A Clinical Utility Study of PrismRA Testing Therapeutic Response for Rheumatoid Arthritis (DRIVE)
Conditions: Rheumatoid Arthritis
Sponsor: Scipher Medicine

Cover Page for ClinicalTrials.gov 
Document:  
Protocol Version 3.0
Official Study Title:  
A Clinical Utility Study of PrismRA Testing Therapeutic Response for
Rheumatoid Arthritis (DRIVE) 
Document Date: 
October 20, 2022 

 
 
 
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A Clinical Utility Study of PrismRA Testing Therapeutic Response for 
Rheumatoid Arthritis (DRIVE) 
 
Protocol Number: SCIPHER-RA-005 
Version: 3.0 
Date: 20-Oct-2022 
  
 
Sponsor: 
Scipher Medicine Corporation  
221 Crescent Street, Suite 103A 
Waltham, MA 02453 
 
 
 
 
 
 
The information contained in this document is supplied as a background for clinical investigatio
ns.  The document contains proprietary and confidential information that is the intellectual 
property of Scipher Medicine Corporation and shall not be disclosed in whole or in part or used 
for any purpose other than set forth in this protocol without the written consent of Scipher 
Medicine Corporation. 
 
 

 
 
 
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Contents 
Protocol Number: SCIPHER-RA-005 ............................................................................................................. 1 
1 
Key Personnel ................................................................................................................................... 5 
2 
Protocol Signature Page ................................................................................................................... 6 
3 
List of Abbreviations and Key Terms ................................................................................................ 7 
4 
Definitions ........................................................................................................................................ 8 
5 
Introduction ...................................................................................................................................... 9 
5.1 
Introduction .................................................................................................................................. 9 
5.2 
Rationale ..................................................................................................................................... 10 
6 
Study Design ................................................................................................................................... 10 
6.1 
Study Type ................................................................................................................................. 10 
6.2 
Study population ......................................................................................................................... 11 
7 
Study Endpoints .............................................................................................................................. 12 
7.1 
Primary Endpoint ....................................................................................................................... 12 
7.2 
Secondary Endpoint ................................................................................................................... 12 
7.3 
Exploratory Endpoints ................................................................................................................ 12 
7.4 
Patient Selection Criteria ............................................................................................................ 13 
7.4.1 
Inclusion Criteria ................................................................................................................. 13 
7.4.2 
Exclusion Criteria ................................................................................................................ 15 
8 
Study Procedures ........................................................................................................................... 18 
8.1 
Pre-Screening ............................................................................................................................. 18 
8.2 
Screening and Enrollment .......................................................................................................... 18 
8.3 
Screen Failures ........................................................................................................................... 18 
8.4 
Summary of Visits and Assessments .......................................................................................... 19 
8.5 
Schedule of Visits ....................................................................................................................... 19 
8.6 
Schedule of Assessments ............................................................................................................ 21 
8.7 
Specimen Collection ................................................................................................................... 23 
8.8 
Study Treatment ......................................................................................................................... 23 
8.8.1 
Randomization .................................................................................................................... 23 
8.8.2 
Stratification ....................................................................................................................... 23 
8.8.3 
Therapy, Dose, Modes of Administration ........................................................................... 23 
8.8.4 
Duration of Follow-up for Outcome Assessment ............................................................... 24 

 
 
 
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8.8.5 
Medication Expenses and Reimbursement (PrismRA arm only) ........................................ 24 
8.9 
Data Collection ........................................................................................................................... 24 
8.10 
Patient Follow-up ....................................................................................................................... 24 
8.11 
Patient Withdrawal/Completion ................................................................................................. 25 
9 
Safety Assessments ........................................................................................................................ 25 
9.1 
Introduction to Safety Assessments ............................................................................................ 25 
9.2 
Anticipated and Unanticipated Adverse Device Effects ............................................................. 25 
10 
Statistical Considerations ............................................................................................................... 26 
10.1 
Sample size ................................................................................................................................. 26 
10.2 
Planned Interim Analysis of the PrismRA Arm ......................................................................... 27 
10.3 
Baseline Analysis of the External Control Arm ......................................................................... 27 
10.4 
Planned Outcome Analysis ......................................................................................................... 28 
10.5 
Missing Data Handling ............................................................................................................... 29 
10.6 
Data Reporting ........................................................................................................................... 29 
10.6.1 
Interim Analyses and Reporting ......................................................................................... 29 
10.6.2 
Final Analyses and Reporting .............................................................................................. 29 
11 
Limitations ...................................................................................................................................... 30 
11.1 
Data Recency .............................................................................................................................. 30 
11.2 
RA Patient Identification ............................................................................................................ 30 
12 
Data Handling and Record Keeping (Study Management) ............................................................. 30 
12.1 
Study Database ........................................................................................................................... 31 
12.2 
Inspection of Records ................................................................................................................. 31 
12.3 
Retention of Records .................................................................................................................. 32 
12.4 
Confidentiality (PrismRA arm Only) ......................................................................................... 32 
12.4.1 
Confidentiality of Records .................................................................................................. 32 
12.4.2 
Review of Records .............................................................................................................. 33 
12.4.3 
Study results ....................................................................................................................... 33 
12.4.4 
Future Use of Data or Specimens ....................................................................................... 33 
13 
Ethics .............................................................................................................................................. 34 
13.1 
Ethics Review ............................................................................................................................. 34 
13.2 
Ethical Conduct of the Study ...................................................................................................... 34 
14 
Quality Control ............................................................................................................................... 34 
14.1 
Data Quality ............................................................................................................................... 34 

 
 
 
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14.2 
Protocol Deviations .................................................................................................................... 35 
15 
Protocol revision history ................................................................................................................ 35 
16 
References ...................................................................................................................................... 36 
 
 
 

 
 
 
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1 Key Personnel 
 
Sponsor: 
 
 
 
 
 
 
 
 
Sam Asgarian, MD 
Chief Medical Officer 
Scipher Medicine Corporation  
221 Crescent Street, Suite 103A 
Waltham, MA 02453 
 
 
 
 
 
 
 
 
 
 

 
 
 
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2 Protocol Signature Page 
Protocol Title: A Clinical Utility Study of PrismRA Testing Therapeutic Response for 
Rheumatoid Arthritis (DRIVE) 
Protocol Version/ Date: 3.0, 20-Oct-2022 
Sponsor Name: Scipher Medicine Corporation 
 
Declaration of Principal Investigator 
I confirm that I have read the above-mentioned protocol and its attachments and understand it. I 
agree to conduct the described study in compliance with all stipulations of the protocol, as well 
as all applicable research regulations and ICH E6 Guideline for Good Clinical Practice (GCP). 
 
Principal Investigator Name: __________________________________________ 
 
Principal Investigator Signature:________________________________________ 
 
Date: _____________________________________________________________ 
 
 

 
 
 
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3 List of Abbreviations and Key Terms 
Abbreviation or Specialist Term 
Explanation 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
bDMARD 
Biologic Disease Modifying Anti-Rheumatic Drug 
CAP 
College of American Pathologists 
CBC 
Complete Blood Count 
CDAI 
Clinical Disease Activity Index 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Comprehensive Metabolic Panel 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
DAS 
Disease Activity Score 
csDMARD 
Conventional Synthetic Disease-Modifying Antirheumatic Drug 
DMARD 
Disease Modifying Anti-Rheumatic Drug 
DNA 
Deoxyribonucleic Acid 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Records 
ESR 
Erythrocyte Sedimentation Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GPP 
Good Pharmacoepidemiology Practices 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IL-1i 
Interleukin-1 inhibitor 
IL-6i 
Interleukin-6 inhibitor 
IL-17i 
Interleukin-17 inhibitor 
IL-23i 
Interleukin-23 inhibitor 
IQR 
Interquartile Range 
IRB 
Institutional Review Board 
JAKi 
Janus Kinase inhibitor 
MCID 
Minimal Clinically Important Difference 
MID 
Minimal Important Difference 
MOA 
Mechanism of Action 
MTX 
Methotrexate 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drug 
PRO 
Patient Reported Outcomes 
PtGA 
Patient Global Assessment 

