Conditions: Healthy Participants Rheumatoid Arthritis (RA) Prevention
Keywords: RA prevention hydroxychloroquine (HCQ) anti-CCP3
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 144
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine if hydroxychloroquine (HCQ) is safe and effective for the prevention of future onset of rheumatoid arthritis (RA) in individuals who have elevations of an autoantibody, anti-cyclic citrullinated peptide (anti-CCP3).

The following recruitment strategies will be employed towards identifying healthy subjects with elevated anti-cyclic citrullinated peptide (anti-CCP3) levels:

-Pre-screening:

* first degree relatives of patients with rheumatoid arthritis (RA);
* subjects at health-fairs; and
* identification of subjects with elevated anti-CCP3 levels in the absence of inflammatory arthritis in rheumatology clinics.

Detailed description:
Rheumatoid arthritis (RA) affects an estimated 1% of the population. RA is a disease where the immune system attacks the joints, leading to joint inflammation and damage that is felt by someone with RA as joint pain, stiffness and swelling.

Recent studies have shown that there are markers in the blood called 'autoantibodies' that precede the onset of joint symptoms of RA. Antibodies are commonly made in the blood to fight infections. Sometimes, these antibodies attack one's own body. These are called autoantibodies.

Certain autoantibodies are specific for certain diseases. The autoantibody known as anti-CCP3 is specific for RA and can predict the development of RA in the future, especially if the level of anti-CCP3 is high. The investigators of this study believe that individuals with elevations of anti-CCP3 ≥2 times the normal value have approximately a 50% chance of developing RA within 3 years.

Hydroxychloroquine (HCQ) is already used successfully and safely in the treatment of malaria, lupus and RA. The objective of this study is to determine whether treatment with HCQ in individuals with elevations of anti-CCP3 without joint inflammation may help prevent the future onset of RA. This will involve a 12-month course of HCQ in the prevention of the development of clinically apparent RA at 36 months in individuals at high-risk for future RA due to high titer elevations of anti-CCP3. This study will recruit for individuals without a history or clinical findings of inflammatory arthritis. Eligible subjects will be randomized in a 1:1 ratio to HCQ versus HCQ placebo.

Arms:
arm 1: Subjects randomized to hydroxychloroquine (HCQ). Subjects will receive 200-400 mg of HCQ (1-2 pills), based upon ideal body weight (IBW), taken daily for 12 months. arm 2: Subjects randomized to placebo HCQ. Subjects will receive 200 - 400 mg of HCQ placebo (1-2 pills), based upon IBW, taken daily for 12 months.

Interventions: intervention 1: Hydroxychloroquine intervention 2: HCQ Placebo
Intervention descriptions: intervention 1: As described. Dosing will be based upon Screening IBW. intervention 2: As described. Dosing will be based upon Screening IBW.

Protocol document:
Prot_002.pdf: 
 
 
  
C O N F I D E N T I A L 
Autoimmunity Centers of Excellence 
Protocol ARA08 
 
Strategy to Prevent the Onset of Clinically-Apparent Rheumatoid Arthritis 
(StopRA) 
 
 
Non-IND 
 
Version 3.0: 01MAY2020 
 
 
Sponsor:  
Division of Allergy, Immunology, and Transplantation (DAIT) 
 
  
National Institute of Allergy and Infectious Diseases (NIAID) 
 
  
National Institutes of Health (NIH) 
 
 
 
 
 
 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of 
the Protocol Chair(s), or the Division of Allergy, Immunology and Transplantation; the National Institute of 
Allergy and Infectious Diseases; and the National Institutes of Health. 
 
 














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ABBREVIATIONS 
ACE 
Autoimmunity Centers of Excellence 
ACPAs 
Antibodies to Citrullinated Protein Antigens 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
Anti-CCP 
Anti-Cyclic Citrullinated Peptide 
APGAR 
Appearance, Pulse, Grimace, Activity, and Respiration 
AST 
Aspartate Aminotransferase 
CDAI 
Clinical Disease Activity Index 
CFR 
Code of Federal Regulations 
CNS 
Central Nervous System 
CRP 
C-Reactive Protein 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DAS28-CRP 
Disease Activity Score (28 joints) – C reactive protein 
DHHS 
Department of Health and Human Services 
DMARDS 
Disease-Modifying Antirheumatic Drugs 
DNA 
Deoxyribose Nucleic Acid 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-Linked Immunosorbent Assay 
ESR 
Erythrocyte Sedimentation Rates 
EULAR 
European League Against Rheumatism 
FDA 
Food and Drug Administration 
FDR 
First Degree Relative 
G-6-PD 
Glucose-6-phosphate Dehydrogenase 
GCP 
Good Clinical Practice 
HCQ 
Hydroxychloroquine 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HTN 
Hypertension 
hs-CRP 
High-Sensitivity C-Reactive Protein 
IA 
Inflammatory Arthritis 
IBW 
Ideal Body Weight 
ICH 
International Conference on Harmonization 
IgM 
Immunoglobulin M 
IL 
Interleukin 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISF 
Investigator’s Study Files 
ITT 
Intention-to-Treat or Intent-to-Treat 


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IV 
Intravenous 
KM 
Kaplan-Meier 
LEF 
Leflunomide 
LLN 
Lower Limit of Normal 
MCPs 
Metacarpophalangeal Joints 
MDHAQ 
Multi-dimensional Health Assessment Questionnaire 
MHC 
Major Histocompatibility Complex 
mITT 
Modified Intent-to-Treat 
MTX 
Methotrexate 
NCI-CTCAE 
National Cancer Institute- Common Terminology Criteria for 
Adverse Events 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NSAIDS 
Non-Steroidal Anti-Inflammatory Drug 
NYHA 
New York Heart Association 
OCT 
Optical Coherence Tomography 
OHRP 
Office of Human Research Protection 
PBMC 
Peripheral Blood Mononuclear Cells 
PI 
Principal Investigator 
PP 
Per Protocol 
PPV 
Positive Predictive Value 
PR 
Palindromic Rheumatism 
PRO 
Patient Reported Outcomes 
PROMIS 
Patient-reported Outcomes Measurement Information System 
RA 
Rheumatoid Arthritis 
RAIN 
Rheumatoid Arthritis Investigator Network 
RAPID-3 
Routine Assessment of Patient Index Data 3 
RF 
Rheumatoid Factor 
RhoFED 
Rho Federal Systems Division, Inc. 
RNA 
Ribonucleic Acid 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SDAI  
Simplified Disease Activity Index 
SD 
Spectral Domain 
SE 
Shared Epitope 
SERA 
Studies of the Etiology of Rheumatoid Arthritis 
SLE 
Systemic Lupus Erythematosus 
SP 
Safety Population 
SSZ 
Sulfasalazine 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
WBC 
White Blood Cells 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS..................................................................................................5
FLOW DIAGRAM OF PROTOCOL...............................................................................7
ABBREVIATIONS ...........................................................................................................8
TABLE OF CONTENTS ................................................................................................10
1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................15
1.1
DESCRIPTION AND EPIDEMIOLOGY OF DISEASE..................................................... 15
1.1.1
Clinical pathophysiology of RA and measurement of disease activity ...........16
1.1.2
Autoantibodies and measures of inflammation in RA ...................................16
1.1.2.1
Biology of RF and ACPAs..................................................................17
1.1.2.2
Diagnostic accuracy of RF and ACPAs ..............................................17
1.1.2.3
Seropositivity and RA severity............................................................18
1.1.2.4
Inflammatory markers and RA ...........................................................18
1.1.3
Classification of RA....................................................................................18
1.1.4
Risk factors for RA .....................................................................................19
1.1.5
Natural history of RA: Focus on preclinical disease development ................20
1.1.6
Prediction of future RA in individuals without current inflammatory 
arthritis......................................................................................................22
1.1.7
Current Treatment for RA ...........................................................................24
1.2
STUDY PLAN ...................................................................................................... 26
1.3
CLINICAL STUDIES OF HYDROXYCHLOROQUINE IN RA.......................................... 27
1.3.1
Hydroxychloroquine Background................................................................27
1.3.2
Current Licensing of Hydroxychloroquine...................................................27
1.3.3
Other Diseases in Which Hydroxychloroquine Use Has Been Described ......27
1.4
KNOWN AND POTENTIAL RISKS AND BENEFITS OF HYDROXYCHLOROQUINE........... 28
1.4.1
Known and Potential Benefits of Hydroxychloroquine in RA and Other 
Diseases.....................................................................................................28
1.4.2
Known and Potential Risks of Hydroxychloroquine .....................................29
1.4.2.1
Ocular Toxicity .................................................................................29
1.4.2.2
Additional Toxicities..........................................................................30
1.5
RATIONALE FOR STUDY DESIGN .......................................................................... 31
1.5.1
Rationale for the Treatment Arm.................................................................31
1.5.2
Rationale for Duration of HCQ Treatment and Post-Treatment Follow-up ...32
1.5.3
Rationale for the Control Arm ....................................................................33
1.5.4
Rationale for the Inclusion Criteria.............................................................33
1.5.5
Rationale for the Exclusion Criteria............................................................33
1.5.6
Rationale for Mechanistic Studies ...............................................................34
2 STUDY OBJECTIVES AND PURPOSE ...................................................................34
2.1
PRIMARY OBJECTIVE .......................................................................................... 34
2.2
SECONDARY OBJECTIVES .................................................................................... 34
3 STUDY DESIGN ........................................................................................................35


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3.1
DESCRIPTION OF STUDY DESIGN.......................................................................... 35
3.1.1
Stratification, Randomization, and Blinding ................................................36
3.1.1.1
Subject Completion and Replacement.................................................36
3.2
DESCRIPTION OF PRIMARY ENDPOINT .................................................................. 36
3.3
DESCRIPTION OF SECONDARY ENDPOINTS ............................................................ 37
3.3.1
Secondary Efficacy Endpoints.....................................................................37
3.3.2
Secondary Safety Endpoints ........................................................................38
3.3.3
Secondary Mechanistic Endpoints...............................................................38
4 SELECTION OF SUBJECTS ....................................................................................38
4.1
INCLUSION CRITERIA .......................................................................................... 38
4.2
EXCLUSION CRITERIA ......................................................................................... 38
4.2.1
Co-enrollment Guidelines ...........................................................................40
4.3
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................. 40
4.3.1
FDRs of probands with RA .........................................................................40
4.3.2
Health-Fair, Biobank, or Population-based Pre-Screening ..........................41
4.3.3
Rheumatology Clinics.................................................................................41
5 TREATMENT OF SUBJECTS..................................................................................42
5.1
DESCRIPTION OF STUDY PRODUCT ....................................................................... 42
5.1.1
Product Description ...................................................................................42
5.1.2
Packaging and Labeling of Study Product ...................................................42
5.1.3
Storage and Handling of Study Product ......................................................43
5.1.4
Study Product Accountability......................................................................43
5.2
DOSAGE REGIMEN .............................................................................................. 43
5.3
ADMINISTRATION OF STUDY PRODUCT ................................................................ 44
5.3.1
Preparation for Administration ...................................................................44
5.3.2
Administration ...........................................................................................44
5.4
TOXICITY MANAGEMENT PLAN FOR STUDY PRODUCT .......................................... 44
5.4.1
Prevention of Known Toxicities to Study Product ........................................44
5.4.1.1
Ocular Toxicity .................................................................................44
5.4.2
Management of Known Toxicities to Study Product .....................................45
5.4.2.1
Hematologic Reactions ......................................................................45
5.4.2.2
Gastrointestinal Reactions .................................................................45
5.4.2.3
Allergic Reactions .............................................................................45
5.4.2.4
Over Dosage .....................................................................................45
5.5
CONCURRENT MEDICATIONS AND THERAPY ......................................................... 46
5.6
PROHIBITED MEDICATIONS ................................................................................. 46
5.7
PROCEDURES FOR MONITORING SUBJECT COMPLIANCE ........................................ 47
5.8
TREATMENT DISCONTINUATION AND SUBJECT WITHDRAWAL ............................... 47
5.8.1
Study Treatment Discontinuation ................................................................47
5.8.1.1
Procedures for Discontinuation of Protocol-Specified Treatment 
Requirements ....................................................................................48
5.8.2
Subject Withdrawal from the Study .............................................................48
5.8.2.1
Procedures for Subject Withdrawal from the Study .............................48
5.8.3
Safety Stopping Guidance ...........................................................................49


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6 ASSESSMENT OF SAFETY AND EFFICACY ........................................................49
6.1
ASSESSMENTS OF SAFETY ................................................................................... 49
6.2
ASSESSMENTS OF EFFICACY ................................................................................ 50
6.2.1
ACR/EULAR Criteria (2010) ......................................................................50
6.2.2
Joint Assessment, Definitions of Inflammatory Arthritis, and Joint 
Tenderness .................................................................................................50
6.2.3
Determination of disease activity ................................................................50
6.2.3.1
Disease Activity Score (DAS) .............................................................50
6.2.3.2
Modified Multi-Dimensional Health Assessment Questionnaire 
(MDHAQ) .........................................................................................51
6.2.3.3
Patient Reported Outcomes Measurement Information System ............51
6.2.3.4
Questionnaire Assessment of Self-Reported Symptoms ........................51
6.2.3.5
X-ray Imaging ...................................................................................51
6.3
ENVIRONMENTAL AND OTHER FACTORS ............................................................... 52
6.4
MECHANISTIC SPECIMENS AND STUDIES .............................................................. 52
6.4.1
Genetic risk factors ....................................................................................52
6.4.2
HCQ Levels ...............................................................................................52
6.4.3
Mechanistic studies ....................................................................................53
6.4.4
Specimen Storage for Future Use and Genetic Research..............................53
6.5
EVALUATIONS BY STUDY VISIT ........................................................................... 54
6.5.1
Pre-Screening ............................................................................................54
6.5.2
Screening Visit ...........................................................................................56
6.5.3
Baseline/Randomization Visit .....................................................................57
6.5.4
Treatment Period .......................................................................................58
6.5.4.1
Treatment Clinic Visits: Week 6, Week 12, & Week 36 (Visit 
Windows: +/- 7 days) ........................................................................58
6.5.4.2
Mid-Treatment Clinic Visit: Week 24 (Visit Windows: +/- 7 days).......59
6.5.4.3
End of Treatment: Week 52 (Visit Window: +/- 14 days).....................60
6.5.4.4
Treatment Telephone Assessments (Weeks 18, 30, & 42, Visit 
Window: +/- 7 days)..........................................................................61
6.5.5
Follow-up Visits .........................................................................................61
6.5.5.1
Follow-up Telephone Assessments (Months 15, 21, 27, & 33,Visit 
Window: +/- 14 days) ........................................................................61
6.5.5.2
Follow-up Clinic Visit: Month 18 (Visit Windows: +/- 14 days) ..........62
6.5.5.3
Follow-up Clinic Visit: Month 24 (Visit Windows: +/- 14 days) ..........63
6.5.5.4
Follow-up Clinic Visit: Month 30 (Visit Windows: +/- 14 days) ..........63
6.5.5.5
End of Study Clinic Visit: Month 36/Early Termination (Visit 
Windows: +/- 14 days) ......................................................................64
6.5.5.6
Time of Diagnosis Clinic Visit ...........................................................66
6.5.6
Early Withdrawal Visit ...............................................................................67
6.5.7
Visit Windows ............................................................................................67
6.5.8
Unscheduled Visits .....................................................................................67
6.5.9
Evaluations Triggered by a Swollen Joint ...................................................68
6.5.10
Procedures for Subjects Diagnosed with Inflammatory or Rheumatoid 
Arthritis by an Outside Physician................................................................70


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Special Considerations for Pregnant Subjects .............................................71
7 SAFETY MONITORING AND REPORTING..........................................................76
7.1
OVERVIEW ......................................................................................................... 76
7.2
DEFINITIONS ...................................................................................................... 76
7.2.1
Adverse Event (or Adverse Experience).......................................................76
7.2.2
Adverse Reaction and Suspected Adverse Reaction ......................................76
7.2.3
Unexpected Adverse Reaction .....................................................................76
7.2.4
Serious Adverse Event ................................................................................76
7.3
COLLECTION AND RECORDING OF ADVERSE EVENTS ............................................ 77
7.3.1
Investigational Product ..............................................................................77
7.3.2
Collection Period .......................................................................................77
7.3.3
Collecting Adverse Events ..........................................................................77
7.3.4
Recording Adverse Events ..........................................................................78
7.3.5
Recording Serious Adverse Events ..............................................................78
7.4
GRADING AND ATTRIBUTION OF ADVERSE EVENTS............................................... 78
7.4.1
Grading Criteria ........................................................................................78
7.4.2
Attribution Definitions ................................................................................79
7.5
REPORTING OF ADVERSE EVENTS ........................................................................ 80
7.5.1
Reporting of Adverse Events to DAIT/NIAID ...............................................80
7.5.1.1
Procedure for Adverse Events Requiring 24 Hour Reporting ..............80
7.5.1.2
Procedure for Standard Adverse Event Reporting...............................80
7.5.2
DAIT/NIAID Reporting to the Health Authority ...........................................80
7.5.3
Reporting of Adverse Events to IRBs ...........................................................81
7.6
PREGNANCY REPORTING ..................................................................................... 81
7.7
REPORTING OF OTHER SAFETY INFORMATION ...................................................... 81
7.8
REVIEW OF SAFETY INFORMATION....................................................................... 81
7.8.1
Medical Monitor Review.............................................................................81
7.8.2
DSMB Review ............................................................................................82
8 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .........................82
8.1
SAMPLE SIZE AND POWER ................................................................................... 82
8.2
ANALYSIS POPULATIONS..................................................................................... 83
8.2.1
Safety Population .......................................................................................83
8.2.2
Modified Intent-to-Treat Population............................................................83
8.2.3
Per Protocol Population .............................................................................83
8.3
STATISTICAL METHODS ...................................................................................... 83
8.3.1
Efficacy Analysis ........................................................................................84
8.3.1.1
Primary Efficacy Analysis..................................................................84
8.3.1.2
Secondary Efficacy Analyses..............................................................84
8.3.2
Safety Analysis ...........................................................................................85
8.3.3
Mechanism/Immunological Analysis ...........................................................86
8.4
INTERIM ANALYSIS ............................................................................................. 86
8.5
OTHER STATISTICAL CONSIDERATIONS ................................................................ 87
8.5.1
Subgroups ..................................................................................................87
8.5.2
Multi-center Studies ...................................................................................87


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8.5.3
Multiple Comparisons and Multiplicity .......................................................87
8.5.4
Missing Data..............................................................................................87
8.5.5
Changes to the Statistical Analysis Plan (SAP) ............................................88
9 ACCESS TO SOURCE DATA AND DOCUMENTS ................................................88
10 DATA COLLECTION, QUALITY CONTROL AND QUALITY ASSURANCE ....88
11 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE ...................................................................................................89
11.1
COMPLIANCE WITH GOOD CLINICAL PRACTICES ................................................... 89
11.2
INSTITUTIONAL REVIEW BOARD .......................................................................... 90
11.3
INFORMED CONSENT........................................................................................... 90
11.4
DATA AND SAFETY MONITORING BOARD ............................................................. 90
11.5
STUDY TERMINATION ......................................................................................... 91
12 FINANCING AND INSURANCE ..............................................................................91
13 PUBLICATION POLICY ..........................................................................................91
14 REFERENCES...........................................................................................................92
15 APPENDICES ..........................................................................................................104
15.1
2010 ACR/EULAR RA CLASSIFICATION CRITERIA............................................ 105
15.2
FLOW DIAGRAMS ............................................................................................. 106
15.2.1
Evaluations Triggered by a Swollen Joint Flow Chart ...............................106
15.2.2
Procedures for Subjects Diagnosed with IA/RA by an Outside Physician 
Flow Chart ..............................................................................................107
15.3
FORMULAS ....................................................................................................... 108
15.4
NYHA CLASSIFICATION ................................................................................... 109
15.5
SUBJECT QUESTIONNAIRES................................................................................ 110
15.5.1
Pre-Screening Questionnaire ....................................................................110
15.5.2
Self-Reported Demographics ....................................................................111
15.5.2.1 Self-Reported Demographics: Screening ..........................................111
15.5.2.2 Self-Reported Demographics: End of Study ......................................115
15.5.3
Self-Reported Joint Symptoms including modified MDHAQ .......................116
15.5.4
Subject Epidemiologic Questionnaire: Baseline & Follow-up ....................120
15.5.4.1 Subject Epidemiologic Questionnaire: Baseline................................120
15.5.4.2 Subject Epidemiologic Questionnaire: Follow-up .............................125
15.5.5
Dietary Assessment Questionnaire ............................................................130
15.5.6
Profile 29 (v2.0) .......................................................................................134


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1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
This clinical trial will evaluate a novel screening and treatment approach for the large-scale 
prevention in individuals who are at high-risk of developing future clinically-apparent RA. The 
success of this trial will represent a substantial shift in the way that we can approach RA, with a 
new emphasis on prevention rather than solely on treatment of clinically-apparent disease – much 
like the focus in clinical practice today is on prevention of cardiovascular disease rather than 
solely treating its consequences.  Additionally, the natural history and mechanism-based studies 
that will be performed as part of this trial, or be possible at a future date using materials collected 
during this study, will provide us with unique insights into the biology of early RA development 
that may further our understanding of this disease and perhaps guide additional preventive 
therapies. Finally, the infrastructure that will be developed as part of this trial, screening very 
large numbers of individuals and identifying those at significant risk of development of clinically-
apparent RA, will enable the implementation of future studies of the development and prevention 
of RA.  
1.1 
Description and Epidemiology of Disease 
Rheumatoid arthritis is a systemic autoimmune inflammatory disease that affects ~1% of the 
population, making it one of the most common chronic autoimmune diseases [1]. It affects 
women more often than men in a ratio of ~3 to 1, and the average age of onset is ~50 years old. In 
terms of clinical manifestations, RA primarily affects the joints, with small joints being the 
primary joints involved (Figure 1.1); however, multiple other systems including respiratory tract 
(e.g. interstitial lung disease), cardiovascular system (e.g. myocardial infarction) and bones (e.g. 
osteoporosis) can be affected [2-6].  
The overall effects of RA lead to substantial morbidity in terms of joint pain and damage due to 
destructive arthritis, decreased quality of life, as well as increased mortality compared to age-
matched non-RA populations [7-9]. In particular, because the average age of onset of RA is ~50 
years-old, people affected by RA are often in their prime working years, further increasing the 
adverse impact of RA on society. As a result of this as well as the expensive therapies that are 
commonly needed to manage the disease, RA leads to substantial financial costs, with estimates 
of >$30 billion annual total health costs in the United States alone [10].  
While improving pharmacologic therapies and treatment strategies for RA, including early 
aggressive therapy have led to improved outcomes [11] (discussed in Section 1.1.7, Current 
Treatment for RA), for the great majority of patients with RA the disease is chronic and requires 
life-long therapy. Specifically, in analyses of 871 subjects with RA followed in clinical practice, 
Prince and colleagues found only 45% met criteria for disease remission, and even when 
remission was reached it was often short-lived (<1 year) [12]. In addition, for many patients with 
RA, therapy with a single agent is inadequate to control the disease and therefore multiple agents 
are required, which increases the costs of treatment. In particular, the addition of a biologic 
therapy, which is necessary in 30-40% of patients with established disease, can lead to medication 
costs alone of over $1000 per month [13]. Additionally, therapies for RA are associated with a 
range of toxicities that require frequent monitoring and include, but are not limited, to infection, 
organ injury (e.g. hepatitis) and gastrointestinal effects [14, 15]. Therefore, strategies to prevent 


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RA prior to its onset may lead to substantial improvements in the public health impact of this 
disease. 
1.1.1 
Clinical pathophysiology of RA and measurement of disease activity 
The hallmark of RA is synovial inflammation/synovitis that leads to joint destruction. To the 
patient, this inflammation is characterized by joint pain, stiffness and swelling, which can all 
contribute to a loss of function and decreased quality of life. In addition, the systemic 
inflammation associated with RA leads to effects such as fatigue and malaise, which can also 
have a major impact on overall well-being in patients with RA [16-18]. On physical examination, 
this inflammatory arthritis (IA) is characterized by joint swelling (both from synovial hypertrophy 
as well as joint effusions), tenderness and warmth, and, potentially, deformity and loss of range of 
motion (Figure 1.1).   
In clinical management of RA, disease activity can be assessed by measuring the number of 
tender and swollen joints on examination, systemic measures of inflammation such as the 
erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as by assessing a 
patient’s self-reported symptoms of pain, fatigue and overall well-being [19-21]. Validated 
measures to assess disease activity include instruments such as the Disease Activity Score (DAS) 
that includes assessment of tender and swollen joints, inflammatory markers (ESR or CRP), and a 
patient’s report of global health. Other validated measures that are used to assess RA disease 
activity include the Modified Multi-Dimensional Health Assessment Questionnaire (MDHAQ), 
the Clinical Disease Activity Index (CDAI), and the Simplified Disease Activity Index (SDAI) 
[22-24]. Importantly, measures of disease activity are now considered essential aspects of 
managing RA as part of ‘treat to target’ strategies where clinicians treat RA to meet a goal of low 
disease activity as measured by a validated instrument [25]. No single instrument has been 
deemed superior in the measurement of RA disease activity; however, the most commonly used 
measures include the MDHAQ, the DAS that includes a 28 or 44 joint count, the CDAI, and the 
measurement of the CRP. 
Radiographically, the classic finding of RA is erosive disease, as demonstrated in Figure 1.2. 
Erosions are seen in a substantial proportion of patients with RA, and are part of the diagnostic 
criteria for RA (see footnote for Table 1.1). Additionally, erosions are indicative of more severe 
disease process. Importantly, erosions and associated joint destruction are now believed to 
develop within a few months after the onset of RA and because of that, as discussed in Section 
1.1.7, Current Treatment for RA, treatment strategies for RA are now designed to control synovial 
inflammation prior to the development of erosions in order to preserve long-term joint integrity 
and function [26-30].                            
1.1.2 
Autoantibodies and measures of inflammation in RA 
Autoantibodies are an important component of both the pathophysiology and diagnosis of RA. 
Numerous autoantibodies have been identified in RA; however, two autoantibody systems have 
the highest prevalence as well as the highest specificity for RA. The first, rheumatoid factor, can 
be tested through several modalities including nephelometry as well as enzyme-linked 
immunosorbent assay (ELISA) testing for specific isotypes, with ELISA testing for the 
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The other autoantibody system is antibodies to citrullinated protein antigens (ACPAs). There are 
several commercially-available methods to test ACPAs, but the most common is the anti-CCP 
antibody test, which now has several generations (CCP, CCP2, CCP3 and CCP3.1)[31].  
 
 
Figure 1.2 Destructive bony erosion in RA. The image on the left demonstrates 
fairly normal appearing bone around the joint. However, over time, a large 
erosion has developed (Arrow, C). These types of erosions are associated with 
joint deformity and loss of function. (c) 2014 American College of 
Rheumatology. Used with permission. 
 
 
1.1.2.1 Biology of RF and ACPAs  
Rheumatoid factor is an autoantibody that targets the Fc portion of another antibody; it is often an 
IgM isotype, although IgA and IgG isotypes are also seen in RA. In terms of pathophysiology of 
RA, RF has been implicated in the formation of immune complexes that can initiate as well as 
propagate synovitis. Citrulline is a post-translationally modified version of arginine, and citrulline 
and its flanking sequences are targeted by ACPAs [32-34]. In RA, there are a number of 
citrullinated proteins that are targeted by ACPAs including vimentin, filaggrin, fibrinogen and 
collagen among others. In animal studies, the presence of ACPAs amplifies experimental arthritis 
[35]. In addition, studies have demonstrated that ACPAs participate in immune complex 
formation in RA, as well as directly targeting structures within the joint [34, 36-39]. ACPAs have 
also been demonstrated to contribute to joint damage in RA by activating osteoclasts [40, 41]. 
Additional details regarding the role of RF and ACPAs in the pathogenesis of RA are discussed in 
Section 1.1.5, Natural history of RA: Focus on preclinical disease development. 
1.1.2.2 Diagnostic accuracy of RF and ACPAs  
Rheumatoid factor and/or ACPAs are present in ~60-80% of patients with RA, and if present, the 
disease is labeled ‘seropositive RA’ (for additional discussion see Section 1.1.3, Classification of 
RA). In particular, in a number of studies, the sensitivity of RF for RA has ranged from 60-80%, 
with specificities of ~60-80%. The anti-CCP tests (which are one of the most well-studied 
 
Figure 1.1. Active rheumatoid arthritis with 
visible swelling across multiple metacarpal 
phalangeal joints (c) 2014 American 
College of Rheumatology. Used with 
permission. 
 


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versions of ACPAs in RA) are also ~60-80% sensitive for RA; however, their specificity is much 
greater than RF for RA, with most studies finding that elevations of anti-CCP of a variety of 
generations (e.g. CCP2, CCP3) are >95% specific for RA [31, 42].  In addition, for both RF and 
ACPAs, higher levels of autoantibodies (e.g. >2-3 times the normal cut-off values) have greater 
specificity for disease.                   
1.1.2.3 Seropositivity and RA severity  
Identification of RF and/or ACPA positivity in RA assists with the classification/diagnosis of a 
patient with IA; in addition, determining autoantibody positivity helps with the prediction of 
disease severity. In particular, seropositive RA is generally thought to be more severe and 
persistent than seronegative RA [43-46], and emerging data suggest that positivity for anti-CCP 
imparts the highest risk for more severe RA [47-51]. As such, identification and treatment of 
seropositive RA is currently a major focus of the rheumatologic community and therefore 
preventive approaches that target seropositive RA will likely have the greatest positive impact. 
1.1.2.4 Inflammatory markers and RA   
Both local and systemic inflammations are present in RA. Multiple tests have been used to assess 
systemic inflammation in RA including ESR and CRP, white blood cell counts and total 
immunoglobulins, and specific cytokines and chemokines [52, 53]. In clinical practice, the 
measures most commonly used are the CRP and ESR, and elevations of these markers in RA have 
been associated with poor outcomes including need for joint replacement and increased mortality 
[4, 9, 54, 55]. These tests are readily available in most clinical laboratories, have been well-
studied as good outcome measures in RA, and in particular, the CRP is quite stable in stored 
blood specimens [53]. Most of the validated disease activity measures for RA, such as the DAS, 
have been developed to include CRP or ESR testing [24]. Finally, as discussed in Section 1.1.3, 
Classification of RA, the 2010 Classification criteria for RA also include CRP and/or ESR testing. 
As such, CRP and ESR form an integral part of assessment in RA. In particular, the version of 
CRP called ‘high-sensitivity CRP’ is particularly useful for assessment of inflammation in RA 
and in particular research-related studies because of its stability in stored samples, and its 
improved ability over standard CRP to measure small changes in levels [56]. 
1.1.3 
Classification of RA 
Rheumatoid arthritis is diagnosed when a patient presents with the signs and symptoms that meet 
classification criteria for disease with these symptoms including presence and duration of joint 
pain, stiffness and swelling, and signs including tenderness and swelling on examination as well 
as imaging and blood test findings that include autoantibodies and inflammatory markers such as 
ESR and CRP.  
There are now 2 sets of classification criteria established for RA: the 1987 American College of 
Rheumatology (ACR) criteria [57], and the 2010 ACR/European League Against Rheumatism 
(EULAR) criteria [58]. These 2 sets of criteria are presented in Table 1.1. As mentioned above, 
for the majority (~60-80%) of patients, RA is characterized by the presence of autoantibodies RF 
and/or ACPAs; if one or both of these autoantibodies are present, RA is termed ‘seropositive’ 
disease [42].  


