be used in an 


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open-label manner, so frequency of product distribution and amount of product dispensed will 
be within open-label guidelines for each specific therapy.   
 For participants choosing to self-inject, we will provide a sharps container for their spent 
certolizumab pegol syringes.  Participants will bring the sharps container to each study visit with 
a list of their unused certolizumab pegol syringes.  Coordinators will log the number of spent 
syringes in the container to verify proper drug dosing. Used syringes, expired certolizumab 
pegol, and unused certolizumab pegol will be returned to the study coordinators, who will 
dispose of it according to the appropriate regulations.  When the rheumatologist or participant 
elects against self-injection, then the certolizumab pegol will be reconstituted and prepared by a 
trained medical professional and administered according to standard operating procedure in that 
clinic.  In these cases, the dosing will be recorded and monitored from the participant’s 
electronic medical records.   
 
5.1.5 Tocilizumab (Actemra) 
 
5.1.5.1   Formulation, Packaging, and Labeling 
 
As stated in the General Statement on Study Agent Acquisition 
at the beginning of Section 5.1, tocilizumab (Actemra) will be 
supplied by the study from Genentech.  No special labels or 
formulation is required in the MAZERATI study. 
 
Pre-filled syringe: Actemra (tocilizumab) is supplied as a sterile 
preservative-free liquid solution in a single-use prefilled syringe, 
providing 162 mg per 0.9mL. The NDC number is 50242-138-01.  
See Figure 5. 
 
Storage and Stability:  Do not use beyond the expiration date on 
the container. Tocilizumab solution must be refrigerated at 2 to 8° 
C (36 to 46° F). Do not freeze tocilizumab. Store in the original 
package to protect from light and keep syringes dry. Patients will 
be instructed to perform a visual inspection of the medication 
before use. If visibly opaque particles, discoloration or other 
foreign particles are observed, the solution should not be used.   
5.1.5.2 Preparation, Administration, Storage, and Dosage of 
Tocilizumab 
As stated in the General Statement on Study Agent Acquisition 
at the beginning of Section 5.1, tocilizumab will be handled by the 
UPMC Investigational Drug Service.  Tocilizumab is supplied as a 
sterile preservative-free liquid solution in a single-use prefilled 
syringe.  The recommended dose of tocilizumab for adult patients 
with rheumatoid arthritis is 162 mg delivered subcutaneously every 
other week for patients < 100 kg, increased to weekly if CDAI > 2.8 and if not opposed by the 
treating physician.  The dose change is determined by the treating physician based on clinical 
response.  For adult patients ≥ 100 kg, the recommended dose is 162 mg delivered 
Figure 5.  Packaging for 
tocilizumab.   


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subcutaneously every week, Participants will be encouraged to continue with tocilizumab for the 
full 6 months of randomization. Clinicians will monitor their patients and change study 
medications, if desired by either the clinician or the participant, as this is a real-world study. 
The prescribing physicians are board-certified rheumatologists, with experience prescribing and 
monitoring patients taking tocilizumab.  In addition to counseling at the outpatient clinic and 
possibly at a UPMC infusion center, patients will be instructed to read the full medication guide 
before receiving tocilizumab.  Unless previously done, all participants will be tested for latent TB 
and hepatitis B and C prior to enrollment in the study, and all participants will be advised to 
consult their rheumatologist if they develop any signs of infection, including TB and hepatitis 
reactivation.  Tocilizumab will be discontinued if a patient develops a serious infection or sepsis 
during treatment.  Other reasons for discontinuing tocilizumab include: 
hypersensitivity/anaphalaxis, elevated AST, thrombocytopenia and low absolute neutrophil 
count. Participants will be advised to seek immediate medical attention if they experience any 
symptoms of severe allergic reactions.  Participants will also be advised to report any signs of 
new or worsening medical conditions such as heart disease, neurological disease, autoimmune 
disorders, or symptoms suggestive of any cytopenia. 
Tocilizumab can be administered subcutaneously by trained clinical personnel or can be self-
administered.  Participants will be counseled in the outpatient clinic on the proper way to 
administer the injection.  The first injection will be performed under the supervision of a qualified 
health care professional. A puncture-resistant container for disposal of needles and syringes will 
be provided. Participants will be cautioned against reuse of these items.  Specific, detailed 
instructions will be provided to participants by the nurse coordinators.  For additional information 
or questions, coordinators or participants can call 1-866-681-3261. 
 
Summary for:  Tocilizumab (Actemra) 
Route: 
Subcutaneous injection by trained participant 
Dosing: 
162 mg every other week initially for participants < 100 kg, 
escalated up to every week if warranted; or 162 mg every 
week for participants ≥ 100 kg 
Duration: 
Full 6 months of MAZERATI study 
Frequency: 
Every other week or every week 
Expiration Time: 
Follow expiration date on the syringe 
 
5.1.5.3   Study Agent Accountability Procedures 
Tocilizumab will be used under the guidance and supervision of a physician and will be 
administered as subcutaneous injection.  Tocilizumab will be used in an open-label manner, so 
frequency of product distribution and amount of product dispensed will be within open-label 
guidelines.   
For participants choosing to self-inject, we will provide a sharps container for their spent 
syringes.  Participants will bring the sharps container to each study visit with a list of their 
unused syringes.  Coordinators will log the number of spent syringes in the container to verify 
proper drug dosing. Used syringes, expired tocilizumab, and unused tocilizumab will be returned 
to the study coordinators, who will dispose of it according to the appropriate regulations.  This 
research study protocol allows the subject to receive up to 30 injections of TCZ. Even if the 
treatment is shown to be of benefit, additional injections of TCZ beyond that allowed in the 
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Tocilizumab will be provided free of charge by Genentech. The Sponsor or designee of the 
study will ensure maintenance of complete and accurate records of the receipt, dispensation, 
and disposal or return of all study drug in accordance with 21 Code of Federal Regulations 
(C.F.R.), Part 312.57 and 312.62 and Genentech requirements. 
 
5.1.5.4   Dose Modification & Toxicity Management 
 
There are limited data available on overdoses with TCZ. One case of accidental overdose was 
reported in which a patient with multiple myeloma received a dose of 40 mg/kg. No adverse 
drug reactions were observed. No serious adverse drug reactions were observed in healthy 
volunteers who received single doses of up to 28 mg/kg, although all 5 patients at the highest 
dose of 28 mg/kg developed dose-limiting neutropenia. 
 
In case of an overdose, it is recommended that the patient be monitored for signs and 
symptoms of adverse reactions. Patients who develop adverse reactions should receive 
appropriate symptomatic treatment. 
 
A number of measures will be taken to ensure the safety of patients participating in this study.  
These measures will be addressed through exclusion criteria (see Section 5.1.2) and routine 
monitoring as follows.  
 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and during their participation in this study.  Safety evaluations will consist of medical 
interviews, recording of adverse events, physical examinations, blood pressure, and laboratory 
measurements.  Subjects will be evaluated for adverse events (all grades), serious adverse 
events, and adverse events requiring study drug interruption or discontinuation at each study 
visit for the duration of their participation in the study.   
 
Opportunistic Infections and Serious Infections  
Physicians should exercise caution when considering the use of TCZ in patients with a history of 
recurring infection or with underlying conditions (e.g., diverticulitis, diabetes), which may 
predispose patients to infections. Tocilizumab should not be administered in patients with active 
infection. The effects of TCZ on CRP, neutrophils, and the signs and symptoms of infection 
should be considered when evaluating a patient for a potential infection.  
Vigilance for timely detection of serious infection is recommended for patients receiving biologic 
agents for treatment of moderate to severe RA as signs and symptoms of acute inflammation 
may be lessened due to suppression of the acute phase reaction. Patients must be instructed to 
contact their physician immediately when any symptoms suggesting infection appear, in order to 
assure rapid evaluation and appropriate treatment.  
 
If a patient develops a serious infection, administration of TCZ is to be interrupted until the 
infection is controlled. The clinician should consider the benefit-risk before resuming treatment 
with TCZ. 


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Gastrointestinal Perforations   
Timely diagnosis and appropriate treatment may reduce the potential for complications of 
diverticulitis and thus reduce the risk of GI perforations. Therefore, patients should be made 
aware of the symptomatology potentially indicative of diverticular disease, and they should be 
instructed to alert their healthcare provider as soon as possible if these symptoms arise. In 
patients with a history of symptomatic diverticulosis, diverticulitis or chronic ulcerative lower GI 
disease such as Crohn’s disease, ulcerative colitis or other chronic lower GI conditions that 
might predispose to perforations, the clinician should consider the benefit-risk before using TCZ.  
Discontinuation of TCZ is recommended for patients who develop GI perforations. 
Demyelinating Disorders  
The impact of treatment with TCZ on demyelinating disorders is not known; events were rarely 
reported.  Patients should be closely monitored for signs and symptoms potentially indicative of 
central demyelinating disorders.  Physicians should exercise caution in considering the use of 
TCZ in patients with pre-existing or recent onset demyelinating disorders. Treatment with TCZ 
should be interrupted during assessment of a potential demyelination event and only resumed if 
the benefit of continuing study drug is favorable.   
Hematologic Abnormalities and Bleeding Events 
Decreases in neutrophil and platelet counts have been observed following treatment with TCZ in 
combination with MTX. In addition, there may be an increased risk of neutropenia in patients 
who have previously been treated with a TNF antagonist. 
The risk mitigation strategies for neutropenia and thrombocytopenia are summarized in Tables 1 
and 2, respectively.  For patients with concomitant medications associated with hematologic 
toxicity, the reduction or interruption of the suspected medication is recommended prior to 
modifying TCZ. 
Table 1: Neutropenia Risk Mitigation  
ANC (cells/mm3) 
Action 
> 1000 
Maintain dose. 
500 – 1000 
Hold tocilizumab dosing. 
When ANC increases to > 1000, resume ACTEMRA at 
every other week and increase frequency to every week as 
clinically appropriate  
 
< 500 
Discontinue tocilizumab. 
ANC = absolute neutrophil count 
Patients withdrawn from tocilizumab treatment due to a reduced neutrophil count should be 
monitored for signs of infection, with treatment as deemed appropriate by the sponsor or 
designee, and should have a repeat white blood cell count with differential performed weekly 
until the ANC is above 1000 cells/mm3 (1.0 x 109/L). If the ANC does not return to above 1000 
cells/mm3 (1.0 x 109/L) within 2 months (or sooner if deemed necessary by the sponsor or 
designee), a hematology referral is recommended. 
 


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Table 2: Thrombocytopenia Risk Mitigation  
Platelet count (cells/mm3) 
Action 
> 100,000 
Maintain dose. 
50,000 – 100,000 
Hold tocilizumab dosing.  
When platelet count increases to > 100,000,  
resume ACTEMRA at every other week and increase 
frequency to every week as clinically appropriate  
 
< 50,000 
Discontinue tocilizumab. 
Patients withdrawn from tocilizumab treatment due to a reduced platelet count should have a 
repeat platelet count performed weekly until the count is above 100,000 cells/mm3 (100 x 109/L). 
If the platelets do not return to above 100,000 cells/mm3 (100 x 109/L) within 2 months (or 
sooner if deemed necessary by the sponsor or designee), a hematology referral is 
recommended. 
 
