Clinical trial NCT03247686
Conditions: Sjogren's Syndrome
Sponsor: Resolve Therapeutics
Start date: 2017-02-01; Completion date: 2019-08-01
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The present study will examine the role of circulating RNA complexed with autoantibodies and immune complexes and its role in activation of inflammatory pathways in patients with primary Sjogren's syndrome. The study will be conducted in a subset of Sjogren's patients who have elevated levels of autoantibodies and a pattern of elevated interferon-stimulated gene expression in blood cells. A number of biochemical and clinical parameters will be analyzed to determine the potential therapeutic utility of nuclease therapy in Sjogren's syndrome.

Detailed description:
This is a multi-center, double-blind, placebo-controlled study to evaluate the impact of 8 intravenous infusions of RSLV-132 in 28 patients with primary Sjogren's syndrome. Each of the subjects will be randomized 3:1 (active:placebo) and will receive 8 infusions of 10 mg/kg of RSLV-132 or placebo as follows on days:

• 1, 8, 15, 29, 43, 57, 71, and 85

Potential subjects will be screened to assess their eligibility to enter the study within 60 days prior to study entry (i.e., prior to Baseline visit). Following Baseline evaluations on Day 1, subjects will receive their first infusion of RSLV-132 or placebo. Subjects will return to the research unit for follow-up visits as described in Appendix A.

Dose selection rationale: The dose level was chosen based on safety and tolerability data from Protocol 132-02 (multiple ascending dose study in SLE patients). Additionally, in a 6-month toxicology study in cynomolgus monkeys, 50 mg/kg of RSLV-132 was administered by IV infusion weekly. No dose-limiting toxicity was noted, therefore the No Observed Adverse Effect Level is at least 50 mg/kg, providing at least a 5-fold safety margin for this study.

RSLV-132 shall be prepared for each subject from individual stock vials provided by Sponsor. Details of dilution, dose preparation, and administration instructions will be provided in the Study Drug Reference Guide. The dose for each individual shall be based on the subject's body weight.

Arms: arm 1: Placebo arm 2: Experimental drug
Interventions: intervention 1: RSLV-132 intervention 2: Placebo
Intervention descriptions: intervention 1: RNase Fc fusion protein intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
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Resolve Therapeutics, LLC Protocol 132-04 – Confidential  
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RSLV-132 
PROTOCOL 132-04 
 
 
A PHASE 2, DOUBLE-BLIND, PLACEBO- 
CONTROLLED STUDY OF RSLV-132 IN SUBJECTS 
WITH PRIMARY SJOGREN’S SYNDROME 
 
 
 
RESOLVE THERAPEUTICS, LLC 
721 1st Avenue North 
St. Petersburg, FL  33701 
 
 
 
 
 
 
 


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Protocol Title: 
A Phase 2, Double-Blind, Placebo-Controlled Study of 
RSLV-132 in Subjects with Primary Sjogren’s Syndrome 
 
Protocol Number: 
132-04 
 
 
Investigational Product: 
RSLV-132 
 
 
 
IND Number: 
117593 
 
 
Eudra-CT Number: 
 
2016-001586-87 
Current Version: 
4.0 
 
 
Prior Version: 
3.0 
04 August 2016 
 
 
Date of Publication: 
19 April 2017 
 
 
Sponsor: 
Resolve Therapeutics, LLC 
721 1st Ave. N. 
St. Petersburg, FL  33701 
(208) 727-7010 (Office Telephone No.) 
(727) 898-7218 (Office Facsimile No.) 
 
 
Sponsor Contact: 
(Authorized to Sign 
Protocol) 
James Posada, PhD 
721 1st Ave. N. 
St. Petersburg, FL  33701 
jp@resolvebio.com 
(208) 727-7010 (Cell) 
 
 
Medical Monitor 
Emergency Sponsor Contact 
Dan Burge, MD 
454 N. 34th Street 
Seattle, WA, 98103 
dan@burgeconsulting.com 
(425) 802-3359 (Cell) 
 
 
EU Legal Representative: 
Alan Boyd Associates 
Electra House, Crewe Business Park 
Crewe, CW1 6GL, United Kingdom 
 
Investigators: 
Multicenter Study: Investigator information on file at 
Resolve Therapeutics.  The Chief Investigator is Prof. Wan 
Fai Ng of Newcastle University, UK. 
 
Study Monitors: 
The study will be monitored by contract clinical research 
associates using Resolve Therapeutics operating procedures. 


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Clinical Laboratories: 
Laboratories involved in this study are listed on the 
delegation of responsibilities documentation. 
 
Sponsor Approval: 
 
 
 
 
 
 
James Posada, PhD 
Chief Executive Officer 
 
Date 
 
 
 
 
10May2017


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1 
  PROTOCOL SYNOPSIS 
1.1 Name of Sponsor  
Resolve Therapeutics, LLC 
 
1.2 Name of Investigational Product 
RSLV-132 
 
1.3 Number and Title of Study 
Protocol 132-04:  A Phase 2, Double-Blind, Placebo-Controlled Study of RSLV-132 in Subjects 
with Primary Sjogren’s Syndrome 
 
1.4 Phase of Development 
Phase 2 
 
1.5 Study Period 
Patient participation period: 60 days of screening followed by 12 weeks of treatment and 18 
weeks of follow-up (approximately 38 weeks total). 
 
Planned study conduct duration:  approximately 21 months total (from enrollment of first subject 
to completion of follow-up for last patient). 
 
1.6 Study Objectives 
The present study will examine the role of circulating RNA complexed with autoantibodies and 
immune complexes and its role in activation of inflammatory pathways in patients with primary 
Sjogren’s syndrome.  The study will be conducted in a subset of Sjogren’s patients who have 
elevated levels of SSA/Ro autoantibodies and a pattern of elevated interferon-stimulated gene 
expression in blood cells. Given the well-established inflammatory properties of RNA, RSLV-
132 will be administered to digest the circulating RNA bound to autoantibodies and thereby 
attenuate the chronic activation of multiple inflammatory pathways.  A number of biochemical 
and clinical parameters will be analyzed to determine the potential therapeutic utility of nuclease 
therapy in Sjogren’s syndrome.   
 
Primary Study Endpoint:  The primary endpoint of the study is to assess the following 
biochemical parameters in the active versus control groups comparing Baseline and Day 99: 
 
• changes in blood cell gene expression or serum protein levels indicative of reduced 
inflammation. 
 


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Secondary Study Endpoint:  The secondary endpoints of the study are to assess the 
following parameters in the active versus control groups comparing Baseline and Day 99: 
 
• safety and tolerability; 
• anti-Ro autoantibody levels; 
• total immunoglobulins; 
• complement levels (C3 & C4) 
• erythrocyte sedimentation rate (ESR) 
• minor salivary gland histopathology 
• minor salivary gland interferon-stimulated gene expression; 
• disease activity (ESSDAI or PGA, Schirmer’s test, stimulated and unstimulated salivary 
flow); 
• patient-reported outcomes as measured by the following: ESSPRI, FACIT, VAS, Profile 
of fatigue, EQ-5D-L, Fatigue VAS, and Neuropsychological analysis scales 
(Neuropsychological analysis to be performed only at Newcastle University); 
• Additional exploratory evaluations may be considered as driven by the evolving 
understanding of the mechanism of action, technical feasibility, and any other clinical or 
immunological information that may become available during the course of the clinical 
study. Note: Additional exploratory endpoints will be specified in a separate laboratory 
manual and will be reported separately to the main safety, tolerability and efficacy 
endpoints of the study. 
 