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Notably, the 2010 criteria were developed in large part to allow for an earlier diagnosis and 
subsequent treatment of RA as compared to the 1987 criteria. Follow-up studies on these criteria 
have shown that indeed the 2010 criteria classify patients with RA earlier than do the 1987 
criteria [59-61]. As such, the 2010 criteria have emerged as the primary criteria for use in patients 
with early IA and are therefore deemed most appropriate to use to define the primary endpoint in 
a prevention trial for RA.  In addition, while the presence of erosions are not included in the main 
2010 criteria largely due to the belief that erosions may not be present in early RA, if erosions are 
present in the setting of other features of disease, the 2010 Criteria suggest that patients should be 
considered to have RA [62]. 
 
Table 1.1. Comparison of the 1987 ACR RA and 2010 ACR/EULAR RA Classification Criteria 
1987 ACR Classification Criteria 
2010 ACR/EULAR Classification Criteria[62] 
1) Morning stiffness >1 hour 
2) Arthritis of ≥3 joint areas 
3) Hand arthritis 
4) Symmetric arthritis 
5) Nodules 
6) Elevation of rheumatoid factor 
7) Radiographic changes 
 
Findings 1-4 must be present for ≥6 weeks. 
 
4/7 criteria must be satisfied to meet the 
definition of RA. 
 
 Arthritis must be observed by a physician. 
Who should be tested?  Patients with ≥1 swollen joint 
consistent with synovitis not better explained by another 
disease.  If the patient meets these initial criteria with a 
score of ≥6/10 they can be classified as having ‘definite 
RA’: 
A.  Joint involvement* 
1 large joint                                   
0 
2-10 large joints                             1 
1-3 small joints                              2 
4-10 small joints                            3 
>10 joints (at least 1 small)           5 
B.  Serology (at least 1 test needed) 
Negative RF and ACPA                0 
Low positive RF or ACPA            2 
High positive RF or ACPA**       
3 
C.  Acute-phase reactants (at least 1 test needed) 
Normal CRP and ESR                   0 
Abnormal CRP or ESR                 
1 
D.  Duration of symptoms 
<6 weeks                                       
0 
 ≥6 weeks                                       1 
* Joint involvement refers to any swollen or tender joint on examination. Distal interphalangeal joints, first carpometacarpal 
joints, and first metatarsophalangeal joints are excluded from assessment. “Large joints “refers to shoulders, elbows, hips, knees, 
and ankles. “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth 
metatarsophalangeal joints, thumb interphalangeal joints, and wrists.  
** High positive is equivalent to >3 times the upper limit of normal based on the reference range of the laboratory that assesses 
the biomarker. 
NOTE: Patients with erosive disease typical of rheumatoid arthritis with a history compatible with prior fulfillment of the 2010 
criteria should be classified as having RA. 
1.1.4 
Risk factors for RA 
The exact etiology of RA is currently unknown; however, multiple genetic and environmental 
risk factors have been associated with disease. In particular, specific gene sequences contained 
within the Major Histocompatibility Complex (MHC), which  are in aggregate termed the shared 






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Figure 1.5 Preventive approach to RA. Pharmacologic interruption of the 
expansion of autoimmunity in preclinical RA could lead to abrogation of 
progression to clinically-apparent RA. 
 
 
 
 
 
 
The precise mechanisms that drive a transition from circulating autoimmunity in absence of 
clinically-apparent synovitis to clinically-apparent synovitis are not yet known. However, studies 
of early synovitis in RA as well as synovial tissue samples from subjects with autoantibody 
positivity in the absence of otherwise clinically-apparent synovitis suggest that immune complex 
deposition and other immune targeting that may lead to infiltration of inflammatory cells are 
likely the factors that initiate synovitis in RA [89]. Importantly, this model of RA development 
strongly suggests that a preclinical intervention with an immunomodulatory agent that could 
decrease autoantibody expansion and epitope spreading, and inflammation in preclinical RA, as 
well as perhaps lead to long-lasting normalization of immune responses, could ultimately lead to 
decreased transition from asymptomatic autoimmunity to clinically-apparent RA (Figure 1.5), 
These concepts form the basis 
of this clinical trial for the 
prevention of RA. 
 
 
 
 
 
 
 
1.1.6 
Prediction of future RA in individuals without current inflammatory 
arthritis 
Autoantibody testing in preclinical RA has led to a greater understanding of the pathogenesis of 
disease development. In addition, autoantibody testing can be used in preclinical RA to predict 
the likelihood as well as timing of future RA in individuals who are currently without IA (Table 
1.2).  
 Figure 1.4 Phases of development of RA. In this model of RA development, disease begins with genetic and 
environmental risks (Phase 1), followed by autoimmunity and inflammation (Phase 2), with eventual 
progression to symptomatic and clinically-apparent inflammatory arthritis (Phase 3) that ultimately can be 
classified as RA by established classification criteria (Phase 4). 


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Importantly, while both RF and ACPAs (including anti-CCP testing) are predictive of future 
disease, anti-CCP testing has emerged as the test with the highest positive predictive value (PPV) 
for future onset of RA. This has been demonstrated in multiple retrospective case-control studies 
where anti-CCP positivity consistently demonstrates PPVs for future RA of >90% (Table 1.2). As 
mentioned above, there are several types of anti-CCP testing clinically available including anti-
CCP2, anti-CCP3, and anti-CCP3.1, all of which have high specificity (>90%) for RA in patients 
with established inflammatory arthritis [90]. As for data regarding specificity for future RA using 
the anti-CCP3 test, using a set of samples from a cohort of 83 United States Armed Forces 
personnel, who ultimately developed RA and 83 matched controls, anti-CCP3 levels of ≥2 times 
the normal cut-off of ≥20 units (or ≥40 units) was 99% specific for future RA (manuscript in 
preparation by Deane KD et al). As such, testing for anti-CCP3 and in particular using a cut-off 
level that is ≥2 times the normal cut-off level in individuals without current IA is highly 
predictive of future development of RA. 
In addition to predicting the overall 
likelihood of RA development, 
autoantibodies, and in particular anti-CCP 
can be used to predict the timing of future 
onset of RA – an important concept when 
considering a clinical trial of limited temporal 
duration. Supporting this, in multiple studies, 
anti-CCP positivity is first identified on 
average 3-5 years prior to the clinical onset of 
RA [76-78, 91]; therefore, if anti-CCP is 
positive, as discussed above it is highly 
specific for the future onset of RA, as well as 
highly indicative of RA within a 5-year time 
period.  In addition, higher levels of 
autoantibody typically develop closer to the 
time of clinical appearance of RA (Figure 
1.6). In particular, in a prospective study of 
subjects who were positive for anti-CCP in 
the absence of inflammation at baseline, van de Stadt and colleagues demonstrated that anti-CCP 
levels >3 times the normal cut-off level were the strongest predictive factor for development of 
future RA with a 2-3 year period [92]. Bos and colleagues have also shown that ~30% of subjects 
with anti-CCP2 positivity developed RA within ~3 years; in addition, subjects with the highest 
levels of anti-CCP2 had the highest rates of progression (>50%) to RA [85]. In addition, Beck 
and colleagues have identified in prospective follow-up of individuals identified with anti-CCP2 
or anti-CCP3 positivity in absence of IA through health-fair screening that anti-CCP2 levels of 
>2-3 times the normal cut-off level were associated with a 70% PPV of development of RA 
within 3 years [86]. Furthermore, Demoruelle and colleagues have demonstrated that anti-CCP2 
levels >2 times the normal cut-off level had a 55% PPV for the onset of clinically-apparent RA 
within 2 years [31], with additional unpublished analyses identifying that an elevation of anti-
CCP3 ≥2 times the normal cut-off had a PPV of ~60% for future RA within 3 years. Finally, in a 
natural history study of initially arthritis-free FDRs of family members with RA, Ramos-Remus 
Figure 1.6 CCP3 levels rise in preclinical RA. In serum samples 
obtained from military subjects prior to the onset of RA, median 
levels (solid black line) of anti-CCP3 increase as the time of 
diagnosis approaches. The horizontal black line represents the 
normal cut-off level for anti-CCP3 positivity (≥20 units). 
Importantly, anti-CCP3 levels that are ≥2 time the normal cut-off 
level (or ≥40 units indicated by the dotted black line) are typically 
found within 5 years of diagnosis (Kevin Deane, Manuscript in 
Development). 




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The mechanisms for improved outcomes associated with earlier therapy are not yet clear, 
although there are some speculations. It may be that early therapy suppresses inflammation before 
the immune system has had time to develop permanent alterations in cellular processes that could 
drive inflammation. For example, in the setting of longstanding inflammation, synovial 
fibroblasts in RA may undergo epigenetic changes that make them less amenable to ‘turn off’ 
their production of damaging enzymes, and early treatment may prevent those changes from 
occurring [97-101]. In addition, as discussed in Section 1.1.5, Natural history of RA: Focus on 
preclinical disease development, epitope spreading is an important feature in the early evolution 
of RA, and may in fact be crucial to the transition from asymptomatic autoimmunity to clinically-
apparent disease; as such, early treatment may reduce inflammation and also epitope spreading 
and therefore lead to less wide-spread tissue damage [84, 102, 103]. In addition, it may be that 
early pharmacologic immunomodulation may allow for endogenous regulatory mechanisms to 
counter the development of autoimmunity and restore tolerance [104, 105].  
However, while the expanding therapeutic armamentarium for RA as well as the finding that 
earlier institution of therapy leads to improved long-term outcomes has been encouraging to the 
field, for the majority of patients and even those who are treated soon after the onset of their RA 
symptoms, the disease requires life-long systemic immunotherapy. In particular, as previously 
mentioned, the study by Prince and colleagues demonstrated that <50% of patients with RA who 
are followed in routine clinical practice achieve remission by defined criteria; furthermore, even 
if remission was reached, it typically lasted <1 year [12]. As such, immunologic therapy even 
initiated soon after the onset of clinically-apparent disease is unlikely to treat disease in a 
sufficient proportion of subjects to avoid the adverse health impacts and high cost of RA; 
therefore, preventive approaches hold great promise to reduce the significant adverse impact of 
RA on public health. 
Importantly, despite the failure to reach remission in the majority of patients with RA seen in 
routine clinical practice, the benefits of early therapy in RA support the notion that therapy 
instituted even prior to the clinical appearance of synovitis has a strong chance to abrogate 
immune responses and halt the progression to clinically-apparent RA. Early therapy may even 
potentially lead to a permanent ‘reset’ of the immune system where even after an 
immunomodulatory intervention is stopped; disease does not progress, or may even regress. 
Moreover, while it is not known whether or not immunomodulatory or other interventions in the 
early phases of autoimmune disease in absence of clinically-apparent organ toxicity (e.g. 
synovitis) could lead to long-lasting drug-free improvements in autoimmunity, several 
observations discussed in more detail below support the premise that the intervention proposed in 
this trial will have lasting benefit.  
Natural history studies of preclinical RA that include control subjects have demonstrated that 
control subjects who do not go on to develop RA can have elevations of RA-related 
autoantibodies yet not progress to disease. Specifically, in longitudinal studies of military 
subjects, it was noted that ~8-10% of healthy controls were positive for one or more RA-related 
autoantibodies, including several with anti-CCP positivity, yet did not develop RA [76-78]. 
Furthermore, some of these individuals were noted to have disappearance of their elevated levels 
of autoantibodies[106]. The factors associated with this lack of progression to disease and in 
some cases disappearance of autoantibodies is not yet known; however, these findings support the 


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idea that autoimmunity may be especially modifiable in very early disease and prior to the clinical 
appearance of significant organ injury. 
Studies of palindromic rheumatism (PR), a disease process that has been described as a form of 
very early RA and even preclinical RA, support the potential benefit of very early 
immunomodulatory therapy, and in particular therapy with HCQ, for preventing future RA [107-
114]. An observational study by Gonzalez-Lopez and colleagues of patients with PR, identified 
that the use of HCQ (or the similar agent chloroquine) halted the progression to classifiable RA 
(1987 criteria) in 44/64 (~69%) of subjects; furthermore, in comparison to observational controls, 
use of antimalarials led to a nearly 3-fold decrease in progression to persistent disease[112]. In 
addition, in a case-series by Hanonen and colleagues, 7/15 (~47%) of patients with PR treated 
with HCQ had complete disease remission [114]. James and colleagues also found that HCQ use 
prior to the fulfillment of full diagnostic criteria for systemic lupus erythematous (SLE) led to a 
delay in progression to classifiable SLE as well as a decreased number of SLE-related 
autoantibodies [115]. While these data are from an uncontrolled study, and HCQ was begun after 
the first clinical manifestations of SLE, they suggest that HCQ may interfere with epitope 
spreading – a mechanism that could also potentially be important in blocking the transition to 
clinically-apparent RA.  
Overall, these findings have led to the central hypothesis of this clinical trial that instituting 
disease-modifying therapy, and in particular HCQ (see Section 1.5.1, Rationale for the Treatment 
Arm), in preclinical disease will lead to a durable decrease of autoimmunity and prevention of 
disease.  
1.2 
Study Plan  
This study is a randomized (1:1), double-blinded, placebo-controlled, phase 2, multicenter trial to 
evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the prevention of future onset of 
clinically-apparent rheumatoid arthritis (RA).  
The study will randomize 200 subjects who are at high-risk for future development of classifiable 
RA although currently without a diagnosis of IA or findings of RA-like synovitis. These subjects 
will be selected because of the presence of elevations of the RA-related autoantibody anti-CCP3 
that are greater than or equal to 2 times the normal cut-off level (i.e. anti-CCP3 ≥ 40 units), a 
biomarker status that is highly specific for future RA (>90%), and also indicative of the imminent 
onset of clinically-apparent disease. These subjects will be recruited through several mechanisms, 
including a large-scale, well-established cohort of first degree relatives (FDRs) of patients with 
RA, established large-scale community-based screening efforts, and through rheumatology clinics 
where anti-CCP (+) subjects without IA are regularly evaluated as part of referral processes. In 
total, these populations represent subjects in whom this type of screening and treatment approach 
for the prevention of clinically-apparent RA could readily be applied in a “real-world” fashion.  
Subjects will be treated daily with HCQ (or placebo) for the initial 12 months after enrollment, 
then drug will be stopped and the subjects followed for an additional 24 months for a total trial 
duration of 36 months. 
The primary endpoint will be the development of “clinically-apparent RA” defined using the 
2010 ACR/ EULAR criteria (See Section 2.1, Primary Objective). Analyses will focus on the 
rates of clinically-apparent RA between subject groups at 36 months in order to test the central 


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hypothesis that a 12-month intervention with HCQ will result in durable decreased rates in 
progression to RA in individuals at high-risk for future RA. 
As discussed in more detail above, the rationale for conducting this trial derives from multiple 
studies demonstrating that RA-related biomarkers are elevated prior to the initial appearance of 
the IA that is characteristic of this disease [73, 74, 76-79, 81, 82, 116]. Importantly, during the 
early period of RA development, it appears that the expansion of RA-related autoimmunity 
measured by increases in autoantibody titers, epitope spreading and increased general 
inflammation are crucial aspects of the mechanism of transition from asymptomatic 
autoimmunity to clinically-apparent IA [76, 102, 117, 118]. There are also growing data 
supporting that early treatment of RA leads to improved long-term outcomes, including increased 
rates of drug-free remission [119, 120]. Together, these findings suggest that an intervention with 
an immunomodulatory agent in individuals who in the preclinical period of RA development 
should interrupt the evolution and expansion of autoimmunity, leading to prevention of future 
onset of clinically-apparent RA.  Furthermore, the highly specific nature of the autoantibody 
inclusion criteria (anti-CCP3 ≥2 times the normal cut-off) for this study allows for their use in 
accurate identification of subjects who are at high-risk for near-term development of future RA. 
1.3 
Clinical Studies of Hydroxychloroquine in RA 
1.3.1 
Hydroxychloroquine Background 
Historically, HCQ was identified after it was noted that individuals who chewed the bark of the 
cinchona tree had improved outcomes from malaria. Based on this observation, HCQ was 
originally developed and used as an antimalarial. However, over time HCQ has had recognized 
benefits in autoimmune disorders including RA and SLE [121]   
1.3.2 
Current Licensing of Hydroxychloroquine 
HCQ is currently FDA approved for suppressive treatment and treatment of acute attacks of 
malaria due to Plasmodium vivax, P. malariae, P. ovale and susceptible strains of P. falciparum. It 
is also indicated for the treatment of discoid and systemic lupus erythematosus and RA. 
1.3.3 
Other Diseases in Which Hydroxychloroquine Use Has Been Described 
Other diseases (rheumatic or otherwise) for which HCQ use has been described include Behcet’s 
disease, Sjögren’s Syndrome, sarcoidosis, Lyme disease, Q fever, dermatomyositis, in 
combination therapy for certain cancers, urticarial syndromes and coagulopathies including the 
antiphospholipid antibody syndrome [121].  


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1.4 
Known and Potential Risks and Benefits of Hydroxychloroquine 
1.4.1 
Known and Potential Benefits of Hydroxychloroquine in RA and 
Other Diseases 
Multiple studies have demonstrated that HCQ alone or in combination with other 
immunomodulatory therapies improves the clinical signs and symptoms of RA [122-134]. 
Specific examples include the Hydroxychloroquine in Early Rheumatoid Arthritis (HERA) study, 
a 36-week randomized, blinded study of HCQ compared to placebo in 120 patients with RA of < 
2 years duration, that demonstrated that HCQ use at up to 400 mg/day was associated with >50% 
improvement in a composite joint index that included joint tenderness, swelling and stiffness 
[131]. Intriguingly, after 3 years of follow-up after the initiation of the HERA study, the 
investigators noted that delay of 9 months in institution of HCQ in these subjects was associated 
with worse composite measure of pain and physical function [135]; these findings suggest that 
even as monotherapy, early institution of HCQ led to improved long-term outcomes and support 
its use in a prevention trial.  
In addition, in a 6-month randomized, blinded study of HCQ compared to placebo in 126 patients 
with RA of <5 years duration, Clark and colleagues demonstrated that HCQ at 400 mg/day was 
associated with >50% improvement in measure of joint inflammation in 71% of treated subjects 
[127]. HCQ has also been shown to be effective when used in combination with other therapies. 
In particular, the Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active 
Disease Despite Methotrexate Therapy (RACAT) trial, adding HCQ and sulfasalazine to patients 
who had failed monotherapy with MTX resulted in improved clinical outcomes, and in particular 
these improvements were similar to those seen in patients taking combination therapy with MTX 
and the biologic agent etanercept [136]. 
HCQ has also been shown in multiple studies in SLE to allow for control of active disease as well 
as reduce the incidence of new flares [115, 121, 122, 128, 137-139]. In particular, in one human 
study, HCQ administered soon after the first onset of symptoms of SLE appeared to decrease the 
development of autoantibodies over time as well as decrease and delay future clinical 
manifestations of disease [115]. HCQ also appears to decrease cytokine production in dendritic 
cells from patients with SLE in response to Toll-like receptor agonists, a potential mechanism of 
reduction of antigen presentation and expansion of autoimmunity [140].  
HCQ has also been demonstrated to have specific effects on the development of autoimmunity. 
This has been shown in many animal studies where use of HCQ blunts or halts immune activation 
related to a variety of inflammatory/autoimmune diseases including experimental arthritis, 
antiphospholipid antibody syndrome [141], and SLE [142, 143]. In particular, in animal models, 
HCQ administered early in the development of disease can have strong effects showing the 
abrogating/halting of inflammation and autoimmunity. In addition, based on data from both 
animal and human studies, HCQ appears to decrease endothelial activation and risk of thrombosis 
and other tissue injury in the antiphospholipid antibody syndrome [141, 144, 145]. Furthermore, 
as discussed above, in humans, HCQ use has been associated with decreased number of 
autoantibodies in SLE [115] and alteration/down regulation of antigen presentation and cellular 
activation [121, 122, 146-150] – factors which are likely to be important in the progression  and 
expansion of RA-related autoimmunity prior to the onset of IA.  


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In sum, evidence from human clinical trials and animal studies strongly suggest that the use of 
HCQ in the preclinical period of RA development should lead to abrogation of the immune 
response and prevention of development of clinically-apparent disease. 
1.4.2 
Known and Potential Risks of Hydroxychloroquine 
1.4.2.1 Ocular Toxicity 
An important potential adverse effect of HCQ is ocular toxicity that can take many forms but is 
most commonly retinal injury.  However, this effect is rare (<1%, [139]), particularly when 
subjects are dosed appropriately and do not have underlying renal or hepatic disease that may 
alter the pharmacokinetics of HCQ. Wolfe and colleagues studied ~4000 patients with RA and 
SLE and found confirmed retinal toxicity in <1% of treated patients, especially those treated for 
<5 years [151]. A newer study has found higher rates of presumed HCQ-related toxicity using 
more sensitive examination techniques including spectral domain optical coherence tomography 
(SD-OCT) in patients using doses of HCQ >5 mg/kg/day based on actual body weight and in 
those using HCQ for >5 years; even within this newer study, the overall the rate of toxicity 
appears to be low (<1%) within the first year of therapy[152].The current (2016) 
recommendations for retinopathy screening with HCQ use as put forward by the American 
Academy of Ophthalmology include a baseline funduscopic exam within the first year of HCQ 
use, with additional testing to include visual field and SD OCT testing if maculopathy is present, 
and then annual screening after 5 years of use[153].  
A more detailed description of potential ocular toxicities is included below:  
• Ciliary body: Disturbance of accommodation with symptoms of blurred vision. This 
reaction is dose-related and reversible with cessation of therapy. 
• Cornea: Transient edema, punctate to lineal opacities, decreased corneal sensitivity. The 
corneal changes, with or without accompanying symptoms (blurred vision, halos around 
lights, photophobia), are fairly common, but reversible. Corneal deposits may appear as 
early as three weeks following initiation of therapy. The incidence of corneal changes and 
visual side effects appears to be considerably lower with hydroxychloroquine than with 
chloroquine. 
• 
Retina: Macula: Edema, atrophy, abnormal pigmentation (mild pigment stippling to a 
"bull's-eye" appearance), loss of foveal reflex, increased macular recovery time following 
exposure to a bright light (photo-stress test), elevated retinal threshold to red light in 
macular, paramacular, and peripheral retinal areas.  Cases of maculopathies and macular 
degeneration have been reported and may be irreversible [154, 155]. Other fundus 
changes include optic disc pallor and atrophy, attenuation of retinal arterioles, fine 
granular pigmentary disturbances in the peripheral retina and prominent choroidal patterns 
in advanced stage. 
• Visual field defects: Pericentral or paracentral scotoma, central scotoma with decreased 
visual acuity, rarely field constriction, abnormal color vision. The most common visual 
symptoms attributed to the retinopathy are: reading and seeing difficulties (words, letters, 
or parts of objects missing), photophobia, and blurred distance vision, missing or blacked 
out areas in the central or peripheral visual field, light flashes and streaks. Retinopathy 
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of daily therapy; a small number of cases have been reported several years after 
antimalarial drug therapy was discontinued. It has not been noted during prolonged use of 
weekly doses of the 4-aminoquinoline compounds for suppression of malaria. Patients 
with retinal changes may have visual symptoms or may be asymptomatic (with or without 
visual field changes). Rarely scotomatous vision or field defects may occur without 
obvious retinal change. Retinopathy may progress even after the drug is discontinued. In a 
number of patients, early retinopathy (macular pigmentation sometimes with central field 
defects) diminished or regressed completely after therapy was discontinued. If allowed to 
develop, there may be a risk of progression even after treatment withdrawal [154, 155]. 
Paracentral scotoma to red targets (sometimes called "premaculopathy") is indicative of 
early retinal dysfunction that is usually reversible with cessation of therapy. A small 
number of cases of retinal changes have been reported as occurring in patients who 
received only HCQ. These usually consisted of alteration in retinal pigmentation that was 
detected on periodic ophthalmologic examination; visual field defects were also present in 
some instances. A case of delayed retinopathy has been reported with loss of vision 
starting one year after administration of hydroxychloroquine had been discontinued. 
1.4.2.2 Additional Toxicities  
The list below contains potential AEs related to HCQ according to package inserts [154, 155], 
and listed in order of most common to least common:  
• Gastrointestinal Reactions: Anorexia, nausea, vomiting, diarrhea, and abdominal 
cramps. Isolated cases of abnormal liver function and fulminant hepatic failure.   
• Dermatologic Reactions: Rash, pruritius, bleaching of hair, alopecia, pruritus, skin and 
mucosal pigmentation, photosensitivity, and skin eruptions (urticarial, morbilliform, 
lichenoid, maculopapular, purpuric, erythema multiforme, erythema annulare centrifugum, 
Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous 
pustulosis, and exfoliative dermatitis). 
• Central Nervous System (CNS) Reactions: Irritability, nervousness, emotional changes, 
nightmares, psychosis, headache, dizziness, vertigo, tinnitus, nystagmus, nerve deafness, 
convulsions, ataxia, and suicidal behavior 
• Neuromuscular Reactions: Skeletal muscle palsies or skeletal muscle myopathy or 
neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups, 
which may be associated with mild sensory changes, depression of tendon reflexes and 
abnormal nerve conduction. 
• Hematologic 
Reactions: 
Various 
blood 
dyscrasias 
such 
as 
aplastic 
anemia, 
agranulocytosis, leukopenia, anemia, thrombocytopenia (hemolysis in subjects with 
glucose-6-phosphate dehydrogenase (G-6-PD) deficiency).  
• Allergic Reactions: Urticaria, angioedema and bronchospasm have been reported. 
• Risks to Pregnant Women: Hydroxychloroquine crosses the placenta and should be 
avoided during pregnancy. 4-aminoquinolines, such as hydroxychloroquine, in therapeutic 
doses have been associated with damage to the central nervous system (including 
ototoxicity, retinal hemorrhages, and abnormal retinal pigmentation) in the fetus[154].  
 
• Miscellaneous Reactions: Weight loss, lassitude, exacerbation or precipitation of 
porphyria, hypoglycemia, and nonlight-sensitive psoriasis have been reported. 


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Cardiomyopathy has been rarely reported with daily dosages of HCQ that exceed the 
recommended dosing levels, or in patients with compromised renal or hepatic function. 
Interactions with other drugs including oral hypoglycemic agents and digoxin may occur. 
Dose adjustments may be required. 
1.5 
Rationale for Study Design 
1.5.1 
Rationale for the Treatment Arm 
Hydroxychloroquine has been selected as the immunomodulatory agent for this study for the 
following reasons listed below. Of note, as discussed above, there are numerous genetic and 
environmental risk factors for RA, and it is intriguing to consider risk factor modification as an 
approach to RA prevention. Indeed, an observational study suggests that smoking cessation may 
decrease future risk for RA[156]. However, to date there has not been convincing data that risk 
factor modification in a prospective manner is beneficial for disease prevention. As such, 
environmental exposures will be assessed in this study, and we will recommend that subjects who 
participate in the trial stop using tobacco products, but these factors will not otherwise be 
addressed for modification as part of the preventive strategy. Instead, modification of immune 
responses and prevention of RA will be approached through the use of HCQ, with rationale for 
the choice of HCQ as follows: 
1. Hydroxychloroquine has been shown in multiple clinical trials to be efficacious in 
improving the signs and symptoms of active RA as monotherapy and combination therapy 
[121, 127, 131].  In particular and as discussed above, monotherapy of HCQ has been 
associated with >50% improvement in symptoms and in number of swollen joints in 
several placebo-controlled studies [157-159]. Furthermore, HCQ has been demonstrated to 
be particularly effective in early classifiable RA, a clinical condition that likely 
approximates the preclinical period of disease development [129]. 
2. Several studies have shown that HCQ use slows or halts the progression to persistently 
active RA in patients with palindromic rheumatism [110, 112, 113], and may decrease the 
production of autoantibodies in SLE, as well as delay the onset of full disease 
classification once early symptoms have developed [115].  Specifically, an observational 
study by Gonzalez-Lopez and colleagues of patients with palindromic rheumatism, 
identified that the use of HCQ (or the similar agent chloroquine) halted the progression to 
classifiable RA (1987 criteria) in 44/64 (~69%) of subjects; furthermore, in comparison to 
observational controls, use of antimalarials led to a nearly 3-fold decrease in progression 
to persistent disease[112]. In addition, in a case-series by Hanonen and colleagues, 7/15 
(~47%) of patients with PR treated with HCQ had complete disease remission [114]. 
3. The growing understanding of the mechanisms of HCQ in abrogating the immune 
response further supports its use in preventing future RA in high-risk individuals. In 
particular, HCQ has been shown to decrease cellular activation including hindering of 
antigen presentation to CD4 (+) T cells [122], actions that may lead to decreased 
autoantibody production. Also, growing evidence suggests that HCQ modulates Toll-like 
receptor function, leading to decreased inflammatory responses to immune complexes, 
decreased antigen presentation by dendritic and other antigen presenting cells, and 
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autoimmune and inflammatory processes especially if initiated early in natural history of 
disease [122, 148].  
4. Hydroxychloroquine is already a Food and Drug Administration (FDA)-approved agent 
for active RA, and widely used in clinical practice.  Therefore, in real-world applications, 
this medication could be used easily to prevent RA in high-risk populations.  Furthermore, 
from unpublished interviews with ~50 rheumatologists, HCQ would be an agent that 
~85% would be comfortable prescribing as a preventive therapy for RA based on issues 
that include cost, safety, tolerability, and monitoring needs. 
5. While there are multiple agents that are effective in RA (e.g. MTX, SSZ, biologic 
therapies), the overall safety and tolerability of HCQ makes it an excellent choice for 
prevention of RA in large-scale interventions if it is indeed effective in preventing future 
RA.  Importantly, from unpublished data in interviews of approximately 40 at-risk subjects 
followed in a natural history study of RA, 80% of subjects reported that they would be 
willing to take a medication with the safety and tolerability profile of orally-administered 
HCQ, although <30% were willing to undergo a more invasive or perceived potentially 
toxic therapy such as an MTX or injection. In addition, in published work from Finckh et 
al, first-degree relatives of patients with RA were willing to undergo a preventive 
intervention (including medication) if their risk for future RA was 30% or greater within 
the next 5 years [160]. 
6. The cost of HCQ is relatively low compared to other immunomodulatory agents. As such, 
if this trial is successful, the cost-effectiveness of HCQ in RA prevention will be more 
readily demonstrated. 
7. Hydroxychloroquine has the potential to impart broad benefits to a variety of health 
conditions. These include reduced risk for thrombosis, improved cardiovascular disease 
events, diabetes and hypertension [161]. 
1.5.2 
Rationale for Duration of HCQ Treatment and Post-Treatment 
Follow-up 
Subjects will be enrolled in the trial for three years, with drug/placebo treatment for the first year, 
and post-drug follow-up for the last two years.  
The rationale for a three-year trial is that this time frame will allow for sufficient numbers of 
subjects reaching the primary endpoint (classifiable RA) to allow for robust evaluation of the 
efficacy of HCQ to prevent RA even after cessation of therapy.  
The optimal duration of HCQ treatment for the prevention of RA is currently unknown; however, 
there are several factors that have led to the selection of this duration of therapy:   
1. While there are very limited data regarding the duration of pharmacologic therapy to 
prevent RA, in a study by Bos and colleagues of autoantibody positive individual without 
IA, 2 doses of intramuscular corticosteroids failed to reduce progression to clinically-
apparent IA [162]. In the PRAIRI study (Prevention of clinically manifest rheumatoid 
arthritis by B-cell directed therapy in the earliest phase of the disease), a single dose of 
rituximab delayed the onset of RA by approximately 12 months compared to placebo; 
however, it did not prevent RA when compared to placebo [163]. As such, using an agent 
for a longer duration is likely necessary to prevent future RA.  