Elevated Liver Enzymes and Hepatic Events 
 
Elevations in ALT and AST have been observed during treatment with the study 
medications 
 
Table 3: 
Lab Value 
Action 
> 1 to 3x ULN 
Dose modify concomitant hepatotoxic medications  
 
For patients receiving subcutaneous ACTEMRA, reduce 
injection frequency to every other week or hold dosing until 
ALT or AST have normalized. Resume ACTEMRA at every 
other week and increase frequency to every week as 
clinically appropriate. 
> 3 to 5x ULN 
(confirmed by repeat 
testing) 
Hold tocilizumab dosing until < 3x ULN and follow 
recommendations above for >1 to 3x ULN 
 
For persistent increases > 3x ULN, discontinue tocilizumab 
> 5x ULN 
Discontinue tocilizumab 
Patients withdrawn from tocilizumab treatment due to elevated liver function tests should have 
repeat tests performed, as clinically appropriate, until levels return to baseline.  If the patient’s 
liver function tests have not returned to baseline within 6 months (or sooner, if deemed 
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Cardiovascular Events and Elevated Lipids 
Patients with RA have an increased risk for cardiovascular disorders, therefore, risk factors for 
cardiovascular disease (e.g., hypertension, hyperlipidemia) should be managed as part of their 
standard of care.  See section on Drug Interactions.   
For patients with LDL cholesterol ≥160 mg/dL, it is strongly recommended that investigators 
advise therapeutic lifestyle changes that may include initiation lipid-lowering agents. Lipid-
lowering agents should also be considered for patients with lower LDL cholesterol levels as part 
of their therapeutic lifestyle changes depending on their overall risk as defined in NCEP ATP III 
or other national guidelines. 
Malignancies 
The impact of immunosuppression on the development of malignancies is not known, however 
an increased rate of some malignancies, notably lymphoma, has been observed in RA patients. 
Although no imbalance of malignancies was observed in controlled clinical trials of TCZ, 
malignancies have been identified as a concern for other biologics.  It is recognized that 
identification of such events in TCZ-treated patients may require a longer period of surveillance.  
TCZ should be discontinued in patients with malignancies (with the exception of local basal or 
squamous cell carcinoma of the skin that is completely excised with free margins). 
Hypersensitivity or Anaphylaxis: 
 
An infusion/injection reaction is defined as an adverse event occurring during and within 24 
hours after the infusion or subcutaneous injection of TCZ. This may include hypersensitivity 
reactions or anaphylactic reactions. 
Signs of a possible hypersensitivity reaction include but are not limited to: 
• 
 fever, chills, pruritus, urticaria, angioedema, and skin rash. 
• 
cardiopulmonary reactions, including chest pain, dyspnea, hypotension or  hypertension. 
Healthcare professionals administering TCZ subcutaneous injections should be trained in the 
appropriate administrative procedures, be able to recognize the symptoms associated with 
potential anaphylactic or hypersensitivity reactions, and have the appropriate medication 
available for immediate use in case of anaphylaxis or hypersensitivity reaction during or after 
administration of TCZ.  Healthcare professionals should also instruct patients to seek medical 
attention if they experience symptoms of a hypersensitivity reaction outside of the clinic. 
If a patient has symptoms of anaphylaxis or hypersensitivity, or requires an interruption of the 
study drug because of symptoms of anaphylaxis or hypersensitivity, administration of TCZ must 
be discontinued permanently and the patient should be withdrawn from the study.  The patient 
should be treated according to the standard of care for management of the hypersensitivity 
reaction.  A blood sample for the presence of anti-TCZ antibodies should be obtained at time of 
event and at least 8 weeks after the last SC dose. 
 
Viral Reactivation 


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Though rarely reported within the TCZ program due to exclusion criteria at study entry, 
reactivation of viral and other serious infections (e.g. EBV or TB) has been observed with 
biologic therapies for RA, including TCZ. 
 
Drug Interaction 
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (eg, IL-
6) during chronic inflammation. Therefore, it is expected that for molecules that antagonize 
cytokine activity, such as TCZ, the formation of CYP450 enzymes could be normalized. When 
starting or stopping therapy with TCZ, patients taking medications which are individually dose-
adjusted and metabolized via CYP450, 3A4, 1A2, or 2C9 (e.g. atorvastatin, calcium channel 
blockers, theophylline, warfarin, phenytoin, ciclosporin, or benzodiazepines) should be 
monitored as doses may need to be adjusted to maintain their therapeutic effect. Given its long 
elimination half-life (t1/2), the effect of TCZ on CYP450 enzyme activity may persist for several 
weeks after stopping therapy. 
 
5.1.6 Abatacept (Orencia) 
 
5.1.6.1  Formulation, Packaging, and Labeling 
 
As stated in the General Statement on Study 
Agent Acquisition at the beginning of Section 
5.1, abatacept (Orencia) will be supplied by the 
study.  No special labels or formulation is 
required in the MAZERATI study. 
Prefilled Syringe:  Abatacept prefilled syringes 
are dispensed with four syringes per box.  Each 
single dose prefilled glass syringe (29 gauge, ½ 
inch) contains 125 mg of abatacept (Orencia) per 
1.0 mL of solution.  The NDC number is 0003-
2188-31.  See Figure 6.   
 
SQ dose:  125 mg SQ q week.   
 
Storage and Stability:  Do not use beyond the 
expiration date on the container. Abatacept 
solution must be refrigerated at 2 to 8° C (36 to 46° F). Do not allow to freeze. Store in the 
original package to protect from light until time of use. 
 
5.1.6.2  Preparation, Administration, Storage, and Dosage of Abatacept (as per package 
insert) 
As stated in the General Statement on Study Agent Acquisition at the beginning of Section 
5.1, abatacept will be supplied by the study when abatacept is chosen.  The process for SQ 
abatacept is described in this section.  The recommended dose of SQ abatacept for adult 
patients with RA is 125 mg every week delivered subcutaneously.  Participants will be 
encouraged to continue with abatacept for the full 6 months of randomization. Clinicians will 
Figure 6.  Packaging for SQ Abatacept.   


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monitor their patients and change study medications, if desired by either the clinician or the 
participant, as this is a real-world study. 
The prescribing physicians are board-certified rheumatologists, with experience prescribing and 
monitoring patients taking abatacept.  In addition to counseling at the outpatient clinic, patients 
will be instructed to read the full medication guide before receiving abatacept.  All participants 
will be tested for latent TB and hepatitis B and C prior to enrollment in the study, and all 
participants will be advised to consult their rheumatologist if they develop any signs of infection, 
including TB and hepatitis reactivation.  Abatacept will be discontinued if a patient develops a 
serious infection or sepsis during treatment.  Participants will be advised to seek immediate 
medical attention if they experience any symptoms of severe allergic reactions.  Participants will 
also be advised to report any signs of new or worsening medical conditions such as heart 
disease, neurological disease, autoimmune disorders, or symptoms suggestive of any 
cytopenia. 
Patients will receive appropriate counseling in the outpatient clinic on administration of the drug 
and safety, as detailed for the other self-administered SQ biologics in previous sections.  For 
additional information or questions, coordinators or participants can call 1-877-920-8039. 
 
 
Summary for:  SQ Abatacept (Orencia) 
Route: 
Subcutaneous administration by trained participant 
Dosing: 
125 mg SQ q week 
Duration: 
Full 6 months of MAZERATI study 
Frequency: 
Every week  
Expiration Time: 
Follow expiration date on the packaging 
 
5.1.6.3   Study Agent Accountability Procedures 
SQ abatacept will be supplied by the study; it has been donated by Bristol Myers Squibb.   
Abatacept will be used in an open-label manner, so frequency of product distribution and 
amount of product dispensed will be within open-label guidelines for each specific therapy.   
We will provide a sharps container for spent abatacept syringes.  Participants will bring the 
sharps container to each study visit with a list of their unused abatacept syringes.  Coordinators 
will log the number of spent syringes in the container to verify proper drug dosing. Used 
syringes, expired abatacept, and unused abatacept will be returned to the study coordinators, 
who will dispose of it according to the appropriate regulations.   
 
5.2 
Assessment of Participant Compliance with Study Agents 
 
As detailed throughout Section 5.1 and its sub-sections, participant compliance will be assessed 
for each study agent.  For agents administered subcutaneously, participants will be provided 
with a sharps container and instructed to place all used or expired syringes in the sharps 
container.  During each study visit, the study coordinator will examine the sharps container and 
record the number of used and expired syringes in the study log.  Participants will also be 
queried regarding their self-administration of the study agents.  The recorded count and the 
participant responses will serve as the means to assess participant compliance of 
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5.3 
Concomitant Medications and Procedures 
 
5.3.1 Permitted concurrent medications: 
 
Methotrexate 
 
In the United States, methotrexate has become the drug of choice for patients with early, 
moderate-to-severe RA [33-37].  Methotrexate is typically used in doses between 15 and 25 
mg/week.  Methotrexate is a DMARD and is a folate antagonist that inhibits cell proliferation and 
has anti-inflammatory properties possibly mediated by effects on adenosine signaling.  The 
toxicities of methotrexate are well known and guidelines for monitoring have been published [33, 
34].  The methotrexate vs. etanercept trial [38] and BeST studies [39] established that higher 
doses of methotrexate (20 mg/week) can be safely administered.  In standard clinical practice, 
methotrexate is routinely co-administered with the study’s biologic drugs. 
 
Leflunomide 
 
The FDA approved leflunomide (Arava) in 1998 as a DMARD for treatment of RA and psoriatic 
arthritis.  Leflunomide is administered orally and works by blocking pyrimidine biosynthesis 
(inhibits dihydroorotate dehydrogenase).  By blocking de novo pyrimidine biosynthesis, 
leflunomide inhibits cell proliferation and has anti-inflammatory properties, likely as a result of 
decreased cell numbers (Product Information: Arava. Hoechst Marion Roussel, US, 98).  It is 
generally administered at 20 mg/day without a loading dose.  Leflunomide has been used 
successfully in combination with NSAIDs (e.g., aspirin) and/or low-dose corticosteroids, and is 
sometimes used in conjunction with MTX due to synergistic effects of the combination, although 
side-effects sometimes limit the utility of this combination [40].  The toxicities of leflunomide are 
well known and guidelines for monitoring have been published [33, 34].  In standard clinical 
practice, leflunomide is routinely co-administered with the study’s biologic drugs. 
 
Hydroxychloroquine 
 
Hydroxychloroquine is approved by the FDA for treating RA, SLE, and malaria.  Overall, 
hydroxychloroquine has a very favorable safety profile with retinal toxicity being the most 
serious, but uncommon side-effect [41, 42].  The American Academy of Ophthalmology [42] 
acknowledges there is minimal risk of toxicity for individuals using less than 6.5 mg/kg/day (300 
or 400 mg/day) of hydroxychloroquine for less than 7 years.  Annual ophthalmologic screening, 
especially after the first 7 years of usage is recommended [33, 34].  In standard clinical practice, 
hydroxychloroquine is routinely co-administered with the study’s biologic drugs. 
 