1.7 Study Design 
This is a multi-center, double-blind, placebo-controlled study to evaluate the impact of 8 
intravenous infusions of RSLV-132 in 28 patients with primary Sjogren’s syndrome. Each of the 
subjects will be randomized 3:1 (active:placebo) and will receive 8 infusions of 10 mg/kg of 
RSLV-132 or placebo as follows on days: 
 
• 1, 8, 15, 29, 43, 57, 71, and 85 
 
Potential subjects will be screened to assess their eligibility to enter the study within 60 days 
prior to study entry (i.e., prior to Baseline visit).  Following Baseline evaluations on Day 1, 
subjects will receive their first infusion of RSLV-132 or placebo.  Subjects will return to the 
research unit for follow-up visits as described in Appendix A.   
Dose selection rationale:  The dose level was chosen based on safety and tolerability data from 
Protocol 132-02 (multiple ascending dose study in SLE patients). Additionally, in a 6-month 
toxicology study in cynomolgus monkeys, 50 mg/kg of RSLV-132 was administered by IV 
infusion weekly. No dose-limiting toxicity was noted, therefore the No Observed Adverse Effect 
Level is at least 50 mg/kg, providing at least a 5-fold safety margin for this study.       
RSLV-132 shall be prepared for each subject from individual stock vials provided by Sponsor.  
Details of dilution, dose preparation, and administration instructions will be provided in the 


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Study Drug Reference Guide. The dose for each individual shall be based on the subject’s body 
weight. 
 
1.8 Inclusion Criteria  
Subjects who meet all of the following criteria may be included in the study: 
1. Meet 4 of the 6 criteria (must include histopathology or autoantibodies) of the 2002 
American-European Consensus Group (AECG) criteria for Primary Sjogren’s Syndrome. 
2. elevated levels of anti Ro-52 or anti Ro-60 antibodies (within laboratory positive range); 
3. positive interferon signature (whole blood cell interferon signature metric > -1); 
4. stable medications used to treat Sjogren’s syndrome for the 30 days prior to the Baseline 
visit; 
5. able to communicate and able to provide valid, written informed consent; 
6. ages 18 to 85 inclusive; 
7. minimum weight of 45 kg; 
8. Female participants shall be either of non-child-bearing potential (permanently sterilized by 
bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy), or menopausal (more 
than one year since last menstrual cycle and confirmed by blood FSH levels > 22 mIU/mL) 
OR practicing highly effective contraception (e.g., oral (but not including progestogen-only 
oral contraceptives), injectable, implantable or transdermal contraceptives, a non-hormonal 
intrauterine device [IUD] or an intrauterine hormone releasing system [IUS]) for at least 2 
months prior to dosing and until 125 days after the last dose.  In terms of sexual relations, 
female participants not practicing highly effective contraception as described above should 
abstain or only engage with male partners who are sterile or vasectomized.  Female 
participants of child-bearing potential will also be required to have a negative serum 
pregnancy test [ß-hCG] at Screening and negative pregnancy urine test at Baseline.  Female 
participants must agree not to donate eggs from the first dose until 125 days after the last 
dose.  
9. Male participants, who are not sterile or vasectomized, must agree to abstain or only engage 
with female partners who use highly effective contraception from the first dose until 125 
days after the last dose.  Male participants must also agree not to donate sperm from the first 
dose until 125 days after the last dose. 
 
1.9 Exclusion Criteria 
Any of the following will exclude potential subjects from the study: 
1. previously diagnosed with systemic lupus, systemic sclerosis, or inflammatory myopathy. 
2. use of hydroxychloroquine within 30 days of Baseline;  
3. use of cyclophosphamide within 180 days of Baseline; 
4. use of belimumab, abatacept, or TNF inhibitors within 90 days of Baseline; 


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5. use of rituximab within 6 months of Baseline (documentation of B-cell counts within the 
normal range for the reference laboratory is required for subjects within 1 year of rituximab 
usage). 
6. use of oral corticosteroids equivalent to prednisone dose of >10 mg/day within 30 days of 
Baseline; 
7. past head and neck radiation; 
8. current untreated lymphoma at Baseline; 
9. known IgG4-related disease 
10. graft versus host disease 
11. the presence of a clinically significant infection in the judgement of the Investigator within 
seven days prior to the receipt of the first dose of study drug; 
12. positive test for hepatitis B, C, or HIV at Screening; 
13. participation in another clinical study with receipt of an investigational product within 3 
months or 5 half- lives, of last administration (whichever is longer) from Baseline; 
14. positive pregnancy test at Screening or Baseline; 
15. female subjects currently pregnant or breast feeding at Baseline; 
16. inability or unwillingness to comply with protocol-specified procedures which, in the opinion 
of the Investigator, would make the subject unsuitable for study participation. 
 
1.10 Criteria for Evaluation 
• Biochemical measures: 
o gene expression profiling of blood cells 
o profiling of serum proteins 
o erythrocyte sedimentation rate (ESR) 
o anti Ro-52/Ro-60, C3, C4, and total immunoglobulins 
o minor salivary gland histopathology 
o minor salivary gland biochemical markers (IFN, B-cell subsets) 
o study drug concentration 
o DNA analysis 
o anti-RSLV-132 antibodies 
o serum RNase activity 
 
• Clinical measures:   
o ESSDAI 
o PGA 
o stimulated and unstimulated salivary flow 
o Schirmer’s test  
 
• Patient-Reported Outcomes:   
o ESSPRI 
o FACIT 
o Profile of fatigue 
o EQ-5D-L 


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o Fatigue VAS (01-100) 
o neuropsychological analysis of fatigue 
 
 
1.11 Evaluations by Day 
• Screening Procedures: 
o informed consent; 
o assess inclusion/exclusion criteria; 
o demographic data; 
o weight and height; 
o physical examination; 
o complete medical and medication history; 
o vital signs; 
o hepatitis B, C, and HIV antibody tests; 
o serum pregnancy test; 
o chem-21 (see Appendix B), CBC, and UA; 
o interferon-stimulated gene expression analysis (whole blood); 
o anti Ro-52/Ro-60 autoantibodies; 
o FSH (when required to confirm menopause in female subjects) 
 
 
• Baseline Procedures: 
o confirmation of inclusion/exclusion criteria; 
o physical examination; 
o adverse event baseline assessment; 
o interim medical and medication history; 
o vital signs; 
o measurement of disease activity (ESSDAI, PGA, Schirmer’s, stimulated and 
unstimulated salivary flow); 
o measurement of patient reported outcomes (ESSPRI, FACIT, Profile of fatigue, EQ-
5D-L, Fatigue VAS, Neuropsychological analysis); 
o optional minor salivary gland biopsy; 
o urine pregnancy test; 
o chem-21 (see Appendix B), CBC, and UA; 
o serum for study drug concentration and RNase activity; 
o serum for serum protein analysis; 
o whole blood for ESR 
o whole blood for DNA analysis; 
o whole blood for measurement of RNA gene expression; 
o serum for anti Ro-52/Ro-60, total immunoglobulins, C3, and C4; 
o serum for anti-RSLV-132 antibodies; 
o study drug administration. 
 