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2. In clinical trials of HCQ in patients with active RA, a duration of therapy of 12 months is 
considered to be sufficient to determine if it will have a clinical effect. As such, 12 months 
duration will likely provide adequate exposure to the drug to identify a biologic effect.  
3. While HCQ use is generally considered safe, there is a potential for toxicity especially 
with prolonged use. Given that the overall benefits of HCQ in the prevention of RA are as 
of yet unknown, 1 year of therapy will limit risk until more information regarding its 
benefit can be gained.  
4. Subjects who are at risk for future RA reported that taking a therapy for 1 year was 
acceptable (manuscript in development by Deane KD et al); however, a longer duration of 
therapy may result in decreased compliance. In addition, studies in other conditions where 
a drug was used to treat a relatively asymptomatic condition such as hypertension (HTN) 
prolonged drug use led to increasing rates of non-compliance over time [164]. As such, 1 
year of therapy will likely maximize adherence to therapy and provide the most robust 
data regarding drug effect.  
5. The trial design specifies that HCQ will be given for 1 year, and subjects will be followed 
for an additional 2 years. This approach will allow for analyses to determine if the effect of 
HCQ on decreasing progression to RA is apparent while subjects are on drug, and wanes 
when subjects are off drug. These results will inform the design of future studies. 
1.5.3 
Rationale for the Control Arm 
In order to determine the therapeutic effect of treatment with HCQ in subjects for the prevention 
of the onset of RA, the response of subjects receiving HCQ will be compared to the response of 
subjects receiving placebo. The use of a control arm will additionally provide data for evaluation 
of safety of HCQ in this subject population as well as natural history data regarding the evolution 
of RA-related autoimmunity in preclinical disease. 
1.5.4 
Rationale for the Inclusion Criteria  
The goal of the inclusion criteria is to identify subjects that are at high-risk for developing IA and 
clinically-apparent RA within 3 years. As discussed above, there are numerous genetic and 
environmental risk factors for RA; however, while  it is intriguing to consider genetic and 
environmental factors in the prediction of RA, there is not clear data to date that evaluating 
genetic and environmental factors adds substantial predictive power to future RA beyond that of 
anti-CCP positivity. In particular, Bos et al. demonstrated that within anti-CCP positive subjects, 
the presence of the SE was not associated with increased risk for progression to RA [85]. As such, 
genetic factors including the presence of the SE as well as environmental exposures will be 
assessed in this study, although these factors will not be used in the development of 
inclusion/exclusion criteria.  
1.5.5 
Rationale for the Exclusion Criteria 
The goal of the exclusion criteria is to ensure that subjects who have already developed RA-like 
synovitis are excluded from the study. Subjects are also excluded to minimize the potential that 
they will receive immunomodulating therapy for conditions other than RA that could affect the 


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outcomes of the study. In addition, subjects are excluded to ensure safety as well as to ensure a 
homogenous study population.  
1.5.6 
Rationale for Mechanistic Studies  
The mechanistic studies will provide insights into the immunobiology of early RA that should 
further the understanding of disease development and potentially lead to additional types of 
preventative approaches for RA, including targeted biologic/small molecule therapeutics and 
potentially antigen-specific tolerance induction.  
2 STUDY OBJECTIVES AND PURPOSE  
2.1 
Primary Objective 
To determine the efficacy of a 12-month course of HCQ to prevent the development of clinically-
apparent RA at 36 months in subjects at high-risk for future RA due to high titer elevations of 
anti-CCP3 (≥ 40 units) but who are without a history or clinical findings of IA at Baseline.  
 
For this study, clinically-apparent RA will be defined using the 2010 ACR/EULAR 
Classification Criteria as either: 
(1) A score of ≥ 6 defining “definite RA” or  
(2) A joint examination consistent with RA-like synovitis with ≥ 1 erosion identified 
via x-ray imaging of the hands, wrists, and feet. 
2.2 
Secondary Objectives  
Secondary objectives for the study include: 
1. To evaluate the safety of a 12-month course of HCQ in subjects who are at high-risk for 
development of RA. 
2. To evaluate the impact of HCQ on development of clinically-apparent RA (as defined 
above in Section 2.1, Primary Objective) in high-risk subjects 12 months after initiation of 
study treatment. 
3. To evaluate the impact of HCQ on development of IA, that may or may not meet criteria 
for RA, in high-risk subjects 12 months after initiation of study treatment. 
4. To evaluate the impact of a 12-month course of HCQ on the timing of development of 
clinically-apparent RA (as defined above in Section 2.1, Primary Objective) over the 
entire study period.  
5. To evaluate the impact of a 12-month course of HCQ on the timing of development of IA, 
that may or may not meet criteria for RA, over the entire study period. 
6. To explore the relationship between baseline and evolving symptoms3, risk factors4 and 
the development of future clinically-apparent RA and response to HCQ. 
                                              
3 Baseline RA symptoms include self-reported joint pain, stiffness, and swelling, and overall fatigue. 


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7. To evaluate the relationship between treatment with HCQ and amelioration of symptoms3 
of RA, and potential delay in onset of symptoms.  
8. To explore underlying immune responses over time in the early natural history of RA 
development and in response to HCQ therapy through measurement of a variety of 
biomarkers.  
3 STUDY DESIGN 
3.1 
Description of Study Design  
This is a phase 2 multicenter, randomized, placebo-controlled, double-blind, parallel-group, 36-
month clinical trial to evaluate the effectiveness and safety of intervention with a 12-month 
course of HCQ to prevent the future onset of clinically-apparent RA (see definition in Section 2.1, 
Primary Objective). At screening, study subjects will be  without IA but will be at high-risk for 
developing future RA within the trial period as indicated by  elevated anti-CCP3 antibodies that 
are ≥40 units (that is a level ≥2 times the normal cut-off of ≥20 units). Two hundred eligible 
subjects will be randomized in a 1:1 ratio to receive either self-administered HCQ or placebo. 
Subjects will provide informed consent prior to any Pre-Screening or Screening procedures. 
Subjects who are found to be eligible after the screening evaluation will return for a 
Baseline/Randomization visit within 30 days of the initial screening visit. Subject eligibility will 
be confirmed prior to randomization. Eligible subjects will be randomized to receive either 200 -
400 mg of HCQ or  placebo daily for 12 months based upon ideal body weight (IBW) at 
Screening. The weight-based dosing regimen for the study is outlined in Section 5.2, Dosage 
Regimen.   
Subjects will return to the study site for planned evaluations at Weeks 6, 12, 24, 36, and 52 (End 
of Treatment),  and Months 18, 24, 30, and 36 (End of Study). During these study visits, subjects 
will have a joint exam and a physical examination. Study personnel will record the subject’s 
interval medical history, assess AEs, and collect samples for safety and mechanistic assessments 
(see Tables 6.1 and 6.2, Schedule of Events, for specific assessment schedule). Information on 
demographics (including socio-economic status and education), and other factors that may 
influence autoimmunity (e.g. tobacco exposure, hormonal status and exposures) will also be 
collected. 
Site coordinators will also call subjects at Week 18, 30, and 42, and at Month 15, 21, 27, and 33 
to answer subject questions, update contact information, and to assess AEs/reactions, study drug 
dosing and pregnancy status (during the treatment period), and  joint symptoms,. If a subject 
indicates that he/she is experiencing joint symptoms suggestive of RA (that include new or 
worsening joint pain, stiffness or swelling since the prior study visit) or symptoms suggestive of 
an AE, the subject will be asked to return to the study site for evaluation via an unscheduled visit 
as soon as possible. Visits and assessments for subjects who develop RA, IA with erosions, or 
who become pregnant prior to the Month 36 visit will be different from subjects who never 
develop these conditions. Details of these assessments may be found in protocol sections 6.5.9, 
Evaluations Triggered by a Swollen Joint, 6.5.10, Procedures for Subjects Diagnosed with 
                                                                                                                                                    
4 Risk factors include but are not limited to age, sex, genetic factors, socio-economic status, education, tobacco 
exposure, medications and medical hormone use, and dietary factors. 


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Inflammatory Arthritis or Rheumatoid Arthritis by an Outside Physician, and 6.5.11, Special 
Considerations for Pregnant Subjects. 
Subject use of non-immunomodulatory agents such as acetaminophen, non-steroidal anti-
inflammatory drugs (NSAIDS), and herbal supplements are allowed. DMARDS, systemic 
corticosteroids, and biologic therapies are prohibited during study participation as outlined in 
Section 5.6, Prohibited Medications.  
After completing the screening period, the expected duration of study participation for each 
subject is 36 months.  
The enrollment period is projected to be approximately 24 months from the opening of the first 
75% of study sites.  
3.1.1 
Stratification, Randomization, and Blinding 
Subjects will be randomized in a 1:1 ratio to either HCQ or placebo. As some study sites may 
only randomize a few subjects, an adaptive randomization procedure based on Pocock and 
Simon[165] minimization concepts will be used to increase the likelihood of balance between 
treatment arms on key factors associated with progression to clinically-apparent RA. The key 
factors will include smoker status (smoker vs. non-smoker), study site, and method of recruitment 
(i.e. FDR, general population, or clinic screening. For additional detail on recruitment strategies, 
see Section 4.3, Strategies for Recruitment and Retention). 
To maintain the study blind, the appearance of the study treatments, HCQ and placebo, and their 
packaging will be identical. Clinical staff will be blinded to the treatment assignments until 
completion of the study with the exception of an unblinded pharmacist. In addition, clinical staff 
members, including the investigators, will not have access to any mechanistic data, and 
mechanistic laboratory staff will not have access to any clinical results until completion of the 
study.  
An individual’s treatment assignment will only be unblinded if the subject experiences a 
suspected adverse reaction that is serious and unexpected (see Section 7.2.2, Adverse Reaction 
and Suspected Adverse Reaction and Section 7.2.3, Unexpected Adverse Reaction) or other 
protocol-specific event(s) determined by DAIT/NIAID to warrant unblinding. 
3.1.1.1 Subject Completion and Replacement 
A subject is considered to have completed the study if he/she has completed the Month 36 visit. 
Subjects who withdraw from the study prior to receiving drug will not be counted towards the 
target accrual of 200 subjects. Eligible subjects receiving at least one dose of study drug will 
count towards target accrual.  
3.2 
Description of Primary Endpoint 
The primary efficacy endpoint is the development of clinically-apparent RA by 36 months, where 
clinically-apparent RA is defined in Section 2.1, Primary Objective.  


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3.3 
Description of Secondary Endpoints 
3.3.1 
Secondary Efficacy Endpoints  
1. Time to development of clinically-apparent RA as defined in Section 2.1, Primary 
Objective. 
2. Time to development of a swollen joint(s) that is (are) consistent with RA-like synovitis. 
3. Development of clinically-apparent RA by 12 months, where clinically-apparent RA is 
defined in Section 2.1, Primary Objective.  
4. Development of a swollen joint(s) that is (are) consistent with RA-like synovitis by 12 
months, where synovitis is determined by joint exam.  
5. Trends in disease activity during the treatment period (i.e. Baseline through Week 52) will 
be evaluated over time using multiple indices: 
• Physician assessed tender joint count 
• Physician assessed swollen joint count 
• DAS28-CRP score 
• Clinical Disease Activity Index (CDAI) 
• Routine Assessment of Patient Index Data 3 (RAPID-3) 
6. Trends in disease activity during the post-treatment follow-up period (Week 52 through 
Month 36) will be evaluated over time using multiple indices (as noted in above). 
7. Trends in patient self-reported evaluations of joint pain, stiffness and swelling will be 
evaluated over the treatment period (i.e. Baseline through Week 52).  The following 
endpoints are of interest: 
• Total number of  painful joints 
• Total number of  stiff joints 
• Total number of  swollen joints 
• Number of  painful joints in the hands, in the wrists, in the feet 
• Number of  stiff joints in the hands, in the wrists, in the feet 
• Number of  swollen joints in the hands , in the wrists, in the feet 
8. Trends in patient self-reported evaluations of joint pain, stiffness and swelling will be 
evaluated over the post-treatment follow-up period (Week 52 through Month 36). See 
specific endpoints noted above. 
9. Trends in patient-reported outcomes (PRO) for physical, mental and social health 
(collected via NIH Patient-reported Outcomes Measurement Information System 
(PROMIS) instrument Profile 29 v2.0) will be evaluated over the treatment period (i.e. 
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10.Trends in PRO for physical, mental and social health will be evaluated over the post-
treatment follow-up period (Week 52 through Month 36).  
3.3.2 
Secondary Safety Endpoints 
Safety for individual subjects will be monitored by assessing AEs and serious adverse events 
(SAEs) and measuring hematology and clinical chemistry parameters at scheduled visits and 
unscheduled visits (as needed) throughout the trial. Safety events that might cause discontinuation 
of treatment for an individual or trigger a safety review of the study by the Data and Safety 
Monitoring Board (DSMB) are described in Sections 5.8.1, Study Treatment Discontinuation and 
5.8.3, Safety Stopping Guidance, respectively.  
Safety analyses are described more fully in Section 8.3.2, Safety Analysis, but the following 
endpoint is of particular interest in describing the safety profile of HCQ for prevention of RA:  
• The proportion of subjects in each arm experiencing a Grade 3 or higher AE according to 
the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) system.  
3.3.3 
Secondary Mechanistic Endpoints  
1. Levels of anti-CCP3 over time 
2. Levels of IgM-RF over time 
3. Levels of hsCRP over time 
4. Gain/Loss of autoantibody reactivity to citrullinated protein as measured by ACPA array. 
5. Expansion/contraction of inflammation as measured by a multiplex cytokine and 
chemokine array.  
 
4 SELECTION OF SUBJECTS 
Written informed consent must be obtained prior to the subject undergoing any study-related 
procedure, including screening tests. 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment into the study: 
1. Able and willing to give written informed consent and comply with requirements of the 
study.  
2. Age ≥18 years-old at the Screening Visit. 
3. Elevation of anti-CCP3 ≥40 units at Screening. 
4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria are ineligible to participate in the study: 


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1. Medical history or current evidence of IA (any type) and/or rheumatic disease and 
immunologic diseases that may be associated with IA. These diseases include but are not 
limited to RA, SLE, seronegative spondyloarthropathies (including ankylosing 
spondylitis, psoriatic arthritis and reactive arthritis), inflammatory bowel disease 
(including Crohn’s and ulcerative colitis), Sjögren’s syndrome, scleroderma, polymyalgia 
rheumatica and vasculitis.  Patients with mild/moderate crystalline arthropathies do not 
need to be excluded. 
2. Prior or current systemic treatment with DMARDs, immunomodulatory agents, or 
glucocorticoids for IA or other rheumatic or immunologic diseases. See Section 5.6, 
Prohibited Medications, for a list of excluded medications.    
3. Tetracycline class antibiotic use for autoimmune conditions, taken within 12 months prior 
to Screening. Note: If a tetracycline class antibiotic is used for non-autoimmune 
conditions, it should be stopped at Day 0/ Randomization visit.   
4. Systemic corticosteroid use for non-IA conditions taken 28 days prior to 
 
Screening. 
5. A history of a chronic condition that in the opinion of the investigator is highly likely to 
require therapy with systemic corticosteroids (oral, intramuscular (IM) or intravenous 
(IV)) within the study period including but not limited to severe asthma and severe 
crystalline arthropathy. 
6. More than 3 local corticosteroid injections, including but not limited to intra-articular, 
epidural, and intra-bursal injections, during the 3 months prior to randomization. 
7. Women who are pregnant, breastfeeding or desire to become pregnant and/or breast feed 
within the duration of the 12-month treatment phase of the study.  
8. Women of childbearing potential not using or agreeing to use adequate birth control 
measures (e.g., total abstinence, oral contraceptives, intrauterine device, barrier method 
with spermicide, surgical sterilization, Depo-Provera, or hormonal implants) during the 
treatment phase of the study. 
9. Functional status of NY Heart Association (NYHA) Class III or higher (see Section 15.4, 
NYHA Classification) at the screening visit.  
10. Medical history of cardiomyopathy, congestive heart failure, or significant cardiac 
conduction disorders. Cases of surgically corrected conduction disorders with no cardiac 
damage, no recurrence, and no need for medication may be eligible. 
11. Medical history of chronic liver disease. 
12. Medical history of psoriasis (due to potential for increased risk for flare of skin disease) or 
porphyria.  
13. Medical history or serologic evidence at Screening of chronic infections including, but not 
limited to, human immunodeficiency virus (HIV), hepatitis B, and untreated hepatitis C.   
• 
Note: A subject who is Hepatitis C antibody positive will be eligible to participate 
in the study if he/she is negative for viral load at Screening or has documentation 
of treatment and negative hepatitis C viral load at least 12 weeks post- treatment.  
14. History of malignancy within the last 5 years, except for treated basal or squamous cell 
carcinoma, treated cervical dysplasia, or treated in situ cervical cancer Grade I. 
15. A history of alcohol or substance abuse within 1 year of randomization. 
16. Ideal or actual body weight ≤24.4 kg (see Table 5.1 in Section 5.2, Dosage Regimen) at 
Screening. 


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17. Any of the following laboratory abnormalities at the Screening  visit:  
• Serum creatinine clearance < 50 ml/min (as calculated by the Cockcroft-Gault 
formula)  
• Alanine Aminotransferase (ALT) > 2x the upper limit of normal (ULN)  
• Aspartate Aminotransferase (AST) > 2x the upper limit of normal (ULN)  
• Total white blood count (WBC) < 3.0 x 109/L 
• Platelet count ≤ 150 x109/L  
• Hemoglobin < 11 g/dL 
• Absolute Neutrophil Count (ANC) < 2.0 x 109/L 
18. Evidence of significant retinal disease upon eye examination during the screening period 
that in the opinion of the examiner would make identification of potential future retinal 
toxicity from HCQ difficult to evaluate.  Note: Retinal exam results may be applied to 
evaluations of subject eligibility for up to 6 months after the initial retinal exam.  
19. The physician may exclude, for any reason, any subject he/she does not believe would be 
a good study candidate. 
4.2.1 
Co-enrollment Guidelines 
Subjects may be in observational registries or cohorts as long as the combined blood draw totals 
do not exceed the limits of NIH or the local institutional review boards. If a subject elects to 
participate in any other sort of study or clinical trial, the subject may be withdrawn at the 
discretion of the NIH/NIAID/DAIT. 
4.3 
Strategies for Recruitment and Retention 
Subjects with elevated anti-CCP levels that meet assay positivity criteria will be identified for this 
trial through three general approaches that will include the following: 
• Pre-screening FDRs of patients with RA. 
• Health-fair, biobank, or other population-based pre-screening. 
• Identification in rheumatology clinics of subjects with ACPA positivity in the absence of 
IA.  
Overall, these three subject pools provide a sampling of the types of subjects for whom this 
preventative approach would be applicable in a real-world fashion at the completion of a 
successful trial. Anticipated recruitment for each pool is discussed in the following subsections. 
4.3.1 
FDRs of probands with RA  
For this prevention trial, FDRs will be targeted for screening, because of their higher rates of 
positivity for RA-related autoimmunity, and higher risk for incident RA when compared to the 
general population (estimated 3-9 fold increased risk) [166]. Importantly, FDRs also represent a 
population that several participating study sites are familiar with in terms of identification and 
recruitment for studies of the history of RA as part of the Studies of the Etiology of Rheumatoid 
Arthritis (SERA) Project [167]. For the SERA project, FDRs without IA/RA are followed 
prospectively to study the natural history of RA [168].  


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For this clinical trial, probands will be identified and contacted via letter or in clinic.  The study 
will be explained to the probands, and the proband will then communicate study information to 
their FDRs. These FDRs will then contact study personnel if they are interested in being 
evaluated for participation in the study. FDRs may also be recruited through distribution of flyers 
or other study promotional materials. Once the FDRs have contacted the site and have been 
consented, the FDRs will be evaluated using a brief questionnaire that assesses if they have a 
prior diagnosis of RA, and tested for anti-CCP. No physician evaluation will be needed at this 
initial Pre-Screening. FDRs meeting the biomarker inclusion criteria and who do not have RA 
based on their questionnaire responses will be invited back for a study screening visit, and invited 
to enroll if they meet study entry criteria.  
Based on published data and pilot analyses in the SERA project, the focus for recruitment will be 
on FDRs of probands with seropositive RA, which will maximize the identification of FDRs who 
are most likely to meet inclusion criteria. To avoid possible issues of familial correlation, our 
strong preference is to randomize only 1 FDR per family. Subjects will be asked about 
participation of immediate family members during the consent process. However, 
recognizing operational barriers to accurately track family membership and our suspicion 
that multiples per family will be a rare occurrence, multiple FDRs per family may be 
randomized. With this approach, based on data from evaluations of ~2,500 FDRs to date at 
several of the sites that will be participating in this trial , it is projected that ~2% of FDRs pre-
screened will be eligible for this study.  Based on a pilot feasibility study, we conservatively 
estimate that ~40% of eligible FDRs will agree to participate in this trial (See Section 1.5.1 
Rationale for the Treatment Arm, bullet 5).  
4.3.2 
Health-Fair, Biobank, or Population-based Pre-Screening  
Subjects who are candidates for this trial may be identified through population-based screening 
activities such as testing for CCP at a health-fair or other similar setting. For example, since 2008, 
under the direction of Kevin Deane, the University of Colorado has collaborated with the 
Colorado-based “9Health Fair”, so named because of its early association with a local television 
station broadcast on Channel 9 [169], to evaluate over 10,000 individuals for undiagnosed RA or 
risk for future RA based on CCP positivity. Through these efforts, 160 (~1.8%) individuals with a 
CCP test ≥2x normal in absence of IA have been identified demonstrating that this method can be 
effective to identify individuals who are at high-risk for future RA. 
For this clinical trial, it is projected that ~ 8-10,000 subjects will be evaluated at health-fairs that 
include the Colorado-based 9Health Fair, as well as health-fairs at other study sites. The 
procedure for initial evaluation will entail a brief questionnaire that assesses if they have a prior 
diagnosis of RA, and blood testing for anti-CCP. Subjects meeting the biomarker criteria for the 
study and who do not have RA based on their questionnaire responses will be invited back for a 
study screening visit, and invited to enroll if they meet study entry criteria.  
4.3.3 
Rheumatology Clinics  
Individuals who are anti-CCP positive in the absence of IA (with testing typically performed by 
primary care providers for evaluation of non-inflammatory musculoskeletal pain) are evaluated 
regularly and with increasing frequency in rheumatology clinics, raising an important clinical 


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issue regarding how to manage these patients, and potentially prevent them from developing 
clinically-apparent RA. Importantly, in discussion with multiple clinicians these patients are on 
occasion being treated with HCQ if they have symptoms that are interpreted as related to RA, 
even in absence of IA. Therefore, formalizing the benefit of this therapy could lead to a 
significantly improvement in clinical care.  
Briefly, these subjects will be identified through IRB-approved means including screening clinic 
registries and medical records, and making practitioners aware of this clinical trial.  Individuals 
meeting inclusion criteria will be approached for trial screening and enrollment.  
 
 
5 TREATMENT OF SUBJECTS 
5.1 
Description of Study Product 
5.1.1 
Product Description  
HCQ is a non-biologic antimalarial drug that is used as a DMARD with the chemical 
configuration of 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate (1:1). This 
colorless, crystalline solid is soluble in water to at least 20 percent and has the following inactive 
ingredients: Dibasic calcium phosphate, hydroxypropyl methylcellulose, magnesium stearate, 
polyethylene glycol 400, Polysorbate 80, corn starch, and titanium dioxide[155]. 
Placebo will be a solid compound consisting of fast-flo lactose (39%, 136.5mg/tablet), Avicel 
(PH102, NF, 60%, 210mg/tablet), and Magnesium Stearate (NF, 1%, 3.5mg/tablet).  
Both the HCQ and placebo will be encapsulated in a blue, opaque, hard gelatin capsule. Any void 
space will be filled with microcrystalline cellulose. The HCQ and placebo tablets will appear 
identical. More information for the HCQ product used in this study can be found at  
http://www.prasco.com/our-products.html (search hydroxychloroquine). 
 
5.1.2 
Packaging and Labeling of Study Product  
HCQ 200 mg tablets (or placebo) will be packaged in a single, light-resistant bottle with a 50 pill 
supply per bottle.  
The label will include conditions for storage, a unique bottle ID, and other pertinent information 
such as Sponsor, expiration date, and caution statement. Neither HCQ nor placebo should be used 
after the expiration date unless a written notification of an expiration date extension is provided 
by the manufacturer. 
 If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the pills or bottles, it should not be used. The study drug in question should be quarantined at the 
study site and the problem immediately reported to DAIT/NIAID or their representative. 


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5.1.3 
 Storage and Handling of Study Product 
The study Site Principal Investigator and site pharmacist are responsible for the appropriate 
storage of study drug at the site. HCQ and placebo must be stored at room temperature, between 
59 and 86°F (15 and 30°C), in a tightly closed, light resistant bottle[155]. 
5.1.4 
Study Product Accountability  
Both the investigational drug that is used during the course of the study, as well as any remaining 
unused investigational drug, must be accounted for on a drug accountability record provided or 
approved by the study sponsor or its designee. This documentation must include complete, 
accurate recording of shipment receipt(s), dispensing, and returns of the study product as required 
by the ARA08 protocol and applicable law. A copy of all completed drug accountability records 
must be placed in the Investigator’s Study Files (ISF) after the closure of the study, once study 
treatment assignments are unblinded to clinical staff, and a copy sent to the study sponsor or its 
designee. Study product must be used only in accordance with the ARA08 protocol and for no 
other purpose, and is non-transferable to any party other than the sponsor/manufacturer; with no 
modification, replication, or other engineering derivative undertaken. 
All bottles of study product that were not dispensed need to be returned to the distribution vendor. 
Bottles of study product that are dispensed, must be returned to the site pharmacy and may be 
sent back to the distribution vendor, or may be destroyed onsite, after a confirmatory pill count is 
completed (see the ARA08 Investigational Product Dispensing and Administration Manual.).    
5.2 
Dosage Regimen  
Subjects participating in this study will be randomized to receive 200 – 400 mg/day (1-2 pills) of 
either active HCQ or 1-2 pills of placebo for 12 months with dosing based upon Screening IBW 
as outlined in Table 5.1.  
 
Table 5.1. Weight-based dosing regimen for HCQ (and placebo) 
Weight (kilograms based on IBW*) 
Number of pills** 
≤ 24.4 kg (ideal or actual body weight) 
 
Excluded from trial 
> 24.4 - < 47 kg 
1 pill daily 
≥ 47 kg 
2 pills daily 
*IBW based on the following calculation:   
• 
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet, or subtract 1kg for 
every inch under 5 feet. 
• 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet, or subtract 1kg 
for every inch under 5 feet. 
Each 200 mg HCQ pill contains 155 mg of active drug.  These dosing regimens are designed to 
not exceed a dose of 6.6 mg/kg/day of active drug.  In subjects ≥ 47 kg, 2 pills daily = 310 
mg/day of active drug. This dose may be lower than 6.6 mg/kg/day; however, given 2 pills daily 
is used commonly in clinical practice and is a dosing regimen that is comfortable for most 
rheumatology practitioners. We will not exceed 2 pills daily for this study. 


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For some individuals, this dose may be somewhat higher than the 2016 recommendation of the 
American Academy of Ophthalmology which has recommended that doses of <5 mg/kg/day of 
actual body weight be used to avoid eye toxicity [153]. For this study we will be using the 
weight-based dosing regimen noted above because  prior studies that have demonstrated the 
efficacy of HCQ in rheumatic disease have used a HCQ dose of ≤ 6.5 mg/kg/day based on ideal 
body weight. In addition, the rates of eye toxicity from HCQ within the first year of therapy at 
doses ≤ 6.5 mg/kg/day are <1%. 
5.3 
Administration of Study Product 
5.3.1 
Preparation for Administration 
Upon subject randomization, the unblinded pharmacist will receive a notification from the 
randomization system, outlining the subject treatment assignment, Screening IBW, and the 
number of pills that should be taken each day.  
The unblinded pharmacist will apply an auxiliary label to the bottle prior to distribution that 
indicates how many pills should be taken by the subject each day.  
5.3.2 
Administration 
Study subjects will be instructed to take 1 or 2 pills of study therapy daily based upon their IBW 
[155]. 
Subjects will take the first dose of study therapy in clinic at the Baseline visit. The subject will be 
observed per institutional standards.  
Study therapy will be dispensed per the table below: 
Table 5.2: Study Therapy Distribution 
Subject IBW at 
Screening 
Baseline 
Week 6 
Week 12 
Week 24 
Week 36 
> 24.4 - < 47 kg 
1 bottle 
2 bottles 
2 bottles 
2 bottles 
3 bottles 
≥ 47kg 
2 bottles 
3 bottles 
4 bottles 
4 bottles 
6 bottles 
5.4 
Toxicity Management Plan for Study Product 
5.4.1 
Prevention of Known Toxicities to Study Product 
5.4.1.1 Ocular Toxicity 
As outlined in protocol section 1.4.2, Known and Potential Risks of Hydroxychloroquine, an 
important AE associated with HCQ use is ocular toxicity and in particular, retinal injury. The 
current (2016) recommendations for retinopathy screening for HCQ use as put forward by the 
American Academy of Ophthalmology include a baseline exam within the first year of HCQ use 
and then annual screening after 5 years of use[153].  While there are not clear associations 


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between baseline eye abnormalities and future risk for HCQ-related eye injury [153, 170] , this 
baseline examination helps to identify underlying problems that may make future identification of 
HCQ toxicity difficult. 
For ARA08, the eye examination will include 3 parts: a) dilated funduscopic examination, b) SD-
OCT, and c) 10-2 visual field testing. Of note, the 2016 American Academy of Ophthalmology 
recommends only a dilated funduscopic evaluation at baseline, and further testing with SD-OCT 
and visual field testing only if there is evidence of retinal disease on the dilated examination 
[153]. However, we will perform all three tests to provide maximal understanding of possible 
retinal disease at baseline. 
The study excludes individuals with a history of renal and/or liver disease, limits HCQ use to 12 
months or less, and restricts HCQ dosing to ≤ 6.5 mg/kg/day of ideal body weight to minimize 
toxicities.   
We will not repeat an ocular examination after subject randomization as part of the official 
study protocol. If a subject develops ocular symptoms, the subject will be referred to clinical 
care. Study therapy will be discontinued if the subject develops ocular symptoms as described in 
Section 1.4.2, Known and Potential Risks of Hydroxychloroquine.  
 
5.4.2 
Management of Known Toxicities to Study Product 
5.4.2.1 Hematologic Reactions 
Subjects in the study will have complete blood counts obtained at Screening, Week 24, and Week 
52. If changes suspicious of HCQ-related effects occur, study therapy will be discontinued (see 
Section 5.8.1, Study Treatment Discontinuation).  
5.4.2.2 Gastrointestinal Reactions 
Gastrointestinal reaction and liver injury will be assessed throughout the subject’s participation in 
the study. (See Section 5.8.1, Study Treatment Discontinuation, for criteria for discontinuation of 
study therapy.) 
5.4.2.3 Allergic Reactions 
Subjects will be counseled during study enrollment about the possible reactions as outlined in 
Section 1.4.2.2, Additional Toxicities, and will be instructed to stop the study drug immediately if 
allergic reactions develop, and seek medical attention.  
5.4.2.4 Over Dosage 
There have been fatal reactions described with overdoses of HCQ and, therefore, individuals that 
overdose on study product must immediately seek emergency medical attention and inform health 
care providers of the possibility of ingestion of HCQ. In the event of an overdose, the subject 
and/or appropriate clinical staff may be unblinded. 