Sulfasalazine 
 
Sulfasalazine has been used as monotherapy and in combination with other DMARDs.  
Myelosuppression is the primary toxicity reported requiring routine monitoring with a CBC [33, 
34].  The standard dose of sulfasalazine used in clinical practice and in published clinical trials is 
2 gm/day in divided doses [43-45].  In clinical practice, the starting dose is 500 mg twice daily 
and increased to 1000 mg twice daily after 6 weeks if no intolerance or toxicity is noted.  The 
maximum dose for the treatment of RA is typically 3,000 mg/day in divided doses.  In standard 
clinical practice, sulfasalazine is routinely co-administered with the study’s biologic drugs. 
 


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Oral Corticosteroids 
 
We will allow use of a low-dose (≤ 10 mg/day) of oral corticosteroids (prednisone or 
prednisolone) at study entry in MAZERATI.  The clinical benefits and adverse effects of low-
dose steroids in RA patients have been well documented [46-50].  If receiving oral steroids, a 
stable dose (≥ 2 weeks) of prednisone will be required at study entry. 
5.3.2 Medication changes and monitoring for toxicity for DMARDs and steroids 
 
The primary rheumatologist will provide ongoing treatment for each patient enrolled in this 
study. They will monitor for toxicities. 
 
If a patient has active disease that requires an increase in DMARD, or change of DMARD, they 
will no longer be considered part of the analysis for mechanistic studies. We will continue to 
monitor the patient for the 6-month period of the study for toxicity of medications.  
 
Regarding corticosteroid, doses of prednisone (≤10 mg/day) are allowed at entry. Doctors may 
decrease the dose if disease activity has improved or adverse events required a lower dose of 
steroids. We will allow two increases in steroids over the 6-month study. These could include a 
one week oral prednisone boost, or a Medrol dose pack. We will record all changes in steroid 
dose from baseline. If more than two transient increases in steroids are needed, then the patient 
will not be considered evaluable for the mechanistic studies. 
 
5.4 
Precautionary and Prohibited Medications and Procedures 
 
5.4.1 Prohibited Medications and Procedures 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their side effects and contraindications. 
All therapies will be used in an open-label manner according to FDA-approved 
guidelines.  The participants and the rheumatologists will not be blinded to the therapies, 
which will allow proper clinical management of these participants, including standard-of-
care toxicity monitoring. 
 
Participants will be randomized to a treatment arm, and will be considered an active 
participant if they take at least one dose of the randomized drug.  Additionally, to be 
considered study participants, MAZERATI subjects must maintain their baseline 
prednisone and oral DMARD medications until they have received their first dose of 
randomized medication.  During the first 3 months of therapy, patients and their 
physicians will be permitted to taper but not increase corticosteroids.  Adjustments of 
study medication or DMARDs will not be permitted except as described above during the 
first 3 months of the study. 
 
Specifically, MAZERATI participants will not be permitted to take more than one biologic 
at a time.  Participants will be asked to avoid unnecessary or routine vaccinations while 
they are participating in the study as vaccination may affect the mechanistic studies.  
Participants randomized to etanercept will be cautioned to avoid taking 
cyclophosphamide due to a higher incidence of non-cutaneous solid malignancies in 
patients receiving both therapies.  Participants randomized to tocilizumab, who are 
already taking a cytochrome P-450 (CYP450) substrate for another condition, will be 


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monitored for the therapeutic effect of their CYP450 therapy, with dose adjustment as 
needed. 
 
5.4.2 Precautionary Medications and Procedures 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their side effects and contraindications. 
All therapies will be used in an open-label manner according to FDA-approved 
guidelines.  The participants and the rheumatologists will not be blinded to the therapies, 
which will allow proper clinical management of these participants, including standard-of-
care toxicity monitoring. 
 
Precautionary medications presented in the product brochures for the MAZERATI 
therapies are similar to the prohibited medications and procedures presented in Section 
5.4.1.  Participants will not be prescribed more than one biologic at one time and will be 
cautioned against taking other biologics for other diseases.  Hepatosplenic T-cell 
lymphoma has been reported in adolescents and young adults receiving TNF blockers 
for Crohn's disease or ulcerative colitis, with concomitant use of azathioprine or 
mercaptopurine.  As a result, clinicians must carefully assess the risk vs. benefit of using 
TNF blockers, azathioprine, and/or mercaptopurine in adolescents and young adults, 
especially for the treatment of Crohn's disease or ulcerative colitis.  Participants will be 
cautioned against receiving vaccines while also receiving these immune-modulatory 
therapies and will be asked to receive any necessary vaccines at least 2 months prior to 
enrollment in the MAZERATI study.  Switching between DMARDs will not be permitted 
during the 6 months of this study.  Participants will be monitored for signs of chronic and 
serious infections, such as hepatitis, TB, etc. 
 
5.5 
Prophylactic Medications and Procedures 
 
All participants receiving MTX will also be prescribed folic acid supplements due to 
MTX’s known depletion of folic acid levels.  There will be no other prophylactic 
medications or procedures in the MAZERATI study. 
 
5.6 
Rescue Medications 
 
Participants enrolling in MAZERATI must be on stable doses of oral steroids (e.g., 
prednisone) for 2 or more weeks at entry, but steroids can be tapered after initiation of 
the study drug at the discretion of the treating physician.  During the first 3 months of the 
study, prednisone can’t be increased and intra-articular and/or intra-muscular injections 
of corticosteroids will not be permitted.  After the 3-month study visit, addition of steroids 
or other oral DMARDS is permitted at the discretion of the treating physician. 
 
 
6. STUDY PROCEDURES/EVALUATIONS 
 
6.1 
Clinical Evaluations 
 
Assessments of Efficacy 
 


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All information needed to compute the CDAI and the DAS28-CRP will be obtained at baseline 
and at the 1-month, 3-month, and 6-month study visits. A physician global assessment of RA 
disease activity and patient measurements as outlined below will also be obtained at each study 
visit.  Information from these assessments will be used to determine the number of subjects: 
 
Achieving a CDAI remission < 2.8; 
Achieving a DAS remission with a DAS28-CRP < 2.6; 
Achieving a ACR20, 50, and 70 response 
 
Joint Assessments 
 
Prior to initiating therapy (baseline), participants will undergo a standardized 28-joint 
examination by a trained, blinded assessor as described (93). The blinded assessor will also 
perform treatment-blinded assessments following treatment initiation at 1-, 3-, and 6- month 
visits. Clinicians can establish any schedule as necessary for office visits, provided that 1-, 3-, 
and 6-month treatment-blinded joint examinations are included among the scheduled visits. 
 
Patient assessment of disease activity 
 
Participants will complete self-assessments that include a RAPID-3, SF-12, WPAI, and visual 
analog scale measurements of RA global disease activity and pain. 
 
6.2 
Laboratory Evaluations 
 
6.2.1 Clinical and Research Laboratory Evaluations and Specimen Collection 
 
C-reactive Protein Measurements 
 
C-reactive protein (CRP) levels will be measured in a clinical laboratory at the University of 
Pittsburgh Medical Center using nephelometry.  CRP levels will be used to calculate the 
DAS28-CRP. 
 
Mechanistic assessments 
 
Participants will provide a blood sample totaling 60 ml (6 x 10-ml heparin tubes for PBMC 
isolation) for the mechanistic studies.   
 
Tocilizumab-specific assessment (Arm 2 participants only) 
 
Anti-TCZ antibodies, TCZ levels and sIL6-R are to be drawn and stored at baseline for all 
patients receiving tocilizumab, but analyzed only for patients who experience anaphylaxis, 
serious hypersensitivity, or discontinuation of study treatment (tocilizumab) due to 
hypersensitivity (serious or non-serious). For patients who meet any of these criteria, additional 
immunogenicity samples will be collected at the time of the event, and then again at least 6 
weeks after the last SC dose of tocilizumab. 
 
Immunogenicity assays: samples will undergo screening to test for anti-TCZ antibody and if 
positive, a confirmatory test will be run. If confirmed, an IgE test will be run. 
 


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PK-PD samples should be collected at the same time points as immunogenicity samples 
Reports of the results of these analyses will be provided to the investigator for patients testing 
positive for anti-TCZ antibodies. 
 
Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention and the National Institutes of Health. 
 
All infectious specimens will be transported using packaging mandated in the Code of Federal 
Regulations, 42 CFR Part 72.  Where applicable, especially for future studies, refer to individual 
carrier guidelines, e.g., Federal Express, for specific instructions. 
 
6.2.2 Specimen Preparation, Handling and Shipping 
 
All potentially infectious specimens will be transported using packaging mandated in the Code 
of Federal Regulations, 42 CFR Part 72.  Where applicable, especially for future studies, refer to 
individual carrier guidelines, e.g., Federal Express, for specific instructions.  Since this is a 
single-site study in the UPMC Rheumatology Network, we will use the usual, approved local 
courier of biospecimens.   
 
Instructions for Specimen Storage 
 
After centrifugation, serum will be carefully removed from the serum separator tubes and 
aliquoted into appropriately-sized aliquots.  These serum aliquots will be labeled in a de-
identified way and stored long-term in ultralow temperature freezers (-80°C).  PBMCs will be 
purified over Ficoll gradients and resuspended in specialized freezing media with dimethyl 
sulfoxide (DMSO).  Subsequently, PBMC aliquots will be prepared and frozen in a controlled 
manner to liquid nitrogen temperatures.   
 
Specimen Shipment Preparation, Handling and Storage 
 
As detailed in the section on biohazard containment, biospecimens will be handled according to 
the current recommendations of the Centers for Disease Control and Prevention and the 
National Institutes of Health.  All biospecimens will be transported using packaging mandated in 
the Code of Federal Regulations, 42 CFR Part 72.  Where applicable, especially for future 
studies, refer to individual carrier guidelines, e.g., Federal Express, for specific instructions.  
Biospecimens will be stored in a de-identified manner, in locked ultralow freezers and liquid 
nitrogen storage units.  All temperature-controlled devices have alarms and auto-dialers in the 
event of power or equipment failure. 
 
For tocilizumab-specific samples (Anti-TCZ antibodies, TCZ levels and sIL6-R), sample logistics 
and handling will be managed by Covance Laboratories. 
 


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6.3 
Substudies 
 
It is not anticipated that substudies will be a part of the MAZERATI protocol, but if a substudy is 
necessary, then we follow the approved guidelines.  Future ancillary studies using banked 
biospecimens will be approved by Drs. Moreland and McGeachy, following the NIH guidelines 
for the sharing of research resources. 
 
7. STUDY SCHEDULE (SEE APPENDIX A) 
 
7.1 
Screening 
 
7.1.1 Evaluations and Procedures 
 
Screening and enrollment in the MAZERATI study can occur as long as one month prior to the 
baseline visit or the same day as baseline.  It is expected that time will be required, after the 
screening visit, but prior to the baseline visit, to secure authorization for subjects randomized to 
TNF inhibitor therapy. 
 