 


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Additional Procedures:   
The following procedures will be performed at various visits during the study.  A total of 9 post-
baseline visits will occur; once weekly for two weeks, then every two weeks for 14 weeks, plus 
one further visit 8 weeks after the last study drug administration.  There will then be two 
additional telephone contacts made to subjects at weeks 13 and 18 after the last dose, to monitor 
any potential late-emerging adverse events.  See section 13 and the schedule of events for the 
specific procedures and collection time points. 
• physical exam; 
• vital signs; 
• adverse event assessment; 
• medication history; 
• measurement of disease activity (ESSDAI, PGA, Schirmer’s test, stimulated and 
unstimulated salivary flow); 
• optional minor salivary gland biopsy; 
• measurement of patient reported outcomes (ESSPRI, FACIT, Profile of fatigue, EQ-5D-
L, Fatigue VAS, Neuropsychological analysis); 
• serum sample for study drug concentration and RNase activity; 
• serum for protein analysis; 
• whole blood for ESR 
• whole blood for DNA analysis; 
• whole blood for gene expression profile; 
• anti-Ro-52/Ro-60, C3, C4, total immunoglobulins 
• chem-21 (see Appendix B), CBC, and UA; 
• serum sample for assessment of antibodies to RSLV-132; 
• pregnancy test; 
• study drug administration. 
 


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2 TABLE OF CONTENTS  
1 
PROTOCOL SYNOPSIS .............................................................................................4 
1.1 
Name of Sponsor ..........................................................................................................4 
1.2 
Name of Investigational Product ..................................................................................4 
1.3 
Number and Title of Study ...........................................................................................4 
1.4 
Phase of Development ..................................................................................................4 
1.5 
Study Period..................................................................................................................4 
1.6 
Study Objectives ...........................................................................................................4 
1.7 
Study Design .................................................................................................................5 
1.8 
Inclusion Criteria ..........................................................................................................6 
1.9 
Exclusion Criteria .........................................................................................................6 
1.10 
Criteria for Evaluation ..................................................................................................7 
1.11 
Evaluations by Day .......................................................................................................8 
2 
TABLE OF CONTENTS ...........................................................................................10 
3 
BACKGROUND ........................................................................................................15 
3.1 
Primary Sjogren’s Syndrome and Immune Complexes ..............................................15 
3.2 
INVESTIGATIONAL AGENT..................................................................................15 
3.3 
Study Rationale ...........................................................................................................16 
3.4 
Dose Rationale ............................................................................................................16 
3.5 
Pre-Clinical Data ........................................................................................................17 
3.6 
RSLV-132 Clinical Data .............................................................................................18 
3.7 
Benefit/Risk Considerations .......................................................................................19 
3.8 
Population ...................................................................................................................20 
4 
STUDY OBJECTIVES AND PURPOSE ..................................................................21 
5 
STUDY DESIGN .......................................................................................................22 
5.1 
Primary Study Endpoint .............................................................................................22 
5.2 
Secondary Study Endpoints ........................................................................................22 
5.3 
Overall Study Design and Plan ...................................................................................22 
5.4 
Number of Subjects and Centers ................................................................................22 
5.5 
Estimated Study Duration ...........................................................................................23 
5.6 
Investigational Product Accountability ......................................................................23 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................24 


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6.1 
Subject Inclusion Criteria ...........................................................................................24 
6.2 
Subject Exclusion Criteria ..........................................................................................24 
6.3 
Subject Withdrawal Criteria .......................................................................................25 
6.4 
Women of Child-Bearing Potential ............................................................................25 
7 
TREATMENT OF SUBJECTS ..................................................................................27 
7.1 
Description of Study Drug ..........................................................................................27 
7.2 
Treatment Compliance ................................................................................................27 
7.3 
Concomitant Medications ...........................................................................................27 
7.4 
Medications not permitted before and during the trial ...............................................27 
7.5 
Randomization and Blinding ......................................................................................27 
8 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................28 
8.1 
Study Drug ..................................................................................................................28 
8.2 
Placebo ........................................................................................................................28 
8.3 
Study Drug Packaging, Labeling, Storage, Shipping, and Preparation ......................28 
8.4 
Study Drug Administration.........................................................................................28 
8.5 
Study Drug Accountability .........................................................................................28 
8.6 
Study Drug Handling and Disposal ............................................................................28 
9 
ASSESSMENT OF EFFICACY ................................................................................29 
10 
ASSESSMENT OF SAFETY .....................................................................................30 
10.1 
Adverse Event Definition ...........................................................................................30 
10.2 
Serious Adverse Event Definitions .............................................................................30 
10.3 
Adverse Event Reporting ............................................................................................31 
10.4 
Serious Adverse Event Reporting Requirements .......................................................31 
10.5 
Non-Serious Adverse Event Reporting Requirements ...............................................32 
10.6 
Adverse Event Follow Up ..........................................................................................32 
10.7 
Severity Assessment ...................................................................................................32 
10.8 
Causality Assessment .................................................................................................32 
10.9 
Abnormal Test Findings .............................................................................................33 
10.10 
Hospitalization ............................................................................................................33 
11 
ASSESSMENT OF PHARMACOKINETICS ...........................................................34 
11.1 
Measurement of RSLV-132 Drug Levels ...................................................................34 
11.2 
Pharmacokinetic Analysis ..........................................................................................34 


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12 
STATISTICS ..............................................................................................................35 
12.1 
Subject Population for Primary Endpoint Analysis ....................................................35 
12.2 
Subject Population for Safety Analysis ......................................................................35 
12.3 
Sample Size ................................................................................................................35 
13 
STUDY PROCEDURES ............................................................................................36 
13.1 
Evaluations .................................................................................................................36 
13.2 
Screening Procedures ..................................................................................................36 
13.3 
Baseline (Day 1) Procedures ......................................................................................37 
13.4 
Procedures on Days 8, 15, 43, and 71 .........................................................................38 
13.5 
Procedures on Days 29, 57, 85, and 99/Early Termination ........................................38 
13.6 
Procedures on Day 141 ...............................................................................................39 
13.7 
Telephone Follow-up on Days 176 and 211 (End of Study) ......................................39 
13.8 
Vital Signs ..................................................................................................................39 
13.9 
Medical/Medication History .......................................................................................39 
13.10 
Minor Salivary Gland Biopsy .....................................................................................39 
13.11 
Study Drug Concentration ..........................................................................................40 
13.12 
Gene Expression Analysis ..........................................................................................40 
13.13 
DNA Analysis .............................................................................................................40 
13.14 
Serum Protein Analysis ..............................................................................................40 
13.15 
Anti-Drug Antibodies .................................................................................................40 
13.16 
RNase Activity Assessments ......................................................................................40 
13.17 
Autoantibody Profile ..................................................................................................40 
14 
STUDY ADMINISTRATION ...................................................................................41 
14.1 
Protocol Amendments ................................................................................................41 
14.2 
Direct access to source data/documents .....................................................................41 
14.3 
Data Handling and Recordkeeping .............................................................................41 
14.4 
Quality Control and Quality Assurance ......................................................................41 
14.5 
Record Retention ........................................................................................................42 
14.6 
End of Study ...............................................................................................................42 
14.7 
Study Discontinuation or Suspension Criteria ............................................................42 
14.8 
Publication of Study Results .......................................................................................43 
15 
ETHICS ......................................................................................................................44 