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5.5 
Concurrent Medications and Therapy 
Agents such as acetaminophen, NSAIDS and herbal supplements are allowed, although the 
subject is required to report all of these medications to the study investigators. Absorption of 
HCQ can be impaired if taken simultaneously with antacids; a four hour window between 
drug administrations is recommended. HCQ has been reported to cause hypoglycemia.  It is 
suggested that subjects taking hypoglycemic agents have their blood sugar monitored and 
medication doses adjusted as necessary. Additionally, digoxin levels may increase with the 
administration of HCQ. Dose adjustment may be needed. All such medications are to be recorded 
in the study documents.  
Use of corticosteroids for non-IA conditions is allowed, as follows: 
• Systemic corticosteroid use may include short courses defined as ≤ 21 days at doses of ≤ 
60 mg daily of prednisone or equivalent for treatment of allergic or infectious conditions 
(e.g. asthma flare, sinusitis), and must be limited to 2 courses of corticosteroids per year.  
• Systemic corticosteroid use within 3 weeks of the Month 36 visit is prohibited. 
• Local steroid injections for non-IA conditions are limited to 3 injections within the 3 
months prior to Month 36.  
• If an intra-articular injection for a non-IA condition occurs within 3 weeks of any visit,  
the impacted joint will not be assessed at the visit. 
 
5.6 
Prohibited Medications 
Use of DMARDS, systemic corticosteroids, and biologic therapies, as noted below are prohibited 
during study participation.  
• Any small molecule for the treatment of RA or other immunologic conditions 
• Any biologic therapy for the treatment of RA or other immunologic conditions 
• Oral, intravenous, intramuscular, or intraarticular systemic corticosteroids for IA  
• MTX 
• LEF 
• Cyclosporine (excluding eye drops) 
• Mycophenolic acid 
• Cyclophosphamide 
• Chlorambucil 
• Penicillamine 
• Azathioprine or 6-mercaptopurine 
• HCQ 
• SSZ 
• Tofacitinib 
• Tacrolimus (excluding topical) 
 
Note: Chronic use of tetracycline class antibiotics is prohibited. Short courses for treatment of 
acute infection are allowed.   


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If there are other agents that the study investigator believes may be immunomodulatory, discuss 
with the protocol team. 
5.7 
Procedures for Monitoring Subject Compliance 
At each visit during the treatment period, subjects must return their drug bottles, and drug/placebo 
will be assessed by study personnel via pill counts. Accountability of study drug must be done in 
the presence of the subject in order to obtain explanations regarding discrepancies in compliance 
with the dosing regimen. Accountability of the study drug must be recorded on the drug 
accountability form. 
5.8 
Treatment Discontinuation and Subject Withdrawal 
5.8.1 
Study Treatment Discontinuation  
Study treatment will be discontinued permanently for any individual subject under the following 
conditions:  
1. At any time during the study at the request of the subject or subject’s guardian. 
2. If investigators or NIAID determine that the subject’s health, safety, and/or well-being are 
threatened. 
3. If the subject is administered any of the medications outlined in Section 5.6, Prohibited 
Medications, whether the medication is prescribed by a study site investigator or an 
outside physician. Study drug should be discontinued at the time the study team becomes 
aware that the subject has started prohibited medications. 
4. Study treatment will be discontinued for any subject who experiences any of the 
following: 
a. Pregnancy 
b. Development of clinically-apparent RA via the 2010 ACR/EULAR Criteria 
(defined as a score ≥ 6, OR findings consistent with RA-like synovitis paired with 
≥ 1 erosion(s) identified by x-ray) at a single study visit.  
c. An AE of Grade 3 or higher by the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) that is probably, possibly, 
or definitely related to HCQ. 
d. Retinal disease consistent with HCQ toxicity as described in Section 1.4.2, Known 
and Potential Risks of Hydroxychloroquine. 
e. Any allergic reaction attributed to study drug (see Section 1.4.2.2, Additional 
Toxicities) 
f. Any of the following persistent lab abnormalities: 
Note: Abnormal lab values meeting a criterion noted below should be confirmed 
within 4 weeks, prior to discontinuation.  
i. Serum creatinine clearance < 50 ml/min;  
ii. ALT or AST ≥ 3.5x the upper limit of normal (ULN);  
iii. WBC ≤ 2.5 x109/L; 


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iv. Platelet count < 75 x109/L;  
v. Hemoglobin < 10 g/dL;  
vi. ANC < 1.5 x109/L 
Subjects who discontinue protocol-specified treatment requirements will be treated as medically 
indicated according to physician discretion. 
5.8.1.1 Procedures for Discontinuation of Protocol-Specified Treatment 
Requirements  
Whenever possible, subjects who have been discontinued from study treatment should complete 
all scheduled study visits including all exams, procedures, assessments, and tests for the duration 
of the study. The HCQ level specimen will be collected at any visit where study therapy is 
discontinued, provided it was not previously collected. Furthermore, if discontinuation is due to 
safety concerns, subjects will be given appropriate care under medical supervision beyond the last 
scheduled study visit, if necessary, until the symptoms of any AE resolve or the subject’s 
condition becomes stable. If the site Principal Investigator (PI) determines that completion of 
these visits is not clinically appropriate for the subject or if the subject or subject’s guardian elects 
not to complete these visits, the subject will be withdrawn from the study per the guidelines in 
Section 5.8.2.1, Procedures for Subject Withdrawal from the Study. 
5.8.2 
Subject Withdrawal from the Study 
When a subject is withdrawn from the study, protocol-specified treatment requirements are 
discontinued, and study-related visits, exams, procedures, assessments, tests and data collection 
are terminated. Individual subjects will be withdrawn from the study under the following 
conditions: 
1. The subject or subject’s guardian withdraws consent. 
2. The investigator or NIAID believes it is in the best interest of the study or the subject. 
3. If the subject elects to participate in any other sort of study or clinical trial (excluding 
observational registries or cohorts), the subject may be withdrawn at the discretion of the 
DAIT/NIAID/NIH. 
5.8.2.1 Procedures for Subject Withdrawal from the Study 
Subjects who plan to withdraw early from the study regardless of the reason will be asked to 
consent to annual phone calls to answer inquiries about the development of RA and related 
information until the subject reaches 3 years past randomization. 
Whenever possible, subjects to be withdrawn from the study will be asked to come in for an end-
of-study evaluation, which includes all scheduled exams, procedures, and laboratory tests planned 
for the Month 36 visit. After this end-of-study visit, the site PI (or designated treating physician) 
may continue to follow the subject to manage clinical care, but no additional study-related data 
will be collected.  


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5.8.3 
Safety Stopping Guidance  
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be 
called upon for ad hoc reviews or emergency meetings. The DSMB will review any event that 
potentially impacts safety at the request of the protocol chair or DAIT/NIAID.  In addition, the 
following events will trigger a safety review: 
1. Any immediately life threatening event or death that is possibly, probably, or definitely 
related to HCQ. 
2. The number of subjects in the HCQ arm who experience an SAE that is at least possibly 
related to HCQ during the 12 month treatment period reaches a level listed in Table 5.3 
• 
The values for the “# of HCQ subjects with an SAE” in Table 5.3 are derived 
under the assumption that the maximum tolerable risk of an SAE is 10% for 
subjects in the HCQ arm.  If this risk is truly ≤ 10%, then the chance of observing 
the indicated “# of HCQ subjects with an SAE” (or more) is small (i.e. probability 
≤ 0.1). As such, hitting this boundary suggests the actual risk may exceed 10%, 
hence, warranting a closer look at the data. 
• 
If a DSMB Emergency Safety Review is called due to this rule, and the decision is 
to continue the study, then the DSMB may also consider how many new SAEs 
should accrue before a subsequent emergency review will be required.  
 
 
Table 5.3. Number of SAEs in the HCQ arm that would trigger a DSMB Emergency Safety Review 
# of HCQ 
subjects  
≤5 
6-11 
12-18 
19-25 
26-32 
33-40 
41-47 
48-55 
56-63 
64-71 
72-79 
80-87 
88-96 
97-100 
# of HCQ 
subjects 
with an SAE 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
For the events noted above, the DSMB chair will review details of the events and decide whether 
or not the full committee should convene for a DSMB Emergency Safety Review. A halt in 
enrollment will occur if the DSMB Emergency Safety Review is not completed within 3 weeks. 
In the event of a temporary halt in enrollment, no new subjects will be consented or start on 
therapy with HCQ or placebo; subjects already on HCQ or placebo will continue on therapy 
unless they are the focus of the DSMB review. Subjects in the screening phase of the study may 
continue to undergo minimal risk procedures (e.g., blood tests), but more than minimal risk 
procedures should be deferred. Randomization will not occur until the DSMB review is complete.  
After careful review of the data, the DSMB will make recommendations regarding study conduct 
and/or continuation. 
6 ASSESSMENT OF SAFETY AND EFFICACY 
6.1 
Assessments of Safety 
To assess safety in this population, chemistries and hematologies will be evaluated at Screening, 
and at visits scheduled at Weeks 24, and 52 (End of Treatment). Physical exams and vital sign 
assessments will be assessed at clinic visits per Tables 6.1 and 6.2, Schedule of Events. These 
safety evaluations may also be performed at any unscheduled Visits.  


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Additionally, medical history will be collected at Screening and Baseline. AEs of NCI-CTCAE 
Grade 2 and above will be recorded at each scheduled visit through Month 18 (see protocol 
section 7.3.2, Collection Period, for additional details). Site coordinators will also collect 
information regarding AEs during the telephone assessments and during the treatment and follow-
up periods. AEs of NCI-CTCAE Grade 3 or greater are of particular interest for safety endpoints. 
6.2 
Assessments of Efficacy 
6.2.1 
ACR/EULAR Criteria (2010) 
The primary outcome of this trial is the development of clinically-apparent RA (see definition in 
Section 2.1 Primary Objective) based on both clinical examination findings and laboratory 
testing.  
If a subject presents with swollen joint(s) that are consistent with RA-like synovitis, all the items 
necessary to establish the fulfillment of the 2010 ACR/EULAR criteria will be ascertained (See 
Table 1.1); however, the laboratory parameters including IgM-RF, CCP and hsCRP will be tested 
at a central laboratory. Hence, the final determination as to whether or not the subject met criteria 
for clinically-apparent RA will be delayed (< 21 days). Of note, due to issues regarding sample 
stability and test reproducibility, hsCRP will be used for the calculation of the ACR/EULAR 
criteria and disease activity measures; ESR will not be used.   
6.2.2 
Joint Assessment, Definitions of Inflammatory Arthritis, and Joint 
Tenderness 
IA: IA is defined as the presence of a swollen joint(s) that is (are) consistent with RA-like 
synovitis, in the determination of the examiner, and graded as present (1) or absent (0). At each 
study visit, the examiner will perform a joint count to identify RA-like synovitis (excluding the 
hip which cannot be evaluated for swelling on physical examination), and record these findings.  
A single examiner across visits for a given subject is highly encouraged, though not required.  
Tenderness: Tenderness is defined as subject-reported sensation of pain with examination 
(examiner direct joint pressure sufficient to blanch the nail bed of the examiner), or with passive 
range-of-motion of the joint by the examiner. At each post-screening study visit, the examiner 
will perform a joint count to identify joint tenderness, and record these findings. 
6.2.3 
Determination of disease activity  
6.2.3.1 Disease Activity Score (DAS) 
The DAS is a validated instrument widely used to assess RA disease activity in research and 
clinical practice [24, 171].  In particular, the versions of the DAS that are commonly used in 
outcomes assessment in RA includes either a 28 or 44 joint count, and measurement of CRP – 
with this being entitled the DAS28 (or 44) CRP. The DAS28-CRP will be the primary measure 
for evaluating disease activity. Results are calculated using an established formula and yield 
continuous variables (See Appendix 15.3, Formulas). The items for the DAS scores will be using 


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the modified MDHAQ for Subject Global Health (see below), joint examination form for tender 
and swollen joints, and the hsCRP from laboratory testing.  
6.2.3.2 Modified Multi-Dimensional Health Assessment Questionnaire (MDHAQ) 
The modified MDHAQ is a validated instrument to assess RA activity in research and clinical 
practice [24, 172]. It contains questions for the self-assessment of current function (e.g. were you 
able to get in/out of bed), as well as scales (0 to 10) for pain, global health, and fatigue. In 
addition, when combined with physician joint counts (tender and swollen) and CRP testing, 
information from the modified MDHAQ can be used to calculate a variety of measures in RA 
including the DAS28-CRP (see above), the CDAI, and the RAPID-3.  This questionnaire will be 
completed at each post-Screening study visit.  
6.2.3.3 Patient Reported Outcomes Measurement Information System  
Patient-reported outcome measures (PROs) use subject responses to questions to produce numeric 
values representing patients' state of well-being or suffering as well as ability or lack of ability to 
function. The NIH funded leading investigators to develop a "psychometrically validated, 
dynamic system to measure PROs efficiently in study participants with a wide range of chronic 
diseases and demographic characteristics." The PROMIS initiative is part of the NIH goal to 
develop systems to support NIH-funded research supported by all of its institutes and centers. 
PROMIS measures cover physical, mental, and social health and can be used across chronic 
conditions. More information is available at: www.nihpromis.org. For this trial, the NIH 
PROMIS measure Profile (29 v2.0) will be used, and will be scored to yield continuous variables. 
For this trial, the NIH PROMIS measure Profile (29 v2.0) will be completed at Baseline, then 
annually and at the time of diagnosis. 
6.2.3.4 Questionnaire Assessment of Self-Reported Symptoms 
Self-reported joint symptoms such as pain, stiffness, and swelling may be important measures in 
predicting future onset of IA [173], as well as in determining response to therapy.  However, 
existing measures of disease activity do not assess joint symptoms in specific areas in adequate 
detail. As such, a novel questionnaire has been developed that can assess patient-reported joint 
symptoms of pain, stiffness and swelling in specific joint regions (e.g. metacarpophalangeal joints 
(MCPs)). These questionnaires will be completed at each post-Screening study visit, and can be 
scored to yield continuous variables, or can be scored to yield joint symptoms by regions.  
6.2.3.5 X-ray Imaging 
The presence of erosions serves to distinguish RA from other forms of IA (e.g. RA from SLE); in 
addition, the presence of erosions is an indicator of disease severity [174, 175]. Therefore, at the 
time of initial identification of a swollen joint(s) that is (are) consistent with RA-like synovitis in 
the clinical trial, subjects will undergo x-ray imaging of bilateral hands, wrists and feet within 14 
days, if possible. Subjects may undergo study-related x-ray imaging a maximum of 4 times 
throughout study participation. Of note, even if RA-like synovitis is identified outside of these 
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evaluated with x-rays in RA and in other joints findings of erosions may be less clear. The feet 
will receive two views (anterior-posterior and lateral oblique) and the hands/wrists will receive 
two views (posterior-anterior and ball catcher).   
All females who have the ability to become pregnant will complete a pregnancy test prior to 
receiving x-rays. A negative result on the pregnancy test must be confirmed prior to the female 
subject undergoing x-ray procedures. If the pregnancy test yields a positive result, see protocol 
section 6.5.11, Special Considerations for Pregnant Subjects, for additional details.  
These x-rays will be read and scored by a central reader who is blinded to the status of the subject 
to determine the presence/absence and location of any erosions, and this result will be reported to 
the study site to determine if a subject has met the study’s primary endpoint, see protocol section 
6.5.9, Evaluations Triggered by a Swollen Joint,, for additional details. In addition, the x-rays will 
be scored using the modified Sharp’s score by a central reader. The presence/absence of erosions 
as well as the Sharp’s score can be analyzed in aggregate at the study’s completion. 
6.3 
Environmental and other factors 
Multiple environmental and other factors have been associated with increased risk for developing 
RA (reviewed in [65]). For example, factors associated with increased risk for RA including 
smoking, parity, recent pregnancy, and periodontal inflammation. Factors associated with 
decreased risk for RA including oral contraceptive use, high fish intake, and moderate alcohol 
intake. As such, certain factors may play a role in the prediction of development of RA in CCP 
positive individuals, or in response to therapy. These factors will be assessed by means of an 
epidemiologic questionnaire (assessed at Baseline, then annually, and at the time of diagnosis, if 
applicable) and a dietary questionnaire (administered at Baseline, the End of Study/Month 36 
visit, and at the time of diagnosis visit, as applicable).  
6.4 Mechanistic Specimens and Studies  
6.4.1 
Genetic risk factors 
Specific gene sequences within the MHC that are, in aggregate, termed the shared epitope (SE) 
are strongly associated with development of RA [63]. DNA extracted from peripheral blood will 
be analyzed to determine the presence of this risk factor for each study subject who consents to 
the optional DNA specimen collection. 
6.4.2 
HCQ Levels 
HCQ levels will be used as a covariant for analyses [176]. A single specimen will be collected 
from all subjects during the treatment phase of the study. At the completion of the study, after 
subject treatment assignments are unblinded, HCQ level specimens from subjects randomized to 
the HCQ treatment arm will be analyzed. Specimens from subjects randomized to the placebo 
treatment arm will be stored for future studies to broaden our understanding of issues related to 
the pathogenesis, prediction, and prevention of classifiable RA.   


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6.4.3 
Mechanistic studies 
Mechanistic studies will be performed to evaluate the relationship between treatment with HCQ 
and alterations in biomarkers suggesting improved autoimmunity and/or reduced inflammation, as 
well as mechanisms of progression to RA.  Specifically, we will explore the following scientific 
hypotheses and concepts: 
Impact of HCQ use on biomarkers 
• 
Decreasing levels of the autoantibodies RF and anti-CCP in the HCQ arm compared to the 
placebo arm would indicate an abrogation of autoimmunity.  
• 
Contraction of the breadth and evolution of specific ACPA reactivities in the HCQ arm 
compared to the placebo arm would indicate improved autoimmunity.   
• 
Lower levels or contraction of the number of inflammatory markers, including hsCRP, 
cytokines, and chemokines, in the HCQ arm compared to the placebo arm represent 
reduced inflammation.  
Progression to RA 
• 
Elevation of certain ACPAs sequences early in the trial period among those who develop 
RA may suggest key antigenic targets in the earliest phases of loss of tolerance in RA. 
• 
Elevations of specific cytokines and chemokines levels among those who develop RA will 
be evaluated to determine when in the time course of development certain processes are 
most important, and which processes may be most important in the transition from 
autoimmunity in absence of clinically-apparent RA to clinically-apparent RA. 
• 
Profiles of autoantibodies and inflammatory markers present at baseline (or developing 
during the study)  that correlate well with (i) the likelihood of IA, (ii)  the timing of 
development of IA, or (iii) the response to HCQ may suggest important pathways in the 
development of IA and/or identify potential predictors of impending RA or response to 
HCQ. 
To evaluate these key hypotheses and concepts, serum for analyses of Core Outcomes (anti-CCP, 
IgM RF, and hsCRP) will be collected at Baseline and approximately every 6 months throughout 
the entirety of the study. Core Outcomes will also be collected at any visit where the joint exam is 
consistent with RA-like inflammatory arthritis.  In addition, serum for the autoantibodies and 
plasma for circulating cytokines/chemokines will be collected at specific time points outlined in 
the Schedule of Events (Tables 6.1 and 6.2).   
6.4.4 
Specimen Storage for Future Use and Genetic Research 
As noted above, serum and plasma are required for the key mechanistic studies. Residual serum 
and plasma from these planned studies as well as additional serum, plasma, peripheral blood 
mononuclear cells (PBMCs), RNA, and urine will also be collected and stored for future studies 
designed to explore the mechanisms underlying the response to HCQ, as well as to broaden our 
understanding of issues related to the pathogenesis, prediction and prevention of classifiable RA. 
These specimens will be collected at specific time points outlined in the Schedule of Events 


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(Tables 6.1 and 6.2) and at any visit where the joint exam is consistent with RA-like 
inflammatory arthritis.  
DNA for identification of the SE risk factor will be optional for all subjects. Residual DNA from 
this analysis will be stored until the end of study and used to confirm results. In addition, if 
subjects also consent to future genetic research, then residual DNA may be stored for future use. 
Serum, plasma, PBMCs, RNA, and urine will be stored for all subjects for future research as 
noted above. 
 
6.5 
Evaluations by Study Visit  
6.5.1 
Pre-Screening  
This study will be explained in lay language to each potential participant. Each participant will 
sign an informed consent form before committing to study Pre-Screening procedures. As noted in 
Section 4.3, Strategies for Recruitment and Retention, study personnel may use 3 different 
approaches for identifying and recruiting potential subjects. Pre-Screening procedures at the study 
site will vary by method of recruitment as outlined below:  
FDRs of probands with RA:  
Study site personnel will do the following:  
a. Explain the study to each proband (i.e. RA patient) and providing them with 
study-approved materials to share with their FDR(s). In addition, study site 
personnel are responsible for distributing letters to probands informing them 
about the trial, and distributing other promotional materials such as hard-copy 
flyers or e-mails that could be used to identify FDRs. 
b. When the site is contacted by the FDR, consent the FDR for an ARA08 Pre-
Screening Evaluation. 
c. Ask the FDR to complete a Pre-Screening Questionnaire (see Appendix 15.5.1, 
Pre-Screening Questionnaire)  
d. Draw an anti-CCP specimen for evaluation at local laboratory.   
• Note: If clinic data collected within the last 12 months indicate that the 
anti-CCP assay -specific positivity criterion is met, do not draw this 
specimen at the Pre-Screening visit; clinic data may be used.  
e. Invite the FDR to an ARA08 Screening Visit if the anti-CCP assay-specific 
positivity criterion is met, and there is no evidence of RA or IA based on the 
Questionnaire.  
• Anti-CCP assay-specific positivity criterion:  
o Anti-CCP3/Anti-CCP3.1 assay result ≥ 40, or  
o Anti-CCP2 or any other ACPA assay yielding a positive result 
per assay normal ranges  
 
Population Screening: 
 


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1. Participants recruited at events or facilities serving a more general population (e.g. 
health fair or clinic) are consented and screened in multiple steps. Study site personnel 
will do the following: 
a. Consent the subject for the ARA08 Pre-Screening Evaluation (which includes 
taking a brief questionnaire and a blood draw).  
b. Ask the subject to complete a Pre-Screening Questionnaire (see Appendix 
15.5.1, Pre-Screening Questionnaire)  
c. Draw an anti-CCP specimen for evaluation at the local laboratory.  
d. Review results of the anti-CCP test and the Pre-Screening Questionnaire.  
e. Invite the participant to an ARA08 Screening Visit if the anti-CCP assay-
specific positivity criterion is met, and there is no evidence of RA based on the 
questionnaire. 
• Anti-CCP assay-specific positivity criterion:  
o Anti-CCP3/Anti-CCP3.1 assay result ≥ 40, or  
o Anti-CCP2 or any other ACPA assay yielding a positive result 
per assay normal ranges  
 
2. Other recruitment strategies may include CCP testing of samples from blood banks 
and biorepositories, providing appropriate consent has been obtained.  
a. Subjects with Anti-CCP levels meeting the anti-CCP assay-specific positivity 
criterion will be contacted per site institutional guidelines.  
  
Rheumatology patients who are anti-CCP positive and without IA: 
Study site personnel are responsible for the following: 
a. Identify potential subjects using clinic registries and medical records, and 
make local practitioners aware of this clinical trial.  
b. Contact individuals who are potential subjects.  
c. If clinic data collected within the last 12 months, indicate that the anti-CCP 
assay-specific positivity criterion is met, and there is no evidence of RA, then 
invite the patient to an ARA08 Screening Visit. 
d. If additional information is needed, then: 
i. Consent the patient for an ARA08 Pre-Screening Evaluation. 
ii. Ask the patient to complete a Pre-Screening  Questionnaire (if needed)  
(see Appendix 15.5.1, Pre-Screening Questionnaire)  
iii. Draw an anti-CCP specimen for evaluation at the local laboratory (if 
needed).  
iv. Invite the subject to an ARA08 Screening Visit if the anti-CCP assay-
specific positivity criterion is met, and there is no evidence of RA based 
on the questionnaire. 
• Anti-CCP assay-specific positivity criterion:  
o Anti-CCP3/Anti-CCP3.1 assay result ≥ 40, or  
o Anti-CCP2 or any other ACPA assay yielding a positive result 
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If the anti-CCP result does not meet the assay-specific positivity criterion, the potential subject 
may be Pre-Screened again 6 months after their initial Pre-Screening anti-CCP test.  
6.5.2 
Screening Visit 
Unless otherwise specified, the screening evaluations must be performed within 30 days prior to 
the Baseline/Randomization Visit. 
The following labs, procedures, and assessments will determine subject eligibility: 
1. Main study informed consent form 
2. Demographics 
3. Medical History 
4. Prior and Concomitant Medications 
5. Physical examination (full) 
6. Vital Signs including heart rate, sitting systolic and diastolic blood pressure, height, 
weight, and waist circumference 
7. NYHA classification assessment for heart disease 
8. Joint Examination – Physician’s Assessment that includes a swollen joint count to 
identify RA-like synovitis 
Note: Midfoot and hip joints are not evaluated for swelling. 
IMPORTANT: Subjects with swollen joints that are consistent with RA-like synovitis 
should NOT be randomized or treated. 
9. Anti-CCP3 analyzed at the University of Colorado  
Note: anti-CCP3 results from the central lab that are assessed within 6 weeks of the 
screening visit are valid for evaluation of eligibility and do not need to be redrawn.   
10. Screening Chemistries/ Hematologies: Serum creatinine, ALT, AST; WBC, platelets, 
ANC, hemoglobin  
11. Infectious disease testing that includes: HIV-1/HIV-2 Antigen/Antibody, Hepatitis B 
Surface Antigen, Hepatitis C Antibody. In addition, if Hepatitis C antibody is positive, 
then viral load should also be tested unless there is documentation of prior Hepatitis C 
treatment and a report confirming an undetectable viral load ≥12 weeks after the 
completion of Hepatitis C therapy. 
Note: If any of the infectious disease tests yield a positive result, the site will report 
these results to the subject and perform other follow-up per institutional guidelines.  
12. A retinal exam by an ophthalmologist or optometrist that includes a dilated 
funduscopic exam, visual field (10-2) and Optical Coherence Tomography (OCT) to 
be conducted prior to the Baseline visit (after all other screening eligibility criteria 
have been confirmed). Note: Results from the initial screening visit retinal 
examination may be used to assess eligibility for up to 6 months. 


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6.5.3 
Baseline/Randomization Visit 
The baseline evaluations must be performed within 30 days of the Screening visit. 
1. Medical History 
2. Prior/Concomitant Medications 
3. Physical Exam (symptom-driven)  
4. Vital Signs including heart rate and sitting systolic/diastolic blood pressure 
5. STAT Urine pregnancy test (for women of child-bearing potential) 
6. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint).    
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
7. Randomization  
IMPORTANT: Subjects with tender joints and/or swollen joints that are 
consistent with RA-like synovitis at the time of the Baseline/Randomization Visit 
should NOT be randomized or treated. 
Note: Sites utilizing a central pharmacy may randomize subjects prior to the 
Baseline visit after initial eligibility at Screening has been confirmed, but if tender 
joints and/or swollen joints that are consistent with RA-like synovitis are noted at 
baseline, do NOT dispense the study medication to the subject. 
8. Subject Questionnaires  
• 
Profile 29 v2.0 
• 
Epidemiologic Questionnaire 
• 
Dietary Assessment Questionnaire 
• 
Self-reported Joint Symptoms, including modified MDHAQ 
• 
Evaluate family member participation 
9. Specimen collection for real-time core outcome testing (hsCRP, IgM-RF, Anti-
CCP3) and serum for mechanistic studies.  
10. Specimen collection for mechanistic studies: PBMC/plasma, RNA, and urine. Note: 
DNA will be collected from subjects who consent to the optional specimen for 
shared epitope analysis. 
11. Dispense study therapy  
Notes:  


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• 
Female subjects cannot receive study therapy until eligibility can be confirmed 
via STAT urine pregnancy test. 
• 
The first dose of study therapy will be given in clinic. The subject will be 
observed per institutional standards. 
6.5.4 
Treatment Period 
6.5.4.1 
Treatment Clinic Visits: Week 6, Week 12, & Week 36 (Visit Windows: +/- 7 
days) 
1. AE Assessment 
2. Concomitant Medications 
3. Physical Exam (symptom-driven)  
4. Vital Signs including heart rate and sitting systolic/diastolic blood pressure 
5. Self-reported Joint Symptoms, including modified MDHAQ 
6. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that 
includes the talo-tibial joint (also called the talo-crural joint), subtalar joint 
(also called talo-calcaneal joint), and inferior tibio-fibular joint).    
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
7. Evaluate family member participation 
Items 8-11 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA at a prior visit. 
8. Procedures conditional on results of the Joint Examination 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis, no additional assessments are needed, proceed as noted below.   
9. Subject self-reported pregnancy status 
10. Dispense study therapy  
Note: If study therapy is discontinued at this visit, the HCQ level specimen will be 
collected, provided it has not been previously collected. 
11. Pill Counts (at each clinic visit) 


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6.5.4.2 
Mid-Treatment Clinic Visit: Week 24 (Visit Windows: +/- 7 days) 
1. AE Assessment 
2. Concomitant Medications 
3. Physical Exam (symptom-driven)  
4. Vital Signs including heart rate and sitting systolic/diastolic blood pressure 
5. Hematology: Hemoglobin, hematocrit, WBC (with differential), and platelet count  
6. Chemistry: Serum creatinine, ALT, and AST  
Note: Abnormal lab values meeting the criteria noted in Section 5.8.1, Study 
Treatment Discontinuation, should be confirmed within 4 weeks, prior to 
discontinuation. 
7. Self-reported Joint Symptoms, including modified MDHAQ 
8. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that 
includes the talo-tibial joint (also called the talo-crural joint), subtalar joint 
(also called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
9. Evaluate family member participation 
Items 10-14 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA at a prior visit. 
10. Procedures conditional on results of the Joint Examination 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis;  
o Specimen collection for future core outcome testing (hsCRP, IgM-RF, 
and anti-CCP3) and serum for mechanistic studies  
11. Specimen collection for HCQ Level analysis 
o Note: This specimen will be collected at the Week 24 visit, provided the 
specimen was not collected previously.  
12. Subject self-reported pregnancy status 
13. Dispense study therapy  


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14. Pill Counts (at each clinic visit) 
6.5.4.3 
End of Treatment: Week 52 (Visit Window: +/- 14 days) 
1. AE Assessment 
2. Concomitant Medications 
3. Physical Exam (full)  
4. Vital Signs including heart rate and sitting systolic/diastolic blood pressure 
5. Subject Questionnaires 
• 
Profile 29 v2.0  
• 
Self-reported Joint Symptoms, including modified MDHAQ  
• 
Evaluate family member participation 
6. Hematology: Hemoglobin, hematocrit, WBC (with differential), and platelet count  
7. Chemistry: Serum creatinine, ALT, and AST  
8. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
Item 9 is only applicable to subjects with a previous diagnosis of clinically-
apparent RA: 
9. Specimen collection for real-time core outcome testing: hsCRP only 
Items 10 - 14 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA. 
10. Procedures conditional on results of the Joint Examination 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis;  
o Specimen collection for real-time core outcome testing (hsCRP, IgM-
RF, and anti-CCP3) and serum for mechanistic studies 