At the MAZERATI screening visit, the following MAZERATI-specific screening, enrollment, and 
randomization procedures will be performed: 
 
1. Obtain written, informed consent 
2.   Urine pregnancy test (if applicable, i.e., pre-menopausal women without a history of 
hysterectomy, bilateral oophorectomy, and/or tubal ligation) 
3.   Radiograph of chest^ and PPD skin test or Quantiferon TB-Gold test£ 
4.   Hepatitis B surface antigen¥ & hepatitis C antibodies¥ 
5.   Medical history  
6. Collect patient demographics and RA medication history  
7.   Assess likelihood of insurance approval for a TNF antagonist 
8.   Assess for RF and CCP autoantibody status 
9.   Randomize the patients to one of the three treatment arms based on the randomization 
scheme described in Section 3.1. 
 
^Chest x-rays taken 1 year prior to screening with no evidence of malignancy or active infection 
are accepted. 
¥The window for Hep B and Hep C screening is 1 year prior to screening. Documentation of 
results must be included in the patient’s study chart. 
£PPD skin test or Quantiferon TB-Gold results taken up to 1 year prior to screening are 
accepted if no risk of exposure has occurred, e.g., travel outside of US or contact with TB+ 
individuals. 
 
 
7.1.2 Instructions for Completing the Screening Visit 
 
Written informed consent MUST be obtained prior to any study-specific procedures being 
performed.  A copy of the Informed Consent should be given to the participant, and the original 
is placed in the medical record (as per institutional guidelines).  Participants should be allowed 


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to read the full consent document and to have their questions answered prior to their signing the 
informed consent. 
 
Potential participants will be randomized to one of the three treatment arms as described in 
Section 3.1.  Between the screening and the baseline visit, the participants’ health insurance 
must be contacted for approval for TNF inhibitor therapy. 
 
 
 
Medical History 
 
Each participant must provide information related to RA disease duration and past and current 
use of medications related to arthritis treatment.  Other demographic information related to 
education level, income, smoking history and comorbidities will also be asked. 
 
 
 
Treating Physician:  Clinical Laboratory Tests 
 
All participant clinical laboratory test results, obtained at the discretion of the treating physician 
primarily for the assessment of drug toxicity must be reviewed, evaluated, and signed off by a 
licensed M.D., D.O., Physician’s Assistant or nurse practitioner.  Screening visit labs MUST be 
reviewed prior to the Participant’s enrollment in the study and baseline visit. Recommended 
evaluations include:  
• 
Hematology: complete blood count (CBC) with differential and platelet count 
• 
Serum chemistries: total bilirubin, SGOT (AST), and SGPT (ALT) 
• 
Lipid panel 
 
 
 
Patient Assessments 
The Patient Demographics and RA Medication History forms will be completed at the screening 
visit. 
 
 
7.2 
Enrollment/Baseline 
 
After the screening visit, the study coordinator and the treating clinician will review the potential 
participant’s screening data.  All entry criteria must be met for the patient to continue in the 
MAZERATI study.  If the patient continues to meet the entry criteria, then the patient will be 
randomized to one of the three treatment arms based on the randomization scheme description 
in Section 3.1.  The clinic nurse will secure approval for the participants randomized to 
treatment Arm 1 from the patient’s insurance company.  Once standard-of-care clinical labs 
have been evaluated and insurance approval received, then the patient can return for the 
baseline visit.  At the baseline visit, baseline labs and forms must be completed.  During the 
baseline visit, clinical personnel will instruct participants on the proper administration of the 
randomized therapy and participants will receive their first dose of study medication.  All 
standard-of-care procedures relevant to each therapy must be used.  MAZERATI is a phase IV 
clinical trial, with therapies used in an open-label manner, and the treating physician, study 
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will be provided all relevant standard-of-care.  The screening visit and the baseline visit can 
occur on the same day, but can occur no more than 30 days apart. 
 
All assessments listed in Section 7.3 (Follow-Up) will be performed at the baseline visit prior to 
administration of the randomized therapy.  This includes Patient Questionnaires, Blinded 
Assessor Assessments, Laboratory Tests, and Adverse Events assessment.  
 
 
 
 
7.3 
Follow-up  
 
Follow-up visits will occur 1 month (3-5 weeks), 3 months (10-14 weeks), and 6 months (22-30 
weeks) after the baseline visit (study drug initiation).  At each follow-up visit the following 
assessments may  be performed: 
 
Patient Questionnaires 
 
Patient questionnaires, consisting of the following assessments: 
Modified Health Assessment Questionnaire (mdHAQ as part of RAPID3) 
Patient’s Assessment of Arthritis Pain (VAS) 
Patient’s Global Assessment of Disease Activity (VAS) 
SF-12 (quality of life survey) 
WPAI (work-productivity survey) 
PROMIS 29 
 
Blinded Assessor Arthritis Assessments 
 
Arthritis assessments, consisting of blinded assessments, must be performed at all study visits 
by a blinded assessor that is different from the patient’s physician.  The blinded assessor’s 
examination will be used to calculate a DAS28-CRP and the CDAI and will consist of the 
following: 
 
28 joint count assessment of joint tenderness 
28-joint count assessment of joint swelling 
Assessor’s Global Assessment of Disease Activity (VAS) 
 
Treating Physician:  Clinical Laboratory Tests 
 
All participant clinical laboratory test results, obtained at the discretion of the treating physician 
primarily for the assessment of drug toxicity must be reviewed, evaluated, and signed off by a 
licensed M.D., D.O., Physician’s Assistant or nurse practitioner.  RACER screening visit labs 
MUST be reviewed prior to the Participant’s enrollment in the study and baseline visit. 
 
Laboratory Tests 
 
A blood sample will be obtained from all subjects for determination of a high sensitivity C-
reactive protein (hsCRP).  The hsCRP will be used to determine the DAS28-CRP for subjects at 
each study visit. 
 


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Mechanistic Study Blood samples 
 
Blood samples will be obtained at the baseline visit and at each follow-up visit for the 
mechanistic studies described in Section 6.2.1. 
 
Adverse Events Data Collection Form 
 
Information related to any adverse events will be collected on a data collection form at each 
follow-up visit. The treating rheumatologists will determine the level of seriousness of all 
adverse events and if they impart any change in therapy. 
 
7.4 
Final Study Visit 
 
The final study visit will occur at the 6-month follow-up.  The assessments described in the 
previous section (Section 7.3) will be performed at the final study visit. 
 
 
7.5 
Early Termination Visit 
 
For subjects that discontinue therapy at any point in the study, these subjects will be asked to 
continue assessments as outlined in the study protocol.  For subjects that discontinue therapy 
and refuse or cannot complete study protocol assessments, these subjects will be evaluated by 
their treating physician and by the blinded assessor at an early termination visit.  This visit will 
be scheduled as soon as possible after study drug discontinuation or where possible, 
participants will be asked to continue study drug until after the early termination visit.  At the 
early termination visit, the information collected in Section 7.3 for each follow-up visit will be 
collected.  If the early termination visit occurs within the time window for a follow-up visit, then 
this visit will also be used in the analysis as a follow-up visit as long as the patient is evaluated 
within one dosing interval of their assigned therapy.  For example, data collected from a study 
participant in the 23rd week of the study treated with etanercept who discontinues therapy and is 
evaluated within one week of their last injection will be included in the analysis of 6 month 
follow-up data. 
 
 
7.6 
Pregnancy Visit 
 
The MAZERATI study uses drugs (e.g., MTX and LEF) are contraindicated in pregnant patients, 
so no pregnant patients will be involved in the study.  Pregnant or lactating females will be 
excluded from the MAZERATI trial, and urine pregnancy tests will be performed during the 
screening visit when appropriate.  Female patients will be counseled regarding the pregnancy 
risks of all medications and advised to use appropriate contraception with their partners during 
the use of these therapies.  In the event that a female participant does become pregnant, they 
will be referred to high-risk obstetrics for follow-up and terminated from the MAZERATI study. 
 
7.7 
Unscheduled Visits 
 
Unscheduled visits related to the treatment of rheumatoid arthritis will be monitored by the study 
coordinators.  Any unscheduled study visits that relate to the safety of the study drugs or to 


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changes in patient disease activity that may alter the outcome of the MAZERATI study will be 
monitored for collection of adverse events and for their potential effects on study participation. 
 
 
8. ASSESSMENT OF SAFETY 
 
MAZERATI is a phase IV clinical trial, and safety parameters are not a primary objective for this 
study. 
 
8.1 
Specification of Safety Parameters 
 
The study drugs, etanercept, adalimumab, infliximab, certolizumab, golimumab, tocilizumab, 
and abatacept are approved by the FDA for treating RA and will only be used in approved ways 
and for approved indications.  The known adverse events of each of the study drugs are well-
defined and included in the package inserts for each medication.  No primary safety endpoints 
will be used to address the goals of the current study.  Anticipated adverse events will not be 
reported to the IRB as part of the MAZERATI study.  However, unanticipated adverse events 
(AEs and SAEs as defined in Sections 8.2 and 8.3) and other unanticipated problems will be 
recorded at each study visit in accordance with the University of Pittsburgh IRB policies and 
procedures and sponsor requirements for the duration of each subject’s participation in the 
study. The University of Pittsburgh IRB policies and procedures related to management of 
reportable events can be found at: http://www.irb.pitt.edu/pandp/default.aspx 
Safety assessments will consist of monitoring and reporting adverse events (AEs) and serious 
adverse events (SAEs) that are considered related to study drugs, all events of death, and any 
study specific issue of concern. 
 
 
8.2 
Definition of an Adverse Event (AE) 
 
Adverse Event (or Adverse Experience) 
 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with 
the use of an investigational medicinal product (IMP) or other protocol-imposed intervention, 
regardless of attribution. 
 
This includes the following: 
• 
AEs not previously observed in the subject that emerge during the protocol-specified AE 
reporting period, including signs or symptoms associated with rheumatoid arthritis that 
were not present prior to the AE reporting period. 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention. 
 


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Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
8.3 
Definition of a Serious Adverse Event (SAE) 
 
Serious Adverse Events 
 
An AE should be classified as an SAE if the following criteria are met: 
• 
It results in death (i.e., the AE actually causes or leads to death). 
• 
It is life threatening (i.e., the AE, in the view of the investigator, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death.). 
• 
It requires or prolongs inpatient hospitalization. 
• 
It results in persistent or significant disability/incapacity (i.e., the AE results in substantial 
disruption of the subject’s ability to conduct normal life functions). 
• 
It results in a congenital anomaly/birth defect in a neonate/infant born to a mother 
exposed to the IMP. 
• 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical intervention 
to prevent one of the outcomes listed above). Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, the 
development of drug dependency or drug abuse, or drug induced liver injury (DILI). 
 
 
8.4 
Methods and Timing for Assessing, Recording, and Analyzing, 
Managing Safety Parameters 
 
8.4.1 Methods and Timing for Assessment 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the FDA, appropriate IRB(s), Genentech, Inc. (per 
Genentech Inc., requirements), and Bristol Myers Squibb as outlined in section 8.6.2, in 
accordance with CFR 312.32 (IND Safety Reports).  
 
8.4.1.1 Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after informed 
consent is obtained and initiation of study treatment and ends 30 days following the last 
administration of study treatment or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs that are attributed to prior study treatment. 
 