 
 
 
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Abbreviation or Specialist Term 
Explanation 
RA 
Rheumatoid Arthritis 
RAPID3 
Routine Assessment of Patient Index Data 3 
RDCI 
Rheumatic Disease Comorbidity Index 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
Standard of Care 
TB 
Tuberculosis 
TNFi 
Tumor Necrosis Factor Inhibitor 
tsDMARD 
Targeted small molecule Synthetic Disease Modifying Anti-Rheumatic Drug 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
 
4 Definitions 
Terms 
Definition of Terms 
DRIVE Study 
The comparative effectiveness study of the PrismRA test comparing the clinical 
outcomes of patients in the PrismRA arm (trial) and the external control arm 
(observational). 
Baseline 
Assessments of patients as they enter the PrismRA arm. For the external control 
arm, the corresponding baseline CDAI assessment window is the 3-month 
period before the index date (defined as the time of study treatment initiation). 
For medical history all available data before the index date will be used in the 
external control arm. 
Enrollment 
The point at which the patient signs the informed consent form for the PrismRA 
arm. Not applicable for the external control arm.   
PrismRA arm 
Trial participants in the trial conducted by Scipher Medicine for whom 
PrismRA test is performed and the Investigator will use the PrismRA test results 
to inform the treatment decision. 
External control 
arm 
OM1 real-world data patients who received standard of care treatment for RA 
with TNFi or non-TNFi b/tsDMARDs without guidance from PrismRA test 
results. 
Study Treatment 
The b/tsDMARDs (FDA approved for RA) that is initiated at Visit 2 (See 
Section 8.5), informed by the PrismRA test in the PrismRA arm and as a part of 
standard of care in the external control arm. This study treatment 
(b/tsDMARDs) can be the very first b/tsDMARD for the patient or a subsequent 
b/tsDMARD after having used one or more TNFi bDMARDs (but not non-
TNFi b/tsDMARDs). 
Study Treatment 
Initiation 
The point at which a study treatment (See “Study Treatment” above) is initiated 
to treat RA. This time point constitutes the index date (beginning of the follow-
up) and is defined as Visit 2  

 
 
 
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Terms 
Definition of Terms 
RA Disease 
Activity 
Disease activity is based on the CDAI score as follows: 
• 
Remission: CDAI ≤ 2.8 
• 
Low: CDAI > 2.8 and ≤ 10.0 
• 
Moderate: CDAI > 10.0 and ≤ 22.0 
• 
High: CDAI > 22.0 
For the PrismRA arm, the CDAI scores will be assessed by the Investigator. 
The CDAI scores for the external control arm in OM1 PremiOM RA consist of 
CDAI scores in structured EMR data, and CDAI scores estimated by machine 
learning based on unstructured data.1CDAI scores from all data sources will be 
used. 
5 Introduction 
5.1 Introduction 
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic 
inflammation primarily involving the joints of the hands and wrists. RA typically presents with 
generalized morning stiffness and musculoskeletal pain followed by joint swelling and 
tenderness. Untreated RA often leads to progressive joint deformity and destruction with 
subsequent disability. The objectives of RA treatment are to stop disease progression, prevent 
irreversible joint destruction, and improve quality of life. Ideally, rheumatologists consult with 
their patients to decide whether disease remission (the absence of signs or symptoms of 
significant inflammatory disease) or low disease activity is the appropriate goal of treatment. 
After therapy is started, RA disease activity is measured regularly utilizing one of several 
validated tools (e.g., DAS, CDAI). Using the treat-to-target approach, therapeutic adjustments 
are made each visit to ensure continued progression to the agreed treatment target. 
To achieve these treatment goals, there are an increasing number of advanced biologic and small 
molecule targeted therapies (e.g., b/tsDMARD) directed at specific components of the immune 
system involved in RA pathogenesis. Treatment options organized by mechanism of action 
(MOA) include tumor necrosis factor-α inhibitors (TNFi), Janus kinase inhibitors (JAKi), 
interleukin-6 inhibitors (IL-6i), interleukin-1 inhibitors (IL-1i), T cell co-stimulation inhibitors, 
and B cell modulators. For approval by the Food and Drug Administration (FDA), these agents 
are required report clinical trial data using ACR20, 50, and 70, defined as a 20%, 50%, and 70% 
improvement respectively in specific disease measures: swollen joint count, tender joint count, 
patient reported outcomes, physician reported outcomes and acute phase reactant measures2.  
Unfortunately, all of these agents report ACR50 response rates of only 25-40% at six months 
following treatment initiation3-6. Hence, two thirds of RA patients receiving their first 
b/tsDMARD fail to achieve ACR50, regardless of the MOA. 
 
The goal of precision medicine is to match patients with a treatment MOA that most closely 
matches his or her individual disease biology to improve disease outcomes in a timely fashion. 
Precision medicine has been most successful in oncology where genetic (DNA) changes in 
patient tumors are analyzed in order to identify the best treatment options for each individual. 
However, DNA data alone is insufficient to determine individual treatment options in complex 
diseases such as RA. Scipher Medicine is using network medicine and artificial intelligence to 

 
 
 
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bring precision medicine to complex diseases through a combined analysis of gene expression 
(RNA) data, clinical metrics, and appropriate laboratory markers. PrismRA® is the first test 
developed using Scipher’s network medicine approach. 
 
PrismRA was developed because the majority of RA patients receive a TNFi therapy as their 
b/tsDMARD7,8. It is a molecular signature test designed to predict the likelihood that a RA patient 
will be a non-responder to TNFi therapies. From a single blood draw taken before the start of 
treatment, the PrismRA test assesses twenty-three (23) biomarkers that are integrated into a 
single predictive model that generates a score on a scale of one (1) to twenty-five (25) that 
represents the likelihood of non-response to TNFi therapies. In a prior PrismRA validation study, 
patients with a molecular signature of non-response were less likely to have an adequate 
response to TNFi therapies than those patients lacking the signature according to ACR50, 
ACR70, CDAI, and DAS28-CRP with significant odd ratios of 3.4-8.8 for targeted therapy naïve 
patients and 3.3-26.6 for TNFi-exposed patients10.  
5.2 Rationale 
The objective of the DRIVE study is to establish the clinical utility of the PrismRA test in 
evaluating therapeutic response for patients with rheumatoid arthritis (RA).  
6 Study Design 
6.1 Study Type 
This is a two-arm, multi-center United States (U.S.)-based study with a prospective, non-blinded 
intervention arm (PrismRA arm) and an observational external control arm designed to 
demonstrate the clinical utility of the PrismRA test in routine clinical care. The study will 
compare outcomes for RA patients with moderate to high disease activity whose treatment is 
informed by PrismRA test results (PrismRA arm) to outcomes among RA patients who receive 
the standard of care (SOC) not informed by PrismRA results (external control arm). 
 
PrismRA arm: 
In this arm, all patients will receive the PrismRA test. The Investigator will receive the PrismRA 
results and use those results to inform treatment selection by Visit 2. Patients may be followed 
indefinitely from the time of signing the informed consent and medical records release form 
unless the patient withdraws from the study, dies, or becomes lost to follow-up. Changes to the 
study b/tsDMARDs do not terminate follow-up. A patient can withdraw from the study at any 
time. 
 
External control arm: 
The observational external control arm will consist of comparable initiators of b/tsDMARDs in 
OM1’s PremiOM RA dataset, in which the specific choice of TNFi or non-TNFi b/tsDMARDs 
was based on the treating physician’s clinical judgement and was not informed by the PrismRA 
test results. Baseline as well as follow-up data will consist of data obtained at routine clinical 
encounters. The index date (start of follow-up) for this external control arm will be defined as the 
time of initiation of the study treatment (very first or subsequent b/tsDMARDs) and patients will 
be followed until week 24, death, or loss to follow-up, whichever occurs first. Changes to the 

 
 
 
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study b/tsDMARDs do not terminate follow-up. Controls may be sampled from time intervals 
contemporaneous with the trial (March 2022 and onward) as well as historical periods. 
 