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15.1 
Ethical Conduct of the Study ......................................................................................44 
15.2 
Institutional Review Board/Independent Ethics Committee ......................................44 
15.3 
Subject Information and Informed Consent ...............................................................44 
15.4 
Sponsor Responsibilities .............................................................................................44 
15.5 
Financing and Insurance .............................................................................................45 
15.6 
Confidentiality ............................................................................................................45 
15.7 
Disclosure ...................................................................................................................45 
16 
REFERENCES ...........................................................................................................46 
17 
APPENDICES ............................................................................................................47 
17.1 
Appendix A:  Study Procedures .................................................................................47 
17.2 
Appendix B: Clinical Laboratory Evaluations ...........................................................49 
17.3 
Appendix C: Investigator Protocol Agreement Page ..................................................50 
17.4 
Appendix D – Summary of Changes ..........................................................................51 
 
List of Tables 
Table 1: 
Abbreviations and specialist terms .............................................................................14 
 
 
 


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Table 1: 
Abbreviations and specialist terms 
Abbreviation or 
specialist term 
Explanation 
ADA 
anti-drug antibodies 
AE 
adverse event/experience 
ß-hCG 
ß-human chorionic gonadotrophin 
CBC 
complete blood count (hematology clinical laboratory evaluations) 
CFR 
code of federal regulations 
Chem-21 
chemistry panel of 21 analytes 
DNase 
deoxyribonuclease 
ELISA 
enzyme-linked immunosorbent assay 
ET 
Early Termination 
ESR 
erythrocyte sedimentation rate 
ESSDAI 
EULAR Sjogren’s syndrome disease activity index 
ESSPRI 
EULAR Sjogren’s syndrome patient reported index 
Fc 
Fragment crystallizable of an antibody 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
HBs Ag 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IC 
immune complex 
ICF 
informed consent form 
ICH 
international committee on harmonization 
IEC 
independent ethics committee 
IFN 
interferon 
IgG 
immunoglobulin G 
IRB 
institutional review board 
IUD 
intrauterine device 
IV 
intravenous 
MHRA 
Medicines and healthcare products regulatory agency 
MTD 
maximum tolerated dose 
pDC 
plasmacytoid dendritic cells 
PGA 
physician’s global assessment 
PK 
pharmacokinetic 
pSS 
primary Sjogren's syndrome 
RNA 
ribonucleic acid 
SAE 
serious adverse event/experience 
TLR 
toll-like receptor 
UA 
urinalysis 


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3 BACKGROUND 
3.1 Primary Sjogren’s Syndrome and Immune Complexes 
Primary Sjogren’s Syndrome (pSS) is an autoimmune disorder that is estimated to afflict 
between 0.5% to 1% of the general population, of whom nine out of ten patients are women 
(Ramos-Casals, 2005; Skopouli, 2000).  The disease is characterized by the lymphocytic 
infiltration of salivary and lacrimal glands with subsequent inflammation, damage and loss of 
function of the glands causing dry eyes and dry mouth.  Involvement of major organ systems 
including lung, kidney, and liver are common systemic manifestations of pSS (Malladi, 2012).  
At a biochemical level, pSS is associated with increased immunoglobulin levels and the 
production of anti-nuclear antibodies against ribonucleoprotein complexes such as SSA/Ro and 
SSB/La (Bave, 2005; Hall 2015). 
 
Once formed, RNA-containing immune complexes are readily internalized into immune system 
cells such as dendritic cells, where the RNA bound to the immune complexes is able to interact 
with Toll-Like Receptors (TLRs), such as the RNA sensor, TLR7.  Although TLRs are thought 
to operate as key elements of the innate immune system by recognizing pathogen-associated 
molecular components, it is now clear that host nucleic acids also can activate specific family 
members including TLR7, TLR8, and TLR9 (Theofilopoulos, 2010).   Cells expressing these 
receptors do so without distributing them to the cell surface; rather, TLRs 7/8/9 are sequestered 
within endosomes (Theofilopoulos, 2010).  This positioning is postulated to minimize interaction 
with host nucleic acids.  However, when present within an immune complex, nucleic acid 
antigens are actively internalized into cells via receptor-mediated endocytosis.  Effector Fc, 
complement, and B-cell receptors all may facilitate entry of nucleic acid containing ICs into 
endosomes (Means, 2005; Lau, 2005; Brkic 2012).  Once internalized, the nucleic acid is 
positioned to bind to and activate resident endosomal TLRs.  Activated TLRs, in turn, promote 
type 1 IFN production from pDCs, activate PMNs, and promote B-cell proliferation and 
autoantibody production.  Thus, the nucleic acid-containing antigens contribute to multiple 
aspects of pSS disease pathophysiology. 
 
3.2 INVESTIGATIONAL AGENT 
RSLV-132 is a novel therapeutic being developed for the treatment of systemic lupus 
erythematosus (SLE) and primary Sjogren’s syndrome.  This fully human biologic (Figure 1) 
consists of RNase1 fused to the N-terminus of the Fc region of IgG1.   The attachment of the Fc 
is intended to extend the circulatory half-life of the RNase and by so doing reduce the frequency 
of administration.  RSLV-132 is designed to significantly increase serum RNase activity to 
enzymatically digest RNA associated with autoantibodies and immune complexes, thereby 
reducing the activation of TLRs, decreasing the production of type 1 IFN and decreasing the 
proliferation of B-cells and autoantibody production.   
 
 
 


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Figure 1: Structure of RSLV-132   
 
3.3 Study Rationale 
There is a preponderance of scientific and clinical evidence that supports the hypothesis that 
RNA associated with autoantibodies triggers multiple inflammatory pathways following uptake 
into FcR-bearing cells. RNA-containing autoantibodies and immune complexes circulating in 
pSS patient blood are specifically delivered to FcR-bearing cells and internalized resulting in the 
activation of TLRs and the activation of several downstream inflammatory pathways.  RSLV-
132 is an enzymatically active RNase with a long circulating half-life that is designed to digest 
the RNA contained in these immune complexes and thereby render them biologically inert.  
Depleting the blood of circulating RNA bound to autoantibodies and immune complexes is 
hypothesized to decrease the activation of multiple pro-inflammatory cascades and thereby 
decrease the overall inflammation characteristic of Sjogren’s syndrome. 
 
3.4 Dose Rationale 
RSLV-132 was administered as an IV infusion in a single ascending dose study in healthy 
volunteers and a multiple ascending dose study in SLE subjects with doses ranging from 0.3 
mg/kg – 10.0 mg/kg.  No MTD was reached in either of these studies.  A study with mild to 
moderate SLE is currently ongoing where the dose is 10 mg/kg administered bi-weekly over a 
period of 24 weeks.  Additionally, in a 6-month toxicology study in cynomolgus monkeys, 50 
mg/kg of RSLV-132 was administered by IV infusion weekly. No dose-limiting toxicity was 
noted, therefore the No Observed Adverse Effect Level is at least 50 mg/kg, providing at least a 
5x safety margin for this study.     The duration of treatment is believed to be sufficient to 
observe changes in biomarkers for this proof-of-concept study. 
 