8.4.2 Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 


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reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and administration of the 
study drug, and the AE cannot be readily explained by the subject’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to the 
study drug; and/or the AE abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the study drug (e.g., preexisting medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE 
has no plausible temporal relationship to study drug administration (e.g., cancer diagnosed 2 
days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or characterized in the 
Package Inserts or current Investigator Brochures.  
 
Unexpected adverse events are those not listed in the Package Inserts (P.I.) or current 
Investigator Brochures (I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. or I.B. For example, under 
this definition, hepatic necrosis would be unexpected if the P.I. or I.B. only referred to elevated 
hepatic enzymes or hepatitis. 
 
 
8.5 
Procedures for Eliciting, Recording, and Reporting Adverse 
Events 
 
8.5.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time-points should be 
adopted. To prevent reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more of these events, but rather non-directive questions should be used to 
elicit information. Examples of non-directive questions include:  
• “How have you felt since your last clinical visit?” 
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8.5.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. 
Avoid colloquialisms and abbreviations. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, it is ok to report the 
information that is currently available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 8.4.1.1), 
regardless of attribution, will be reported to the appropriate parties. When recording a death, the 
event or condition that caused or contributed to the fatal outcome should be reported as the 
single medical concept. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death”. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. Such conditions 
should be reported as medical and surgical history. A preexisting medical condition should be 
re-assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including applicable 
descriptors (e.g., “more frequent headaches”). 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a subject is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be 
reported as the SAE. For example, if a subject is hospitalized to undergo coronary bypass 
surgery, record the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study or 
• Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or within 90 days 
after the last dose of study drug, a report should be completed and expeditiously submitted to 


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the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in 
a child born to a female subject exposed to the study drug should be reported as an SAE. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject has completed or 
discontinued study participation if attributed to prior study drug exposure. If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study, this should be reported as 
an SAE.  
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will 
agree to the reconciliation periodicity and format, but agree at minimum to exchange monthly 
line listings of cases received by the other party. If discrepancies are identified, the Sponsor and 
Genentech will cooperate in resolving the discrepancies. The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory resolution. 
 
AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the product (see listing in section 8.7). 
 
8.6 
Reporting of Serious Adverse Events 
8.6.1 Reporting of Serious Adverse Events Associated with Tocilizumab (Arm 2 
only) 
Immediate Reporting Requirements 
 
The Investigator must report the following events to Genentech Drug Safety within 24 hours 
after learning of the event, regardless of relationship to study drug: 
SAEs. 
Non-serious and serious AEs of special interest. 
Pregnancies. 
 
The Investigator must report new significant follow-up information for these events to Genentech 
Drug Safety within 24 hours after becoming aware of the information.  New significant 
information includes the following: 
New signs or symptoms or a change in the diagnosis. 
Significant new diagnostic test results. 


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Change in causality based on new information. 
Change in the event’s outcome, including recovery. 
Additional narrative information on the clinical course of the event. 
 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
SAE Reporting 
Investigators must report all SAEs to Genentech within the timelines described above. The 
completed Medwatch/case report should be faxed, along with the fax cover sheet (Appendix B) 
immediately upon completion to Genentech Drug Safety at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
 
• 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon 
as it becomes available. 
• 
Serious AE reports that are related to the tocilizumab and AEs of Special Interest 
(regardless of causality) will be transmitted to Genentech within 24 hours of the 
Awareness Date. 
• 
Serious AE reports that are unrelated to the tocilizumab will be transmitted to Genentech 
within 24 hours of the Awareness Date. 
• 
Additional Reporting Requirements to Genentech include the following: 
• 
Any reports of pregnancy following the start of administration with the tocilizumab will be 
transmitted to Genentech 24 hours of the Awareness Date.  
• 
All Non-serious Adverse Events originating from the Study will be forwarded in a 
quarterly report Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
MedWatch 3500A Reporting Guidelines 
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome if known 
• 
Supportive laboratory results and diagnostics 
• 
Investigator’s assessment of the relationship of the adverse event to each investigational 
product and suspect medication 
Follow-up Information 
Additional information may be added to a previously submitted report by any of the following 
methods: 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 


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• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including patient identifiers 
(i.e. D.O.B. initial, patient number), protocol description and number, if assigned, brief 
adverse event description, and notation that additional or follow-up information is being 
submitted (The patient identifiers are important so that the new information is added to 
the correct initial report) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the patient for whom and adverse event was reported. For questions regarding 
SAE reporting, you may contact the Genentech Drug Safety representative noted above or the 
MSL assigned to the study. Relevant follow-up information should be submitted to Genentech 
Drug Safety as soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/medwatch/getforms.html  
8.6.2 Reporting of Serious Adverse Events Associated with Abatacept (Arm 3 
only) 
 
All SAEs whether related or unrelated to abatacept, and all pregnancies must to be reported to 
Bristol Myers Squibb (by the investigator or designee) within 24hours of being made aware of 
the event. SAEs related to abatacept must be reported to Bristol Myers Squibb (BMS) within 1 
business day of becoming aware of the event. AEs related to abatacept must be reported within 
7 business days of becoming aware of the event. 
All SAEs should be reported via confirmed facsimile (fax) transmission, or scanned and reported 
via electronic mail to: 
 
SAE Email Address:  Worldwide.Safety@BMS.com 
 
SAE Fax Number:  609-818-3804 
 
8.7 
AEs of Special Interest (AESIs)  
8.7.1 AESIs for Tocilizumab (Arm 2) Only 
 
Adverse events of special interest (non-serious and serious) are required to be reported by the 
Investigator to Genentech Drug Safety within 24 hours after learning of the event (see Section 
8.6 for reporting instructions).  Non-serious and serious AEs of special interest for this study 
include the following: 
Infections including all opportunistic infections and non-serious infections as 
defined by those treated with IV anti-infectives 
Myocardial infarction/acute coronary syndrome. 


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GI perforation and related events. 
Malignancies. 
Hypersensitivity reactions. 
Demyelinating disorders. 
Stroke. 
Bleeding events. 
Hepatic events. 
8.7.2 AESIs for Abatacept (Arm 3) Only 
 
Adverse events of special interest are considered serious must to be reported by the 
Investigator to Bristol Myers Squibb within 24 hours after learning of the event.  SAEs of special 
interest for this study include the following: 
Cancer 
Overdose 
Pregnancy 
Drug-induced liver injury, defined as: 
a) AT (ALT or AST) elevation > 3 times ULN, and 
b) Total bilirubin > 2 time ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), and  
c) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
 
8.8 
Modification of Study Agent(s)/Intervention(s) for a Participant 
 
8.8.1 Dose/Schedule Modifications for a Participant 
 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their dosage scheduling.  All therapies will be 
used in an open-label manner according to FDA-approved guidelines.  The participants and the 
rheumatologists will not be blinded to the therapies, which will allow proper clinical management 
of these participants, including standard-of-care toxicity monitoring.  Treating rheumatologists 
will be permitted to prescribe each treatment within that treatment’s specific FDA-approved 
dosing and scheduling, and non-approved dose and schedule modifications will not be 
permitted for any participants. 
 
8.9 
Halting Rules for the Protocol 
 


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MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their dosage scheduling.  All therapies will be 
used in an open-label manner according to FDA-approved guidelines.  The participants and the 
rheumatologists will not be blinded to the therapies, which will allow proper clinical management 
of these participants, including standard-of-care toxicity monitoring.  Treating rheumatologists 
will be permitted to prescribe each treatment within that treatment’s specific FDA-approved 
dosing and scheduling, and non-approved dose and schedule modifications will not be 
permitted for any participants.  There are no plans to halt MAZERATI after enrollment begins. 
 
8.10 Stopping Rules for an Individual Participant/Cohort 
 
Discontinuation of Study Therapy 
 
Protocol-specified requirements for the treatment of participants, including regimens for 
investigational or concomitant medications, as well as, restrictions for disallowed medications, 
will be discontinued for any individual participant under the following conditions: 
 
• 
At the request of the participant;  
• 
The participant’s health, safety, and/or well-being is threatened; 
• 
For any participant who experiences any of the following:  
• 
Suspicion of a serious bacterial or opportunistic infection requiring hospitalization 
or parenteral treatment;  
• 
Development of any of the exclusion criteria; or  
• 
Toxicities to the assigned study drug as per Section 1.3. 
• 
Per the study sponsor Genentech, tocilizumab-specific criteria for discontinuation 
includes the following: 
• 
anaphylaxis or hypersensitivity reaction or requires an interruption of the study 
drug because of symptoms of anaphylaxis or hypersensitivity (TCZ should be 
permanently discontinued from these patients) 
• 
ALT or AST value > 5X ULN or persistent elevation > 3X ULN 
• 
Platelet count (cells/mm3) < 50,000 
• 
ANC (cells/mm3) < 500 
 
Finally, protocol-specified treatment requirements will be discontinued as a natural 
consequence in participants who are withdrawn from the study. 
 
Procedures for Discontinuation of Study Therapy 
 
Participants who discontinue study treatment prematurely due to their concerns or the concerns 
of their treating rheumatologist will be given appropriate care under medical supervision.  
Participants who discontinue study treatment for any reason will be encouraged to complete all 
remaining scheduled follow-up visits.  If the participant elects not to complete these visits, 
participants will be asked to complete an end-of-study evaluation, which includes the treatment-
blinded, standardized joint assessment planned for the end-of-treatment study visit (6 month). 
 
8.11 Premature Withdrawal of a Participant 
 
When a participant is withdrawn from the study, protocol-specified treatment requirements are 
discontinued, and study-related visits, exams, procedures, assessments, tests, and data 


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collection are terminated. Individual participants will be withdrawn from the protocol under any of 
the following conditions: 
 
• 
The subject withdraws consent;  
• 
The investigator or participant’s clinician believes it is in the best interest of the 
participant; or 
• 
The study is terminated.   
 
 
9. CLINICAL MONITORING STRUCTURE 
 
9.1 
Site Monitoring Plan 
 
The MAZERATI study will occur at a single site:  the UPMC Rheumatology Network in 
Pittsburgh, PA.  The University of Pittsburgh has and maintains all required federal assurances 
for human participant research.  We will submit to the standard institutional and governmental 
audits as required.  In Section 9.2, we describe our safety monitoring plan.  Site monitoring will 
be a part of the regular and usual safety monitoring plan.  Dr. Moreland will have the final 
responsibility for monitoring the treating physicians and study personnel and will have discretion 
to recommend actions regarding study conduct and continuation as a consequence of any 
planned or unplanned monitoring activity.  Participants in MAZERATI are treated by their 
primary rheumatologist, and both of those parties are unblinded to the therapy.   
 
9.2 
Safety Monitoring Plan 
 
The biologic medications that will be used in this study are currently FDA-approved for the 
treatment of RA patients that are refractory to therapy with MTX.  As such the biologic 
medications used in this study are consistent with the normal standard-of-care for patients at 
this stage of RA.  Therefore, rather than convening a Data and Safety Monitoring Board, we will 
implement a Data and Safety Monitoring Plan (DSMP).  The DSMP will review accumulating 
data at least every 6 months during planned DSMP Data Review Meetings that will include Drs. 
Moreland and McGeachy, and the coordinators working on the project.  Data for the planned 
safety reviews will include, at a minimum, a listing of all unanticipated problems during the trial 
and assessment of the relatedness of each to MAZERATI.  DSMP members will also review 
study progress, adverse events and outcome data, external factors, relevant information, 
procedures in place to protect participant privacy and confidentiality, and the conduct of the 
various study members for compliance with the protocol.   
 