6.2 Study population 
PrismRA arm: 
This arm will enroll approximately 600 RA patients at approximately 33 clinical sites who are at 
least 18 years of age. All patients in the PrismRA arm will undergo PrismRA testing at their first 
study visit (Visit 1). See Patient Selection Criteria for details. 
 
External control arm: 
Patients with RA in the OM1 PremiOM RA Dataset will be selected based on the same eligibility 
criteria as in the PrismRA arm and adapted for real-world data availability where necessary. 
Patients in the external control arm will be balanced with patients in the PrismRA arm using a 
propensity score model developed with the primary goal of achieving balance in baseline 
characteristics between the comparison groups. The external control arm is expected to have at 
least 1,500 eligible patients after propensity score modeling, with no less than 750 patients 
having CDAI scores at both baseline and Week 24. The data from patients who initiated 
b/tsDMARDs in the contemporaneous period (March 2022 and onward) and if needed, the recent 
historical period (6-month to 3-year period prior to March 2022) will be used to maximize the 
size of the patient pool while minimizing confounding by the potential secular trends in 
treatment patterns. The smallest historical time window that can provide the planned number of 
external control arm patients comparable to the PrismRA arm patients will be used. The overlap 
in propensity score distributions between the external control and trial arms will inform the 
ultimate sample size.   
 
The data source for the analysis is the OM1 PremiOM RA Dataset within the OM1’s Real-World 
Data Cloud (OM1, Inc, Boston, MA, US). The OM1 Real-World Data Cloud is derived from 
deterministically linked, de-identified, individual-level health care claims, electronic medical 
record (EMR), and other data. EMR data are from sources geographically representative of the 
U.S. population and include medication history and prescription information, laboratory results, 
and diagnoses as documented by a physician. Additional medical and pharmacy claims data are 
linked to the clinical data to fill gaps in patients’ clinical care. The medical and pharmacy claims 
contain billing and coding history on inpatient and outpatient encounters from acute care 
facilities, ambulatory surgery centers, and clinics. The OM1 Real-World Data Cloud includes 
data from January 2013 to present day.   
 
To qualify for the OM1’s PremiOM RA dataset, each patient must be at least 16 years old at the 
time of the qualifying diagnosis and meet at least one of the following conditions: 
● At least two diagnosis codes for RA, at least 30 days apart, each coming from an 
encounter with a rheumatologist 
● At least one inpatient RA diagnosis code 
● At least two outpatient RA diagnosis codes, at least 30 days apart and within a year, 
regardless of physician specialty 

 
 
 
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● At least one outpatient RA diagnosis code and a prescription or fill for a DMARD and no 
diagnosis for any of the non-RA conditions for which those drugs may also be prescribed 
Non-RA conditions are defined as juvenile idiopathic arthritis, psoriatic arthritis/psoriasis, 
ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, cryopyrin-
associated periodic syndromes, renal transplant, malaria, systemic lupus erythematosus, giant 
cell arteritis, cytokine release syndrome, all cancers, hydatidiform mole. 
7 Study Endpoints  
7.1 Primary Endpoint 
The proportion of patients with moderate or high disease activity at baseline who achieve a 
minimal important difference (MID) 11 in CDAI of ≥ 6 (baseline moderate) or ≥12 (baseline high) 
at 24 weeks after study treatment initiation. 
 
7.2 Secondary Endpoint 
Secondary endpoints include the following: 
 
a) The proportion of patients with moderate or high disease activity at baseline who achieve 
CDAI ≤ 10 (low disease activity (LDA)) or CDAI ≤ 2.8 (remission) at 12 and 24 weeks 
after study treatment initiation 
b) The change in CDAI scores from baseline to 12 and 24 weeks among patients with 
moderate or high disease activity at baseline who initiate study treatment. 
c) The proportion of patients with moderate or high disease activity at baseline who achieve 
an MID in CDAI of ≥ 6 and ≥12, respectively, 12 weeks after study treatment initiation  
d) The proportion of patients with moderate or high disease activity at baseline who achieve 
a meaningful reduction (defined as ≥ 10 on the scale of 0–100) of patient global 
assessment (PtGA) compared to the baseline PtGA 12 and 24 weeks after study 
treatment initiation.  
e) The proportion of patients with moderate or high disease activity at baseline who achieve 
a minimal clinically important difference (MCID) in RAPID3 (≥ 3.8 on the scale of 0–
30)12compared to the baseline RAPID3 at 12 and 24 weeks after study treatment 
initiation. 
f) The proportion of patients with moderate or high disease activity at baseline who achieve 
an MCID in patient pain visual analogue scale 13(≥ 1.1 on the scale of 0–10) compared 
to the baseline pain at 12 and 24 weeks after initiation of a b/tsDMARD therapy. 
g) The proportion of treatment decisions that were guided by PrismRA test results (in the 
PrismRA arm only) 
 
7.3 Exploratory Endpoints 
• The proportion of moderate to high disease activity patients that achieve ACR50 
therapeutic response 12 and 24 weeks after study treatment initiation (in the PrismRA 
arm only; analysis in the external control arm may only be descriptive in nature if the 
constructed ACR50 is not sufficiently available in real world data). 

 
 
 
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• The proportion of patients receiving TNFi therapy and non-TNFi b/tsDMARDs as the 
study treatment at the index date. 
• The number of patients that stop or change the study treatment due to an intolerance 
during the 24-week follow-up period (in the PrismRA arm only; analysis in the external 
control arm may only be descriptive in nature if the reason for the study treatment 
discontinuation is not sufficiently available in real world data). 
 
7.4 Patient Selection Criteria 
7.4.1 Inclusion Criteria 
Table 1 shows the inclusion criteria that will be used prospectively in the PrismRA arm and the 
best approximation for the selection of comparable patients in the observational external control 
arm. 
 
Table 1. Inclusion criteria by study arm 
 PrismRA arm 
External control arm 
1 Patient is eighteen years of age or older (≥ 18) at 
time of consent. 
All patients are ≥ 18 years at the initiation of 
b/tsDMARDs (which can be the first ever 
b/tsDMARD or subsequent b/tsDMARDs). 
2 Patient must meet the criteria for RA as defined 
by the 2010 ACR/EULAR classification at Visit 
1. 
Patients are in the OM1 PremiOM RA dataset 
(See Section 6.2 Study Population). 
3 Patient has active, moderate to severe RA with a 
CDAI of >10 at Visit 1. 
Patient has a CDAI of > 10 based on the most 
recent CDAI assessed during the 3-month period 
prior to the b/tsDMARDs initiation. 
4 Patient has swollen and tender joint count of ≥ 2 
each, as determined by CDAI assessment at Visit 
1 using a 28-joint count. 
Patient has swollen and tender joint counts of ≥ 2 
each, based on the most recent joint counts 
assessed during the 3-month period prior to the 
b/tsDMARDs initiation. 

 
 
 
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5 Patient is eligible for treatment with any 
b/tsDMARD therapy at Visit 1 based on all of the 
following: 
 
• 
Investigator determination that patient 
satisfies clinical criteria 
• 
Patient consents to the use of non-csDMARD 
therapy during shared investigator-patient 
decision making 
• 
Absence of any financial or logistical 
limitations to the initiation of a b/tsDMARD 
therapy 
Only patients who initiate a b/tsDMARD will be 
enrolled to ensure the treating rheumatologist 
determination of indication, patient consent, and 
financial/logistical feasibility. 
 
The list of b/tsDMARDs approved for RA 
includes the following: 
• 
TNFi (infliximab, etanercept, certolizumab 
pegol, golimumab, adalimumab) 
• 
IL-6i (tocilizumab, sarilumab) 
• 
IL-1i (anakinra) 
• 
T-cell co-stimulation inhibitor (abatacept) 
• 
B-cell depletion agent (rituximab) 
• 
JAKi (tofacitinib, baricitinib, upadacitinib) 
 
Biosimilars/generics of these b/tsDMARDs will 
also be included. 
6 Concomitant treatments including but not limited 
to the following are permitted per standard of 
care: 
• 
csDMARDs (e.g., methotrexate, 
sulfasalazine, leflunomide, or 
hydroxychloroquine) 
• 
Non-steroidal anti-inflammatory drugs 
(NSAIDs) 
• 
Corticosteroids 
• 
Prednisone (or equivalent) at a stable ≤ 10 
mg per day for at least 2 weeks prior to Visit 
1 
• 
Intra-articular or parenteral corticosteroids ≤ 
2 weeks prior to Visit 1 
Concomitant treatments per standard of care will 
be allowed and recorded. 
 