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3.5 Pre-Clinical Data 
3.5.1 Pharmacology  
RSLV-132 has been developed to digest RNA bound to immune complexes present in Sjogren’s 
patients. An extensive series of in vitro studies demonstrated that RSLV-132 degrades RNA in a 
dose-responsive and time-dependent manner and digest immune complex RNA collected from 
SLE patient serum. The in vitro results support the concept that maintaining RSLV-132 exposure 
in the blood will result in the degradation of RNA associated with autoantibodies in Sjogren’s 
patients. In vivo experiments involving administration to mice confirmed the ability for RSLV-
132 to degrade double stranded RNA and information obtained from intravenous studies in rats 
and monkeys indicated that the pharmacodynamic properties of RSLV-132 are continually 
maintained with repeated dosing.  
 
3.5.2 Toxicokinetics  
Pharmacokinetic studies in rats and monkeys demonstrated that RSLV-132 exposure (Cmax and 
AUC) was dose proportional and did not change with repeat administration. Adequate exposure 
and pharmacodynamic responsiveness was demonstrated at all doses employed in the toxicology 
studies over the entirety of the intended treatment period in both species. Furthermore, RNase 
catalytic activity correlated well with RSLV-132 protein concentrations, suggesting there was no 
decrease in drug exposure due to neutralizing anti-drug antibodies in either species.  
 
3.5.3 Toxicology  
The toxicology of RSLV-132 has been assessed in rats for periods up to 28 days and for up to 26 
weeks in monkeys using either every-three-day dosing or weekly dosing schedules, respectively.  
In animal toxicology studies, RSLV-132 was well tolerated in rats and monkeys when given 
intravenously at doses up to 50 mg/kg/dose in monkeys, and up to 100 mg/kg/dose in rats for 4 
weeks (5-10 doses) and for 26 weeks (26 doses) in the monkey (up to 50 mg/kg).  
 
These dose levels were considered maximum feasible doses based upon dose volume and 
formulation concentration constraints. Clinical findings were limited to a minor increase in blood 
fibrinogen seen only in rats. Given the absence of effects upon any other coagulation parameters 
or any correlating anatomical pathology change, this transient observation was not considered 
adverse.  
 
In the 4-week monkey study low titer (1:25) ADA responses were observed in several monkeys 
across all dose groups. In the 26-week monkey study five of the forty animals had high titer 
ADA responses which impacted exposure. However, in the rat study high titer ADA responses 
were observed across all dose groups, but the response had no impact on RSLV-132 exposure or 
pharmacological activity in either the monkey or rat studies. Comprehensive anatomical 
pathology evaluations in rats and monkeys did not elucidate any target organs aside from 
lymphoid hyperplasia in the spleen consistent with an immunogenic response to a foreign 
protein. Safety pharmacology parameters (CNS, respiratory, and cardiovascular systems) were 
examined in the context of the definitive monkey toxicology study. There were no test article-
related clinical signs, or changes in, cardiovascular or respiratory parameters 
(electrocardiography, blood pressure, heart and respiration rates, and pulse oximetry). In 


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addition, the brain, lungs, and heart were evaluated microscopically in the rat and monkey 
studies. There were no microscopic changes in any of these tissues attributable to the test article 
with the exception of the presence of small numbers of hemosiderin-containing macrophages 
noted in the choroid plexus of the brains in 13 rats. These findings correlated with a strong ADA 
response. No further findings were noted in brain tissue.  
 
In the 26-week monkey study, one female given 30 mg/kg was sacrificed in moribund condition 
on Day 127 of the dosing phase; clinical observations included hunched posture and red 
periorbital skin while microscopic findings of perivascular/vascular inflammation and/or 
hemorrhage were present in multiple tissues. Although these changes were test article-related, 
they likely represented an immunogenic or hypersensitivity reaction to RSLV-132 and not a 
direct toxic effect. All remaining animals survived to their scheduled sacrifice and no other 
RSLV-132-related clinical observations were noted.  
 
As RSLV-132 was well tolerated in animals following repeated injections occurring over a one 
to six-month period, the dosing regimen proposed for the clinical trial is not anticipated to be 
associated with any significant adverse events. Based upon the results of nonclinical studies, 
there are no findings which would preclude the continued investigation of RSLV-132 in clinical 
trials. 
 
3.6 RSLV-132 Clinical Data 
Two safety studies in humans have been conducted to date with RSLV-132; a single ascending 
dose study in 32 healthy volunteers, and a multiple ascending dose study in 32 subjects with 
SLE. 
 
3.6.1 Study 132-01 - Single Ascending Dose Study Summary 
This first-in-man study was a double-blind, placebo-controlled study conducted in healthy 
volunteers in a phase one unit to assess the safety and tolerability of a single, escalating IV dose 
of RSLV-132 (0.3 mg/kg – 10.0 mg/kg).  There were no SAEs, or drug discontinuations due to 
an AE.  The drug was well tolerated at all doses tested and an MTD was not reached.  The serum 
half-life of the drug was measured to be approximately 16 days.  None of the subjects in the 
study were positive for anti RSLV-132 antibodies.  
 
3.6.2 Study 132-02 -  Multiple Ascending Dose Study Summary 
This was a multi-center, double-blind, placebo-controlled study with successive escalating 
cohorts to assess the safety and tolerability of repeated IV doses (0.3 mg/kg – 10.0 mg.kg) of 
RSLV-132 in SLE subjects with inactive or mild disease.  The MTD was not reached at the 
highest dose of RSLV-132 tested.  Repeated administration of RSLV-132 doses was generally 
well tolerated by the subjects in this study. Across all dose cohorts, AEs were observed at the 
same overall incidence in RSLV-132 subjects as placebo subjects (6/8 subjects [75%] versus 
18/24 subjects [75%]). The incidence of AEs and the average number of events per subject did 
not increase with increasing dose level. The most frequently reported AEs in the RSLV 132 arm 
were headache, nausea, and upper respiratory tract infection, each of which occurred in 5 
subjects (20.8%). The majority of AEs in this study were Grade 1 in severity; 13 subjects 


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(10 RSLV-132 and 3 placebo subjects) experienced Grade 2 AEs, and one subject in Cohort 1 of 
the RSLV-132 arm experienced a Grade 3 AE of acute cholecystitis (this event was also reported 
as the only SAE in the study). No Grade 4 or Grade 5 events occurred. Adverse events judged to 
be related to blinded study drug were reported for 38% of placebo subjects and 29% of RSLV 
132 subjects. No dose-related trends were observed for any adverse event. No deaths due to AEs 
occurred. All subjects had at least one out-of-range chemistry, hematology, or urinalysis value, 
but no values were considered clinically significant in RSLV-132 subjects. No dose-dependent 
trends were observed in the incidence of out-of-range values and no concerning patterns of 
laboratory abnormalities were detected. No notable differences between treatment groups and no 
trends over the course of the study were observed in vital signs or physical findings. No 
clinically significant ECG abnormalities were reported during the study. No confirmed positive 
anti-RSLV-132 antibodies were detected in any of the subjects in this 113-day study. 
 
3.7 Benefit/Risk Considerations 
Potential Risks 
RSLV-132 has been studied in 24 healthy volunteers and 24 patients with SLE.  The most 
frequently reported adverse events were headache, nausea, and upper respiratory tract infection, 
each of which occurred in 5 subjects.  Infection of hair follicles was also reported in one subject.  
Reactions at the site of the injection, such as redness, bleeding and bruising, were reported in 
several subjects.  
 