In addition to the pre-scheduled data reviews and planned safety monitoring, it may be 
necessary to have ad hoc reviews or emergency meetings related to Data and Safety 
Monitoring.   
 
Dr. Moreland will have discretion to recommend actions regarding study conduct and 
continuation as a consequence of any planned or unplanned monitoring activity. 
 
Routine EDC Review 
 
The EDC will generate reports that compile all newly submitted and accumulated unanticipated 
problems.  A subsequent review of periodic reports will be performed by the PI. 


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10. STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Study Objectives 
 
The MAZERATI study is designed to test hypotheses related to the effects of TNF antagonists, 
tocilizumab and abatacept on B cell and T cell function in RA patients.  We believe that these 
studies will 1.) determine the pathogenic pathways regulating B and T cell function in RA 
patients, 2) provide a means to understand clinical responsiveness to different RA medications 
and 3.) provide a mechanistic basis to understand the relative merits of combination therapy 
directed at different pathogenic pathways.  Therefore, the MAZERATI study is primarily powered 
to answer questions related to the mechanistic specific aims of this protocol. 
 
 
10.2 
Study Population 
 
Analysis Populations 
 
Three analysis populations, the Safety (SAF) population, Intent-to-Treat (ITT) Population, and 
the Per Protocol (PP) Population, will be defined for this study.  Each subject's status with 
respect to each analysis population will be established at a blinded data review meeting prior to 
initiating the statistical analyses and reasons for excluding subjects from analysis populations 
will be documented. 
 
Safety Population 
The SAF population includes all subjects who receive at least one dose of study treatment.  The 
Safety population will be used for all safety analyses when related to unanticipated adverse 
events and problems. 
 
Intent-to-Treat Population 
The ITT population will include all randomized subjects.  Subjects, who for whatever reason do 
not complete their assigned therapy, will be included in the ITT population in the groups to 
which they were randomized.  One set of secondary outcome measures will be based on 
analyses of the ITT population and the PP population described below. 
 
Per Protocol Population 
For the purposes of the mechanistic studies and the primary outcome analyses, the PP 
population will be defined as those subjects who complete all visits and receive the study drug 
as scheduled up to Month 3.  For the purposes of the efficacy analyses and secondary outcome 
analyses, the PP will be defined as those subjects who receive at least one dose of study drug, 
whether they complete all visits or not. 
 
10.3 
Description of the Analyses 
 
Primary Analysis Statistical Considerations 
 
For statistical analyses, we will compare the baseline characteristics across the three treatment 
groups. For continuous characteristics (disease duration, disease activity/DAS28, CRP, 
erythrocyte sedimentation rate) an analysis of variance, either parametric or nonparametric, as 


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appropriate, will be used. For discrete characteristics (sex, race, smoking) a chi-square test will 
be used. We will determine if the frequencies or changes in the frequencies of T and B cell 
populations, within treatments and among treatments, correlate with disease activity or changes 
in disease activity as measured by the CDAI and DAS28­CRP using Spearman’s rank 
correlation coefficients. The analysis of correlations between changes in frequencies of T and B 
cell populations with changes in disease activity will represent the primary outcome analysis. 
For the secondary mechanistic statistical analyses, we will determine whether there are 
longitudinal changes in T and B cell populations, within treatments and between treatments, 
using a linear mixed effect model with random intercept to assess the effects of treatment over 
time. Baseline levels of T and B cell populations will be included as a covariate in the mixed 
effect model, along with the main effect treatment, as fixed effects. Time and disease activity (as 
measured by the CDAI and DAS28-CRP) will also be included as fixed effects. The differential 
effect of treatment by time will be investigated by including a treatment by time interaction in the 
mixed effect model. All assumptions of the model, such as normality of residuals, will be 
assessed. If assumptions are violated, transformations will be utilized, such as ranking the post 
baseline values of the T and B cell population frequencies and analyzing the ranked scores in 
the mixed effects model. Additional main effects will be included for baseline characteristics, 
which were not balanced by random assignment. If significant treatment effects are identified, 
pairwise post-hoc comparisons will be conducted maintaining the overall type I error of 0.05. All 
analyses will be conducted using the Per Protocol (PP) population of subjects.  
 
Together, these data will provide a comprehensive analysis of the common and unique cellular, 
molecular and genetic changes that are mediated by TNF inhibitors, tocilizumab and abatacept 
in RA. These data will pave the way for more effective patient therapy, including rationalizing the 
use of biologics other than TNF inhibitors as first-line therapies after methotrexate failure. 
 
Efficacy Analysis  
 
Primary Efficacy Analysis 
 
Given the limited sample size of the study, there will be no primary efficacy analysis.  The study 
is powered to meet primary endpoints based on the mechanistic studies. 
 
Secondary Efficacy Analyses 
 
For the secondary efficacy analyses we will compare the following measures of disease activity 
and other measurements of efficacy between subjects receiving a TNF antagonist, tocilizumab 
or abatacept. 
 
Continuous variables 
1.)  Efficacy as measured by change in CDAI from baseline 
2.)  Efficacy as measured by change in DAS28-CRP from baseline 
3.)  Efficacy as measured by ACR20, 50 and 70 response 
 
Discrete variables 
1.)  Efficacy as measured by CDAI remission < 2.8 
2.)  Efficacy as measured by DAS remission with a DAS28-CRP < 2.6 


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3.)  Adherence to drug regimen for 6 months 
4.)  Reason for discontinuation of treatment (side effects, lack of efficacy, or other (cost, 
patient compliance, etc.)) 
 
The main secondary efficacy analysis of change in CDAI score from Baseline to Month 6 will be 
performed on the PP and ITT populations.  A longitudinal data analysis based on a mixed model 
repeated measures method will be used to test for a treatment effect between treatment groups 
(TNF antagonist vs. abatacept vs. tocilizumab) with the change in CDAI score from Baseline at 
each follow-up time-point (1, 3 and 6 months) as the dependent variable. Terms in the model 
will include treatment group, month, treatment group by month, original TNF inhibitor failure 
group (etanercept, adalimumab, infliximab, certolizumab or golimumab), any DMARDs used at 
the start of the study, and clinic.  Additional covariates will include those characteristics not 
balanced through random assignment.  A similar analytic plan will be utilized for other 
continuous variables (DAS28-CRP, ACR 20/50/70 response, EULAR response and average 
corticosteroid dose).  The approach for discrete secondary variables will utilize mixed effects 
models, though the link function will be modified based on the type of discrete variable (e.g., 
logit link for binary, Poisson like for count).  
 
The fit of all models will be assessed.  If the models do not adequately fit, transformed data will 
be investigated.  If an adequate transformation cannot be identified, nonparametric approaches 
will be investigated. 
 
The CDAI is a calculated measure based on the following:  sum of number of swollen joints, 
number of tender joints, patient’s global disease activity (PGA) (on a scale of 0 -10) and 
physician’s global disease activity (PGA) (on a scale of 0 -10). 
 
The DAS28-CRP is a calculated measure based on the following: number of swollen joints, 
number of tender joints, CRP, and patient’s global disease activity (PGA) measured on a Visual 
Analogue Scale (VAS):  DAS28-4(CRP) = 0.56*sqrt(tender28) + 0.28*sqrt(swollen28) + 
0.36*ln(CRP+1) + 0.014*PGA + 0.96 
 
For the discrete efficacy-related variables, we will perform comparisons between the different 
treatments using contingency tables and two-tailed chi square tests.  Corrections for multiple 
testing will not be made since all of these analyses are exploratory. 
 
Safety Analysis 
 
All safety analyses will be performed using the Safety population.  The safety analysis is done 
for unanticipated problems or adverse events.   
 
Unanticipated AEs including changes in laboratory values will be graded according to the NCI 
CTCAE (http://ctep.cancer.gov/reporting/ctc.html).  The frequency of unanticipated AEs will be 
summarized by system organ class, preferred term, severity (grade), and relationship to study 
treatment.  For each of these summaries, participants will be counted at most once within each 
organ class or preferred term at the greatest severity.  For these summaries, relationship to 
study treatment will be categorized as either treatment related (unlikely, possibly, probably, or 
definitely related to study medication) or unrelated.  Similar analyses will be performed for 
unanticipated SAEs.  The proportion of treatment-related adverse events of Grade 3 or higher 
will also be reported for each treatment group.  In an exploratory fashion, chi-square tests, or 
Fisher’s exact test when appropriate, will be conducted to compare the rate of each 


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unanticipated AE in the treatment groups.  These comparisons and associated p-values are 
considered exploratory and, especially given the number of tests conducted, will be interpreted 
with care. 
 
Laboratory parameters will be summarized both overall and by treatment group using 
appropriate descriptive statistics.  For quantitative safety parameters, change from the last pre-
randomization assessment to the final visit assessment will be summarized overall and by 
treatment group.  For qualitative parameters, descriptive information on shifts in pre- to post-
randomization findings will be provided. In addition, abnormal and clinically significant 
abnormalities will be summarized and listed separately. 
 
 
10.4 
Measures to Minimize Bias 
 
Enrollment will be available to any patient with RA within the UPMC Rheumatology Network, 
meeting the entry criteria.  Upon successful screening, the participants will be randomized to 
one of the three treatment arms.  The treating rheumatologist, the participant, and the study 
coordinators will NOT be blinded or masked to the participant’s drug treatment.  Participants will 
be randomized using the randomization methods described in Section 3.1.  This is a real-world 
study, so treating rheumatologists will be permitted to restrict some of the treatment options for 
their participants who are randomized to the anti-TNF group (Arm 1).  The UPMC 
Rheumatology Network is a large network with more than 44,000 rheumatology outpatient visits 
each year.  Based upon planning meetings with the rheumatologists in this network, we don’t 
expect a large number of randomization restrictions.   We will enroll enough patients to enter 
adequate numbers of subjects as outlined. The disease activity assessments will be handled by 
fully-trained, blinded assessor.   
 
10.5 Appropriate Methods and Timing for Analyzing Outcome 
Measures 
 
Definition of Subject Completion 
 
A subject is considered to have completed the study if he/she has completed the 6-month study 
visit.  For the purposes of the secondary endpoint analyses, a subject’s results will be 
considered eligible for analysis if the subject receives their first dose of study medication.  For 
subjects that do not complete all study visits but are eligible for analysis because they received 
their first dose of study drug, non-mechanistic outcome analyses will be based on the last 
observation carried forward.  Mechanistic study outcome analyses will only be conducted on the 
90 subjects that complete the 6-month study visit.  Secondary efficacy study outcome analyses 
will be conducted on all subjects that receive the first dose of study drug. 
 