7 Patient is willing and able to complete the 
informed consent process and comply with study 
procedures and visit schedule. 
This criterion is not replicable with real world 
dispensing data and will not be used. 
  
8 This additional point does not apply to the 
PrismRA arm. 
Patients will have ≥ 1 CDAI measured in the 3-
month period prior to the b/tsDMARD initiation 
to ensure patients from practices where CDAIs 
are routinely used and baseline CDAI is well 
defined in this 3-month window. There will be a 
further required ≥ 3 CDAI measurements in the 
12-month period prior to the b/tsDMARD 
initiation. If possible to retain enough patients to 
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required ≥ 4 CDAI measurements in the 12-
month period prior to the b/tsDMARD initiation. 
 
To ensure sufficient medical history information 
and past b/tsDMARDs usage history, at least 12 
months of enrollment in the database prior to the 
study treatment initiation will be required. All 
history information prior to 12 months will also 
be utilized. 
 
7.4.2 Exclusion Criteria 
 
Table 2 shows the exclusion criteria that will be used prospectively in the PrismRA arm and the 
best approximation for the selection of comparable patients in the observational external control 
arm. 
 
 
Table 2. Exclusion criteria by study arm 
 
PrismRA arm 
External control arm 
1 Patient has any non-study limitation precluding patient 
receipt of the PrismRA test (e.g., financial, or 
logistical limitations). 
  
The assumption will be made that patients 
who used b/tsDMARDs did not have such 
limitations that would have prevented the 
potential receipt of the PrismRA test had it 
been offered. 
2 Concurrent treatment with an investigational product 
or use of an investigational product less than 4 weeks 
prior to Visit 1. 
  
This criterion is not replicable with real 
world dispensing data and will not be used. 
3 Patient cannot have participated in an observational 
study at least 4 weeks prior to Visit 1. 
  
This criterion is not replicable in real-
world data and will not be used. 
4 The use of RA therapies outside of FDA-approved 
indication. 
  
This criterion is not replicable with real-
world dispensing data and will not be used. 

 
 
 
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5 Patient has been previously exposed to any non-TNFi 
b/tsDMARDs (FDA approved or experimental). 
 
Patients who have been previously exposed 
to any non-TNFi b/tsDMARDs any time 
during their history prior to the study 
treatment initiation will be excluded. 
 
The list of non-TNFi b/tsDMARDs 
approved for RA includes the following: 
• 
IL-6i (tocilizumab, sarilumab) 
• 
IL-1i (anakinra) 
• 
T-cell co-stimulation inhibitor 
(abatacept) 
• 
B-cell depletion agent (rituximab) 
• 
JAKi (tofacitinib, baricitinib, 
upadacitinib) 
 
The list of non-TNFi b/tsDMARDs not 
currently approved for RA includes the 
following: 
• 
IL-23i (guselkumab, risankizumab, 
tildrakizumab, ustekinumab [IL-12/IL-
23i]) 
• 
IL-17i (secukinumab, ixekizumab, 
brodalumab) 
6 Women who are known to be pregnant or breast-
feeding or plan to get pregnant during the study. 
Patients who have relevant pregnancy-
related codes in the past 12 months or 
during the 24-week follow-up will be 
excluded. 
 
7 Patient is currently receiving systemic antimicrobial 
treatment for viral, bacterial, fungal, or parasitic 
infection at the time of Visit 1. 
 
Patients who received antimicrobial 
medications in the 30-day period prior to 
the b/tsDMARD initiation will be 
excluded. 
 

 
 
 
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8 Patient has any active, chronic, or recurrent invasive 
infection (e.g., listeriosis and histoplasmosis) and/or a 
viral infection, that based on the Investigator’s clinical 
assessment, makes the patient an unsuitable candidate 
for the study. This includes hepatitis B virus (HBV) or 
hepatitis C virus (HCV), recurrent or disseminated 
(even a single episode) herpes zoster, disseminated 
(even a single episode) herpes simplex, or human 
immunodeficiency virus (HIV). 
  
Patients with the relevant diagnostic codes 
for chronic, or recurrent invasive infections 
any time prior to the study treatment 
initiation. 
 
This includes listeriosis, histoplasmosis, 
coccidioidomycosis, tuberculosis, non-
tuberculosis mycobacterial infections, 
cryptococcosis, pneumocystis pneumonia, 
toxoplasmosis, HBV, HCV, varicella 
zoster virus (VZV), herpes simplex virus 
(HSV), HIV. 
 
9 Patients with malignancy except non-melanoma skin 
cancer, localized prostate cancer treated with curative 
intent with no evidence of progression, low risk or 
very low risk (per standard guidelines) localized 
prostate cancer under surveillance/watchful waiting 
(without intent to treat), or carcinoma in situ of any 
type (complete resected). 
 
Patients with cancer diagnostic codes any 
time prior to the study treatment initiation 
will be excluded. This includes all 
malignancies except non-melanoma skin 
cancer. 
 
Allowing for localized and cured cancers is 
not replicable in real-world data and will 
not be attempted. 
 
10 Patients who are unable to understand the protocol and 
unable to provide informed consent. 
  
This criterion is not replicable in real-
world data and will not be used. 
11 Patients who are not indicated for PrismRA.  
  
This criterion is not replicable in real-
world data and will not be used. 
 
The assumption will be made that the 
careful replication of the above inclusion 
and exclusion criteria will ensure a 
comparable indication for PrismRA in the 
external control arm. 
 
12 This point does not apply to the PrismRA arm. 
Patients will be excluded if they have been 
cared for by rheumatologists who have 
participated in the PrismRA arm any time 
in the past to avoid including patients using 
PrismRA. 
 

 
 
 
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8 Study Procedures 
8.1 Pre-Screening 
PrismRA arm: 
Prior to Visit 1, potential patient charts may be reviewed to determine eligibility for the study.  
At the discretion of the Investigator, pre-screening lab tests (i.e., Complete Blood Count (CBC), 
Clinical Metabolic Panel (CMP), Tuberculosis (TB), and/or C-reactive Protein (CRP)) may be 
ordered and analyzed per standard of care if the patient has not already received these lab tests 
within 3 months of the planned study Visit 1. 
External control arm: 
The entirety of data for each patient (no less than 12 months) prior to the study treatment 
initiation will be used to assess their medical history and past medication use and to determine 
their eligibility (see above). For variables required to be up to date at the time of the study 
treatment initiation, the most recent value within the 3-month period prior to the study treatment 
initiation will be used, unless otherwise stated (see Table 1, Table 2). 
 
8.2 Screening and Enrollment 
PrismRA arm: 
At Visit 1, patients will complete the informed consent process. A written, signed informed consent 
form (ICF) must be obtained prior to the recording or collection of any data under this protocol. 
Upon signing the ICF, the patient will be considered enrolled into the study.  
At the discretion of the Investigator, patients will also be asked to review and sign a medical 
records release form providing access to their medical records outside of the study. Sponsor or 
Sponsor designees may access patients’ medical records upon study completion for only those 
patients that provide proper authorization.  
Following patient consent, each patient will be assigned a unique study identification number that 
will be used to track their de-identified data throughout their participation in the study. 
 
External control arm: 
Screening/enrollment activities are not applicable for the external control arm of patients 
identified from real-world data.    
 
8.3 Screen Failures 
PrismRA arm: 
Screen failures are defined as those patients who consent to participate in the clinical study but 
did not meet one or more criteria for participation in the study. 
 
External control arm: 
Non-initiators of b/tsDMARDs are considered screen failures and will not be in the analysis 
dataset. 