In addition to the risks listed above, there may be some unknown or infrequent and unforeseeable 
risks, including that of unknown drug interactions associated with the use of RSLV-132.  The 
administration of protein drugs like RSLV-132 may result in serious and potentially life-
threatening anaphylactic reactions.  While none of these reactions have occurred in the previous 
studies with RSLV-132, it is possible they could occur in the future.  Genotoxicity, 
Carcinogenicity and Reproductive Toxicity studies have not been conducted for RSLV-132 and 
therefore the risks of these events, while considered low for the class of compound and 
mechanisms of action, are unknown. 
 
Potential Benefits 
Of the evaluable subjects in the 132-02 multi-dose SLE study, 7/16 (44%) had an improvement 
in SLEDAI score, however given the small size of the study the data are not statistically 
significant.  No studies in pSS have been conducted to date, therefore no data are available to 
evaluate potential benefits. 
 
Risk minimization 
The study population will be carefully chosen using the inclusion and exclusion criteria to 
minimize the potential for adverse events.  Subjects will be informed in a timely manner of any 
new information about the study drug and allowed to decide if they wish to continue the study.  
Subjects will be advised to seek medical attention at the appearance of any potential side effects.   
All subjects will be followed up for 18 weeks following the last infusion of RSLV-132 to allow 
early detection and management of any delayed significant AE. 
 


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The medical monitor will continually review the safety data to identify any trends that may pose 
significant risk. In addition, processes are in place to communicate serious adverse events to the 
sponsor and for reporting SUSARs to the relevant regulatory agencies and the Eudra Vigilance 
Clinical Trial Module.   
 
3.8 Population 
Subjects aged 18 to 85 years of age diagnosed with Primary Sjogren’s Syndrome and meet the 
inclusion / exclusion criteria will be enrolled in the study. 
 


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4 STUDY OBJECTIVES AND PURPOSE 
The present study will examine the role of circulating RNA complexed with autoantibodies and 
immune complexes and its role in activation of inflammatory pathways in patients with primary 
Sjogren’s syndrome.  The study will be conducted in a subset of Sjogren’s patients who have 
elevated levels of SSA/Ro autoantibodies and a pattern of elevated interferon-stimulated gene 
expression in blood cells.  Given the well-established inflammatory properties of RNA, RSLV-
132 will be administered to digest the RNA which is circulating bound to autoantibodies and 
thereby attenuate chronic activation of multiple inflammatory pathways.  A number of 
biochemical and clinical parameters will be analyzed to determine the potential therapeutic 
utility of nuclease therapy in Sjogren’s syndrome.   
 
 


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5 STUDY DESIGN 
5.1 Primary Study Endpoint 
The primary endpoint of the study is to assess the following biochemical parameters in the active 
versus control groups comparing Baseline with Day 99: 
 
• changes in blood cell gene expression or serum protein levels indicative of reduced 
inflammation. 
 
5.2 Secondary Study Endpoints 
The secondary endpoints of the study are to assess the following parameters in the active versus 
control groups comparing Baseline with Day 99: 
 
• safety and tolerability; 
• Ro52/60 autoantibody levels; 
• total immunoglobulins; 
• erythrocyte sedimentation rate (ESR); 
• complement levels (C3 & C4) 
• minor salivary gland histopathology 
• minor salivary gland interferon-stimulated gene expression; 
• disease activity (ESSDAI or PGA, Schirmer’s test, stimulated and unstimulated salivary 
flow) (assessment worksheets provided in study regulatory binder); 
• patient-reported outcomes as measured by the following: ESSPRI, FACIT, Profile of 
fatigue, EQ-5D-L, Fatigue VAS, and Neuropsychological analysis scales (assessment 
worksheets provided in study regulatory binder); 
• Additional exploratory evaluations may be considered as driven by the evolving 
understanding of the mechanism of action, technical feasibility, and any other clinical or 
immunological information that may become available during the course of the clinical 
study. Note: Additional exploratory endpoints will be specified in a separate laboratory 
manual and will be reported separately to the main safety, tolerability and efficacy 
endpoints of the study. 
 
5.3 Overall Study Design and Plan 
This is a double-blind, placebo-controlled study of 28 subjects with primary Sjogren’s syndrome.  
Potential subjects will be screened to assess their eligibility to enter the study within sixty days 
prior to study entry (i.e., prior to Baseline visit).  Following Baseline evaluations on Day 1 
subjects will receive their first intravenous infusion of RSLV-132.  Subjects will return to the 
research unit for additional visits as described in Appendix A.  The subjects will be randomized 
3:1 (active:placebo) to receive 8 intravenous administrations of 10 mg/kg of study drug or 
placebo on days:  1, 8, 15, 29, 43, 57, 71, and 85. 
5.4 Number of Subjects and Centers 
Up to 28 subjects will be enrolled at approximately 2-3 clinical centers in the UK.  


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5.5 Estimated Study Duration 
The duration of the study from Baseline to the End of Study visit is approximately 30 weeks. 
5.6 Investigational Product Accountability 
The unblinded pharmacist will maintain an accurate record of the receipt of the Investigational 
Product as shipped by the Sponsor (or designee), including the date received.  In addition, an 
accurate drug disposition record will be kept, specifying the amount dispensed to each subject 
and the date of dispensation.  The product accountability will be periodically monitored by an 
unblinded pharmacy monitor. 
 
 


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6 SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects who meet all of the inclusion criteria at Screening, and none of the exclusion criteria 
will be eligible to be enrolled into the study. 
 
6.1 Subject Inclusion Criteria 
Subjects who meet all of the following criteria may be included in the study: 
1. Meet 4 of the 6 criteria (must include histopathology or autoantibodies) of the 2002 
American-European Consensus Group (AECG) criteria for Primary Sjogren’s Syndrome. 
2. elevated levels of anti Ro-52 or anti Ro-60 antibodies (within laboratory positive range); 
3. positive interferon signature (whole blood cell interferon signature metric > -1); 
4. stable medications used to treat Sjogren’s syndrome for the 30 days prior to the Baseline 
visit; 
5. able to communicate and able to provide valid, written informed consent; 
6. ages 18 to 85 inclusive; 
7. minimum weight of 45 kg; 
8. Female participants shall be either of non-child-bearing potential (permanently sterilized 
by bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy), or menopausal 
(more than one year since last menstrual cycle and confirmed by blood FSH levels ≥ 22 
mIU/mL) OR practicing highly effective contraception (e.g., oral, but not including 
progestogen-only oral contraceptives), injectable, implantable or transdermal 
contraceptives, a non-hormonal intrauterine device [IUD], or an intrauterine hormone 
releasing system [IUS]) for at least 2 months prior to dosing and until 125 days after the 
last dose.  In terms of sexual relations, female participants not practicing highly effective 
contraception as described above should abstain or engage with male partners who are 
sterile or vasectomized. Female participants of child-bearing potential will also be 
required to have a negative serum pregnancy test [ß-hCG] at Screening and negative 
pregnancy urine test at Baseline. Female participants must agree not to donate eggs from 
the first dose until 125 days after the last dose.  
9. Male participants, who are not sterile or vasectomized, must agree to abstain or only 
engage with female partners who use highly effective contraception from the first dose 
until 125 days after the last dose.  Male participants must also agree not to donate sperm 
from the first dose until 125 days after the last dose. 
 