10.6  Study Hypotheses 
 
See section 2.1 
 
10.7  Sample Size Considerations 
 


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For the power analysis and sample size estimates, we based our primary estimates on the 
analyses described in Aim 1a, which focus on within treatment analyses of responsiveness to 
therapy following therapy with TNF antagonists, tocilizumab, or abatacept by analyzing the 
correlation between changes in T and B cell populations with changes in disease activity as 
measured by the DAS28-CRP and CDAI.  These sample size estimates were based on using 
Spearman’s rank correlation coefficients and an alpha of 0.05 and a beta of 0.2 (80% power) 
(Table 4).  The estimates in Table 4 suggest that about 20 subjects per treatment arm will 
provide enough subjects for a correlation analysis within treatments to achieve a correlation of 
at least 0.5 if a correlation exists between changes in T and B cell populations and changes in 
disease activity following treatment with TNF antagonists, tocilizumab, or abatacept. However, 
because we aim to assess immunological changes that occur in responders to each therapy, 
and estimate a 60% response rate, we will enroll 30 patients per treatment arm to gain around 
20 responders per group.   
 
Table 4: Sample size estimates for correlation analysis of changes 
in mechanistic studies with changes in disease activity 
Correlation coefficient (rho) 
Number / treatment arm 
0.30 
67 
0.40 
37 
0.50 
23 
0.55 
19 
0.60 
16 
0.70 
11 
 
For the other aims, with no adjustments for multiple comparisons, there is at least 80% power to 
detect an effect size of 0.30.  For the other aims, an effect size of 0.30 is likely to result in 
statistically significant differences between groups based on prior published studies by others 
and by our group. 
 
10.8 
Maintenance of Trial Treatment Randomization Codes 
 
Dr. Wisniewski and the data management team (Epidemiology Data Center – EDC) will program 
the randomization.  The randomization process is described in detail in section 3.1.  The 
randomization codes will be maintained in the database, in a secure area inaccessible to the 
blinded assessors.  The treating rheumatologist, the participant, and the study coordinators will 
NOT be blinded or masked to the participant’s drug treatment.  The blinded assessor of disease 
activity WILL be blinded to the treatment options. 
 
10.9 
Participant Enrollment and Follow-Up 
 
While a potential patient-participant is in the clinic with their treating physician, they will be 
approached by the treating physician for potential enrollment in the MAZERATI study.  If the 
patient agrees to discuss the study further, then a study coordinator will discuss the MAZERATI 
study.  The details of the study will be discussed and the informed consent will be presented.  
The patient will be provided plenty of time to ask questions and to review the consent and study 
documents.  MAZERATI is a standard-of-care, randomized observation study, so patients will 
continue to be seen by the treating rheumatologists according to the appropriate standard-of-
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(unscheduled visits) at the discretion of a participant’s treating physician.  Where possible 
follow-up visits will be coordinated with visits to the treating physician. 
 
10.10 
Planned Interim Analyses (if applicable) 
 
Interim Analysis 
An interim analysis will not be performed.  An interim analysis will likely be of limited value given 
the limited size of the MAZERATI study and given the low likelihood of significant unanticipated 
adverse events from the FDA approved medications that will be studied in this protocol. 
 
10.11 
Safety Review 
 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their side effects and contraindications.  All 
therapies will be used in an open-label manner according to FDA-approved guidelines.  The 
participants and the rheumatologists will not be blinded to the therapies, which will allow proper 
clinical management of these participants, including standard-of-care toxicity monitoring as 
appropriate.  Unanticipated events will be collected but safety outcomes will not be a part of this 
study. 
 
10.12 
Immunogenicity or Efficacy Review 
 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their side effects and contraindications.  All 
therapies will be used in an open-label manner according to FDA-approved guidelines.  The 
participants and the rheumatologists will not be blinded to the therapies, which will allow proper 
clinical management of these participants, including standard-of-care toxicity monitoring as 
appropriate.  Some of the biologic therapies are recognized as potentially immunogenic, but the 
treating physicians are aware of these precautions.  The primary outcome of the MAZERATI 
study is mechanistic, and the study is not powered for efficacy.  Nevertheless, Dr. Moreland will 
monitor the safety of the study on a regular basis. 
 
10.13 
Final Analysis Plan 
 
The statistical analysis plans for the study are described in detail in Section 10.3. 
 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
 
MAZERATI is a single-site clinical trial, occurring within the UPMC Rheumatology Network.  
Within this network, each clinic has similar standard operating procedures (SOPs) for quality 
management.  Dr. Moreland and Dr. Wisniewski will be responsible for monitoring and assuring 
quality of the data collected, and will designate a MAZERATI study monitor for this purpose.  
Data will be evaluated for compliance with protocol and accuracy in relation to source 
documents.  The study will be conducted in accordance with procedures identified in this 
protocol and the MAZERATI standard operating procedures as presented in the MAZERATI 
MOP.   
 


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Following written standard operating procedures, the study monitor will verify that the clinical 
trial is conducted and data are generated, documented (recorded), and reported in compliance 
with the protocol, GCP, and the applicable regulatory requirements.  The treating physicians will 
provide direct access to all trial-related source data and documents and reports for the purpose 
of monitoring and auditing by the study monitor and for inspection by local and regulatory 
authorities.  The statistical manager and data manager will implement quality control procedures 
beginning with the data entry system and generate data quality control checks that will be run 
on the database.  Any missing data or data anomalies will be communicated biweekly to the 
study coordinators for clarification and resolution. 
 
The training of new and future study coordinators and staff will be done by the lead MAZERATI 
coordinator and the study monitor, under the supervision of Dr. Moreland. 
 
 
12. ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
12.1 Institutional Review Board/Ethics Committee 
 
The University of Pittsburgh holds a current Federal Wide Assurance issued by the Office of 
Human Research Protection (OHRP) at the Department of Health and Human Services (DHHS) 
and will provide for the review and approval of this protocol and associated informed consent 
documents.  Any amendments to the protocol or consent materials must be approved before 
they are placed into use. 
 
The investigators will inform the IRB of serious or unexpected AEs that might occur during the 
study and are likely to affect the safety of the subjects, or the conduct of the study.  The 
investigators will comply fully with all IRB requirements for reporting AEs, protocol or consent 
form changes, as well as any new information pertaining to the use of the study medication that 
might affect the conduct of the study.  
 
The study will be conducted according to Good Clinical Practice (GCP) guidelines, U.S. 21 CFR 
Part 50 – Protection of Human Subjects, and Part 56 – Institutional Review Boards. 
 
Compliance with Good Clinical Practices  
This trial will be conducted in compliance with the protocol, current GCPs recommended by the 
International Conference on Harmonization (ICH) and the applicable regulatory requirements for 
the University of Pittsburgh.  These include the tenets of the Declaration of Helsinki and review 
and approval by the IRB.  
 
Study drugs will be used in an open-label manner and patients will receive the usual counseling 
on study medications from their physician.  Laboratory monitoring will also be performed 
according to the physician’s judgment.  Since this study uses standard-of-care surveillance and 
open-label therapies, the potential risks to the participants are minimized. 
 
12.2 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continuing throughout the individual’s study participation.  Extensive discussion of 
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Consent forms describing in detail the therapies, procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting the study 
agent.  Consent forms will be IRB approved, and the participant will be asked to read and 
review the document.  Upon reviewing the document, the study coordinator will explain the 
research study to the participant and answer any questions that may arise.  The participants will 
sign the informed consent document prior to any procedures being done specifically for the 
study.  The participants will have sufficient opportunity to discuss the study and process the 
information in the consent process prior to agreeing to participate.  The participants may 
withdraw consent at any time throughout the course of the trial. 
 
The principles of informed consent in the current edition of the Declaration of Helsinki, as well 
as compliance with all IRB requirements, will be implemented in the MAZERATI study, before 
any protocol-specified procedures are carried out.  The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 
After completion, an unsigned copy of the consent form will be given to the subject for her/his 
records. Paper and electronic versions of this form are identical in appearance.  If the consent 
form is recorded electronically on the PC tablet, it will be saved to a secure location on the 
UPMC server, separate from study data.  If consent is recorded using a paper form, it will be 
kept in a locked file drawer, in the coordinators’ locked office.  Both electronic and paper 
consent forms will be available for inspection by regulatory authorities, both federal and 
institutional. 
 
12.2.1 Assent or Informed Consent Process (in Case of a Minor) 
 
The MAZERATI trial is a trial for adults with RA.  No children will be recruited for this trial. This 
study is designed to investigate adults with RA.  Juvenile chronic arthritis is thought by many to 
be pathogenetically different from adult-onset RA.  Therefore, children will not be studied in the 
trial, but information gained could be used in an independent fashion for potential, future studies 
in children. 
 
12.3 Exclusion of Women, Minorities, and Children (Special 
Populations) 
 
This study will not involve fetuses, neonates, pregnant women, prisoners, institutionalized 
individuals, or others who may be considered vulnerable populations.  Fetuses and neonates 
will not be included since the study is for patients with uncontrolled adult rheumatoid arthritis.  
Several of the study therapies are contraindicated in pregnant females, so they will be excluded. 
Prisoners, institutionalized individuals, and others will be excluded as well. 
 
All participants will be carefully evaluated to select patients that meet entry criteria and will be 
capable of signing an IRB-approved consent form, which will include the risks and benefits of 
the study. 
 
12.4  Participant Confidentiality 
 
Every effort will be made to protect the subject’s privacy and information will be handled in a 
confidential manner.  Participants involved in MAZERATI will not be identified by name, but with 


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a specific code that will protect their identity.  Electronic files that link the subjects name to the 
code number will be stored in a password protected secure server, and only the study staff will 
have access to them.  Paper-based files will be kept in a locked file cabinet, within a locked 
office. Data will be published in aggregate format only, without the possibility of identifying 
individual participants. 
 
12.5 Study Discontinuation 
 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their side effects and contraindications.  All 
therapies will be used in an open-label manner according to FDA-approved guidelines.  The 
participants and the rheumatologists will not be blinded to the therapies, which will allow proper 
clinical management of these participants, including standard-of-care toxicity monitoring.  All of 
the randomized arms of the MAZERATI study are equally potential interventions for patients 
with the entry criteria of the MAZERATI study.  In the event that MAZERATI is discontinued, 
then participants will continue standard care with their treating rheumatologists. 
 
13. DATA HANDLING AND RECORD KEEPING 
 
13.1 Data Management Responsibilities 
 
Accurate records to ensure the conduct of the study is fully documented will be maintained and 
the period of retention will be consistent with National Institutes of Health (NIH) requirements. 
 
Data will be collected using the subject’s screening or enrollment number to ensure the strictest 
confidence.  The Data Management group (EDC), headed by Dr. Steve Wisniewski, will not 
collect personally identifying information such as the subject’s name or social security number. 
 
Personally identifying information as well as demographic information such as race, ethnicity, 
and birth date are collected in a database, which is housed in a separate location, with access 
limited to the PI and research coordinators to protect patients from access that could reveal 
personally identifying information about any subject in the trial. 
 
Research coordinators and research specialists (lab personnel) will verify the completeness, 
consistency and accuracy of documented clinical data. 
 