 
 
 
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8.4 Summary of Visits and Assessments  
PrismRA arm: 
Data will be collected at Screening/Baseline, Study Treatment Initiation (2–6 weeks after, and 
then at follow up visits approximately 12 weeks and 24 weeks after Study Treatment Initiation. 
The allowable time windows are explained in Section 8.5. 
 
External control arm: 
Data from clinical encounters over time will be used to provide information for (1) the baseline 
period (for CDAI assessment), (2) study treatment initiation time point; (3) the 12-week follow-
up period; and (4) the 24-week follow-up period. The allowable time windows are explained in 
Section 8.5. 
 
8.5 Schedule of Visits 
 
 
PrismRA arm: 
The timing for the follow-up visits (visits 3 and 4) should be projected based on the date of Study 
Treatment Initiation (index date).  
 
External control arm: 
The date of study treatment initiation constitutes the index date for the beginning of the follow-
up. The 3-month period prior to the index date will be used to ascertain the baseline CDAI. The 
12-week follow-up will be defined as the clinical encounter closest to the 12-week time point 
within the 12 (± 4) week visit window. The 24-week follow-up will be defined the visit closest to 
the 24-week time point within the 24 (± 4) week visit window. Depending on feasibility, we will 
Baseline CDAI 
most recent 
within 3 months 
of index date
12 (± 4) 
week 
CDAI 
24 (± 4) 
week 
CDAI 
External 
Control 
Arm
PrismRA
Arm
12 (± 2) 
week 
CDAI 
24 (± 2) 
week 
CDAI 
Baseline CDAI 
2-6 weeks prior 
to index date
Index date
Study 
b/tsDMARD
initiation
Visit 1
Visit 2
Visit 3
Visit 4
Visit 1
Visit 2
Visit 3
Visit 4

 
 
 
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attempt follow-up windows, such as ± 6 week window, ± 3 week window, and ± 2 week 
window. Sensitivity analyses with different follow-up windows will be conducted as needed. 
 
 

 
 
 
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8.6 Schedule of Assessments 
PrismRA arm: 
 
Procedure 
Visit 1 
(Screening/ 
Baseline) 
Visit 2 
(Study 
Treatment 
Initiation)7 
Visit 3 
(12 Week 
Follow-up) 
Visit 4 
(24 Week 
Follow-up) 
Visit Windows 
N/A 
2-6 weeks 
±2 weeks 
±2 weeks 
Informed Consent  
X 
 
 
 
Medical Records Release Form 
X 
 
 
 
Eligibility Criteria 
X 
 
 
 
RA Medical History 
X 
 
 
 
Smoking8 
 
 
 
X 
Comorbidities8 
 
 
 
X 
Weight 
X 
 
X 
X 
28 Joint-Count for Tenderness & Swelling 
X 
 
X 
X 
PrismRA1 
X 
 
 
 
CRP2 
X 
 
X 
X 
RF3 
 
 
 
 
Vectra DA3 
 
 
 
 
TB Test4 
 
 
 
 
Urine Pregnancy Test5 
 
 
 
 
Physician Global Assessment of Disease Activity 
X 
 
X 
X 
Patient Global Assessment of Pain 
X 
 
X 
X 
Patient Global Assessment of Disease Activity 
X 
 
X 
X 
Health Assessment Questionnaire 
X 
 
X 
X 
RAPID3 Assessment 
X 
 
X 
X 
Imaging6 
 
 
 
 
Targeted Therapy Questionnaire 
X 
X 
 
 
RX Adherence Check 
 
 
X 
X 
Initiation or Change of Targeted Therapy 
 
X 
 
 
Current RA Medications 
X 
X 
X 
X 
Socioeconomic Status8 
 
 
 
X 
Abbreviations: CRP (C-Reactive Protein), N/A (Not Applicable), RA (Rheumatoid Arthritis), RF (rheumatoid factor), and RX 
(Treatment). 
Note: At the discretion of the Investigator, pre-screening standard of care lab tests (e.g., CBC, CMP, and/or CRP) may be ordered 
if patient does not have lab tests within 3 months of Visit 1. 
1 PrismRA results will be provided to the Investigator based on the patient’s assigned treatment selection arm.  Investigators will 
receive the test results only for those patients in the informed treatment selection arm.  
2 Performed via standard lab practices utilizing the same local lab. Visit 1 results can be from a test within 3 months prior to Visit 
1. 
3 If available, results can be provided from patient’s medical records. 
4 If required by the Investigator, test can either be QuantiFERON Gold TB Test, local PPD TB test, or T-Spot. 
5 If required by the Investigator, a urine pregnancy test for child-bearing potential females should be completed. 

 
 
 
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6 If available, results for imaging (e.g., X-rays, ultrasound, magnetic resonance imaging, or total sharp score) to be pulled from 
patient’s medical records. 
7 PrismRA results must be received and reviewed prior to study treatment initiation for the PrismRA arm only. 
8 Smoking, comorbidities, and socioeconomic status information collected at Visit 4 reflects patient’s status at Baseline. 
 
External control arm: 
No prospective data collection schedule is enforced, and the data collection is based on routine 
clinical encounters. Existing data will be mapped from these routine clinical encounters in the 
following manner. 
 
Data Element 
Baseline 
Study 
Treatment 
Initiation 
12 Week 
Follow-up 
Visit 4 
(24 Week 
Follow-up) 
Visit Windows 
3 months 
(Precise index 
date) 
±4 weeks 
±4 weeks 
Informed Consent  
X 
 
 
 
Medical Records Release Form 
X 
 
 
 
Eligibility Criteria 
X 
 
 
 
RA Medical History 
X 
 
 
 
Smoking 
X 
 
 
 
Comorbidities 
X 
 
 
 
Weight 
X 
 
X 
X 
28 Joint-Count for Tenderness & Swelling 
X 
 
X 
X 
PrismRA1 
N/A 
 
 
 
CRP 
X 
 
X 
X 
RF 
X 
 
 
 
Vectra DA 
N/A 
 
 
 
TB Test 
N/A 
 
 
 
Urine Pregnancy Test 
N/A 
 
 
 
Physician Global Assessment of Disease Activity 
X 
 
X 
X 
Patient Global Assessment of Pain 
X 
 
X 
X 
Patient Global Assessment of Disease Activity 
X 
 
X 
X 
Health Assessment Questionnaire 
X 
 
X 
X 
RAPID3 Assessment 
X 
 
X 
X 
Imaging6 
N/A 
 
 
 
Targeted Therapy Questionnaire 
N/A 
 
 
 
RX Adherence Check (defined as continuation of the 
study treatment) 
 
 
X 
X 
Initiation or Change of Targeted Therapy 
 
N/A 
 
 
Current RA Medications 
X 
 
X 
X 
Socioeconomic Status1 
X 
 
 
 
Abbreviations: CRP (C-Reactive Protein), N/A (Not Applicable), RA (Rheumatoid Arthritis), RF (rheumatoid factor), and RX 
(Treatment). 
1 Socioeconomic status information will be available for a subset of patients. 
 

 
 
 
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8.7 Specimen Collection 
PrismRA arm: 
Blood will be collected at Visits 1, 3, and 4. Blood will not be collected at Visit 2. 
Blood will be collected in two 2.5 mL PAXgene tubes and one 8-10 mL serum separator tube for 
a total of 15 mL at Visit 1. Blood will be collected using the PrismRA sample collection kit at 
Visit 1 and processed according to the study sample collection process. Blood for the CRP test 
will be collected at Visits 1, 3, and 4 utilizing the same local lab and processed per standard lab 
practices.   
Anticipated volume of blood to be drawn per patient over the scheduled study visits should not 
exceed 45 mL. If the initial blood draw in Visit 1 fails sample quality assessments, a patient may 
have an unscheduled study visit performed for an additional blood draw prior to Visit 2. 
External control arm: 
No specimen collection schedule is enforced, and the specimen collection is based on routine 
clinical encounters. OM1 does not handle specimens and utilizes the laboratory results only. 
 
8.8 Study Treatment 
PrismRA arm: 
Patients are to initiate a b/tsDMARD or change to a study-indicated b/tsDMARD per clinical 
guidance of the Investigator on Visit 2. 
 