6.2 Subject Exclusion Criteria 
Any of the following will exclude potential subjects from the study: 
1. Previously diagnosed with systemic lupus, systemic sclerosis, or inflammatory myopathy. 
2. Use of hydroxychloroquine within 30 days of Baseline;  
3. use of cyclophosphamide within 180 days of Baseline; 


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4. use of belimumab, abatacept, or TNF inhibitors within 90 days of Baseline; 
5. use of rituximab within 6 months of Baseline (documentation of B-cell counts within the 
normal range for the reference laboratory is required for subjects within 1 year of rituximab 
usage). 
6. use of oral corticosteroids equivalent to prednisone dose of >10 mg/day within 30 days of 
Baseline; 
7. past head and neck radiation; 
8. current untreated lymphoma at Baseline; 
9. known IgG4-related disease 
10. graft versus host disease 
11. the presence of a clinically significant infection in the judgement of the Investigator within 
seven days prior to the receipt of the first dose of study drug; 
12. positive test for hepatitis B, C, or HIV at Screening; 
13. participation in another clinical study with receipt of an investigational product within 3 
months or 5 half- lives, of last administration (whichever is longer) from Baseline; 
14. positive pregnancy test at Screening or Baseline; 
15. female subjects currently pregnant or breast feeding at Baseline; 
16. inability or unwillingness to comply with protocol-specified procedures which, in the opinion 
of the Investigator, would make the subject unsuitable for study participation. 
 
6.3 Subject Withdrawal Criteria 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. A subject should be discontinued from study drug treatment for any of the following 
reasons: AE which is either intolerable or poses safety concerns, pregnancy or disease 
worsening.  The Investigator may also remove a subject from investigational treatment if, in the 
Investigator's opinion, it is not in the best interests of the subject to continue. Notification of 
discontinuation of investigational treatment will be made immediately to the Sponsor. In case of 
premature discontinuation of investigational treatment, efforts will be made to perform all 
protocol specified procedures for remaining study visit time points or at a minimum perform 
early termination assessments specified in Appendix A.   
 
If a subject wishes to withdraw from the study, the site staff should confirm whether the subject 
is agreeable to continue the assessments without the investigational treatment or if they wish no 
further involvement in the study. In the latter case no further study-related evaluations will be 
performed and no additional data will be collected.   
The date and the reason for discontinuation of investigational treatment or withdrawal from the 
study will be recorded on the subject’s case report form. Subjects that withdraw after receiving 
study drug will not be replaced. 
 
6.4 Women of Child-Bearing Potential 
All women will be considered to be of child-bearing potential unless: 


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• the subject has undergone a surgical sterilization procedure (e.g. bilateral oophorectomy, 
hysterectomy, or bilateral tubal ligation, occlusion); 
• the subject is more than one year past her last menstrual cycle and menopause is 
confirmed by ensuring blood FSH levels ≥ 22 mIU/mL at Screening. 
Pregnancy tests will be performed at Screening, prior to dosing at all visits with study drug 
administration, and at the  Day 141 visit (8 weeks after the last dose) for women of childbearing 
potential.  Any subject having a positive pregnancy test will no longer receive study drug and 
will be followed until birth or end of pregnancy to determine the outcome. 
 
 


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7 TREATMENT OF SUBJECTS 
7.1 Description of Study Drug 
RSLV-132 is a novel therapeutic candidate.  This fully human molecule consists of the enzyme 
RNase1 fused to the N-terminus of the Fc portion of IgG1.   The attachment of the Fc domain is 
intended to extend the serum half-life of the RNase and reduce the frequency of administration.  
RSLV-132 is provided in single-use vials as a 9.5 mg/mL sterile liquid concentrate for dilution 
for intravenous infusion. 
7.2 Treatment Compliance 
Study drug will be administered at the clinical site by trained study staff according to the Study 
Drug Reference Guide provided by the Sponsor. 
7.3 Concomitant Medications 
Subjects entering the study who had no changes to their medications used to treat pSS in the 
previous 30 days prior to the Baseline visit shall remain on the background medications at the 
same doses until Day 141 of the study. The use of pilocarpine or cevimeline during the trial is 
allowed, however subjects shall not use these medications within 12 hours prior to clinical 
disease activity measurements on days 1, 29, 57, 85, and 99 or use eye drops within 6 hours prior 
to clinical disease activity measurements on days 1, 29, 57, 85, and 99. 
 
7.4 Medications not permitted before and during the trial 
No changes in Sjogren’s medications shall be permitted during the study with the exception of 
eye drops and analgesics.  Medications prohibited prior to the study are listed in the exclusion 
criteria.  The following medications are prohibited during the trial: hydroxychloroquine 
cyclophosphamide, belimumab, abatacept, TNF inhibitors, rituximab, and oral corticosteroids 
>10 mg/day. 
 
7.5 Randomization and Blinding 
This will be a double-blind, placebo-controlled study. As such, except for the specifically 
designated unblinded study site pharmacist, the investigator, sponsor, and remaining study site 
clinical staff will be blinded as to treatment.  Ongoing drug accountability will be monitored by 
an unblinded monitor.  Except in a medical emergency, the investigator or designee and blinded 
study site clinical staff will remain blinded during the conduct of the study and until such time 
that all discrepancies in the clinical database are resolved (i.e., at the time of the database lock). 
If unblinding is required, the investigator will contact  the unblinded study pharmacist to obtain 
the study treatment.  The investigator must document the date, time and the need for unblinding 
and promptly inform the Sponsor. 


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8 STUDY DRUG MATERIALS AND MANAGEMENT 
8.1 Study Drug 
RSLV-132 is presented at a concentration of 9.5 mg/mL in a single-use vial containing 5.3 mL of 
preservative-free sterile solution for dilution for intravenous infusion.  The formulation buffer 
contains 10 mM sodium citrate pH 6.0, 220 mM trehalose and 50 mM L-arginine. All excipients 
meet multiple compendia requirements and are not of animal origin.  The Sponsor, or designee, 
will provide the investigator with adequate quantities of the study drug. 
8.2 Placebo 
The placebo will be sterile, 0.9% sodium chloride solution for infusion and will be provided by 
each site and prepared by the unblinded pharmacist.  
 
8.3 Study Drug Packaging, Labeling, Storage, Shipping, and Preparation 
The study drug will be provided to the sites in single use vials, clearly labeled with the drug 
name, lot number, protocol number, and expiration date.  Study drug will be stored at < -20°C 
under secure conditions and protected from light. Prior to administration to the subject, 
individual dosing solutions will be prepared from vials as detailed in the Study Drug Reference 
Guide.   Details of study drug packaging, labeling, storage, shipping, and preparation, including 
preparation of matching placebo doses, will also be provided in the Study Drug Reference Guide.  
8.4 Study Drug Administration 
A total of 8 intravenous infusions of RSLV-132 or placebo will be administered at Baseline, 
weekly for two weeks (three doses), and then once every 2 weeks for the next 10 weeks. The 
preparation of the study drug and rate of infusion will be provided in the Study Drug Reference 
Guide. For each dose, the date, actual infusion rate, start and stop time of infusion will be 
recorded in the source documents and transcribed into the case report forms. 
8.5 Study Drug Accountability 
The unblinded pharmacist will maintain an accurate record of the receipt of the Investigational 
Product as shipped by the Sponsor (or designee), including the date received. In addition, an 
accurate drug disposition record will be kept, specifying the amount dispensed to each subject 
and the date of dispensation.  
8.6 Study Drug Handling and Disposal 
At the completion of the study, all unused drug supplies will be destroyed by the sites or returned 
to the Sponsor after final accountability and reconciliation with the dispensing log. 