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o Specimen collection for mechanistic studies: PBMC, plasma, RNA, and 
urine. Note: DNA will be collected from subjects who consent to future 
genetic testing. 
11. Specimen collection for HCQ Level analysis 
• 
Note: This specimen will be collected at the Week 52 visit, in the event the 
specimen collection was missed at Week 24 and has not been previously 
collected.  
12. Subject self-reported pregnancy status 
13. Epidemiologic Questionnaire 
14. Pill Counts  
6.5.4.4 
Treatment Telephone Assessments (Weeks 18, 30, & 42, Visit Window: +/- 7 
days) 
After the Baseline visit, subjects will be contacted by study personnel (via a telephone call) at 
Week 18, 30, and 42. The following information will be obtained during the telephone 
assessments: 
1. 
Assessment of toxicities and adverse reactions  
2. 
Review of study drug dosing, administration and storage  
3. 
Assessment of joint symptoms  
4. 
Assessment of pregnancy status (if applicable) 
5. 
Invitation for questions 
6. 
Update of contact information 
If joint symptoms suggest evidence of new IA defined as new or worsening joint pain, stiffness or 
swelling since the last study visit or symptoms suggestive of an AE, then the subject will be 
instructed to return to the clinic for an unscheduled visit as soon as possible (see Section 6.5.8, 
Unscheduled Visits). 
Telephone assessments will not occur after a subject is diagnosed with definite RA, IA with 
erosion(s), or is found to be taking a prohibited medication for the treatment of IA/RA (see 
Section 5.6, Prohibited Medications).  
6.5.5 
Follow-up Visits 
6.5.5.1 
Follow-up Telephone Assessments (Months 15, 21, 27, & 33,Visit Window: +/- 
14 days) 
After the Week 52 visit, subjects will be contacted by study personnel (via a telephone call) at 
Months 15, 21, 27, and 33. The following information will be obtained during the telephone 
assessments: 
1. AE Collection (Month 15 only) 
2. Assessment of joint symptoms  


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3. Invitation for questions 
4. Update of contact information 
If there is evidence of new IA defined as new or worsening joint pain, stiffness or swelling since 
the last study visit or symptoms suggestive of an AE, the subject will be instructed to return to the 
clinic for an unscheduled visit as soon as possible (see Section 6.5.8, Unscheduled Visits). 
Telephone assessments will not occur after a subject is diagnosed with definite RA, IA with 
erosion(s), or is found to be taking a prohibited medication for the treatment of IA/RA (see 
Section 5.6, Prohibited Medications).  
6.5.5.2 
Follow-up Clinic Visit: Month 18 (Visit Windows: +/- 14 days) 
1. AE Assessment (see Section 7.3.2, Collection Period) 
2. Concomitant Medications 
3. Physical Exam (symptom-driven)  
4. Self-reported Joint Symptoms, including modified MDHAQ 
5. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
6. Evaluate family member participation 
Items 7 & 8 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA. 
7. Procedures conditional on results of the Joint Examination: 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis;  
o Specimen collection for the future core outcome testing (hsCRP, IgM-
RF, and anti-CCP3) and serum for mechanistic studies   
8. Subject self-reported pregnancy status 
 


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6.5.5.3 
Follow-up Clinic Visit: Month 24 (Visit Windows: +/- 14 days) 
1. SAE Assessment (see Section 7.3.2, Collection Period) 
2. Concomitant Medications 
3. Physical Exam (symptom-driven)  
4. Vital Signs including heart rate and sitting systolic/diastolic blood pressure  
5. Subject Questionnaires  
• 
Profile 29 v2.0  
• 
Self-reported Joint Symptoms, including modified MDHAQ  
• 
Evaluate family member participation 
6. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
Items 7 - 9 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA. 
7. Procedures conditional on results of the Joint Examination 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis;  
o Specimen collection for future core outcome testing (hsCRP, IgM-RF, 
and anti-CCP3) and serum for mechanistic studies  
8. Epidemiologic Questionnaire 
9. Subject self-reported pregnancy status  
6.5.5.4 
Follow-up Clinic Visit: Month 30 (Visit Windows: +/- 14 days) 
1. SAE Assessment (see Section 7.3.2, Collection Period) 
2. Concomitant Medications 
3. Physical Exam (symptom-driven)  
4. Self-reported Joint Symptoms, including modified MDHAQ 


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5. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
6. Evaluate family member participation 
Items 7 & 8 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA. 
7. Procedures conditional on results of the Joint Examination 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis; 
o  Specimen collection for future core outcome testing (hsCRP, IgM-RF, 
and anti-CCP3) and serum for mechanistic studies  
8. Subject self-reported pregnancy status  
 
6.5.5.5 
End of Study Clinic Visit: Month 36/Early Termination (Visit Windows: +/- 14 
days) 
1. Demographics 
2. SAE Assessment (see Section 7.3.2, Collection Period) 
3. Concomitant Medications 
4. Physical Exam (full)  
5. Vital Signs including heart rate and sitting systolic/diastolic blood pressure and 
weight and waist circumference  
6. Subject Questionnaires  
• 
Profile 29 v2.0  
• 
Self-reported Joint Symptoms, including modified MDHAQ  
• 
Evaluate family member participation 
7. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  


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• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
Item 8 is only applicable to subjects with a previous diagnosis of clinically-
apparent RA. 
8. Specimen collection for real-time core outcome testing: hsCRP only 
Items 9 - 11 are only applicable to subjects who have not been diagnosed with 
clinically-apparent RA. 
9. Procedures conditional on results of the Joint Examination: 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.  Note: After the results of these evaluations are received and the 2010 
ACR/EULAR score has been calculated, the site will call the subjects to inform 
them of their results and the subjects will be referred to clinical care. Subjects 
will not return to the clinical site after the Month 36 visit for additional 
diagnosis follow-up.    
• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis; 
o Specimen collection for real-time core outcome testing (hsCRP, IgM-
RF, and anti-CCP3) and serum for mechanistic studies  
o Specimen collection for mechanistic studies: PBMC, plasma, RNA, and 
urine. Note: DNA will be collected from subjects who consent to future 
genetic testing. 
10. Subject Questionnaires: 
• 
Epidemiologic Questionnaire 
• 
Dietary Assessment Questionnaire 
11. Subject self-reported pregnancy status 
12. Specimen collection for HCQ Level analysis  
• 
Note:  This specimen will be collected at the Early Termination visit if the 
specimen was not collected previously and the visit occurs during the treatment 
period. 
 


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6.5.5.6 
Time of Diagnosis Clinic Visit 
If a subject is diagnosed with clinically-apparent RA (as defined in protocol section 2.1, Primary 
Objective) prior to the Month 36 visit, the subject will return for a Time of Diagnosis visit, which 
will supersede any regularly scheduled visit with which it overlaps. During the Time of Diagnosis 
visit the following evaluations will occur:  
1. Demographics 
2. Concomitant Medications 
3. AE Assessment (see Section 7.3.2, Collection Period) 
4. Physical Exam (full)  
5. Vital Signs including heart rate and sitting systolic/diastolic blood pressure and 
weight and waist circumference  
6. Subject Questionnaires  
• 
Profile 29 v2.0  
• 
Epidemiologic Questionnaire  
• 
Dietary Assessment Questionnaire  
• 
Self-reported Joint Symptoms, including modified MDHAQ 
• 
Evaluate family member participation 
7. Joint Examination – Physician’s Assessment (including a swollen/tender joint 
count). Note: The count will include 66 tender/64 swollen joints.  
• The ankle joint(s) on each limb will be counted as a single joint that includes 
the talo-tibial joint (also called the talo-crural joint), subtalar joint (also 
called talo-calcaneal joint), and inferior tibio-fibular joint). 
• The midfoot joints will not be evaluated for either tenderness or swelling.  
• The hip joints will not be evaluated for swelling.  
8. Specimen collection for future core outcome testing (hsCRP, IgM-RF, and anti-
CCP3) and serum for mechanistic studies will be completed.   
9. Specimen collection for mechanistic studies: PBMC, plasma, RNA, and urine. Note: 
DNA will be collected from subjects who consent to future genetic testing. 
10. Specimen collection for HCQ Level analysis 
• Note: This specimen will be collected at the Time of Diagnosis visit if the specimen 
was not collected previously and the visit occurs during the treatment period. 
11. Discontinue study therapy 
12. Pill Counts (if subject is diagnosed during the treatment period) 
13. Refer subject to clinical care 


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14. Encourage subject to return for all remaining planned study visits.  See Section 
6.5.9, Evaluations Triggered by a Swollen Joint, for testing that will no longer be 
completed at post-diagnosis visits. 
6.5.6 
Early Withdrawal Visit 
Subjects who withdraw early from the study will be asked to complete an Early Withdrawal Visit 
(aka End of Study Clinic Visit/Month 36). All scheduled exams, procedures, and laboratory tests 
scheduled for the Month 36 visit will be performed at this visit. Data from subjects who do not 
complete all study visits will still be included in the Intent-to-Treat (ITT) and safety analyses. 
Subjects who withdraw from the study regardless of the reason and have not been diagnosed with 
clinically-apparent RA will be asked to consent to annual phone calls (Weeks 52, Month 24, 
Month 36) to answer inquiries about the development of RA and related information. 
Note: Premature discontinuation of study drug is not a reason for early withdrawal from the 
study. Subjects who discontinue study drug early should be encouraged to continue in the study. 
(See Section 5.8.1, Study Treatment Discontinuation.) 
6.5.7 
Visit Windows 
All study procedures should be performed within the designated visit window (i.e., ± n days) for 
each scheduled visit (see Tables 6.1 and 6.2, Schedule of Events). Whenever possible, a 
rescheduled visit should remain within the designated visit window. The coordinating center 
should be notified if the study procedures for any scheduled visit cannot be performed within the 
designated window. 
6.5.8 
Unscheduled Visits 
Unscheduled visits may occur if a subject has developed adverse effects or joint symptoms that 
need to be evaluated by study personnel. Subjects will be instructed to contact study personnel if 
these symptoms/AEs develop, and the subject will be seen for a study visit, as soon as possible. 
At these unscheduled visits, the same procedures will be performed as are done at the other 
interval study visits.  Additionally, other safety assessments (e.g. physical examination, 
laboratory assessments) may be performed at the discretion of the investigator. 
The following evaluations will be performed at each unscheduled visit: 
1. AE Assessment (If visit occurs prior to Month 18) 
2. Concomitant Medications 
3. Physical Exam (symptom-driven, including joint exam) 
• 
If the subject has 1 or more swollen joints that are consistent with RA-like 
synovitis and the subject has not been previously diagnosed with clinically-
apparent RA, refer to protocol section 6.5.9, Evaluations Triggered by a Swollen 
Joint, for a list of additional assessments that are required to be completed at this 
visit.     


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• 
If the subject does not have a swollen joint that is consistent with RA-like 
synovitis, the subject will continue with the visit as noted below. Specimens for 
core outcome testing and mechanistic studies will not be collected at this visit.  
4. Vital Signs including heart rate, sitting systolic/diastolic blood pressure  
5. Self-reported Joint Symptoms, including modified MDHAQ 
6. Subject self-reported pregnancy status  
7. If study therapy is discontinued at this visit, the HCQ level specimen will be 
collected, provided it has not been previously collected. 
8. If needed for evaluation of safety related to drug toxicity during the treatment 
period, the following assessments will be performed: 
• 
Hematology: hemoglobin, hematocrit,  WBC (with differential) , and platelet 
count 
• 
Chemistry: serum creatinine, ALT, and AST 
Note: Abnormal lab values meeting the criteria noted in Section 5.8.1, Study 
Treatment Discontinuation, should be confirmed within 4 weeks, prior to 
discontinuation. 
9. Evaluate family member participation 
 
Additional evaluations may be performed according to investigator discretion. 
6.5.9 
Evaluations Triggered by a Swollen Joint 
At any study visit, either regularly scheduled or unscheduled, if a swollen joint(s) that is 
consistent with RA-like synovitis is identified during the joint examination, the following items 
will be completed during the study visit: 
• 
Specimen collection for real-time core outcome testing: hsCRP, IgM-RF, and 
anti-CCP3 and serum for mechanistic studies 
• 
Specimen collection for mechanistic studies (at the initial occurrence of RA-like 
synovitis only): PBMC/plasma RNA, and urine. Note: DNA will be collected 
from subjects who consent to future genetic testing. 
• 
X-rays will be performed (at the first occurrence and every 6 months thereafter, 
if applicable).  See protocol section 6.2.3.5, X-ray Imaging, prior to conducting 
x-rays on female subjects (who have the ability to become pregnant).  
• 
A follow-up visit will be scheduled within the next 3 to 6 weeks.  This visit may 
coincide with a regularly scheduled visit or may be conducted as an unscheduled 
visit.  
• 
Note: Subjects will continue to take study medication until the diagnosis of 
clinically-apparent RA has been confirmed and the subject returns to the site for 
a Time of Diagnosis Visit (see Section 6.5.5.6, Time of Diagnosis Clinic Visit).  


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After the study visit, once the results from the core outcome tests and x-ray are available, the 
score for the 2010 ACR/EULAR Classification Criteria will be calculated, and at the 3-6 week 
follow-up visit, the following may occur:  
1) If the subject has definite RA per the 2010 ACR/EULAR Classification Criteria (i.e. score 
≥ 6), the follow-up visit will become a Time of Diagnosis visit (refer to Section 6.5.5.6, 
Time of Diagnosis Clinic Visit). 
2) If a swollen joint consistent with RA-like synovitis is identified by joint examination, the 
ACR/EULAR score is <6, and x-rays identify the presence of at least 1 erosion the follow-
up visit will become a Time of Diagnosis visit (refer to Section 6.5.5.6, Time of Diagnosis 
Clinic Visit).  
Note: After the Time of Diagnosis visit, the subject will resume routine study clinic visits in 
order to follow the natural history of RA; with the following exceptions: 
• Scheduled telephone assessments at Weeks 18, 30, and 42, and Months 15, 21, 27, 
and 33 will not occur.  
• After the Time of Diagnosis visit, biologic samples (blood, urine) for mechanistic 
specimens and core outcome specimens (anti-CCP3, IgM-RF, and hs-CRP) will 
not be collected and the dietary and epidemiologic questionnaires will not be 
completed.  
• Routine safety labs samples will be collected at Week 24 and Week 52 regardless 
of subject diagnosis and prohibited medications.  
• HsCRP will be collected at Week 52 and Month 36.  
Note: See Appendix 15.2.1, Evaluations Triggered by a Swollen Joint Flow Chart, for a 
figure containing the information noted above.  
 
3) If a swollen joint consistent with RA-like synovitis is identified by joint examination, but 
the ACR/EULAR score is <6, and no erosions are observed on the x-ray, the subject will 
be informed of this at the 3-6 week follow-up visit, and the following will occur:  
• The subject will be instructed to continue taking the study therapy. 
• The subject will be instructed to return to the clinic every 6 weeks (for either an 
unscheduled visit or a regularly scheduled visit that falls within the next 6 weeks) 
until: 
• The synovitis resolves and is not present at two consecutive visits 
(unscheduled or planned) 6 weeks apart, then the subject will resume 
routine interval study visit follow-up with routine core outcome testing and 
mechanistic specimen draws.  
• The subject develops definite RA by 2010 ACR/EULAR Classification 
Criteria or erosions on follow-up x-rays then the follow-up visit will 
become a Time of Diagnosis visit as outlined above (refer to Section 
6.5.5.6, Time of Diagnosis Clinic Visit).   


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• Note: If synovitis persists but does not meet 2010 ACR/EULAR 
Classification Criteria for RA, x-rays may be repeated at 6-month intervals 
to assess for development of erosions provided the subject is not pregnant. 
If a swollen joint(s) that is consistent with RA-like synovitis is identified 
during the joint examination during the 3-6 week follow-up visit, follow 
blood draws according to Appendix 15.2.1, Evaluations Triggered by a 
Swollen Joint Flow Chart. 
6.5.10 
Procedures for Subjects Diagnosed with Inflammatory or Rheumatoid 
Arthritis by an Outside Physician 
If a subject is diagnosed with IA or RA outside of the ARA08 study, the subject will return to the 
study site as soon as possible (this may be accomplished through a planned routine study visit or 
an unscheduled visit).  During the visit, the site personnel will obtain additional information 
regarding the diagnosis including any medications the subject is taking in response to the 
diagnosis. Study drug should be discontinued at the time the study team becomes aware 
that the subject has started prohibited medications. 
Procedures for this visit are dependent upon medications taken in response to the diagnosis of 
IA/RA and are outlined below. A graphic representation of this decision process can be found in 
Appendix 15.2.2, Flow Diagram: Procedures for Subjects Diagnosed with IA/RA by an Outside 
Physician. 
1) If the subject is taking a medication for IA/RA (see Section 5.6, Prohibited Medications): 
a.  The study medication will be permanently discontinued, if this visit occurs during 
the treatment period. 
b. Assessments for an Time of Diagnosis Clinic Visit will be conducted  (see Section 
6.5.5.6, Time of Diagnosis Clinic Visit)  
c. The subject will undergo x-ray imaging provided an x-ray has not been conducted 
in the past 6 months and the subject is not pregnant. See protocol section 6.5.11, 
Special Considerations for Pregnant Subjects, prior to conducting x-rays on 
female subjects (who have the ability to become pregnant). 
d. The subject will be referred to clinical care, and will be encouraged to return for 
all remaining planned study visits. 
After this visit, the subject returns for routine follow-up visits according to the planned 
study visit schedule outlined in Sections 6.5.4, Treatment Period, and 6.5.5, Follow-up 
Visits.  However, several assessments will not be conducted at subsequent visits, as 
outlined below:  
• Scheduled telephone assessments at Weeks 18, 30, and 42, and Months 15, 21, 27, 
and 33 will not occur.  
• Biologic samples (blood, urine) for mechanistic specimens and core outcome 
specimens (anti-CCP3, IgM-RF, and hs-CRP) will not be collected. 


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• The dietary and epidemiologic questionnaires will not be completed at visits 
occurring after this visit.  
• Routine safety labs samples will be collected at Week 24 and Week 52 regardless 
of subject diagnosis and prohibited medications.  
• HsCRP will be collected at Week 52 and Month 36 for the evaluation of the 
DAS28 – CRP secondary efficacy endpoint.  
2) If the subject is not taking a medication for the IA/RA diagnosis, the site investigator will 
conduct a joint examination.  
a. If the site investigator identifies a swollen joint during the joint examination, 
he/she will follow the steps outlined in Section 6.5.9 Evaluations Triggered by a 
Swollen Joint.  
b. If the joint examination does not identify any swollen joints, the subject will 
continue with routine study visits as planned.  No specimens will be collected at 
this visit.  
Note: See Appendix 15.2.2, Procedures for Subjects Diagnosed with IA/RA by an Outside 
Physician Joint Flow Chart, for a figure containing the information noted above.  
 
6.5.11 
Special Considerations for Pregnant Subjects 
A subject who becomes pregnant during her participation in the study:   
• Will discontinue study therapy per protocol section 5.8.1, Study Treatment 
Discontinuation, if the pregnancy occurs during the treatment period.  
• Cannot receive x-rays during the pregnancy  
• Will otherwise be followed as all other subjects participating in the study.   
 




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Pill Count 
 
 
 
 
 
X8 
X8 
X8 
X8 
X8 
X 
 
 
                                              
1 Subjects identified through the first degree relative or general population recruitment strategies will be given, and subjects identified through a review of clinic records may be given, a Pre-Screening consent form to indicate 
their consent to undergo Pre-Screening procedures as described in Section 6.5.1, Pre-Screening. 
2 Physical Exam: Full PE at Screen, Week 52, Time of Diagnosis and Month 36/Early Termination. Symptom-driven PE at all other clinic visits. 
3 NHYA Classification: See Section 15.4, NYHA Classification. 
4 If a subject develops ocular symptoms, the subject will be referred to clinical care (see section 5.8.1, Study Treatment Discontinuation). 
5 A retinal exam by an ophthalmologist or optometrist that includes a dilated funduscopic exam, visual field (10-2) and OCT should be conducted prior to the Baseline visit (after all other screening eligibility criteria have been 
confirmed). Note: Results from the initial screening visit retinal examination may be used to assess eligibility for up to 6 months. 
6 Subjects with swollen joints that are consistent with RA-like synovitis at the time of the Baseline/Randomization Visit should NOT be randomized or treated. Sites utilizing a central pharmacy may randomize 
subjects prior to the Baseline visit after initial eligibility at Screening has been confirmed, but if swollen joints that are consistent with RA-like synovitis are noted at baseline, do NOT dispense study therapy to the 
subject. Note: The first dose of study therapy will be given in clinic. The subject will be observed per institutional standards. 
7 All participants should complete the “ Participation of First Degree Relatives” questionnaire. If the subject consents to linking his/her information with a participating family members, please follow the Process for Linking First 
Degree Relatives in the Manual of Operations. 
8 These procedures will be conducted if the subject has not been previously diagnosed with clinically-apparent RA.  
9 Telephone Assessment: Coordinators will call subjects at Week 18, 30, and 42 to assess toxicities to HCQ, AEs, a review of study drug dosing and storage, joint symptoms, pregnancy status, answer subject questions, and 
confirm contact information. 
10 Subjects who have withdrawn from the study and consent to annual phone calls will be asked about development of RA and related information. 
11 If a subject has a swollen joint consistent with RA-like synovitis, do not randomize or dispense study drug to the subject. 
12 Note: The count will include 66 tender/64 swollen joints. The midfoot joints will not be evaluated for either tenderness or swelling. The hip joints will not be evaluated for swelling. 
13 If the subject has 1 or more swollen joints that are consistent with RA-like synovitis, then complete additional assessments as outlined in section 6.5.9, Evaluations Triggered by a Swollen Joint. 
14 If a subject found through the rheumatology clinic has already had Anti-CCP levels assessed in the previous 12 months, historical results may be used to assess eligibility at Pre-Screening. Pre-Screening specimens will be 
analyzed at the site local laboratory. 
15 Results from real time core outcome testing specimens will be reported back to the sites for review of the 2010 ACR/EULAR criteria.   
16 Collection of core outcome test and mechanistic studies specimens will be discontinued after a subject has been diagnosed with clinically-apparent RA and the Time of Diagnosis visit has been completed. Subjects who have 
swollen joints consistent with RA-like synovitis with no erosions will follow the normal schedule for core outcome testing collection. 
17 Subjects who have been previously diagnosed with clinically-apparent RA will have hsCRP (only) assessed at Week 52.  
18 X-rays may be conducted every 6 months if needed. All subjects with swollen joints consistent with RA-like synovitis will have at least 1 x-ray but follow-up x-rays are not needed if clinically-apparent RA is diagnosed (see 
Section 3.1, Description of Study Design). At most, a subject may undergo study-related x-ray imaging 4 times throughout his/her participation in the study. Female subjects who have child bearing potential cannot undergo x-ray 
imaging unless a STAT urine pregnancy test is negative. 
19 If any of the infectious disease tests yield a positive result, consult exclusion criteria in Section 4.2, Exclusion Criteria, for subject eligibility. The site will report these results to the subject and perform other follow-up per 
institutional guidelines. 
20 Female subjects cannot receive the initial dose of study product until eligibility can be confirmed via a STAT urine pregnancy test.  
21 Note: Abnormal lab values meeting the criteria noted in Section 5.8.1, Study Treatment Discontinuation, should be re-tested within 4 weeks, prior to discontinuation.  
22 If needed for evaluation of safety related to drug toxicity during the treatment period, the chemistry and hematology draws will be collected. 
23 DNA collection is optional. This specimen will be collected at the Baseline visit for subjects who consent to the collection for analysis of the shared epitope. DNA will be collected at subsequent visits for subjects who consent 
to future genetic testing.  
24 Specimens for mechanistic studies will be collected at the initial finding of RA-like synovitis.  
25 It is strongly recommended that the HCQ level specimen be drawn 4 or more hours after the last HCQ dose. 
26  The HCQ level specimen will be collected at one time point for each subject. The specimen collection may occur at the Week 24, Week 52, or at any visit where study therapy is discontinued (including Time of Diagnosis and 
Early Termination visits) provided the specimen was not collected previously. 
27 Please refer to protocol section 5.3.2, Administration, for the study therapy distribution schedule.  




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28 See protocol section 6.5.9, Evaluations Triggered by a Swollen Joint, for additional details. 
29 Physical Exam: Full PE at Screen, Week 52, Time of Diagnosis and Month 36/Early Termination. Symptom-driven PE at all other clinic visits. 
30 Non-serious adverse events will not be collected after Month 18.  SAEs will be collected for the duration of the study.  
31 These procedures will be conducted if the subject has not been previously diagnosed with clinically-apparent RA. 
32 All participants should complete the “ Participation of First Degree Relatives” questionnaire. If the subject consents to linking his/her information with a participating family members, please follow the Process for Linking 
First Degree Relatives in the Manual of Operations. 
33 Follow-up Telephone Assessments: Coordinators will call subjects at Months 15, 21, 27, and 33 to assess AEs (until Month 15); joint symptoms, answer subject questions, and confirm contact information. 
34 Subjects who have withdrawn from the study and consent to annual phone calls will be asked about development of  RA and related information. 
35 Note: The count will include 66 tender/64 swollen joints. The midfoot joints will not be evaluated for either tenderness or swelling. The hip joints will not be evaluated for swelling. 
36 If the subject has 1 or more swollen joints that are consistent with RA-like synovitis, then complete additional assessments as outlined in section 6.5.9, Evaluations Triggered by a Swollen Joint. 
37 Results from real time core outcome testing specimens will be reported back to the sites for review of the 2010 ACR/EULAR criteria.  
38 Collection of core outcome tests and mechanistic studies specimens will be discontinued after a subject has been diagnosed with clinically-apparent RA and the Time of Diagnosis visit has been completed. Subjects who 
have swollen joints consistent with RA-like synovitis with no erosions will follow the normal schedule for core outcome testing collection.  
39 Subjects who have been previously diagnosed with clinically-apparent RA will only have hsCRP assessed at this time point. 
40 Review the 2010 ACR/EULAR Criteria results if subject has 1 or more swollen joints that are consistent with RA-like synovitis. 
41 X-rays may be conducted every 6 months if needed. All subjects with swollen joints consistent with RA-like synovitis will have at least 1 x-ray but follow-up x-rays are not needed if clinically-apparent RA is diagnosed 
(see Section 3.1, Description of Study Design). At most, a subject may undergo study-related x-ray imaging 4 times throughout his/her participation in the study. Female subjects who have child bearing potential cannot 
undergo x-ray imaging unless a STAT urine pregnancy test is negative. 
42Chemistry and hematology assessments may be performed, if needed.  
43 DNA will be collected for subjects who consent to future genetic testing. 
44 Specimens for mechanistic studies will be collected at the initial finding of RA-like synovitis.  
45 It is strongly recommended that the HCQ level specimen be drawn 4 or more hours after the last HCQ dose. 
46 The HCQ level specimen will be collected at one time point for each subject. The specimen collection may occur at the Week 24, Week 52, or at any visit where study therapy is discontinued (including Time of Diagnosis 
and Early Termination visits)provided the specimen was not collected previously. 


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7 SAFETY MONITORING AND REPORTING 
7.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines 
the procedures for appropriately collecting, grading, recording, and reporting that data. AEs that 
are classified as serious must be reported promptly (per Section 7.5, Reporting of Adverse Events) 
and appropriately to the sponsor (DAIT/NIAID), principal investigators in the trial, and IRBs. 
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, ICH Guideline E-6: Guideline for Good 
Clinical Practice, and applies the standards set forth in the NCI-CTCAE), Version 4.0: 
http://ctep.cancer.gov/reporting/ctc.html. 
7.2 Definitions 
7.2.1 
Adverse Event (or Adverse Experience) 
Any untoward or unfavorable medical occurrence in a human subject, including any abnormal 
sign, symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research (modified from the 
definition of AEs in the 1996 International Conference on Harmonization E-6 Guidelines for 
Good Clinical Practice)." [From OHRP "Guidance on Reviewing and Reporting Unanticipated 
Problems Involving Risks to Subjects or Others and AEs (1/15/07)" 
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm.] 
7.2.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction means any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Suspected adverse reaction (SAR) means any AE for which there is a reasonable possibility that 
the drug caused the AE. For the purposes of safety reporting, ‘reasonable possibility’ means there 
is evidence to suggest a causal relationship between the drug and the AE. A SAR implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by a drug 
(21 CFR 312.32(a)). 
7.2.3 
Unexpected Adverse Reaction 
A SAR is considered “unexpected” if it is not listed in the hydroxychloroquine package insert or 
is not listed at the specificity or severity that has been observed. 
7.2.4 
Serious Adverse Event 
An AE or SAR is considered “serious” if, in the view of either the investigator or DAIT/NIAID, it 
results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death 


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2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of 
either the investigator or DAIT/NIAID, its occurrence places the subject at immediate risk 
of death. It does not include an AE or SAR that, had it occurred in a more severe form, 
might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization (The event is 
considered an AE if the subject enters the emergency room of a hospital but is not 
admitted, but is considered a SAE if the subject is admitted into the hospital for at least 24 
hours.) 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
5. Congenital anomaly or birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
7.3 Collection and Recording of Adverse Events 
7.3.1 
Investigational Product 
The investigational product in this protocol is hydroxychloroquine.  
7.3.2 
Collection Period  
AEs of NCI-CTCAE Grade 2 and above will be collected from the time the subject signs the main 
clinical trial informed consent until he/she initiates study intervention or until he/she is 
determined to be ineligible to receive study intervention, if the investigator determines that the 
AE is related to a study-mandated procedure, treatment, or change in treatment. 
Regardless of whether the above is applicable, for all participants, AEs of NCI-CTCAE Grade 2 
and above will be collected from the time of initiation of study intervention (i.e., the 
administration of the first dose of study drug (HCQ/placebo), as defined in Section 6.5.3, 
Baseline/Randomization Visit), until Month 18 or until 30 days after he/she prematurely 
withdraws (without withdrawing consent) or is withdrawn from the study.  
Serious adverse events will be collected throughout the duration of the subject’s participation in 
the study.  
7.3.3 
Collecting Adverse Events  
AEs (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject. 
• 
Questioning the subject in an objective manner. 
• 
Receiving an unsolicited complaint from the subject. 
• 
An  abnormal value or result from a clinical or laboratory evaluation (including, but 
not limited to, a radiograph, an ultrasound, or an electrocardiogram) can also 


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indicate an AE, as defined in Section 7.4, Grading and Attribution of Adverse 
Events. 
7.3.4 
Recording Adverse Events  
AEs of NCI-CTCAE Grade 2 and above will be recorded from the time the subject signs the main 
clinical trial informed consent until he/she initiates study intervention or until he/she is 
determined to be ineligible to receive study intervention, if the investigator determines that the 
AE is related to a study-mandated procedure, treatment, or change in treatment. 
From the initiation of study therapy through Month 18 or until 30 days after the subject 
prematurely withdraws or is withdrawn from the study, the investigator will record and grade AEs 
of NCI-CTCAE Grade 2 and above on the appropriate AE electronic case report form (AE eCRF) 
regardless of their severity or relation to study medication or study procedure. 
Once recorded, an AE will be followed until it resolves with or without sequelae, or until the end 
of study participation, or until 30 days after the subject prematurely withdraws (without 
withdrawing consent)/or is withdrawn from the study, whichever occurs first. 
7.3.5 
Recording Serious Adverse Events 
Serious AEs will be recorded on the appropriate AE eCRF and on the SAE eCRF throughout the 
subject’s participation in the study. All requested information on the AE eCRF and SAE eCRF 
should be provided, if available, for submission to the Statistical and Clinical Coordinating Center 
(SACCC) and DAIT/NIAID. 
If a site investigator discovers a new SAE within 30 days after the end of study participation, the 
SAE will be reported. 
Once recorded, an SAE will be followed until it resolves with or without sequelae.  
7.4 Grading and Attribution of Adverse Events 
7.4.1 
Grading Criteria 
The study site will grade the severity of AEs experienced by the study subjects according to the 
criteria set forth in the NCI-CTCAE v4.0. This document (referred to herein as the NCI-CTCAE 
manual) provides a common language to describe levels of severity, to analyze and interpret data, 
and to articulate the clinical significance of all AEs. The NCI- CTCAE has been reviewed by the 
Protocol Chair(s) and has been deemed appropriate for the subject population to be studied in this 
protocol. 
AEs will be graded on a scale from 1 to 5 according to the following standards in the NCI-
CTCAE manual:  
Grade 1 = mild adverse event, not recorded. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 




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7.5 Reporting of Adverse Events  
7.5.1 
Reporting of Adverse Events to DAIT/NIAID 
This section describes the responsibilities of the site investigator to report AEs to the SACCC. 
Timely reporting of AEs is required by 21 CFR and ICH E6 guidelines. For this study, AEs of 
NCI-CTCAE Grade 2 and higher will be reported. 
Unless otherwise noted below in Section 7.5.1.1, Procedure for Adverse Events Requiring 24 
Hour Reporting, as requiring 24 hour reporting, AEs must be recorded on the appropriate AE 
eCRF within five (5) business days of the site learning of the event(s). 
7.5.1.1 Procedure for Adverse Events Requiring 24 Hour Reporting  
The AEs that are bulleted below must be reported by site investigators to the SACCC regardless 
of relationship or expectedness to study intervention within a 24 hour period of discovering the 
AE: 
• 
All SAEs per 21 CFR 312.32 definitions (see Section 7.2.4, Serious Adverse Event). 
• 
All NCI-CTCAE Grade 3 or greater events possibly, probably, or definitely related to 
HCQ; 
• 
Any event that the site considers serious but is not easily categorized. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol-mandated 
procedures are not to be reported as an SAE unless hospitalization is prolonged due to 
complications. 
The following process for reporting of the AEs bulleted above ensures compliance with the ICH 
guidelines and the FDR CFR regulations. When an investigator identifies such an AE, he or she 
must notify the SACCC within 1 business day of discovering the AE, and complete and submit 
the AE/SAE eCRF within one business day following initial notification. The SACCC is 
responsible for notifying DAIT/NIAID upon receipt of the site’s notification of the AE and 
sending a SAE report form to DAIT/NIAID within two business days after receipt of the AE/SAE 
eCRF from the site. 
7.5.1.2 Procedure for Standard Adverse Event Reporting 
All other AEs (Section 7.3.3, Collecting Adverse Events) must be recorded by the site on the 
appropriate AE eCRF within 5 business days of the site learning of the AE(s). 
7.5.2 
DAIT/NIAID Reporting to the Health Authority  
This clinical study has been granted exemption from investigational new drug application (IND) 
regulations by the FDA in accordance with 21 CFR 312.2(b) of the regulations, therefore, AEs 
will not be reported to the FDA by the study sponsor (NIAID).  