External control arm: 
b/tsDMARDs initiated by the treating physician according to the standard of care will be deemed 
as the study treatment. The study treatment can include the very first b/tsDMARD (new 
initiation) or subsequent b/tsDMARD (switch). 
 
8.8.1 Randomization 
No randomization will be performed for this study. 
 
8.8.2 Stratification 
There will be no stratification for this study. 
 
8.8.3 Therapy, Dose, Modes of Administration 
PrismRA arm: 
• Dosage and selection of b/tsDMARD are at the Investigator’s discretion but should be 
within the FDA approved label. 
• Dose adjustments for a particular b/tsDMARD will be permitted only in accordance with 
the FDA approved label. Changes should be documented in the patient’s medical records. 
 
External control arm: 

 
 
 
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The selection and the initial dosage and dose adjustments are at the discretion of the treating 
physician and are assumed to be compatible with FDA approval. 
 
8.8.4 Duration of Follow-up for Outcome Assessment 
• 
24 weeks from the index date, defined as the date of b/tsDMARDs initiation (See Section 
8.5 for allowable time windows) 
 
8.8.5 Medication Expenses and Reimbursement (PrismRA arm only) 
• The Sponsor will not cover any b/tsDMARD medication costs associated with this study. 
• Patients may be reimbursed for their time at the discretion of the Investigator.  
 
8.9 Data Collection 
PrismRA arm: 
Patient data will be collected from clinical assessments, medical records, imaging, laboratory 
results, and surveys at screening/baseline, treatment initiation and follow-up visits and entered in 
the study database. 
 
If a completed medical records release form is on file, comprehensive demographic, medical, and 
health information (if available) may be directly collected from the patient’s electronic medical 
records by the Sponsor. Electronic Medical Records (EMR) data may be obtained indefinitely 
following a patient’s enrollment unless the patient withdraws authorization.  
 
Data from the PrismRA (Visit 1) samples will be stored at Scipher Medicine’s Clinical 
Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists 
(CAP)-accredited laboratory. 
 
External control arm: 
In the external control arm, the existing data in OM1’s PremiOM RA will be utilized. No new 
data collection will be performed. 
 
8.10 Patient Follow-up 
PrismRA arm: 
In order to reduce the loss of patients to follow-up, all patients will be asked for their personal 
contact information and an alternate person’s contact information. Patients may be directly 
contacted by the Investigator or Sponsor/designee in order to support study follow-up. The 
designated alternate contact person may also be directly contacted in the event the patient cannot 
be reached. 
 
For patients who are lost to follow-up, Investigator or Sponsor/designee will search available 
health status databases to determine vital status and cause of death in case of mortality. 
 
External control arm: 

 
 
 
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To ensure the availability of sufficient quality of data, at least one CDAI measurement during the 
baseline 3-month period prior to the index date (initiation of b/tsDMARDs) will be required. As 
needed, we will further require CDAI during the follow-up. 
 
8.11 Patient Withdrawal/Completion 
PrismRA arm: 
Patients may withdraw from the study at any time without prejudice to their care.   
The Investigator and/or the Sponsor may withdraw patients at any time who violate the study 
protocol or, to protect the subject for safety or administrative reasons at any time. It will be 
documented whether or not each patient completes the determined follow-up visits. Changes to 
the study treatment during follow-up as indicated by clinical practice does not constitute a 
protocol violation or withdrawal. 
 
Early withdrawals will include, but are not limited to, those patients who consent to participate in 
the clinical study but fail to initiate a b/tsDMARD at Visit 2 within 6 weeks of Visit 1. 
 
 
External control arm: 
As existing data from routine clinical care will be utilized, this point does not apply. 
 
9 Safety Assessments 
9.1 Introduction to Safety Assessments 
PrismRA arm: 
There are no investigational therapies being evaluated per the protocol. For patients in the 
informed treatment selection arm, Investigators will receive the PrismRA test results and use the 
results to inform their treatment decision. PrismRA was developed and its performance 
characteristics determined by Scipher Medicine. The laboratory is certified under CLIA and 
accredited under CAP. This commercially available test is used for clinical purposes. It should 
not be regarded as investigational, or for research. The Investigator is expected to follow all 
aspects of the prescribing information when administering a pharmaceutical therapy in the course 
of the treatment of patients included in this study. 
 
External control arm: 
Data arise from routine clinical practice and are not subject to study-specific safety assessment. 
 
9.2 Anticipated and Unanticipated Adverse Device Effects  
PrismRA arm: 
PrismRA is not expected to result in either anticipated or unanticipated adverse device effects 
(UADE) as it involves the analysis of ex-vivo blood samples from the participating patients.  
 
This study does include a potential source of harm to the patient as a result of the venipuncture 
procedure, unrelated to the study device: 

 
 
 
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• Faintness, inflammation of the vein, bruising, temporary discomfort, and bleeding at the 
site of puncture may occur.  
• Infection may also occur, though rare. 
 
External control arm: 
Data arise from routine clinical practice and do not involve the use of the PrismRA test. Thus, no 
study-relevant adverse device effect exists. 
 
10 Statistical Considerations 
Data collected throughout this study will be analyzed by Sponsor or its designee.  
10.1 Sample size 
The study is powered to detect a difference of 10% in the proportion of patients with 
improvement in CDAI from baseline to Week 24 by at least MID as defined in Section 7.1 
between the PrismRA arm and the external control arm. Results are shown in Table 3. It is 
estimated that the attrition rate at Week 24 (defined as the proportion of patients with missing 
CDAI scores at Week 24 for any reason) can be up to 45% in the PrismRA arm and up to 50% in 
the external control arm. The sample sizes below have been inflated accordingly to account for 
the patient attrition mentioned above.   
 
With a sample size of 600 in the trial arm and 1,500 in the external control arm, the study has  
88% power to establish the superiority of the PrismRA intervention as compared to the standard 
of care by detecting a difference of 10% between the two study arms based on Fisher’s exact test 
of independent proportions assuming the proportion of patients with improvement in CDAI by 
MID are 40% and 30% in the PrismRA arm and the external control arm, respectively. 
 
Table 3. Study power for comparing proportion of patients with improvement in CDAI 
from baseline by at least MID between the two study arms 
Sample 
size in the 
trial arm 
before 
attrition 
Sample in 
the 
external 
control 
arm 
before 
attrition 
Proportion of 
patients in the 
PrismRA arm 
with MID 
improvement in 
CDAI 
Proportion of 
patients in the 
external control 
arm with MID 
improvement in 
CDAI 
Study 
power 
Alpha 
(two-
sided) 
600 
1,000 
0.45 
0.35 
80% 
0.05 
600 
1,000 
0.40 
0.30 
82% 
0.05 
600 
1,000 
0.35 
0.25 
85% 
0.05 
600 
1,500 
0.45 
0.35 
86% 
0.05 
600 
1,500 
0.40 
0.30 
88% 
0.05 
600 
1,500 
0.35 
0.25 
90% 
0.05 
600 
2,000 
0.45 
0.35 
88% 
0.05 

 
 
 
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600 
2,000 
0.40 
0.30 
90% 
0.05 
600 
2,000 
0.35 
0.25 
92% 
0.05 
 
The sample size calculation was performed with SAS (version 9.4, Cary, NC). 
 
10.2 Planned Interim Analysis of the PrismRA Arm 
Data will be assessed by the Scipher Medicine team in one interim analysis when 50% of 
enrollees in the PrismRA arm have completed the treatment initiation visit. Refer to the study’s 
SAP for additional details. 
 
10.3 Baseline Analysis of the External Control Arm 
The OM1 team will identify an eligible pool of patients for an external control arm in the OM1’s 
PremiOM RA dataset. 
 
The baseline study data from the PrismRA arm will be provided by the Scipher Medicine team in 
a format ready for analysis (fully quality controlled), with a corresponding dataset specification 
document to help the OM1 team understand the data. 
 
From the pool of the study-eligible RA patients in the OM1 PremiOM RA dataset, the external 
control patients will be selected based on propensity scores. Analytic approaches which adjust 
for differences in patient baseline characteristics will be used. These approaches include but are 
not limited to propensity score weighting, matching and covariate adjustment in a multivariable 
regression model. 
 