13.2 Data Capture Methods 
 
Data will be obtained from a variety of sources including, but not limited to laboratory notebooks, 
automated instrument output files, clinical subject charts (EMR) and electronically collected 
patient and physician questionnaires and joint examination findings.  Data from these source 
materials will be transmitted to the EDC via one of two mechanisms.  Data collected 
electronically in Dr. Moreland’s laboratory will be transferred electronically directly from the 
laboratory to the EDC using standard secure data transfer procedures.  Data collected in the 
clinical sites will be transmitted to the EDC using a secure wireless data entry system.  Clinical 
site personnel use tablet PCs to enter data into electronic CRFs (e-CRFs); each CRF page is 
submitted to the secure UPMC server electronically as the page is completed.  The central 
database, which resides on the UPMC server, is backed up nightly.  At any time, authorized site 
personnel may log in to the wireless data entry system, review and correct previously entered 


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data, or key additional data.  The data will be further validated per the study data validation plan 
via a series of computerized and manual edit checks, and all relevant data queries will be raised 
and resolved on an ongoing basis.  Complete, clean data will be frozen to prevent further 
inadvertent modifications.  All discrepancies will be reviewed and any resulting queries will be 
resolved with the research coordinators and amended in the database.  All elements of data 
entry (i.e., time, date, verbatim text, and the person performing the data entry) will be recorded 
in an electronic audit trail to allow all data changes in the database to be monitored and 
maintained in accordance with federal regulations. 
 
13.3 Types of Data 
 
The MAZERATI study will collect safety data, laboratory data, mechanistic data, and outcome 
measures data.  Since this is a phase IV clinical trial, safety data will not be collected in a 
separate database, but will be monitored within the MAZERATI database to monitor AEs and 
SAEs.  The laboratory data collected will be a hsCRP for calculation of the DAS28-CRP.  The 
percentage of various leukocyte isoforms will be collected as part of the mechanistic data.  
Various patient, rheumatologist, and blinded assessor questionnaires will be collected as part of 
the outcomes measures for quality-of-life.  Standardized joint counts by the participant’s 
physician and by the blinded assessor will be collected as well for the DAS28-CRP. 
 
13.4 Source documents and Access to Source Data/Documents 
 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH-GCP, regulatory and institutional requirements for the protection of 
confidentiality of participants.  Each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study safety 
and progress. 
 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participants’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. 
 
13.5 Timing/Reports 
 
MAZERATI is a phase IV clinical trial.  All medications will be dispensed by practicing 
rheumatologists familiar with these therapies and their side effects and contraindications.  All 
therapies will be used in an open-label manner according to FDA-approved guidelines.  The 
participants and the rheumatologists will not be blinded to the therapies, which will allow proper 
clinical management of these participants, including standard-of-care toxicity monitoring.  The 
data safety-monitoring plan is described in detail in Section 9.  Dr. Moreland, the rheumatologist 
who is also PI of this study will hold weekly meetings with the study coordinators to review the 
safety data and MAZERATI reports described in Section 9.  During these meetings, any data 


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which has the potential to stop a participant from continuing is monitored and evaluated.  
Rheumatologists will be required to sign off on all toxicity monitoring lab results in the timeframe 
compatible with standard-of-care. Meeting agendas and notes will be stored by the PIs for at 
least 7 years after the close of MAZERATI. 
 
13.6 Study Records Retention 
 
Study records consist of electronic and paper records generated as a result of the MAZERATI 
study.  These records must be retained for a minimum of three years after the use of the last 
biospecimen from the study.  The principal investigator (Moreland) must give concurrence for 
the destruction of study records. 
 
13.7 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements.  The noncompliance may be either on the part of 
the participant, the investigator, or the study staff.  As a result of deviations, corrective actions 
are to be implemented promptly.  In general, deviations to the MAZERATI clinical protocol are 
not allowed, except when required for the health and safety of the participants. 
These practices are consistent with Good Clinical Practice (GCP ICH E6) Sections: 
 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
 
Quality Assurance and Quality Control, section 5.1.1 
 
Noncompliance, sections 5.20.1, and 5.20.2 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
according to the guidelines of the MAZERATI principal investigators, UPITT, UPMC, and the 
NIH. 
 
The PI will be responsible for the conduct of the trial and for verifying adherence to the protocol 
as well as adherence to all IRB requirements.  All protocol deviations will be reported to the IRB, 
PI and EDC per the instructions in the Manual of Operations. 
 
14.   PUBLICATION POLICY 
 
Following completion of the MAZERATI study, the investigators will publish the results of this 
research in scientific journals.  The International Committee of Medical Journal Editors (ICMJE) 
member journals has adopted a trials-registration policy as a condition for publication.  This 
policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov, which is sponsored by the National Library of Medicine.  MAZERATI will be 
registered at this site prior to its commencement. 
 
A Publications Committee will be formed to review all requests for the use of data derived from 
this clinical trial. The Publications Committee will be chosen during the first 6 months of funding.  
The Publication Committee will be charged with maintaining publication and authorship policies.  
Final authorship determinations will be made by the Publication Committee in consultation with 
Drs. Moreland, McGeachy, Hwang and Wisniewski in accordance with ICMJE guidelines. 


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Publication of the results of this trial will be governed by NIAMS publication policies.  Any 
presentation, abstract, or manuscript will be made available for review by the NIAMS supporters 
prior to its submission.   
 
Drs. Moreland and McGeachy will maintain control of all MAZERATI-generated biospecimens 
and will decide on the scientific merit of any future sub-studies. They will adhere to the letter and 
the spirit of the prevailing NIH and NIAMS guidelines on the sharing of research resources 
produced from federally-funded research. 
 
 
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Williams HJ, Ward JR, Dahl SL, Clegg DO, Willkens RF, Oglesby T, Weisman 
MH, Schlegel S, Michaels RM, Luggen ME, et al.: A controlled trial comparing 
sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. 
Arthritis Rheum 1988, 31(6):702-713.   
http://www.ncbi.nlm.nih.gov/pubmed/2898244 
46. 
Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafstrom I: 
Low-dose prednisolone in addition to the initial disease-modifying 
antirheumatic drug in patients with early active rheumatoid arthritis 
reduces joint destruction and increases the remission rate: a two-year 
randomized trial. Arthritis Rheum 2005, 52(11):3360-3370.   
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=
Citation&list_uids=16255010 
47. 
Todoerti M, Scire CA, Boffini N, Bugatti S, Montecucco C, Caporali R: Early 
disease control by low-dose prednisone comedication may affect the 
quality of remission in patients with early rheumatoid arthritis. Ann N Y 
Acad Sci 2010, 1193(1):139-145.   
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=
Citation&list_uids=20398020 
48. 
Wassenberg S, Rau R, Steinfeld P, Zeidler H: Very low-dose prednisolone in 
early rheumatoid arthritis retards radiographic progression over two years: 
a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2005, 
52(11):3371-3380.   
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=
Citation&list_uids=16255011 


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73 
49. 
Moreland LW, O'Dell JR: Glucocorticoids and rheumatoid arthritis: back to 
the future? Arthritis Rheum 2002, 46(10):2553-2563.   
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=
Citation&list_uids=12384910 
50. 
van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW: Low-
dose prednisone therapy for patients with early active rheumatoid arthritis: 
clinical efficacy, disease-modifying properties, and side effects: a 
randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 
2002, 136(1):1-12.   
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=
Citation&list_uids=11777359 
 


MAZERATI Clinical Protocol 
Appendix A – Study Visits Schedule 
Version 3.0 
 
 
 
 
20 Apr 2015 
 ____________________________________________________________________________________________ 
74 
STUDY VISIT 
Screening-
≤30 days 
Enrollment/Randomization 
≤30 days 
Baseline 
Day 0 
1 
month 
(3-5 
wks) 
3 
months 
(10-14 
wks) 
6 
months 
(22-30 
wks) 
Unscheduled 
visit 
Early 
termination 
VISIT # 
0 
0 
1 
2 
3 
4 
UT 
ET 
Informed consent 
X 
 
 
 
 
 
 
 
Confirm eligibility 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Insurance approval1 
 
X 
 
 
 
 
 
 
Receive first dose of study drug2 
 
 
X 
 
 
 
 
 
Research Laboratory 
 
 
 
Research blood samples 
 
 
X 
X 
X 
X 
 
X 
PK-PD/Immunogenicity samples4 
 
 
X 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
Quantiferon TB-Gold Test⁶ or 
PPD/CXR⁶  
X 
 
 
 
 
 
 
 
Assessments 
 
 
 
Patient questionnaires 
X 
 
X 
X 
X 
X 
 
X 
CDAI exam by physician 
X 
 
X 
X 
X 
X 
 
X 
Blinded joint exam for CDAI/DAS 28 
 
 
X 
X 
X 
X 
 
X 
Drug accountability/ Compliance 
monitoring 
 
 
 
X 
X 
X 
 
X 
AE monitoring 
 
 
X 
X 
X 
X 
X 
X 
Assess RF and/or  CCP autoantibody 
status 
       X 
 
 
 
 
 
 
 
Clinical lab review 
 
CBC/diff/plt/ANC 
 
X 
 
 
X 
X 
X 
X⁷ 
X 
Liver function tests (ALT/AST/ 
T. bili) 
 
 
         X 
 
 
X⁵ 
X⁵ 
X⁵ 
X⁷ 
X⁵ 
Lipid profile 
 
X 
 
 
X⁵ 
X⁵ 
X⁵ 
X⁷ 
X⁵ 
HepBsAg and HepCAb⁶ 
 
X 
 
 
 
 
 
 
 
Urine pregnancy3 
 
X 
 
 
 
 
 
 
 


MAZERATI Clinical Protocol 
Appendix A – Study Visits Schedule 
Version 3.0 
 
 
 
 
20 Apr 2015 
 ____________________________________________________________________________________________ 
75 
 
1 TNF (Arm 1) Only 
2 counseling and training to be provided as standard of care in the outpatient clinic 
3 women of childbearing potential (WOCBP) 
4 Only required for TCZ (Arm 2) at baseline, at time of hypersensitivity/anaphylaxis event (if applicable), and at 6 weeks post-event (if applicable) 
5 Only required for TCZ (Arm 2) patients (per TCZ packaging) 
⁶Results within one year of screening may be used (PPD/Quantiferon TB-Gold test may be used if no risk of exposure has occurred, e.g. travel 
outside the US or contact with TB infected individuals) 
⁷To be completed at the discretion of the treating MD. 


MAZERATI Clinical Protocol 
 
Version 1.0 
Appendix B – Genentech Safety Reporting Fax Cover Sheet 
 
 
 
 ____________________________________________________________________________________________ 
76 
 
 
SAFETY REPORTING FAX COVER SHEET 
Investigator Sponsored Trials 
 
SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-4683 
 
Study Number 
(Genentech study number) 
 
Principal Investigator 
 
Site Name 
 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
(DD/MON/YYYY) 
____ / _____ /_____ 
Follow-up Report Date 
(DD/MON/YYYY) 
____ / _____ /_____ 
 
 
Subject Initials 
(Please enter a dash if the patient 
has no middle name) 
____ - ____ -____ 
 
 
PLEASE PLACE MEDWATCH REPORT or IND SAFETY REPORT BEHIND THIS COVER 
SHEET 
 
 
Please contact Genentech Safety for any questions regarding SAE or IND Safety reporting 
at (888) 835-2555 
 
 
 
 
PAGE 1 OF ___