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7.5.3 
Reporting of Adverse Events to IRBs 
All investigators must report AEs and SAEs in a timely fashion to their respective IRBs in 
accordance with applicable regulations and local reporting guidelines. 
7.6 Pregnancy Reporting 
This study includes pregnancy information as safety data. Although pregnancy is not an SAE, 
information about any pregnancy should be reported promptly to the SACCC on the same 
timeline as an SAE for tracking purposes (Section 7.5.1.1, Procedure for Adverse Events 
Requiring 24 Hour Reporting). 
All pregnancies identified during the study must be followed to conclusion and the outcome of 
each must be reported. The investigator should be informed immediately of any pregnancy in a 
study subject. A pregnant subject should be instructed to stop taking study medication. The 
investigator should report to the SACCC all pregnancies within one business day (as described in 
Section 7.5.1.1, Procedure for Adverse Events Requiring 24 Hour Reporting) using the 
Pregnancy eCRF. The investigator should counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. Monitoring of the pregnant subject 
should continue until the conclusion of the pregnancy, and a follow-up Pregnancy eCRF detailing 
the outcome of the pregnancy should be submitted to the SACCC.  
Information requested about the delivery will include: 
• 
Subject’s enrollment ID 
• 
Gestational age at delivery 
• 
Birth weight, length, and head circumference 
• 
Gender 
• 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at one 
minute, five minutes, and 24 hours after birth, if available 
• 
Any abnormalities. 
Should the pregnancy result in a congenital abnormality or birth defect, an SAE must be 
submitted to the SACCC using the SAE reporting procedures described above. 
7.7 Reporting of Other Safety Information 
An investigator should promptly notify the SACCC when an “unanticipated problem involving 
risks to subjects or others” is identified, which is not otherwise reportable as an AE. 
7.8 Review of Safety Information 
7.8.1 
Medical Monitor Review 
The study management team will receive monthly reports from the SACCC compiling new and 
accumulating safety information on, including but not limited, to AEs, SAEs, and pregnancies 
recorded by the sites on appropriate eCRFs.  


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In addition, the Medical Monitor will receive SAE and pregnancy reports for review and triage 
after the SACCC is made aware of these events (See Sections 7.5.1, Reporting of Adverse Events 
to DAIT/NIAID, and 7.6, Pregnancy Reporting). 
7.8.2 
DSMB Review 
The Data and Safety Monitoring Board (DSMB) will review accumulating safety data at least 
yearly during planned DSMB Data Review Meetings. Data for the planned safety reviews will 
include, at a minimum, a listing of all reported AEs and SAEs.  
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be 
called upon for ad hoc reviews or emergency meetings (see Section 5.8.3, Safety Stopping 
Guidance). The DSMB will have the discretion to recommend actions regarding study conduct 
and continuation as a consequence of any planned or unplanned monitoring activity.  
8 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
8.1 Sample Size and Power  
For the primary analysis, we are interested in demonstrating a long-term impact (3 year) of a 1- 
year course of HCQ treatment on preventing the development of clinically-apparent RA (defined 
in Section 2.1, Primary Objective) in high-risk subjects.  As such, rather than comparing full 
survival curves between treatment arms, the sample size for this study was selected to achieve 
sufficient power to compare survival curves at a fixed point 3 years after initiating treatment with 
HCQ. Survival for this study is defined as absence of clinically-apparent RA.  Estimated risks 
will be derived from a Kaplan-Meier curve using censored time-to-event data to account for 
attrition under the assumption of non-informative censoring.  
For the assumptions used in these calculations, we relied on the published data summarized in 
Section 1.1.3, Classification of RA [85, 86, 90, 173]. Since this study will be enrolling subjects 
with ≥2 times the ULN for anti-CCP3 (i.e. ≥40 units) and following them for 3 years, we assume 
that the untreated subjects in the ARA08 study should have at least a 50% risk of developing 
clinically-apparent RA by 3 years.  In the HCQ arm, we hope to achieve a 50% reduction in risk, 
to ~25% developing clinically-apparent RA (or 75% survival), over the 3 year time frame.   
For the primary analysis, the test statistic will be computed using a method described by Klein 
(2007) [177]. Klein et al compared performance of several Wald-type chi-square statistics derived 
by dividing the difference of transformed Kaplan-Meier (KM) survival estimates for each arm by 
the associated variance derived using the delta-method. For this study, we compared the 
performance of the log(-log) and logit transformations (referred to as Χ23 and Χ25, respectively, in 
Klein (2007)). The logit transformation was selected for this study, because it had slightly higher 
power in simulation studies. To estimate power, the test statistic was computed for 1000 
simulated trials, and power was estimated as the percentage of simulated trials where the test was 
rejected at α=0.05. We assumed time to failure follows an exponential distribution. As such, a 
50% risk (or 50% survival) at 3 years implies the hazard per year (λ) equals 0.231 for the control 
arm. If the risk falls to 25% (or 75% survival) at 3 years for the treatment arm, then λ = 0.096, 
and the hazard ratio equals 2.4 for untreated compared to treated subjects.  In a retrospective 


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cohort study of subjects with palindromic rheumatism, the hazard ratio (HR) for development of 
RA based on 3 1/3 years of follow-up was ~3 for untreated subjects compared to subjects treated 
with anti-malarials [112].  As such, attaining a hazard ratio of 2.4 for this study is a reasonable 
goal.  
For example, with 80 subjects per arm, the study has 90% power to detect a reduction in risk from 
50% to 25% at 3 years. Under the null case (hazard ratio=1), the test was rejected 4.6% of the 
time. If the risk for controls is 50%, but the HR drops to 2.1, then power is 81%.  If the risk for 
controls is 35% and the HR remains at 2.4, then power is 77%. Given the long duration of follow-
up, the sample size will be increased to 100 subjects per arm to allow for attrition of up to 20% 
(equally distributed across groups). 
8.2 Analysis Populations 
8.2.1 
Safety Population 
The safety population (SP), which will be used for all safety analysis, will include all subjects for 
whom study treatment is initiated. 
8.2.2 
Intent-to-Treat Population 
The Intent-to-Treat population will include all randomized subjects.  
8.2.3 
Modified Intent-to-Treat Population  
The modified Intent-to-Treat (mITT) population will include all randomized subjects who receive 
at least one dose of study drug and meet entry criteria. The primary efficacy analyses will be 
based on the mITT population. Subjects who, for whatever reason, do not complete their assigned 
therapy will be included in the mITT population in the groups to which they were randomized. 
8.2.4 
Per Protocol Population 
The Per Protocol (PP) population will be defined as those subjects in the mITT population who 
receive at least 80% of the assigned treatment protocol with no substantive deviations from 
protocol procedures that would impact evaluation of efficacy. A masked data review panel will 
evaluate deviations from the protocol including, for example, violations of entry criteria, 
departures from assigned treatment regimen, use of prohibited therapy or HCQ prescribed outside 
of the study, failure to complete study visits, or to complete visits within the specified visit 
windows. The panel may exclude subjects from the PP population if protocol deviations would be 
expected to impact the primary efficacy endpoint. Primary and secondary efficacy analyses may 
be replicated on the PP population. 
8.3 Statistical Methods  
In presenting data from this trial, continuous data will be summarized in tables listing the mean, 
standard deviation or standard error, median, and number of subjects in a group. Categorical data 


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will be summarized in tables listing the frequency and the percentage of subjects in a group. 
These summaries will be presented separately for subjects on the two treatment arms. 
8.3.1 
Efficacy Analysis 
8.3.1.1 Primary Efficacy Analysis  
The primary efficacy analysis is designed to test the hypothesis that HCQ will slow or prevent the 
onset of clinically-apparent RA in high-risk subjects.  The analysis will be based on the KM 
estimated risk of clinically-apparent RA at 36 months. The KM curves will be plotted along with 
95% confidence intervals. The null hypothesis, “H0: survival at 3 years is equal across arms”, 
will be tested against the two-sided alternative with α=0.05.  The test statistic will be a Wald-type 
chi-square statistic derived by dividing the difference of the logit-transformed KM survival 
estimates for each arm by the associated variance derived using the delta-method.  The logit-
transformed Wald-type chi-squared statistic has better test performance than the untransformed 
version in that the nominal Type I error is better retained. Subjects who choose to take off-study 
HCQ on a continuous basis will be censored at the time this therapy begins. This analysis will 
ignore stratification by site and method of recruitment, because the unstratified test statistic has 
been shown to have better test performance [177].  
 
The primary analysis ignores the possible impact of within-family correlation. The propensity to 
progress to RA could be more similar within families than between families or across individuals 
in the population, in which case observations in this study would not be independent. Due to 
operational difficulties in linking family members, we expect to have incomplete information on 
familial clustering, so we will not be able to account for this potential correlation in the primary 
analysis.  Because families tend to be small and not all family members will be eligible or willing 
to participate, we anticipate the impact of clustering to be small.  We will, however, perform 
sensitivity analyses to assess the potential impact of clustering. We are asking participants if they 
have FDRs who are participating. If the proportion who answer affirmative is small, the impact of 
clustering is likely to be minimal.  In addition, participants have the option of linking their study 
records with those of their relatives.  If family clusters are identified through this process, we can 
estimate the treatment effect from a marginal Cox model for clustered data using the method of 
Lee, Wei, and Amato [178] and compare these to estimates derived from the usual Cox model 
assuming independent observations.  We could also compare estimates for the risk of developing 
RA derived from logistic regression models fit using generalized estimating equations under 
difference assumptions about the within-family correlation structure; independent versus 
exchangeable [179].   
8.3.1.2 Secondary Efficacy Analyses 
All secondary analyses will be conducted in an exploratory fashion with p-values and confidence 
intervals presented as descriptive statistics with no adjustments for multiple comparisons. Tests 
will be two-sided and interval estimates will be generated at the 95% confidence level. All 
efficacy analyses will be repeated using the PP population.  


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The KM estimates for the two arms will be compared using the log-rank test, and survival at 12 
months will be compared using methods analogous to those described for the primary efficacy 
analysis.  The two arms will also be compared after control of appropriate covariates using a Cox 
proportional hazards model. The modeling will also evaluate the relationship between time to 
onset of clinically-apparent RA (or IA) and covariates such as site, method of recruitment, age, 
sex, race, baseline characteristics, genetic and environmental factors, and biomarkers.  
Treatment group comparisons of longitudinal changes in secondary efficacy endpoints, including 
disease activity scales, subject self-evaluation scores, and patient reported outcome scores (See 
Section 3.3.1, Secondary Efficacy Endpoints) will be evaluated using repeated measures random 
regression models.  Models will be fit to allow piece-wise fixed-effect for time during the 12-
month treatment period and during the subsequent follow-up period through 36 months. A 
random slope and intercept will be fit for each subject assuming an unstructured covariance 
matrix. Additional models may be developed to evaluate the relationship of endpoints with 
appropriate covariates. 
8.3.2 
Safety Analysis  
All safety analyses will be performed using the Safety Population. 
The frequency of AEs will be summarized by system organ class, preferred term, severity (grade), 
and relationship to study treatment. Relationship to study treatment will be categorized as either 
treatment related (possibly, probably, or definitely related to study medication) or unrelated 
(unlikely related or unrelated). Similar analyses will be performed for SAEs. To account for 
differential duration of study participation among subjects, the summaries will also include the 
event rate (i.e. number of events per person-time) in addition to the number and percent of events 
and subjects experiencing events. 
For each key safety endpoint defined in Section 3.3.2, Secondary Safety Endpoints the proportion 
of subjects experiencing at least one event in each treatment group will be reported and the 
treatment groups compared based on Fisher’s Exact Test. 
Laboratory parameters will be summarized both overall and by treatment group using appropriate 
descriptive statistics. For each lab parameter, the number and percent of subjects that have an 
increase, decrease, or no change from Baseline to Week 52, Month 24, and 36 will be displayed 
for each treatment group and pooled across treatment arms. For parameters with an explicit NCI-
CTCAE grading criterion, change from baseline will be indicated by a change in grade. For 
parameters that do not have an explicit NCI-CTCAE grading criterion, observed values will be 
categorized as ‘high’ (defined as >ULN), ‘normal’ (defined as ≥ lower limit of normal (LLN) and 
≤ ULN), or ‘low’ (defined as <LLN).  Then, a change from baseline will be indicated as a change 
in category. 
Laboratory data will also be plotted to show patterns over time.  Summary statistics including 25th 
percentile, median, and 75th percentile will be plotted for each visit by treatment group.  Lines 
connecting individual subject results from subjects with Grade 2 or higher values will be overlaid 
on each figure. For lab results that are not gradable, results from subjects with values outside of 2 
*ULN or 0.5*LLN will be overlaid. 


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All safety comparisons and associated p-values are considered exploratory, not as formal tests of 
hypothesis. As such, no adjustments will be made for multiple comparisons and all p-values must 
be interpreted cautiously. 
8.3.3 
Mechanism/Immunological Analysis 
Descriptive statistics and plots (including, but not limited to, those described subsequently) will 
be used to gain an understanding of the data prior to developing any statistical models. Means, 
medians, standard deviations, minimums, and maximums will be computed for each continuous 
biomarker at each time point for treatment groups and separately for subjects who do/do not 
experience clinically significant disease reactivation. For dichotomous biomarkers (i.e. + or -), 
frequencies and percents will be computed at each time point for treatment groups and separately 
for subjects who do/do not experience clinically-apparent RA. In addition, the biomarkers can be 
treated as ‘counts’ – for example, the number of autoantibodies positive in the ACPA array, and 
then analyzed as continuous variables to test a hypothesis that HCQ treatment results in decreased 
number of ACPAs. To gain a better understanding of trends over time, summary statistics (e.g., 
means, medians, or percents) will be plotted versus time at the relevant time points. Plots for 
individual subjects may also be useful. 
Multivariate model may be considered to evaluate the relationships between treatment group and 
alterations of biomarkers that may suggest improved underlying autoimmunity and/or 
inflammation. 
8.4 Interim Analysis  
Results of interim analyses will be reported to the DSMB for planned Data Review Meetings. 
Reports prepared for these meetings will focus on study conduct and subject safety and may 
include information on enrollment, randomization, site activation status and site performance, 
subject status (including premature discontinuations from study treatment and early withdrawals 
from the study), demographics, baseline characteristics, and safety analyses.  
If subject accrual is slower than expected or the rate of conversion to clinically-apparent RA is 
lower than anticipated, a non-binding futility analysis will evaluate the prospects for study 
success under these conditions. Because of this study’s potential for providing insight on the 
progression of RA in this high-risk population, “study success” for ARA08 is broadly defined. If 
the primary analysis fails to demonstrate a treatment group difference at Month 36, the study 
would still be considered successful if the secondary analysis demonstrated a significant 
difference in survival curves over the course of the study.  Furthermore, even in the absence of 
significant treatment effects for primary or secondary analyses, the mechanistic studies to 
evaluate changes associated with the onset of RA may still be worthwhile.     
Final interim analysis plans for efficacy and futility will be finalized upon completion of 
enrollment. A single nonbinding futility analysis will be performed at a time point when at least 
50% of expected information is available. If this analysis indicates that there is little chance of 
detecting a significant difference between the arms, the study may be stopped for futility. To 
evaluate futility, we will compute a Z-score test statistic based on the difference of logit 
transformed survival estimates (HCQ-placebo). A Z-score <0.3 would suggest the futility. For 
example, a simulation study assuming a study of 140 subjects showed that if the risk of RA is the 


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same for both groups (i.e. 50% for both arms), then chance of triggering the futility criterion is 
62%.  On the other hand, if the design assumptions are correct (50% risk for placebo, 25% for 
HCQ), then the chance of triggering the futility criterion is 2%, and power is 82%.  
In addition, up to 3 interim analyses may be conducted to stop the study early for overwhelming 
evidence of efficacy provided the overall power for the primary endpoint analysis is maintained at 
greater than 80%. For example, under the design assumptions in Section 8.1, Sample Size and 
Power, and assuming enrollment is stopped at 4.5 years with 140 independent subjects (i.e. no 
other family members participating), and 20% loss over 3 years of follow-up (i.e. exponential 
loss), a simulation study using an O’Brien-Fleming alpha-spending rule showed that power would 
be 82% with 2 interim analyses at 4.75 and 5.75 years compared to 83% power with no interim 
analyses.   
  
8.5 Other Statistical Considerations  
8.5.1 
Subgroups 
Exploratory analyses of the primary and secondary objectives may be conducted for the following 
subgroups defined by age, sex, race, baseline characteristics, genetic and environmental factors, 
and biomarkers.  Additionally, exploratory analyses of responder subgroups and/or subgroups 
defined through the mechanistic and immunological studies may be conducted. 
Subgroups that are differentially distributed between treatment groups and may be considered as 
potential covariates for adjustment in the Cox proportional hazard and longitudinal models noted 
above. 
8.5.2 
Multi-center Studies 
As noted above, analyses of survival estimates at fixed points in time will not be stratified.  Site 
and method of recruitment will be included as fixed covariates in models for secondary efficacy 
analyses. All safety analyses will be based on pooled data with no adjustment or stratification. 
8.5.3 
Multiple Comparisons and Multiplicity 
This study has a single primary analysis to be tested at α=0.05. Consequently, no adjustments for 
multiplicity are needed for Type I error protection.  
The secondary efficacy analyses are considered to be supportive with p-values and confidence 
intervals presented as descriptive measures of strength of evidence rather than formal statistical 
inference. Therefore, no multiplicity adjustments are needed for this study. 
8.5.4 
Missing Data 
Standard procedures will be used to ensure that data are as complete and accurate as possible. A 
full accounting will be made for all missing endpoint data.  
For the primary efficacy analysis, we assume non-informative censoring for subjects who leave 
the study prior to Month 36 with no evidence of clinically-apparent RA.  For withdrawn or lost 


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subjects who consented to yearly phone calls, data collected on RA diagnoses and HCQ use will 
be used to inform sensitivity analyses on the KM curves. Additional sensitivity analyses may be 
performed by estimating KM curves under different assumptions about the disease status of 
subjects lost prior to Month 36. Attrition and compliance rates will be compared between arms.  
For the random regression models, all available data for subjects will be included and contribute 
to the analysis without imputation.  If diagnostics suggest that the models are inadequate, 
sensitivity analyses (e.g. analysis of covariance (ANCOVA)) may be considered.  
8.5.5 
Changes to the Statistical Analysis Plan (SAP) 
A detailed description of the planned analyses will be provided in a SAP to be completed and 
signed off prior to the completion of the trial. Major changes from this protocol will be noted in 
the SAP. If there is sufficient reason to do so, revised plans may be issued during the course of 
the study. Changes to the SAP that are made subsequent to database lock will be documented in 
the clinical study report. 
9 ACCESS TO SOURCE DATA AND DOCUMENTS 
Each participating site will maintain the highest degree of confidentiality permitted for the 
clinical and research information obtained from subjects participating in this clinical trial. 
Medical and research records should be maintained at each site in the strictest confidence. After 
study completion, the data may be placed in a DAIT- approved central storage location. However, 
as a part of the quality assurance and legal responsibilities of an investigation, each site must 
permit authorized representatives of the sponsor(s) and the SACCC 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. Unless required by the laws 
permitting copying of records, only the coded identity associated with documents or other subject 
data may be copied (obscuring any personally identifying information). Authorized 
representatives as noted above are bound to maintain the strict confidentiality of medical and 
research information that may be linked to identified individuals. Participating sites will normally 
be notified in advance of auditing visits. 
All subject records and study documentation will be kept for at least 2 years after the protocol is 
completed. This will include all documentation of AEs, records of study drug receipt and 
distribution, and all IRB correspondence.  
10 DATA COLLECTION, QUALITY CONTROL AND QUALITY 
ASSURANCE 
The investigator is required to keep accurate records to ensure the conduct of the study is fully 
documented. The period of record retention should be consistent with the record retention policies 
of the sponsoring agency or applicable regulatory agencies. However, in certain instances, 
documents should be retained for a longer period if required by the applicable regulatory agency 
or by the National Institutes of Health. 
The investigator will report all major protocol deviations to DAIT and the SACCC per the 
instructions in the Autoimmunity Centers of Excellence (ACE) Manual of Procedures. The 


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SACCC will forward reports of protocol deviations to the responsible DAIT/NIAID medical 
officer for review as specified in the Manual of Procedures. 
The SACCC is responsible for regular inspection of the conduct of the trial, for verifying 
adherence to the protocol, and for confirming the completeness, consistency, and accuracy of all 
documented data. 
Data will be obtained from a variety of sources including, but not limited to laboratory notebooks, 
automated instrument output files, and clinical subject charts. Data from these source materials 
will be transmitted to the SACCC via one of two mechanisms. Data collected electronically at 
central laboratories will be transferred electronically directly from the laboratory to the SACCC 
using standard secure data transfer procedures. Data collected at the clinical sites will be 
transmitted to the SACCC using an internet-based remote data entry system. Clinical site 
personnel use an internet browser to key data into eCRFs; each CRF page is submitted to the 
clinical database electronically as the page is completed. Univariate data validation tests are 
performed as the data are keyed. The clinical database is backed up nightly; backup tapes are 
saved in a secure, off-site location. At any time, authorized site personnel may log in to the 
remote data entry system, review and correct previously entered 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 investigators 
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. 
The SACCC will periodically visit the participating clinical sites and audit the source documents 
in order to validate the data in the SACCC central database. Data will be provided using the 
subject’s screening or enrollment number, the SACCC will not collect personally identifying 
information such as the subject’s name or social security number. Subjects will provide 
demographic information such as race, ethnicity, and birth date. 
Data collected by the SACCC will be held in the strictest confidence, and are protected from 
access that could reveal personally identifying information about any subject in the trial. 
11 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
The study will be conducted according to GCP guidelines, U.S. 21 CFR Part 50 – Protection of 
Human Subjects, and Part 56 – Institutional Review Boards. 
11.1 Compliance with Good Clinical Practices 
This trial will be conducted in compliance with the protocol, current GCPs recommended by the 
ICH and the applicable regulatory requirements for participating institutions. These include the 
tenets of the Declaration of Helsinki and review and approval by the appropriate ethics review 
committee or IRBs of participating organizations. The SACCC will assure compliance through a 
program of quality assurance audits performed both at participating sites and within the SACCC 


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for data quality and adherence to protocol requirements. The SACCC is operated by Rho Federal 
Systems Division, Inc. (RhoFED), Durham, North Carolina under a cooperative agreement with 
NIAID. 
11.2 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and 
associated informed consent documents by an appropriate ethics review committee or IRB. Any 
amendments to the protocol or consent materials must be approved by the IRB before they are 
placed into use. In both the United States and in other countries, only institutions holding a 
current Federal Wide Assurance issued by the Office of Human Research Protection (OHRP) at 
the Department of Health and Human Services (DHHS) may participate. 
The investigator 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 both the reporting of 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.  
11.3 Informed Consent 
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 study, before any protocol-
specified procedures are carried out. A standard consent form for subject participation will be 
provided with the protocol to each institution. Any modifications to the standard information in 
the template will require review and approval by DAIT/NIAID. Informed consent will be 
obtained in accordance with 21 CFR 50.52. Information may be given to subjects in oral, written, 
or video form by the investigator. All prospective subjects will be given ample time to read the 
consent form, and ask questions, before signing. 
If subjects are to be enrolled who do not speak and read English, the consent materials must be 
translated into the language appropriate for the enrolling subject. Translated documents must be 
certified to contain the complete descriptions provided in the English version of the document. If 
an interpreter is used to provide or assist in describing the consent materials to an enrolling 
subject, the interpreter must also sign the consent materials certifying their involvement with the 
consent process. 
After completion, a copy of the signed consent form will be given to the subject. The original 
signed consent form will be kept on file in the subject’s study chart, available for inspection by 
regulatory authorities, both federal and institutional. 
11.4 Data and Safety Monitoring Board 
The responsibility for reviewing the ethical conduct of the study and for monitoring reports of 
evidence of adverse or beneficial effect is assigned to the DAIT Autoimmunity DSMB. The 
DSMB is an independent group composed of biomedical ethic experts, physicians, and other 
scientists who are responsible for continuing review of study information. The DSMB makes 


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recommendations to DAIT/NIAID on issues affecting the course and conduct of this clinical 
study. 
11.5 Study Termination  
In the event that the study is discontinued, sites will immediately notify subjects to terminate 
study agent and return for a close-out visit to the site within 30 days. 
12 FINANCING AND INSURANCE 
Participating institutions must comply with their institution’s policies on compensation, 
insurance, and indemnity. Institutions must have adequate liability insurance coverage to satisfy 
their local and national requirements for study participation. 
13 PUBLICATION POLICY 
The ACE Publication Policy will apply to publication of study results. Authorized participants 
may find details regarding the policy statement on the ACE internet website. Site investigators are 
encouraged to communicate and publish study results with prior notification of and review by 
DAIT, NIAID. 
 


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121. 
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Girgis, L., P.G. Conaghan, and P. Brooks, Disease-modifying antirheumatic drugs, 
including methotrexate, sulfasalazine, gold, antimalarials, and penicillamine. Curr 
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127. 
Clark, P., et al., Hydroxychloroquine compared with placebo in rheumatoid arthritis. 
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131. 
A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA 
Study. Am J Med, 1995. 98(2): p. 156-68. 
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hydroxychloroquine in patients with rheumatoid arthritis. Clin Rheumatol, 1984. 3 
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1984. 27(3): p. 267-76. 
134. 
Das, S.K., et al., Efficacy and safety of hydroxychloroquine sulphate in rheumatoid 
arthritis: a randomized, double-blind, placebo controlled clinical trial--an Indian 
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Tsakonas, E., et al., Consequences of delayed therapy with second-line agents in 
rheumatoid arthritis: a 3 year followup on the hydroxychloroquine in early 
rheumatoid arthritis (HERA) study. J Rheumatol, 2000. 27(3): p. 623-9. 
136. 
O'Dell, J.R., et al., Therapies for active rheumatoid arthritis after methotrexate 
failure. N Engl J Med, 2013. 369(4): p. 307-18. 
137. 
Dall'era, M. and E.F. Chakravarty, Treatment of mild, moderate, and severe lupus 
erythematosus: focus on new therapies. Curr Rheumatol Rep, 2011. 13(4): p. 308-16. 
138. 
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systemic lupus erythematosus: 59 cases. J Rheumatol, 2002. 29(1): p. 75-83. 
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rheumatic diseases. Ann Rheum Dis, 1998. 57(10): p. 582-7. 
140. 
Sacre, K., L.A. Criswell, and J.M. McCune, Hydroxychloroquine is associated with 
impaired interferon-alpha and tumor necrosis factor-alpha production by 
plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res Ther, 
2012. 14(3): p. R155. 
141. 
Edwards, M.H., et al., Hydroxychloroquine reverses thrombogenic properties of 
antiphospholipid antibodies in mice. Circulation, 1997. 96(12): p. 4380-4. 
142. 
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of action and efficacy in vivo. Mol Pharmacol, 2014. 85(3): p. 429-40. 
143. 
Gomez-Guzman, M., et al., Chronic hydroxychloroquine improves endothelial 
dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. 
Hypertension, 2014. 64(2): p. 330-7. 
144. 
Yang, P., J.N. Kruh, and C.S. Foster, Antiphospholipid antibody syndrome. Curr Opin 
Ophthalmol, 2012. 23(6): p. 528-32. 


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capillaritis and diffuse alveolar hemorrhage: a case series and literature review. 
Semin Arthritis Rheum, 2005. 35(3): p. 154-65. 
146. 
Kuznik, A., et al., Mechanism of endosomal TLR inhibition by antimalarial drugs and 
imidazoquinolines. J Immunol, 2011. 186(8): p. 4794-804. 
147. 
Kalia, S. and J.P. Dutz, New concepts in antimalarial use and mode of action in 
dermatology. Dermatol Ther, 2007. 20(4): p. 160-74. 
148. 
Lafyatis, R., M. York, and A. Marshak-Rothstein, Antimalarial agents: closing the 
gate on Toll-like receptors? Arthritis Rheum, 2006. 54(10): p. 3068-70. 
149. 
Fox, R.I., Mechanism of action of hydroxychloroquine as an antirheumatic drug. 
Semin Arthritis Rheum, 1993. 23(2 Suppl 1): p. 82-91. 
150. 
Fox, R.I. and H.I. Kang, Mechanism of action of antimalarial drugs: inhibition of 
antigen processing and presentation. Lupus, 1993. 2 Suppl 1: p. S9-12. 
151. 
Wolfe, F. and M.F. Marmor, Rates and predictors of hydroxychloroquine retinal 
toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. 
Arthritis Care Res (Hoboken), 2010. 62(6): p. 775-84. 
152. 
Melles, R.B. and M.F. Marmor, The risk of toxic retinopathy in patients on long-term 
hydroxychloroquine therapy. JAMA Ophthalmol, 2014. 132(12): p. 1453-60. 
153. 
Marmor, M.F., et al., Recommendations on Screening for Chloroquine and 
Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology, 2016. 123(6): p. 
1386-94. 
154. 
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sulfate) Tablet 200mg, in Package Insert. 2014: Laval, Quebec. 
155. 
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Mason, OH. 
156. 
Liu, X., et al., Impact and timing of smoking cessation on reducing risk for 
rheumatoid arthritis among women in the Nurses' Health Studies. Arthritis Care Res 
(Hoboken), 2019. 
157. 
Aletaha, D., et al., Practical progress in realisation of early diagnosis and treatment 
of patients with suspected rheumatoid arthritis: results from two matched 
questionnaires within three years. Ann Rheum Dis, 2002. 61(7): p. 630-4. 
158. 
Machold, K.P., et al., Early arthritis therapy: rationale and current approach. J 
Rheumatol Suppl, 1998. 53: p. 13-9. 
159. 
Suarez-Almazor, M.E., et al., Cyclophosphamide for treating rheumatoid arthritis. 
Cochrane Database Syst Rev, 2000(4): p. CD001157. 
160. 
Novotny, F., et al., Primary prevention of rheumatoid arthritis: A qualitative study in 
a high-risk population. Joint Bone Spine, 2013. 
161. 
Penn, S.K., et al., Hydroxychloroquine and glycemia in women with rheumatoid 
arthritis and systemic lupus erythematosus. J Rheumatol, 2010. 37(6): p. 1136-42. 
162. 
Bos, W.H., et al., Effect of dexamethasone on autoantibody levels and arthritis 
development in patients with arthralgia: a randomised trial. Annals of the rheumatic 
diseases, 2010. 69(3): p. 571-4. 
163. 
Gerlag, D.M., et al., Effects of B-cell directed therapy on the preclinical stage of 
rheumatoid arthritis: the PRAIRI study. Ann Rheum Dis, 2019. 78(2): p. 179-185. 