Baseline covariates including the following will be considered (defined in a 6-month window 
prior to the index date unless otherwise specified elsewhere). 
 
Domain 
Variables 
Patient Characteristics 
• 
Age (calculated from birth year) 
• 
Sex 
• 
Race/Ethnicity 
• 
Geography 
• 
Body mass index 
Lifestyle 
• 
Smoking (current, former, or never 
smoker) 
Comorbidities (based on at least two 
diagnostic codes at least 30 days apart in the 
external control arm; based on an additional 
questionnaire in the PrismRA arm.) 
• 
Lung disease 
• 
Myocardial infarction 
• 
Other cardiovascular 
• 
Stroke 
• 
Hypertension 
• 
Fractures spine, hip, or leg 
• 
Depression 
• 
Diabetes mellitus 

 
 
 
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• 
Ulcer or stomach problem 
• 
Fibromyalgia 
The Rheumatic Disease Comorbidity Index 
(RDCI) will be derived. 
RA Related 
• 
Duration of RA (Defined as the number 
of days between the date of the first RA 
diagnosis code and the index date for the 
external control arm) 
• 
Seropositivity (rheumatoid factor or anti-
citrullinated peptide antibody) 
• 
CDAI at baseline 
• 
Previous use of TNFi (yes, no) 
Concurrent RA Medications 
• 
Methotrexate 
• 
Folic acid 
• 
Non-methotrexate major csDMARDs 
(Sulfasalazine, Leflunomide, 
Hydroxychloroquine) 
• 
Glucocorticoids (with prednisone 
equivalent dose) 
 
 
 
 
 
The choice of TNFi vs. non-TNFi b/tsDMARDs as the study treatment will be excluded from the 
list of potential propensity score variables, as this variable is temporally subsequent to the 
study’s exposure variable (use or non-use of PrismRA in the trial arm and external control arm, 
respectively) and is considered a mediator of the potential benefit of PrismRA. 
 
The baseline characteristics of patients will be compared across the PrismRA arm and the 
external control arm both before and after the propensity score modelling procedure in a table. In 
general, each continuous variable will be reported as mean, standard deviation (SD) or median, 
interquartile range (IQR), and range where appropriate. Each categorical variable will be 
summarized as a number and proportion. The baseline characteristics after propensity score 
modeling will be examined for improved covariate balance via the absolute standardized mean 
metric for each covariate. 
 
Complete details regarding the planned analyses are available in the study SAP. 
 
10.4 Planned Outcome Analysis 
The previously stated outcome measures will be compared across the PrismRA arm and the 
external control arm after propensity score modelling. For all outcome measures, point estimates 
as well as two-sided 95% confidence intervals (CIs) will be provided. Hypothesis testing will be 

 
 
 
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two-sided with an alpha level of 5%. For proportion outcome measures, Pearson’s χ2 test will be 
utilized. For continuous outcome measures, unpaired t-test will be used. 
 
Refer to the study’s SAP for additional details. 
 
10.5 Missing Data Handling 
Missing data will be handled with two approaches: (1) minimizing the chance of missing data in 
the study design and conduct stages, and (2) handling missing data with statistical methods in the 
analysis phase. 
 
The following measures will be taken to reduce missing data in the analysis datasets. 
 
PrismRA arm: 
Missing data will be minimized through rigorous conduct of data collection as described in 
Section 8.9. See below for the handling of missing follow-up data. 
 
External control arm: 
At least one observed CDAI in the 3-month period prior to the index date (b/tsDMARD 
initiation) will be required to ensure patients are selected from practices where CDAI are 
recorded as a part of routine care.  
 
The following statistical methods will be considered in handling missing data in the analyses. 
 
• 
For outcome measures, the appropriate methods depend on the magnitude of missing 
data, and whether data are assumed to be missing at random. This will be evaluated prior 
to the final analysis and will be evaluated for the PrismRA arm and the external control 
arm separately. Considerations will be given to multiple imputation, estimating the CDAI 
outcome (whether MID was achieved at Week 24) based on previous outcome measures 
and treatment status, and complete case analyses. A sensitivity analysis will be conducted 
to assess the robustness of the analysis results. Details will be provided in the SAP. 
10.6 Data Reporting 
10.6.1 Interim Analyses and Reporting 
A single interim analysis will be conducted at the time that 50% of PrismRA arm patients (the 
first 300 patients enrolled) have completed Visit 2 or have dropped out of the study.  All data 
available in the PrismRA arm at the time of the interim analysis will be included, but 
effectiveness of PrismRA will not be evaluated to protect the integrity of the study. Instead, the 
interim analysis will be restricted to baseline characteristics and data completeness analyses. 
 
10.6.2 Final Analyses and Reporting 
A final study report will be generated after all data collection is complete. The final report will 
encompass all planned analyses, including a description of the complete study population and 
study results, as described in the SAP. 

 
 
 
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11 Limitations 
11.1 Data Recency 
An ideal observational external control arm is fully contemporaneous to the single arm trial with 
prospective real-world data collection specifically tailored to the corresponding PrismRA arm14.  
The approach is based on retrospective real-world data collection (secondary use of routinely 
collected data). Due to the need to have enough patients for the propensity score process, the 
external control arm may have a mixture of contemporaneous external control patients (observed 
during the PrismRA arm study period) and historical external control patients (observed before 
the PrismRA arm study period). In the SOC for RA, an increasing uptake of late-comer 
b/tsDMARDs has been reported for the 2001–2015 time period 15. The market uptake trend may 
have been less dramatic in the more recent time period due to the paucity of new FDA approvals 
(last FDA approval: upadacitinib in 2019) and market saturation. However, the recent 
announcement (September 2021) by the FDA of a boxed warning for JAK inhibitors’ regarding 
cardiovascular safety may have had an influence. In the current study, the historical external 
control patients will be limited to those who initiated their index b/tsDMARDs with the 1-3 year 
period prior to the trial enrollment (March 2022; minimum years that allows sufficient 
propensity score model patients). This approach should minimize the potential impact of a 
secular trend in the SOC (particularly the increasing uptake of non-TNFi b/tsDMARDs) while 
allowing for sufficient power. 
 
11.2 RA Patient Identification 
External control arm: 
The identification of RA patients in the external control arm is based on the claims algorithm 
implemented in OM1’s PremiOM RA dataset rather than the 2010 ACR/EULAR classification 
criteria. The algorithm uses RA diagnostic codes as well as DMARDs use. The combination of 
RA diagnostic code and DMARD use has a high positive predictive value (86.2%-88.9% against 
physician diagnosis gold standard) 16 and is a well-accepted standard in the real-world data 
studies of RA. The OM1 claims algorithm likely has a higher positive predictive value as it 
incorporates further exclusion of patients with non-RA diagnoses for which DMARDs are 
indicated. 
 
12 Data Handling and Record Keeping (Study Management) 
PrismRA arm: 
The design and conduct of the PrismRA arm will be governed by Scipher Medicine and its 
designees. OM1 will provide input to ensure the smooth execution of the subsequent analyses. 
 
External control arm: 
The design and execution of the observational external control arm and subsequent analyses will 
be performed by OM1, with the guidance, input, review, and approval of the Scipher Medicine 

 
 
 
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team. To ensure the quality and integrity of research, this study will be conducted under the 
Guidelines for Good Pharmacoepidemiology Practices (GPP) issued by the International Society 
for Pharmacoepidemiology (ISPE), the principles outlined in the Belmont Report (Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research), and any applicable 
national guidelines. 
 
12.1  Study Database 
PrismRA arm: 
Data will be collected into the study database through a secure, electronic database capture 
(EDC) system or an electronic data transfer via an encrypted secure sockets layer protocol to the 
Scipher Medicine data lake.  
Electronic case report forms will be maintained in the EDC, and all relevant observations and 
data related to the protocol-defined assessments will be recorded. This will include, at minimum, 
demographics, medical history, physical examinations, laboratory results, clinical assessments, 
treatment information, and patient reported outcomes.  
Prior to recording data in the paper CRF, Investigators and site staff will be trained on how to 
accurately capture data. Trained and qualified Investigators and site staff will be responsible for 
recording data in the paper CRFs. 
The study database will be password protected and access will be provided only to trained and 
authorized personnel. Data collected into the study database may include protected health 
information (PHI). This PHI will not be shared beyond the Sponsor/designee or site without 
specific institutional review board (IRB) approval and additional patient consent.  
 
External control arm: 
An analytic dataset of eligible RA patients, built upon the underlying OM1 enterprise data 
warehouse, will be created for this study. The OM1 data warehouse is built on OM1 Origin 
Plus™, a scalable cloud computing platform with high availability and dependability. The 
analytic dataset will contain data ingested from multiple sources in multiple formats and will 
serve as a repository of centralized, standardized, normalized, and integrated data from the 
different sources. Where necessary and possible, data from disparate sources will be linked with 
other data that are attributed to a common patient creating a longitudinal record. Data will be 
standardized and normalized as necessary, for example, classifications of text documents such as 
lab reports and pathology reports. A detailed technical data management plan describing 
processes for transferring data, managing data quality, and maintaining data security will be 
developed and implemented for the study. 
 
12.2 Inspection of Records 
PrismRA arm: 
Sponsor or its designee will be allowed to conduct site visits either remotely or at the 
Investigator’s clinical research facilities for the purpose of monitoring any aspect of the study, as 

 
 
 
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applicable. The Investigator agrees to allow the Sponsor or its designee to inspect the facilities, 
patient medical records, source documents, and other records relative to study conduct. Source 
documents containing PHI will be protected and transferred to the Sponsor or its designee via a 
secure, HIPAA compliant portal. Study records containing patient health information will be 
maintained in a confidential manner. 
 
12.3 Retention of Records 
PrismRA arm: 
All primary data collected as a result of the original observations and activities of the study and 
that are necessary for the reconstruction and evaluation of any study report will be retained in a 
secure archive at the study site for a period not less than 6 years after the last approval of a 
marketing application in an International Council for Harmonization (ICH) region, and until 
there are no pending or contemplated marketing applications in an ICH region, or until at least 6 
years have lapsed since the formal discontinuation of the clinical development of the 
investigational product. All country and region-specific requirements that may be more stringent 
than the 6 years included in ICH shall be followed. 
The site will maintain an Investigator Site File (ISF), which will be maintained at the study site 
and in accordance with local and Federal regulations, as applicable. The site must keep this ISF 
current and available for review by the Sponsor, IRB, and/or regulatory bodies. 
 
External control arm: 
Based on recommendations from International Society for Pharmacoepidemiology Guidelines 
for GPP, all analysis datasets used for the final analysis will be archived for at least five years 
after the delivery of the final tables to Scipher Medicine unless specific requests are made during 
the report process. 
 
12.4 Confidentiality (PrismRA arm Only) 
12.4.1 Confidentiality of Records  
PrismRA arm: 
All study sites, laboratories, and parties supporting this study must comply with HIPAA, where 
applicable. All data and records generated throughout this study will be kept confidential in 
accordance with local and Federal policies and HIPAA on patient privacy.   
At consent, personal identifying information, including patient name, birth date, and contact 
information, will be collected and stored on a secure and HIPAA-compliant research database.  
Following consent, each patient will be assigned a unique study identification number that will 
be used to track their de-identified data.  
Records that may have patient identifying information will be kept confidential in accordance 
with applicable guidelines, regulations, and laws.  

 
 
 
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External control arm: 
The study utilizes a de-identification and secure patient key software tool to create statistically 
de-identified data sets and to create de-identified keys for patients. The tool generates tokens 
based on a patient’s primary information (first name, last name, date of birth, and gender) and all 
study analysis performed will use the statistically de-identified data. Only a few limited data set 
data elements, including dates of service and date of death, will be part of the study data set. All 
parties will ensure protection of patient personal data and will not include patient identifiable 
information on any study forms, reports, publications, or in any other disclosures, except where 
required by law. 
 
The database is housed on a secure cloud computing platform on which all OM1 technical 
operations, data processing, and storage are conducted. The global infrastructure is designed and 
managed according to security best practices as well as a variety of security compliance 
standards making it one of the most secure computing infrastructures in the world. The system 
also meets the standards of the ICH E6 (R2) guideline regarding electronic study data handling 
and is available for audit upon request. Patient confidentiality will be strictly maintained. 
 
12.4.2 Review of Records 
Sponsor and/or its designee will review source documents (i.e., medical records, laboratory 
results) and data collected throughout the study. In addition, an auditor, IRB, FDA, or national or 
local regulatory authorities may access and review applicable source documents, records, and 
data. All patients will be notified of and consent to this possibility during the consenting process. 
 
12.4.3 Study results 
 If any results of the study are published, the patient’s identity will remain confidential. 
 
12.4.4 Future Use of Data or Specimens 
PrismRA arm: 
Data collected throughout the study and subsequently de-identified will be used for future 
research and/or distributed to other investigators for future research.  
PrismRA samples from patients processed at Scipher Medicine’s CLIA-certified CAP-accredited 
laboratory will also be de-identified and used for future research and/or distributed to other 
investigators for future research. Future research will include extracting and sequencing DNA 
isolated from the blood samples, in addition to the RNA that is extracted and sequenced for 
PrismRA. Future research may also include discovering novel biomarkers for disease diagnosis, 
monitoring, or progression as well as discovering new disease mechanisms, therapeutic targets, 
and therapies for autoimmune disorders.   

 
 
 
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De-identified data may be stored indefinitely, and de-identified specimens may be stored for up 
to 10 years following study completion. The de-identified data and specimens may be shared 
with researchers/institutions outside of Scipher without additional informed consent from the 
subject or the legally authorized representative. This could include for-profit companies. 
 
External control arm: 
Patients in the external control arm are from the OM1 PremiOM RA dataset, owned and 
maintained by OM1. OM1 PremiOM RA data may be used for analyses in the future per 
agreement. 
 
13 Ethics 
13.1  Ethics Review 
The protocol, ICF, and any advertisements must be approved or given a favorable opinion in 
writing by an IRB. The Investigator must submit written and dated verification of the IRB 
approval to Sponsor before he or she can enroll any patient into the study. 
The Sponsor/designee or Investigator will inform the IRB of any amendment to the protocol in 
accordance with local requirements. The protocol must be re-approved by the IRB upon receipt 
of amendments and annually, if required per local and IRB regulations. 
Initial IRB approval, and all materials approved by the IRB for this study including the patient 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
 
13.2 Ethical Conduct of the Study 
The Sponsor, Investigators, study staff and designees will conduct the study in accordance with 
the ethical principles that have their origin in the Declaration of Helsinki and are consistent with 
ICH, GCP, and other applicable local and federal laws, regulations, and guidelines. 
14 Quality Control 
14.1 Data Quality  
PrismRA arm: 
Site and data monitoring will occur in accordance with the clinical monitoring plan, if applicable. 
Data captured in the study database will be compared against the source data for completeness 
and accuracy. Discrepancies will be addressed and corrected, if required, by qualified site 
personnel.  

 
 
 
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eCRF data will also be routinely reviewed for timeliness, errors, accuracy, and omissions. Any 
data issues will be submitted to the site for further clarification. Qualified site personnel will 
address queries and correct data in the study database or paper source files. 
14.2 Protocol Deviations 
PrismRA arm: 
Study sites and databases will be evaluated for protocol deviations.  
At study completion, the number and type of protocol deviations will be analyzed by the study 
biostatistician to review the events by site to determine if the deviations could affect the integrity 
of the study data. The study biostatistician will report findings to the Sponsor.  
15 Protocol revision history 
Rev. # 
Effective Date 
Summary of Changes 
3.0 
20-Oct-2022 
Change to an external control arm design and sample 
size adjustment. 
2.0 
04-Feb-2022 
Change in study title, endpoints, clarification of study 
design, and general edits. 
1.0 
23-Jul-2021 
Initial Release  
 
 
 

 
 
 
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16 References 
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