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164. 
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medication adherence: lessons learned and future directions. Res Social Adm Pharm, 
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165. 
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prognostic factors in the controlled clinical trial. Biometrics, 1975. 31(1): p. 103-15. 
166. 
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diseases and related conditions. Arthritis Rheum, 2009. 60(3): p. 661-8. 
167. 
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preclinical rheumatoid arthritis (RA) using first‐degree relatives of probands with 
RA. Arthritis Care & Research, 2009. 61(12): p. 1735-1742. 
168. 
Kolfenbach, J.R., et al., A prospective approach to investigating the natural history of 
preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with 
RA. Arthritis Rheum, 2009. 61(12): p. 1735-42. 
169. 
Deane, K.D., et al., Identification of undiagnosed inflammatory arthritis in a 
community health fair screen. Arthritis Rheum, 2009. 61(12): p. 1642-1649. 
170. 
Marmor, M.F., et al., Revised recommendations on screening for chloroquine and 
hydroxychloroquine retinopathy. Ophthalmology, 2011. 118(2): p. 415-22. 
171. 
Wells, G., et al., Validation of the 28-joint Disease Activity Score (DAS28) and 
European League Against Rheumatism response criteria based on C-reactive protein 
against disease progression in patients with rheumatoid arthritis, and comparison 
with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis, 2009. 
68(6): p. 954-60. 
172. 
Pincus, T., et al., RAPID3 (Routine Assessment of Patient Index Data) on an MDHAQ 
(Multidimensional Health Assessment Questionnaire): agreement with DAS28 
(Disease Activity Score) and CDAI (Clinical Disease Activity Index) activity 
categories, scored in five versus more than ninety seconds. Arthritis Care Res 
(Hoboken), 2010. 62(2): p. 181-9. 
173. 
van de Stadt, L.A., et al., A prediction rule for the development of arthritis in 
seropositive arthralgia patients. Ann Rheum Dis, 2012. 
174. 
Smolen, J.S., et al., Progression of radiographic joint damage in rheumatoid 
arthritis: independence of erosions and joint space narrowing. Ann Rheum Dis, 
2009. 68(10): p. 1535-40. 
175. 
Lagana, B., et al., Imaging progression despite clinical remission in early rheumatoid 
arthritis patients after etanercept interruption. Int J Immunopathol Pharmacol, 2009. 
22(2): p. 447-54. 
176. 
Costedoat-Chalumeau, N., et al., Low blood concentration of hydroxychloroquine is a 
marker for and predictor of disease exacerbations in patients with systemic lupus 
erythematosus. Arthritis Rheum, 2006. 54(10): p. 3284-90. 
177. 
Klein, J.P., et al., Analyzing survival curves at a fixed point in time. Stat Med, 2007. 
26(24): p. 4505-19. 
178. 
Lee, E.W., et al., Cox-Type Regression Analysis for Large Numbers of Small Groups 
of Correlated Failure Time Observations, in Survival Analysis: State of the Art, J.P. 
Klein and P.K. Goel, Editors. 1992, Springer Netherlands: Dordrecht. p. 237-247. 


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179. 
Liang, K.-Y. and S.L. Zeger, Longitudinal Data Analysis Using Generalized Linear 
Models. Biometrika, 1986. 73(1): p. 13-22. 
 


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15 APPENDICES  
 
Appendices may include: 
• 
2010 ACR/EULAR RA Classification Criteria 
• 
Flow Diagrams:  
 Evaluations Triggered by a Swollen Joint 
 Procedures for Subjects Diagnosed with IA/RA by an Outside 
Physician 
• 
Formulas (IBW, Cockcroft-Gault, DAS28-CRP) 
• 
NHYA Classification 
• 
Subject Questionnaires 


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15.1 2010 ACR/EULAR RA Classification Criteria 
 
2010 ACR/EULAR RA Classification Criteria[62] 
Who should be tested?  Patients with ≥1 swollen joint consistent with 
synovitis not better explained by another disease. If the patient meets these 
initial criteria with a score of ≥6/10 they can be classified as having ‘definite 
RA’: 
A.  Joint involvement* 
          1 large joint                                             0 
          2-10 large joints                                      1 
          1-3 small joints                                       2 
          4-10 small joints                                     3 
          >10 joints (at least 1 small)                    5 
B.  Serology (at least 1 test needed) 
          Negative RF and ACPA                         0 
          Low positive RF or ACPA                     2 
          High positive RF or ACPA**                3 
C.  Acute-phase reactants  
           Normal CRP                                          0 
           Abnormal CRP                                      1 
D.  Duration of symptoms 
           <6 weeks                                                0 
           ≥6 weeks                                            1    
* Joint involvement refers to any swollen or tender joint on examination. Distal 
interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal 
joints are excluded from assessment. “ Large joints “ refers to shoulders, elbows, hips, 
knees, and ankles. “ Small joints” refers to the metacarpophalangeal joints, proximal 
interphalangeal joints, second through fifth metatarsophalangeal joints, thumb 
interphalangeal joints, and wrists. 
*Categories of joint distribution are classified according to the location and number of 
involved joints, with placement into the highest category possible based on the pattern 
of joint involvement. 
**High positive is equivalent to >3 times the upper limit of normal based on the 
reference range of the laboratory that assesses the biomarker. 
 


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15.2 Flow Diagrams 
15.2.1 
Evaluations Triggered by a Swollen Joint Flow Chart 
 


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15.2.2 
Procedures for Subjects Diagnosed with IA/RA by an Outside Physician Flow Chart 
 


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15.3 Formulas 
 
• 
Ideal Body Weight (Kg) 
o Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet, or subtract 1kg 
for every inch under 5 feet. 
o Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet, or subtract 
1kg for every inch under 5 feet. 
• 
Cockcroft-Gault Formula: CrCl = (140-age [in years]) * (Wt [in kg]) * (0.85 if 
female) / (72 * Cr [in mg/dl]) 
• 
DAS28-CRP Formula: DAS28-4(crp) = 0.56*SQRT(TJC28) + 
0.28SQRT(SJC28) + 0.36*ln(CRP+1) + 0.014*GH + 0.96  
 TJC28 = # tender joints of 28 counted 
 
SJC28=#swollen joints of 28 counted 
 
GH = Patient Global Assessment on a 21 point scale 
 
CRP = C-reactive protein (mg/L) 
 
 


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15.4 NYHA Classification  
 
 
Class 
Patient Symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, or 
dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at 
rest, but ordinary physical activity results in fatigue, 
palpitation, or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at 
rest, but less than ordinary activity causes fatigue, 
palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without 
discomfort. Symptoms of cardiac insufficiency at rest. 
If any physical activity is undertaken, discomfort is 
increased. 
 


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15.5 Subject Questionnaires 
15.5.1 
Pre-Screening Questionnaire 
 


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Self-Reported Demographics 
15.5.2.1 
Self-Reported Demographics: Screening 
 


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Self-Reported Demographics: End of Study 
 
 


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15.5.4 
Subject Epidemiologic Questionnaire: Baseline & Follow-up 
15.5.4.1 
Subject Epidemiologic Questionnaire: Baseline 
 


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Subject Epidemiologic Questionnaire: Follow-up 
 
 


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Dietary Assessment Questionnaire 
 


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Profile 29 (v2.0) 
 


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SAP_003.pdf: 


Autoimmunity Centers of Excellence  
Statistical Analysis Plan – ARA08 StopRA 
Page 2 of 44 
Version Date: 2023-05-08 
Version: 1.0  
 
 
 
ACKNOWLEDGEMENT AND SIGNATURE SHEET 
 
 
 
 
 
Approved: 
________________________________ 
Date: 
_______________ 
 
Kevin Deane, MD, PhD 
 
 
 
Protocol Chair 
 
 
 
 
 
 
Approved: 
__________ 
Date: 
_______________ 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
 
Approved: 
_________ 
Date: 
_______________ 
 
 
 
 
 
Scientist 
 
 
 
 
 
 
Approved: 
_______________ 
Date: 
_______________ 
 
 
 
 
 
Statistician 
 
 
 
 
 
 


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VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
1.0 
2023-05-08 
Final version 
 
 
 
 
 
 
 
 
 
 
 


Autoimmunity Centers of Excellence  
Statistical Analysis Plan – ARA08 StopRA 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
PURPOSE OF THE ANALYSES ................................................................................9 
3. 
PROTOCOL SUMMARY ..........................................................................................10 
4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................12 
5. 
ANALYSIS POPULATIONS ....................................................................................13 
5.1. 
Safety Population ........................................................................................................13 
5.2. 
Intent-to-Treat Population ..........................................................................................13 
5.3. 
Modified Intent-to-Treat Population ...........................................................................13 
5.4. 
Per Protocol Population ..............................................................................................13 
6. 
STUDY PARTICIPANTS ..........................................................................................14 
6.1. 
Disposition of Participants ..........................................................................................14 
6.2. 
Demographic and Other Baseline Characteristics ......................................................14 
6.3. 
Prior and Concomitant Medications ...........................................................................16 
6.4. 
Medical History ..........................................................................................................16 
7. 
STUDY OPERATIONS .............................................................................................17 
7.1. 
Protocol Deviations ....................................................................................................17 
7.2. 
Randomization ............................................................................................................17 
7.3. 
Blinding ......................................................................................................................18 
7.4. 
Measures of Treatment Compliance ...........................................................................18 
8. 
EFFICACY EVALUATIONS ....................................................................................20 
8.1. 
Overview of Efficacy Analysis Methods ....................................................................20 
8.1.1. 
Multicenter Studies .....................................................................................................20 
8.1.2. 
Assessment Time Windows ........................................................................................20 
8.1.3. 
Timing of Analyses .....................................................................................................21 
8.1.4. 
Multiple Comparisons/Multiplicity ............................................................................21 
8.1.5. 
Intercurrent Event Strategies (IES) for Time to Event Analysis ................................21 
8.2. 
Primary Objective .......................................................................................................22 
8.2.1. 
Computation of the Primary Clinical Endpoint ..........................................................22 
8.2.2. 
Primary Estimand of the Primary Clinical Endpoint ..................................................23 
8.2.3. 
Sensitivity Estimands of the Primary Endpoint ..........................................................24 
8.3. 
Secondary Objectives .................................................................................................24 


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8.3.1. 
Study Objective 2 .......................................................................................................25 
8.3.2. 
Study Objective 3 .......................................................................................................25 
8.3.3. 
Study Objective 4 .......................................................................................................26 
8.3.4. 
Study Objective 5 .......................................................................................................26 
8.3.5. 
Study Objective 6 .......................................................................................................27 
8.3.6. 
Study Objective 7 .......................................................................................................29 
8.3.7. 
Study Objective 8 .......................................................................................................30 
8.4. 
Exploratory Endpoints ................................................................................................31 
8.4.1. 
Physician-reported Joint Counts .................................................................................31 
8.4.2. 
Disease Activity Assessments ....................................................................................32 
9. 
SAFETY EVALUATIONS ........................................................................................34 
9.1. 
Overview of Safety Analysis Methods .......................................................................34 
9.2. 
Extent of Exposure .....................................................................................................34 
9.3. 
Adverse Events ...........................................................................................................34 
9.4. 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................35 
9.5. 
Clinical Laboratory Evaluation ...................................................................................35 
10. 
OTHER ANALYSES .................................................................................................36 
11. 
INTERIM ANALYSES AND DATA MONITORING .............................................37 
11.1. 
Interim Analysis of the Primary Objective .................................................................37 
12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................38 
13. 
REFERENCES ...........................................................................................................39 
14. 
APPENDIX.................................................................................................................40 
14.1. 
Interim Statistical Analysis Plan .................................................................................40 
14.2. 
Schedule of Events .....................................................................................................41 
 
 


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LIST OF TABLES 
Table 1: 
List of Abbreviations ....................................................................................................7 
Table 2: 
Weight-based dosing regimen for HCQ (and placebo) ..............................................18 
Table 3: 
Study Therapy Distribution ........................................................................................18 
Table 4: 
Visit Target Days and Windows for Scheduled Visits ...............................................20 
Table 5: 
Intercurrent Event Strategies (IES) for Time to Event Analyses ...............................21 
Table 6: 
2010 ACR/EULAR Classification Criteria ................................................................23 
Table 7: 
Primary Estimand of Primary Objective .....................................................................24 
Table 8: 
Sensitivity Estimands of Primary Objective ...............................................................24 
Table 9: 
Estimand of Study Objective 2 ...................................................................................25 
Table 10: Estimand of Study Objective 3 ...................................................................................25 
Table 11: Estimands of Study Objective 4 .................................................................................26 
Table 12: Estimands of Study Objective 5 .................................................................................27 
Table 13: Estimand of Study Objective 6 ...................................................................................28 
Table 14: Estimands of Study Objective 7 .................................................................................30 
Table 15: Estimands of Study Objective 8 .................................................................................31 
Table 16: Estimands of Physician-reported Joint Counts ...........................................................32 
Table 17: Estimands of Disease Activity Assessments ..............................................................33 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
ACPAs 
Antibodies to Citrullinated Protein Antigens 
ACR/EULAR 
American College of Rheumatology/ European League Against Rheumatism 
AEs 
Adverse Events 
Anti-CCP3 
Anti-cyclic citrullinated peptide-3 
BMI 
Body mass index 
CDAI 
Clinical Disease Activity Index 
CL-RA 
Clinically Apparent Rheumatoid Arthritis 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DAS28-CRP 
Disease Activity Score (28 joints) – C reactive protein 
DMARD 
Disease-Modifying Antirheumatic Drug 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
EOS 
End of Study 
ESR 
Erythrocyte Sedimentation Rate 
FDR 
First degree relative 
GED 
General Educational Development 
HCQ 
Hydroxychloroquine 
HR 
Hazard Ratio 
hs-CRP 
High-Sensitivity C-Reactive Protein 
IA 
Inflammatory Arthritis 
IBW 
Ideal Body Weight 
ICH 
International Conference on Harmonization 
ID 
Participant Identifier 
IES 
Intercurrent Event Strategy 
IgM-RF 
Immunoglobulin M – Rheumatoid Factor 
IRB 
Institutional Review Board 


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ITT 
Intent-to-Treat Population 
kg 
kilogram 
KM 
Kaplan-Meier 
LLN 
Lower Limit of Normal 
Max 
Maximum 
MDHAQ 
Multi-dimensional Health Assessment Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
mITT 
Modified Intent-to-Treat Population 
mg 
milligram 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
PLS 
Population Level Summary 
PP 
Per Protocol Population 
PRO 
Patient Reported Outcome 
PROMIS 
Patient-reported Outcomes Measurement Information System 
RA 
Rheumatoid Arthritis 
RAPID-3 
Routine Assessment of Patient Index Data 3 
RF 
Rheumatoid Factor 
SAEs 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SDAI 
Simple Disease Activity Index 
SE 
Shared Epitope 
SOC 
System Organ Class 
SP 
Safety Population 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
Y/N 
Yes/No 
 


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2. 
PURPOSE OF THE ANALYSES 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and data 
displays to be included in the Clinical Study Report (CSR) for Protocol ARA08 StopRA. This 
document provides details on study populations, how the variables will be derived, how missing 
data will be handled and details on statistical methods to be used to analyze the safety and 
efficacy data. 
The statistical analysis plan (SAP) is based on ICH guidelines E3 and E9 (Statistical Principles 
for Clinical Trials). 






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4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following analyses and reporting conventions will be used: 
• Categorical variables will be summarized using counts (n) and percentages (%) and will be 
presented in the form “n (%).” Percentages will be rounded to one decimal place. 
• Numeric variables will be summarized using n, mean, standard deviation (SD), median, 
minimum (min), maximum (max). 
o The median, min and max will be reported at the same level of significance as the 
original data. 
o The mean will be reported at one more significant digit than the precision of the data. 
o SD will be reported at two more significant digits than the precision of the data.  
o The median will be reported as the rounded average of the two middle numbers if the 
dataset contains an even number of observations. 
• Test statistics including t and z test statistics will be reported to two decimal places. 
• P-values will be reported to three decimal places if greater than or equal to 0.001. If less than 
0.001, the value will be reported as “<0.001.” A p-value can be reported as “1.000” only if it 
is exactly 1.000 without rounding. A p-value can be reported as “0.000” only if it is exactly 
0.000 without rounding. 
If departures from these general conventions are present in the specific evaluations section of this 
SAP, then those conventions will take precedence over these general conventions. 


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5. 
ANALYSIS POPULATIONS 
Four analysis populations, the Intent-to-Treat (ITT), modified Intent-to-Treat (mITT), Per 
Protocol, and safety population will be defined for this study. 
5.1. 
Safety Population 
The safety population (SP), which will be used for all safety analysis, will include all participants 
for whom study treatment is initiated. 
5.2. 
Intent-to-Treat Population 
The Intent-to-Treat population (ITT) will include all randomized participants. 
5.3. 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) population will include all randomized participants who 
receive at least one dose of assigned study drug and meet entry criteria. The primary efficacy 
analyses will be based on the mITT population. Participants who, for whatever reason, do not 
complete their assigned therapy will be included in the mITT population in the groups to which 
they were randomized. 
5.4. 
Per Protocol Population 
The Per Protocol (PP) population will be defined as those participants in the mITT population 
who receive at least 80% of the assigned study treatment regimen with no substantive deviations 
from protocol procedures that would impact evaluation of efficacy.  
A data review panel that will include the Protocol Chair (Deane) and participants from DAIT and 
Rho, Inc., will evaluate deviations from the protocol including, for example, violations of entry 
criteria, departures from assigned treatment regimen, use of prohibited therapy or HCQ 
prescribed outside of the study, failure to complete study visits, or to complete visits within the 
specified visit windows.  The participant ID numbers will be replaced with randomly generated 
ID numbers for the PP population review.   
The ARA08 study conducted an interim analysis in April 2022 as part of the regularly scheduled 
DSMB review.  The Interim Statistical Analysis Plan is provided in Appendix 14.1.  Due to the 
evidence of futility in the interim analysis results, the DSMB recommended that the ARA08 
study stop early, and that the treatment assignments be released to the participants.  Since the 
ARA08 study treatment assignments will be unmasked prior to database lock, the data review 
panel evaluation of the participants to include and exclude from the PP population will take place 
after the treatment assignments have been unmasked. 
Levels of HCQ analyzed from serum samples taken during the study treatment period will not be 
used in the masked data review panel’s evaluations of deviations from the protocol. The panel 
may exclude participants from the PP population if protocol deviations would be expected to 
impact the primary efficacy endpoint. Primary and secondary efficacy analyses may be 
replicated on the PP population. 


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6. 
STUDY PARTICIPANTS 
6.1. 
Disposition of Participants 
The disposition of all enrolled participants will be summarized in tables and listed. Enrollment is 
defined as participants who have signed the informed consent. 
The numbers and percentages of randomized participants who qualify for each analysis 
population, completed study treatment and completed the study will be presented by treatment 
arm and overall.  For participants who did not complete study treatment, the reasons for early 
discontinuation of study treatment will be presented by treatment arm.  For participants who did 
not complete the study, the reasons for early termination of study participation will be presented 
by treatment arm. 
6.2. 
Demographic and Other Baseline Characteristics 
Summary descriptive statistics for baseline and demographic characteristics will be reported for 
the ITT, mITT and PP samples by treatment group. Characteristics to be summarized include:  
• Age 
• Race (White, Black, Asian, Native Hawaiian or Other Pacific Islander, American Indian 
or Alaska Native, Other/Unknown) 
• Hispanic ethnicity (Hispanic, Not Hispanic) 
• Jewish ethnicity (Jewish, Not Jewish, Unknown) 
• Sex (Male, Female) 
• Body Mass Index (BMI) 
• Recruitment Method (First Degree Relative (FDR), Clinic Patient, General Population) 
• Participant Has a FDR with RA   (Yes/No) 
• Smoking Status (Smoker, Non-smoker)  
o For current smokers, baseline pack years at the current level will be computed as: 
The average # cigarettes per currently smoked * the average # years at this level 
• Baseline Cigar Use (Yes/No) 
o Cigar Users: Average Cigars per Day 
o Cigar Users: Number of Years Used Cigars 
• Baseline Tobacco Pipe Use (Yes/No) 
o Tobacco Pipe Users: Average Bowls per Day 
o Tobacco Pipe Users: Number of Years Used Pipes 
• Baseline Chewing Tobacco or Snuff Use (Yes/No) 
o Chewing Tobacco or Snuff Users: Average Wads per Day 


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o Chewing Tobacco or Snuff Users: Number of Years Used Chewing Tobacco or 
Snuff 
• Baseline Electronic Cigarettes Use (Yes/No) 
o Electronic Cigarettes Users: Electronic Cigarette Use Frequency (≤1 Day a Week, 
2-4 Days a Week, ≥5 Days a Week) 
o Electronic Cigarette Users: Number of Years Used Electronic Cigarettes 
• Baseline Anti-CCP3 (units) 
• Baseline Anti-CCP3 Positivity  (Negative (< Upper Limit of Normal (ULN), Low 
Positive (1.0 - <2.0 x ULN), Medium Positive (2.0 - <3.0 x ULN), High Positive (≥3.0 x 
ULN)) 
• Baseline IgM-RF (U/mL) 
• Baseline IgM-RF Positivity (Negative (< Upper Limit of Normal (ULN), Low Positive 
(1.0 - <2.0 x ULN), Medium Positive (2.0 - <3.0 x ULN), High Positive (≥3.0 x ULN)) 
• Baseline hs-CRP (mg/L) 
• Baseline hs-CRP Positivity (≤ 3.0 mg/L, > 3.0 mg/L) 
• Baseline Shared Epitope (SE) Positivity (Negative on all epitopes and specific alleles 
(e.g. *0401,*0404, etc.), Positive on at least 1 epitope or specific allele) 
• Baseline Shared Epitope Number of Positive Results (0, 1, 2, etc.) 
• Baseline Pain Score 
• Baseline Fatigue Score 
• Baseline Morning Stiffness Duration 
• Baseline Number of Tender Joints from Physician Joint Exam 
• Baseline Disease Activity Score (28 joints) – C reactive protein (DAS28CRP) 
• Baseline Routine Assessment of Patient Index Data 3 (RAPID3) 
• Baseline Simple Disease Activity Index (SDAI) 
• Baseline Clinical Disease Activity Index (CDAI) 
• Baseline Patient-reported Outcomes Measurement Information System (PROMIS) Profile 
29 Physical Health Score 
• Baseline PROMIS Profile 29 Mental Health Score 
• Baseline PROMIS Profile 29 Social Health Score 
A listing of the demographic and baseline characteristics of randomized participants by treatment 
arm will be prepared. 


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6.3. 
Prior and Concomitant Medications 
Medications will be coded according to the World Health Organization (WHO) Drug Dictionary 
(version V2016.01). Medications reported on the case report form (CRF) will be categorized for 
analysis as prior, concomitant, or post-treatment by comparing the medication start and stop 
dates with the first and last dose dates of study treatment.  Medications that the participant had 
taken from 12 weeks prior enrollment through the end of study participation were recorded in the 
CRF. Prior medications will have both the medication start and stop dates prior to the date of the 
first dose of study treatment. Post-treatment medications will have the medication start date after 
the date of the last dose of study treatment. All other medications will be classified as 
concomitant, indicating that use of the medication overlapped with use of the study treatment by 
at least one day. 
A listing of all medications reported in all participants in the safety population by treatment arm 
will be prepared. 
6.4. 
Medical History 
Medical histories are captured at screening for all randomized participants in the Medical History 
CRF.  Body systems classified as abnormal in the Medical History CRF will be listed by 
treatment arm for all participants in the safety population. 


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7. 
STUDY OPERATIONS 
7.1. 
Protocol Deviations 
Major protocol deviations occurring throughout the duration of the study are captured on the 
Protocol Deviations CRF. 
Major protocol deviations will be summarized and listed.  The deviations will be summarized by 
whether the deviation was site-level or participant-level and by type of deviation:  
• IRB Approval/Regulatory 
• Informed Consent 
• Entry Criteria Violations 
• Study Treatment or Study Drug Related 
• Protocol Mandated Concurrent Therapy Related 
• Adverse Event/Serious Adverse Event Reporting Procedures 
• Assessments and Laboratory Procedures 
• Blind Break 
The deviations will be listed by site, site-level deviations and participant level deviations, and by 
date of occurrence. 
7.2. 
Randomization 
Participants were randomized in a 1:1 ratio to either HCQ or placebo. Anticipating that some 
study sites would only randomize a few participants, an adaptive randomization procedure based 
on Pocock and Simon [1] minimization concepts was used to increase the likelihood of balance 
between treatment arms on key factors associated with progression to clinically-apparent RA. 
The factors used in the adaptive randomization procedure were smoker status (smoker vs. non-
smoker), study site, and method of recruitment (i.e., first degree relative (FDR), general 
population, or clinic patient).  Participants with elevated anti-CCP levels that met assay positivity 
criteria were identified for this trial through three general approaches that included the following: 
• Pre-screening FDRs of patients with RA. 
• Health-fair, biobank, or other population-based pre-screening. 
• Identification in rheumatology clinics of participants with ACPA positivity in the absence of 
IA.  
These three participant pools provided a sampling of the types of participants for whom this 
preventative approach would be applicable. 
To avoid possible issues of familial correlation, our strong preference was to randomize only 1 
FDR per family. Participants were asked about participation of immediate family members 
during the consent process and during study participation. However, recognizing operational 


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barriers to accurately track family membership and our suspicion that multiples per family would 
be a rare occurrence, randomization of multiple FDRs per family was allowed.   
7.3. 
Blinding  
Clinical staff were blinded to the treatment assignments until completion of the study with the 
exception of an unblinded pharmacist. In addition, clinical staff members, including the 
investigators, did not have access to any mechanistic data, and mechanistic laboratory staff did 
not have access to any clinical results until completion of the study.  
No participant treatment assignments were unblinded prior to the end of the study. 
7.4. 
Measures of Treatment Compliance 
Both the investigational drug that was used during the course of the study, as well as any 
remaining unused investigational drug, were required to be accounted for on a drug 
accountability record provided or approved by the study sponsor or its designee. 
Study participants received 1-2 pills of either HCQ or 1-2 pills of placebo for 12 months with 
dosing based upon Screening IBW as outlined in Table 2.  
 
Table 2: 
Weight-based dosing regimen for HCQ (and placebo) 
Weight (kilograms based on IBW*) 
Number of pills** 
≤ 24.4 kg (ideal or actual body weight)  
Excluded from trial 
> 24.4 - < 47 kg 
1 pill daily 
≥ 47 kg 
2 pills daily 
*IBW based on the following calculation:   
Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet, or subtract 1kg for every inch under 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet, or subtract 1kg for every inch under 5 feet. 
** Each 200 mg HCQ pill contains 155 mg of active drug 
Study therapy was dispensed per the schedule in Table 3. 
 
Table 3: 
Study Therapy Distribution 
Participant IBW at 
Screening 
Baseline 
Week 6 
Week 12 
Week 24 
Week 36 
> 24.4 - < 47 kg 
1 bottle 
2 bottles 
2 bottles 
2 bottles 
3 bottles 
≥ 47kg 
2 bottles 
3 bottles 
4 bottles 
4 bottles 
6 bottles 
 
Each bottle of study medication dispensed was recorded on the Study Drug Accounting Log 
CRF, along with the date the bottle was dispensed, the date the bottle was returned, the number 
of pills returned, and the number of pills lost. 


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The number of pills taken from each bottle will be computed as the number of pills in the bottle 
(i.e., 50) minus any pills lost or returned. The total number of pills expected to be taken will 
calculated as the participant’s treatment period duration (treatment end date – treatment start date 
+ 1) multiplied by the number of pills the participant was expected to take each day (1 pill or 2 
pills) based on the participant’s Screening IBW. 
For bottles that were not returned to the site, the total number of pills expected will be imputed 
from the date the bottle was dispensed until the date the next study drug bottle is dispensed, or 
until the participant’s treatment discontinuation date, whichever occurs earlier.  The total number 
of pills taken will be imputed under 2 scenarios: 
• Case 1 (best): the number of pills taken is assumed to equal the number expected, 
• Case 2: the number of pills taken is assumed to equal 50 (all pills in bottle). 
 
Percent treatment compliance for each participant will be calculated as: 
% 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= 𝑇𝑜𝑡𝑎𝑙  𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑡𝑎𝑘𝑒𝑛
𝑇𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑖𝑙𝑙𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑥 100 
Compliance for individuals who failed to return bottles will be reviewed by the masked data 
review committee for exclusion from the PP population. 
Study drug dosing will be listed by participant, visit and bottle. Information will include the date 
of dispense and return, number of pills returned, and number of pills lost. 


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8. 
EFFICACY EVALUATIONS 
8.1. 
Overview of Efficacy Analysis Methods 
8.1.1. 
Multicenter Studies 
Study participants were consented at 15 study sites.  The analyses of survival estimates at fixed 
points in time will not be stratified.  Site and method of recruitment will be considered as 
possible fixed covariates in models for secondary efficacy analyses. All safety analyses will be 
based on pooled data with no adjustment or stratification. 
8.1.2. 
Assessment Time Windows 
Visit windows for each scheduled visit are provided in Table 4.  The Baseline visit must be 
performed within 30 days of the Screening visit. 
Table 4: 
Visit Target Days and Windows for Scheduled Visits 
Visits 
Target Day 
Visit Type 
Window 
Baseline 
0 
Clinic 
≤30 days from Screening 
Week 6 
42 
Clinic 
±7 days from target 
Week 12 
84 
Clinic 
Week 18 
126 
Telephone 
Week 24 
168 
Clinic 
Week 30 
210 
Telephone 
Week 36 
252 
Clinic 
Week 42 
294 
Telephone 
Week 52 
364 
Clinic 
±14 days from target 
Month 15 
457 
Telephone 
Month 18 
548 
Clinic 
Month 21 
639 
Telephone 
Month 24 
731 
Clinic 
Month 27 
822 
Telephone 
Month 30 
913 
Clinic 
Month 33 
1004 
Telephone 
Month 36 
1096 
Clinic 
Data collected outside of the visit window will not be removed from analyses categorized by 
visit and will be included in analyses where time is a continuous variable. 






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be used for the calculation of the ACR/EULAR criteria and disease activity measures; ESR will 
not be used. 
Table 6: 
2010 ACR/EULAR Classification Criteria 
Who should be tested?  Patients with ≥1 swollen joint consistent with synovitis 
not better explained by another disease.  If the patient meets these initial criteria 
with a score of ≥6/10 they can be classified as having ‘definite RA’: 
A.  Joint involvement* 
1 large joint                                    0 
2-10 large joints                             1 
1-3 small joints                              
2 
4-10 small joints                            
3 
>10 joints (at least 1 small)           
5 
B.  Serology (at least 1 test needed) 
Negative RF and ACPA                
0 
Low positive RF or ACPA            
2 
High positive RF or ACPA**       
3 
C.  Acute-phase reactants (at least 1 test needed) 
Normal CRP and ESR                   
0 
Abnormal CRP or ESR                  1 
D.  Duration of symptoms 
<6 weeks                                        0 
 ≥6 weeks                                       1 
* Joint involvement refers to any swollen or tender joint on examination. Distal interphalangeal joints, first 
carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. “Large joints“ 
refers to shoulders, elbows, hips, knees, and ankles. “Small joints” refers to the metacarpophalangeal joints, 
proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, 
and wrists.  
** High positive is equivalent to >3 times the upper limit of normal based on the reference range of the 
laboratory that assesses the biomarker. 
NOTE: Patients with erosive disease typical of rheumatoid arthritis with a history compatible with prior 
fulfillment of the 2010 criteria should be classified as having RA. 
 
8.2.2. 
Primary Estimand of the Primary Clinical Endpoint 
The primary estimand for the primary clinical endpoint of the development of clinically-apparent 
RA (CL-RA) at 36 months will be analyzed according the following specifications: 












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• Baseline PROMIS Profile 29 Physical Health Score 
• Baseline PROMIS Profile 29 Mental Health Score 
• Baseline PROMIS Profile 29 Social Health Score 
• Baseline Anti-CCP3 (units) 
• Baseline Anti-CCP3 Positivity  (Negative (< Upper Limit of Normal (ULN), Low 
Positive (1.0 - <2.0 x ULN), Medium Positive (2.0 - <3.0 x ULN), High Positive (≥3.0 x 
ULN)) 
• Baseline IgM-RF (U/mL) 
• Baseline IgM-RF Positivity (Negative (< Upper Limit of Normal (ULN), Low Positive 
(1.0 - <2.0 x ULN), Medium Positive (2.0 - <3.0 x ULN), High Positive (≥3.0 x ULN)) 
• Baseline hs-CRP (mg/L) 
• Baseline hs-CRP Positivity (≤ 3.0 mg/L, > 3.0 mg/L) 
• Baseline age (years) 
• Sex (male/female) 
• BMI 
• Baseline Shared Epitope (SE) Positivity) (Yes, No) 
• Baseline Shared Epitope Number of Positive Results (0, 1, 2) 
• Participant has a FDR with RA (Yes, No) 
• Salary level (< $50,00; $50,000 - < $75,000; ≥$75,000) 
• Highest education level achieved (up to High School/GED, College, Graduate School) 
• Tobacco exposure 
o Smoking status (Never smoked, Former smoker, Current smoker) 
o Baseline Pack Years at Current Level for Smokers 
o Years as Adult Living with Smoker 
• Baseline Medications 
o Statin use (Yes/No) 
o Medical hormones (Yes/No) 
 
Each fixed effect will be evaluated for its impact on the time to development of CL-RA by fitting 
a Cox proportional hazards model with independent variables for treatment arm, risk factor and 
treatment arm * risk factor interaction.  The risk factors with significant p-values for the Wald 
chi-square test statistic, along with significant interaction terms, will be included in the final Cox 
proportional hazards model. 
 
8.3.6. 
Study Objective 7 
Study Objective 7 is to evaluate the relationship between treatment with HCQ and amelioration 
of symptoms of RA, and potential delay in onset of symptoms.  RA symptoms include self-
reported joint pain, stiffness, and swelling, and overall fatigue.  The clinical endpoint to evaluate 
this objective will be the self-reported joint symptom counts assessed at each clinic visit. 
Participants use the Participant Self-Reported Joint Symptoms assessment to identify painful, 
stiff, and swollen joints. These data are used to count the number of (1) painful, (2) stiff, and (3) 
swollen joints, as well as the count of (4) painful, (5) stiff, and (6) swollen joints in the hands, 
wrists, and feet. 










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9. 
SAFETY EVALUATIONS 
9.1. 
Overview of Safety Analysis Methods 
All safety analyses will be carried out using the Safety Population defined in Section 5.1 unless 
otherwise noted. Missing safety information will not be imputed. These analyses will not be 
stratified by site. 
Safety will be analyzed in both treatment arms through the reporting of adverse events (AEs), 
vital signs, physical examination findings, and changes in routine laboratory values. 
Listings will be prepared for all safety measurements. All listings will be sorted in order of 
treatment, participant identifier (ID), and time of assessment (e.g., visit, time, and/or event). 
9.2. 
Extent of Exposure 
Duration of exposure will be defined as the last dose date – first dose date + 1.  Descriptive 
statistics will be presented by treatment arm. 
9.3. 
Adverse Events 
All AEs will be classified by system organ class (SOC) and preferred term, according to a 
standardized thesaurus (Medical Dictionary for Regulatory Activities [MedDRA] version 23.0). 
The severity of AEs will be classified using the National Cancer Institute’s (NCI’s) Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Each AE is entered on the electronic 
case report form (CRF) once at the highest severity. As such, no additional data manipulation is 
needed to identify events. 
AEs will be collected starting at consent for Grade 2 or higher AEs related to a study-mandated 
procedure, treatment, or change in treatment, and will be collected starting from the first dose of 
study treatment through Month 18 or until 30 days after the participant prematurely terminates 
from the study, whichever occurs first.  SAEs are collected for participants throughout the 
duration of their participation in the study. Treatment-emergent AEs will be identified as those 
with an onset date on or after the first dose of study medication. If the start of the AE in relation 
to the start of study medication cannot be established (e.g., the start date for the AE is missing), 
then the AE will be considered treatment-emergent. If an abnormal laboratory finding is reported 
as an AE on the first day of study drug (Day 1), these events will not be considered treatment 
emergent since these assessments occur prior to treatment initiation. All data tabulations will be 
of only treatment-emergent events while non-treatment-emergent AEs will be included in the 
listing of all AEs. 
The frequency of AEs will be summarized by system organ class, preferred term, severity 
(grade), and relationship to study treatment. Relationship to study treatment, as determined by 
masked investigators, will be categorized as either treatment related (possibly, probably, or 
definitely related to study medication) or unrelated (unlikely related or unrelated). Similar 
analyses will be performed for SAEs. To account for differential duration of study participation 
among participants, the summaries will also include the event rate (i.e., number of events per 
person-time) in addition to the number and percent of events and participants experiencing 
events. 


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For the secondary safety endpoint of the proportion of participants in each arm experiencing a 
Grade 3 or higher AE according to the National Cancer Institute-Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) system, the proportion of participants experiencing at least 
one event in each treatment group will be reported and the treatment groups compared based on 
Fisher’s Exact Test. 
9.4. 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
The frequency of SAEs will be summarized by system organ class, preferred term, severity 
(grade), and relationship to study treatment. Relationship to study treatment, as determined by 
masked investigators, will be categorized as either treatment related (possibly, probably, or 
definitely related to study medication) or unrelated (unlikely related or unrelated). To account for 
differential duration of study participation among participants, the summaries will also include 
the event rate (i.e., number of events per person-time) in addition to the number and percent of 
events and participants experiencing events. 
9.5. 
Clinical Laboratory Evaluation 
For these analyses, clinical laboratory measurements include serum chemistry and hematology, 
and exclude autoantibody and CRP levels, which will be evaluated in the Secondary Objectives. 
Laboratory results will be reported from a central lab. However, sites can additionally report 
unscheduled results performed locally in the EDC. Local results will be converted to 
standardized units where possible. Changes in laboratory parameters that represent increases 
NCI-CTCAE severity grade over time are captured as AEs and summarized as described in 
Section 9.3. 
Laboratory parameters will be summarized both overall and by treatment group using 
appropriate descriptive statistics. For each lab parameter, the number and percent of participants 
that have an increase, decrease, or no change from Baseline to Week 24 and Week 52 will be 
displayed for each treatment group and pooled across treatment arms. For parameters with an 
explicit NCI-CTCAE grading criterion, change from baseline will be indicated by a change in 
grade. For parameters that do not have an explicit NCI-CTCAE grading criterion, observed 
values will be categorized as ‘high’ (defined as >ULN), ‘normal’ (defined as ≥ lower limit of 
normal (LLN) and ≤ ULN), or ‘low’ (defined as <LLN). Then, a change from baseline will be 
indicated as a change in category. 
Laboratory data will also be plotted to show patterns over time. Summary statistics including 
25th percentile, median, and 75th percentile will be plotted for each visit by treatment group. 
Lines connecting individual participant results from participants with Grade 2 or higher values 
will be overlaid on each figure. For lab results that are not gradable, results from participants 
with values outside of 2 *ULN or 0.5*LLN will be overlaid. 


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10. 
OTHER ANALYSES 
Other analyses that may be considered post-hoc include: 
• For participants who developed CL-RA during the study, we may examine characteristics 
and features of the diagnosis by treatment group.  The features of diagnosis may include 
(but are not limited to) disease activity measures (e.g. DAS28CP), x-ray findings (e.g. 
presence of erosions and Sharp’s scores) and persistence of tender and swollen joints 
post-diagnosis. 
• For participants who developed CL-RA during the study, we may examine the severity of 
the CL-RA symptoms at the time of diagnosis by treatment group. Severity can be 
measured using DAS28-CRP, CDAI, RAPID-3, and PROMIS scores at the time of 
diagnosis. 
• We may examine relationships between dietary intake and/or other environmental 
exposures and development of the CL-RA. 
Additional mechanistic analyses may be performed, and the details of those analyses will be 
specified in separate statistical analysis plans. 
 
 
 


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11. 
INTERIM ANALYSES AND DATA MONITORING 
 
11.1. 
Interim Analysis of the Primary Objective 
The details for the planned interim analyses are provided in the ARA08 Interim Statistical 
Analysis Plan, which was finalized as version 1.0 on December 17, 2021.  The ARA08 Interim 
Statistical Analysis Plan is included as Appendix 14.1. 
The first interim analysis was conducted in April 2022, and the results of the interim analysis, 
“Interim Analysis for the April 2022 DSMB”, were included as an appendix in the closed report 
to the Data and Safety Monitoring Board on April 6, 2022 as part of the regularly scheduled 
review of the ARA08 study.  


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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
• Protocol section 8.3.1.2 states "All efficacy analyses will be repeated using the PP 
population." We have modified this plan for secondary efficacy analyses. PP analyses 
maybe conducted at the discretion of the study team if warranted by results of the mITT 
analyses. 
• Protocol section 8.3.1.1 states “The primary analysis ignores the possible impact of 
within-family correlation. The propensity to progress to RA could be more similar within 
families than between families or across individuals in the population, in which case 
observations in this study would not be independent. Due to operational difficulties in 
linking family members, we expect to have incomplete information on familial 
clustering, so we will not be able to account for this potential correlation in the primary 
analysis. Because families tend to be small and not all family members will be eligible or 
willing to participate, we anticipate the impact of clustering to be small. We will, 
however, perform sensitivity analyses to assess the potential impact of clustering. We are 
asking participants if they have FDRs who are participating. If the proportion who answer 
affirmative is small, the impact of clustering is likely to be minimal. In addition, 
participants have the option of linking their study records with those of their relatives. If 
family clusters are identified through this process, we can estimate the treatment effect 
from a marginal Cox model for clustered data using the method of Lee, Wei, and Amato 
[178] and compare these to estimates derived from the usual Cox model assuming 
independent observations. We could also compare estimates for the risk of developing 
RA derived from logistic regression models fit using generalized estimating equations 
under difference assumptions about the within-family correlation structure; independent 
versus exchangeable [179].”   
Upon review of the data collected in ARA08 regarding members of the same family 
participating in ARA08, it was discovered that no participants reported having an FDR 
who was also participating in the study.  As a result, sensitivity analyses to assess the 
impact of family clustering will not be performed. 


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13. 
REFERENCES 
 
1. Pocock, S.J. and R. Simon, Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics, 1975. 31(1): p. 103-15. 
2. Klein, J.P., et al., Analyzing survival curves at a fixed point in time. Stat Med, 2007. 26(24): 
p. 4505-19. 
3. Lee, E.W., et al., Cox-Type Regression Analysis for Large Numbers of Small Groups of 
Correlated Failure Time Observations, in Survival Analysis: State of the Art, J.P. Klein and 
P.K. Goel, Editors. 1992, Springer Netherlands: Dordrecht. p. 237-247. 
4. Zhu, H., et al., Zero-inflated count models for longitudinal measurements with heterogeneous 
random effects. Stat Methods Med Res. 2017 August; 26(4): 1774–1786 


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14. 
APPENDIX   
14.1. 
Interim Statistical Analysis Plan 
 
 






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VERSION HISTORY 
 
SAP Version 
Version Date 
Change(s) 
Rationale 
1.0 
17Dec2021 
 
Final Version 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
PURPOSE OF THE ANALYSES ...........................................................................6 
2. 
PROTOCOL SUMMARY ......................................................................................7 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS...............................9 
4. 
ANALYSIS POPULATION ................................................................................. 10 
5. 
ENDPOINT EVALUATION ................................................................................ 11 
5.1. 
Overview of Analysis Methods ............................................................................. 11 
5.1.1. 
Multicenter Studies............................................................................................... 11 
5.1.2. 
Assessment Time Windows .................................................................................. 11 
5.2. 
Primary Estimand ................................................................................................. 12 
5.2.1. 
Definition............................................................................................................. 12 
5.2.2. 
Interim Analysis of the Primary Estimand ............................................................. 13 
5.2.3. 
Interim Analysis of the Sensitivity Estimand ......................................................... 15 
6. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ................... 16 
7. 
REFERENCES..................................................................................................... 17 
8. 
APPENDICES ..................................................................................................... 18 
8.1. 
Power Estimates ................................................................................................... 18 
 
 


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LIST OF ABBREVIATIONS 
Table 1: List of Abbreviations 
Abbreviation 
Term 
ACPAs 
Antibodies to Citrullinated Protein Antigens 
Anti-CCP3 
Anti-cyclic citrullinated peptide-3 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
FDR 
First-degree relative 
HCQ 
Hydroxychloroquine 
IA 
Inflammatory arthritis 
ISAP 
Interim Statistical Analysis Plan 
IBW 
Ideal body weight  
ITT 
Intent-to-Treat Population 
KM 
Kaplan-Meier 
Max 
Maximum 
Min 
Minimum 
mITT 
Modified Intent-to-Treat Population 
PP 
Per Protocol Population 
RA 
Rheumatoid Arthritis 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SP 
Safety Population 
 


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1. 
PURPOSE OF THE ANALYSES 
We will conduct one or possibly two interim analyses to stop the study early for overwhelming 
evidence of efficacy or futility.  Results from the first interim analyses will supplement the usual 
safety and study conduct information presented to the Data and Safety Monitoring Board 
(DSMB) at the spring 2022 meeting.  Results of these analyses are not binding.  The DSMB will 
provide recommendations on study continuation to DAIT.  In the event of a recommendation to 
stop the study, DAIT will convene an unmasked panel to consider the recommendations. 
The purpose of this interim statistical analysis plan (ISAP) is to describe the planned interim 
efficacy and futility analyses and associated data displays to be included in the interim analysis 
reports for Protocol ARA08. This document provides details on the analysis population, 
derivation of variables, plans for handling of missing data, and statistical methods to be used in 
these analyses.  
This ISAP is based on ICH guidelines E3 and E9 (Statistical Principles for Clinical Trials). 
 






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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this study: 
• Categorical variables will be summarized using counts (n) and percents (%) and will be 
presented in the form n (%). 
• Moment statistics including mean will be reported at 1 more significant digit than the 
precision of the original data. The standard deviation will be reported at 2 more 
significant digits than the precision of the original data. The level of precision may be 
modified on specific displays based on clinical judgement. 
• Order statistics including median, min and max will be reported to the same level of 
precision as the original observations. If any values are calculated to have more 
significant digits then the value should be rounded so that it is the same level of precision 
as the original data. 
• Following SAS default rules, the median will be reported as the average of the two 
middle numbers if the dataset contains an even number of observations. 
• Test statistics including t and z test statistics will be reported to two decimal places.  
• P-values will be reported to 3 decimal places if greater than 0.001. If less than 0.001 then 
report ‘<0.001’. Report p-values and significant levels as 0.05 rather than .05. A p-value 
can be reported as “1.000” only if it is exactly 1.000 without rounding. A p-value can be 
reported as “0.000” only if it is exactly 0.000 without rounding. 
• In general, listings will be displayed by treatment group and participant and will be sorted 
in the order that columns are displayed, starting with the first column on the left.  
• All analyses will be performed using the SAS System version 9.4. 


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4. 
ANALYSIS POPULATION 
All interim analyses for efficacy and futility will utilize the modified intent-to-treat population 
defined for this study, as follows: 
Modified Intent-to-Treat Population 
The modified Intent-to-Treat (mITT) population will include all randomized participants who 
receive at least one dose of study drug and meet entry criteria. The primary efficacy analyses will 
be based on the mITT population. Participants who, for whatever reason, do not complete their 
assigned therapy will be included in the mITT population in the groups to which they were 
randomized. 


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5. 
ENDPOINT EVALUATION 
5.1. 
Overview of Analysis Methods 
5.1.1. 
Multicenter Studies 
Study participants will be recruited from up to 20 study sites.  The analyses of survival estimates 
at fixed points in time will not be stratified for the interim analyses.   
5.1.2. 
Assessment Time Windows 
Visit windows for each scheduled visit are provided in Table 2.  The Baseline visit must be 
performed within 30 days of the Screening visit. 
 
Table 2: Visit Target Days and Windows for Scheduled Visits 
Visits 
Target Day 
Visit Type 
Window 
Baseline 
0 
Clinic 
≤30 days from Screening 
Week 6 
42 
Clinic 
±7 days from target 
Week 12 
84 
Clinic 
Week 18 
126 
Telephone 
Week 24 
168 
Clinic 
Week 30 
210 
Telephone 
Week 36 
252 
Clinic 
Week 42 
294 
Telephone 
Week 52 
364 
Clinic 
±14 days from target 
Month 15 
457 
Telephone 
Month 18 
548 
Clinic 
Month 21 
639 
Telephone 
Month 24 
731 
Clinic 
Month 27 
822 
Telephone 
Month 30 
913 
Clinic 
Month 33 
1004 
Telephone 
Month 36 
1096 
Clinic 
Data collected outside of the visit window will not be removed from analyses.  Data collected 
from unscheduled visits and Time of Diagnosis visits will be included in analyses, except for by-
visit summaries. 


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5.2. 
Primary Estimand 
5.2.1. 
Definition 
The primary objective of the study is to determine the efficacy of a 12-month course of HCQ to 
prevent the development of clinically-apparent RA at 36 months in participants at high-risk for 
future RA due to high titer elevations of anti-CCP3 (≥ 40 units) but who are without a history or 
clinical findings of IA at Baseline.  For this study, clinically-apparent RA will be defined using 
the 2010 ACR/EULAR Classification Criteria as either: 
(1) A score of ≥ 6 defining “definite RA” or 
(2) A joint examination consistent with RA-like synovitis with ≥ 1 erosion identified via 
x-ray imaging of the hands, wrists, and feet. 
The primary hypotheses to be evaluated at interim and end-of-study analyses are: 
H0: RA-free survival at 3 years (36 months) is equal across arms; 
HA: RA-free survival at 3 years (36 months) is not equal across arms. 
Variable:  
Time to development of clinically-apparent RA  
Population:  
The mITT population will be used for these analyses. 
Intercurrent Events Strategies (IES):  
1. Participants who terminate early from the study prior to a diagnosis of RA will be 
censored at the time of early termination.   
2. Participants who choose to take off-study HCQ on a continuous basis will be censored at 
the time this therapy began.  
The rationale for this decision is that our ability to evaluate the impact of a short 12-
month course of HCQ on development of RA is confounded if individuals choose to take 
HCQ, provided by physicians outside of the study.  Further, data for individuals assigned 
to 12-months of placebo and then take off-study HCQ could further confound results. 
3. Participants who were diagnosed with RA by an outside physician and started prohibited 
medications will be censored at the time the RA medications were started. Only cases 
where data collected on-study confirm the diagnosis using the study-defined primary 
endpoint definition will count as RA/IA cases in the primary analysis.   
4. Participants who started prohibited medications during study participation to treat 
conditions other than RA will be censored as follows:  
o If a participant is taking a prohibited medication other than corticosteroids, then 
time-in-study will be censored at the start of the first prohibited medication.  
o If a participant is taking corticosteroids, two courses at a dose ≤60 mg/day for ≤21 
days are allowed. If either of these conditions is violated, then time-in-study will 
be censored at the time when the permitted conditions are violated. 


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The rationale for this decision is that inflammatory arthritis cannot be accurately 
diagnosed by the study assessments once prohibited medications have been started. 
5. Participants who discontinue study-provided HCQ/placebo prematurely or who are not 
compliant with planned dosing will be included in the analysis and will not be censored 
at the time of study drug discontinuation or noncompliance. 
Population Level Summary:   
Estimated risk at 36 months for each treatment arm and the difference between the treatment 
arms (with 95% confidence intervals) will be derived from Kaplan-Meier (KM) curves and using 
the Greenwood formula for estimating the variance. 
5.2.2. 
Interim Analysis of the Primary Estimand 
This section presents details on the analysis plans for each interim evaluation. Power estimates 
are presented in Appendix 8.1. 
5.2.2.1. 
Efficacy 
The analysis will be based on the KM estimated risk of clinically-apparent RA at 36 months, 
where risk = (1-KM estimated probability of “survival”).  Survival for this analysis is defined as 
absence of clinically-apparent RA. Estimated risks will be derived from a Kaplan-Meier curve 
using censored time-to-event data to account for attrition under the assumption of non-
informative censoring.   
The test statistic will be a Wald-type chi-square statistic derived by dividing the difference of the 
logit-transformed KM survival estimates for each arm by the associated variance derived using 
the delta-method.  This analysis will ignore stratification by site and method of recruitment, 
because the unstratified test statistic has been shown to have better test performance (Klein, et. 
al. 2007) 
The test statistic at each interim analysis stage will be calculated as the logit transformed test 
statistic in Klein et al (𝑋5
2): 
𝑋5
2
𝑘= 
[log
𝑆𝐻𝑘
̂ (𝑡36)
1 −𝑆𝐻𝑘
̂ (𝑡36)− log
𝑆𝑃𝑘
̂ (𝑡36)
1 −𝑆𝑃𝑘
̂ (𝑡36)]
2
𝜎̂𝐻𝑘
2 (𝑡36)
[1 −𝑆𝐻𝑘
̂ (𝑡36)]
2 + 
𝜎̂𝑃𝑘
2 (𝑡36)
[1 −𝑆𝑃𝑘
̂ (𝑡36)]
2
 
where: 
𝑋5
2
𝑘 = Test statistic at interim analysis stage k, k = 1 to 2 
𝑆𝐻𝑘
̂ (𝑡36) = KM estimated probability of RA-free survival in the HCQ treatment arm at 
month 36 for interim analysis stage k 
𝑆𝑃𝑘
̂ (𝑡36) = KM estimated probability of RA-free survival in the placebo treatment arm at 
month 36 for interim analysis stage k 
𝜎̂𝐻𝑘
2 (𝑡36) = Estimated variance of KM estimated probability of RA-free survival in the 
HCQ treatment arm at month 36 for interim analysis stage k, calculated via Greenwood’s 
formula 
𝜎̂𝑃𝑘
2 (𝑡36) = Estimated variance of KM estimated probability of RA-free survival in the 
placebo treatment arm at month 36 for interim analysis stage k, calculated via 
Greenwood’s formula 


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The criteria at each interim analysis stage k to determine if the primary null hypothesis should be 
rejected will be determined by O’Brien-Fleming (OBF) boundary values for the standardized Z 
scores (ZOBFk).  PROC SEQDESIGN will be used to calculate the OBF boundary criteria using 
information levels based on the proportion of the maximum person-time accumulated on the date 
of data snapshot for the planned DSMB meeting.  Enrollment closed on November 1, 2021 with 
144 participants randomized to the study.  Hence, the maximum person-years for the study is 144 
participants * 3 years = 432 person-years.  On the date of the data snapshot, we will compute the 
information fraction as the sum of time accrued from the day of randomization over all 
individuals divided by 432.  Person-time for individuals randomized more than 3 years prior to 
the date of the data snapshot will be set at 3.0 person-years.  In the example below, we are 
assuming data snapshot dates of 01FEB2022 and 01FEB2023 for the spring 2022 and spring 
2023 DSMB meetings, respectively. Based on the study progress of all randomized participants, 
the information proportions for each interim analysis stage would be as follows: 
 
Table 3: Estimated Information 
Interim 
Analysis 
Stage (k) 
Time Point 
Elapsed Study 
Time 
(years) 
Elapsed Study 
Time 
(person-years) 
Estimated 
Information 
Proportion (Ik) 
1 
Spring 2022 DSMB 
[01FEB2022] 
5.8 
366.5  
0.848 
2 
Spring 2023 DSMB 
[01FEB2023] 
6.8 
405.4  
0.938 
Final 
End of Study 
[01NOV2024] 
8.5 
432.0 
1.000 
 
Note the actual information proportions will vary depending on the information available on the 
dates of data cuts. 
At each interim analysis stage k, the primary hypothesis will be tested as follows: 
• If  𝑋5
2k ≥ (ZOBFk)2, the null hypothesis H0 that the RA-free survival at 3 years (36 months) 
is equal across arms is rejected, indicating there is strong evidence of a treatment effect.   
• If  𝑋5
2
k < (ZOBFk)2, the null hypothesis H0 that the RA-free survival at 3 years (36 months) 
is equal across arms is not rejected. 
5.2.2.2. 
Futility 
To evaluate futility, we will compute a Z-score test statistic based on the difference of logit 
transformed survival estimates, calculated as: 
𝑍𝑘= 
log
𝑆𝐻𝑘
̂ (𝑡36)
1 −𝑆𝐻𝑘
̂ (𝑡36)− log
𝑆𝑃𝑘
̂ (𝑡36)
1 −𝑆𝑃𝑘
̂ (𝑡36)
√
𝜎̂𝐻𝑘
2 (𝑡36)
[1 −𝑆𝐻𝑘
̂ (𝑡36)]
2 + 
𝜎̂𝑃𝑘
2 (𝑡36)
[1 −𝑆𝑃𝑘
̂ (𝑡36)]
2
 
 
A Z-score <0.3 would suggest that there is little chance of detecting a significant survival 
advantage for the HCQ arm.  The test for futility will be conducted as follows: 


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• If  𝑍𝑘< 0.3, the futility test criterion has been met, and there is a small chance of 
detecting a significant treatment difference in RA-free survival rates at month 36 at the 
end the of the study. 
• If  𝑍𝑘≥0.3, the futility test criterion has not been met. 
5.2.3. 
Interim Analysis of the Sensitivity Estimand 
The estimand for these sensitivity analyses will be identical to the primary estimand except for 
the following updates to the Intercurrent Events Strategy for handling cases for individuals who 
withdrew from the study early or who began treatment for an unconfirmed diagnosis of RA. 
Changes to Intercurrent Events Strategies defined in Section 5.2.1:  
1. For participants who terminate early from the study prior to a diagnosis of RA and have 
consented to be contacted via phone, a participant-reported diagnosis of RA that is (or 
was) treated will be counted in the sensitivity analysis as a case of RA/IA at the time of 
initiation of the RA/IA medications.  For participants without a reported RA/IA 
diagnosis, data will be censored at the date of last phone contact.  For participants who 
cannot be contacted, data will be censored at the time of early termination.   
2. Participants who choose to take off-study HCQ on a continuous basis will not be 
censored at the time this therapy began. 
3. Participants who were diagnosed with RA by an outside physician and started prohibited 
medications will be included in the analysis as RA cases at the time the prohibited 
medications were initiated, regardless of whether or not the diagnosis can be confirmed 
using study-defined criteria and study data. 
4. For participants who terminate early from the study prior to a diagnosis of RA and have 
consented to be contacted via phone, data for a participant who reports use of a prohibited 
medication to treat conditions other than RA will be censored at the time the prohibited 
medication was started. 
 
 


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6. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
In protocol version 3.0, we provided initial details on the plans for the interim analyses to be 
performed for efficacy and futility for ARA08.  Below are changes to the protocol details for the 
interim analyses: 
• The assumptions about enrollment expectations, duration of enrollment and timing of 
interim analyses presented in protocol version 3.0 are inaccurate. Hence, updated power 
calculations are presented in Appendix 8.1. 
• In the protocol, we stated that a single nonbinding futility analysis will be performed.  
With the option to perform 2 interim analyses for efficacy, the study team decided that a 
futility analysis may be performed at the time of each efficacy interim analysis. 
 
 


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7. 
REFERENCES 
Klein, J.P., et al., Analyzing survival curves at a fixed point in time. Stat Med, 2007. 26(24): p. 
4505-19. 
 




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Table A2: Probability of Finding Futility (Z-score<0.3) 
Final Sample 
Size 
Interim 
Analysis 
RA-Free Survival for 
Placebo/HCQ 
50%/75% 
50%/50% 
150 
1st 
1.2% 
62.1% 
2nd 
0.5% 
62.1% 
140 
1st 
1.5% 
61.4% 
2nd 
0.9% 
60.9% 
 
 
 


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14.2. 
Schedule of Events 
 


Autoimmunity Centers of Excellence  
Statistical Analysis Plan – ARA08 StopRA 
Page 42 of 44 
Version Date: 2023-05-08 
Version: 1.0  
 
 


Autoimmunity Centers of Excellence  
Statistical Analysis Plan – ARA08 StopRA 
Page 43 of 44 
Version Date: 2023-05-08 
Version: 1.0  
 
 


Autoimmunity Centers of Excellence  
Statistical Analysis Plan – ARA08 StopRA 
Page 44 of 44 
Version Date: 2023-05-08 
Version: 1.0  
 
 








ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time,
. (we, us or Company) may be required by law to provide to you 
certain written notices or disclosures. Described below are the terms and conditions for providing 
to you such notices and disclosures electronically through the DocuSign system. Please read the 
information below carefully and thoroughly, and if you can access this information electronically 
to your satisfaction and agree to this Electronic Record and Signature Disclosure (ERSD), please 
confirm your agreement by selecting the check-box next to ‘I agree to use electronic records and 
signatures’ before clicking ‘CONTINUE’ within the DocuSign system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 2/14/2020 11:29:51 AM
Parties agreed to: Ellen Goldmuntz, Kevin Deane, Lynette Keyes-Elstein


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact 
  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to:
 
 
To advise 
 of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at
 and in the 
body of such request you must state: your previous email address, your new email address.  We 
do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from 
  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to
 and in the body 
of such request you must state your email address, full name, mailing address, and telephone 
number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with 
  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to
 and in the body of such request you must state 
your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
• 
You can access and read this Electronic Record and Signature Disclosure; and 
• 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
• 
Until or unless you notify 
 as described above, you consent to receive 
exclusively through electronic means all notices, disclosures, authorizations, 
acknowledgements, and other documents that are required to be provided or made 
available to you 
 during the course of your relationship with