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9 ASSESSMENT OF EFFICACY 
The study is not powered to demonstrate statistically significant clinical improvement.  However, 
symptoms of primary Sjogren’s syndrome will be evaluated and clinical parameters will be 
compared between the treatment and control arms.  The following measurements will be used to 
assess efficacy; ESSDAI, PGA, stimulated and unstimulated salivary flow, and Schirmer’s test. 
 
 


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10 ASSESSMENT OF SAFETY 
Safety of the treatment will be compared between the two groups by assessing adverse events 
and laboratory results as well as any physical findings that have changed from baseline. 
All patients who have received an infusion with either RSLV-132 or placebo will be included in 
the overall analysis of safety. All data relating to safety will be listed and summarized by 
treatment group using descriptive statistics. The change from baseline for each of the vital signs 
parameters will also be computed and included in individual patient listings and descriptive 
summaries.  
Deaths that occur during the study and the proportion of subjects discontinuing the study due to 
adverse events will be summarized by treatment group. 
All adverse events will be coded and tabulated by MedDRA System Organ Class (SOC) and 
preferred term (PT) and presented in descending frequency. Adverse events will also be 
tabulated by severity and relationship to the study medication. Serious adverse events will be 
summarized separately. 
10.1 Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment. 
Adverse events may be reported by the subject, discovered by Investigator questioning, or detected 
through physical exam, a laboratory test requiring further attention, or other means. 
Adverse events can therefore be any unfavorable or unintended sign, symptom or disease 
temporally associated with the use of an investigational medicinal product, whether or not 
considered related to the investigational medicinal product. Adverse events include: 
• Any sign, medical diagnosis or symptom 
• Any new undesirable medical experience or unfavorable and unintended worsening of an 
existing condition that occurs during or after treatment, whether or not considered related 
to study drug 
• Abnormal laboratory results that have associated symptoms or findings, require specific 
treatment, or require a change in subject management.   
Whenever possible, the Investigator should group signs or symptoms that constitute a single 
diagnosis under a single event term. For example, cough, rhinitis and sneezing might be grouped 
together as “upper respiratory tract infection”. If possible, abnormal laboratory results that meet 
the definition of an AE (that warrant management, investigation or treatment) should be reported 
as a clinical diagnosis rather than the abnormal value itself (e.g., “anemia” rather than “decreased 
blood count”).  Adverse events will be graded according to the Rheumatology CTC (Woodworth 
et al., J. Rheumatology 2007; 34(6): 1401-1414). 
10.2 Serious Adverse Event Definitions 
An AE is classified as serious if it meets any of the following criteria: 


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• Results in death 
• Is life-threatening 
o This definition implies that the subject, in the view of the Investigator, was at 
immediate risk of death at the time of the event. It does not include an event that, 
had it occurred in a more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongs an existing hospitalization 
o Hospitalizations for surgeries planned before study entry, for social reasons, or for 
normal disease management procedures (including treatment adjustment) are not to 
be considered SAEs according to this criterion. 
• Results in persistent or significant disability and/or incapacity 
• Results in an adverse outcome in a child or fetus of a patient exposed to the study treatment 
regimen before conception or during pregnancy. 
• Otherwise considered medically important in the judgment of a health care professional. 
Medical and scientific judgment should determine whether an AE is classified as an SAE 
in many situations. Medically important conditions that may not result in death, not be life-
threatening, nor require hospitalization, may be considered SAEs when they may 
jeopardize the subject or may require intervention to prevent one of the outcomes listed 
above. Examples of such events are allergic bronchospasm requiring intensive treatment 
in an emergency room, blood dyscrasias or convulsions that do not result in in-patient 
hospitalization. 
AEs which meet the following criteria: 
• Serious 
• Unexpected (i.e. is not consistent with the applicable product information contained in the 
Investigator’s Brochure) 
• There is at least a reasonable possibility that there is a causal relationship between the event 
and the investigational medicinal product will be classified as Suspected Unexpected 
Serious Adverse Reactions (SUSARs).   
10.3 Adverse Event Reporting 
All AEs, both serious and non-serious, will be recorded on the AE CRF at each visit from the 
time the subject receives the first dose of study medication until Day 211, the final telephone 
contact with the subject.   Any untoward event occurring between screening and baseline and 
deemed directly related to a study procedure by the investigator will be recorded on the AE CRF.  
10.4 Serious Adverse Event Reporting Requirements 
SAEs will be reported to Resolve at safety@resolvebio.com on the SAE report form within 24 
hours of awareness of the event by the investigator.   
In the event that the investigator does not become aware of the occurrence of an SAE 
immediately, the investigator is to report the event within 24 hours of his/her first awareness of 
the SAE. 
Any SAE occurring any time after the reporting period must be promptly reported if a causal 
relationship to investigational product is suspected.   


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The initial report should include as much relevant information as possible but at a minimum 
should include subject number, date of event onset, event term/description of event, 
investigator’s assessment of relationship to study drug. 
For all SAEs, the investigator is obligated to pursue and provide information to Resolve or its 
designee in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Resolve to obtain specific additional follow-up information in 
an expedited fashion.  This information may be more detailed than that captured on the AE case 
report form.  In general, this will include a description of the AE in sufficient detail to allow for a 
complete medical assessment of the case and independent determination of possible causality.  
Information on other possible causes of the event, such as concomitant medications and illnesses 
must be provided.  All new information including final outcome should be submitted as soon as 
possible. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are subjected to expedited 
reporting and should be unblinded prior to submission to the regulatory authority.  Fatal or life-
threatening SUSARs must be reported to regulatory agencies and IEC by the sponsor as soon as 
possible, but no later than 7 days after first awareness of the reaction.  Any additional relevant 
information must be sent within 8 days of the first report.  Non-fatal or non-life-threatening 
SUSARs must be reported as soon as possible but no later than 15 days after first awareness of 
the reaction. 
All UK-relevant SUSARs should be reported to the MHRA.  “UK-relevant” includes SUSARs 
originating in the UK and SUSARs originating outside the UK where the sponsor has an ongoing 
trial in the UK involving the same medicinal product.   For the IEC, only SUSARs occurring 
within the UK should be reported.  
10.5 Non-Serious Adverse Event Reporting Requirements 
Non-serious AEs are to be reported on the AE CRFs, which are to be submitted as outlined in the 
study guidelines. 
10.6 Adverse Event Follow Up 
For adverse events with a causal relationship to the investigational product, follow-up by the 
investigator is required until the event or its sequelae resolve, stabilize or are explained.  
10.7 Severity Assessment 
As required on the AE case report forms, the investigator will assess the severity of an event 
according to the Rheumatology CTC (Woodworth et al., J. Rheumatology 2007; 34(6): 1401-
1414).  The Rheumatology CTC will be provided to sites in the study regulatory binder. 
10.8 Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and non-
serious).  Causality is determined as not related, possibly related, or definitely related according 
to the following definitions:   


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• Not related: The event can be readily attributed to other factors such as the subject’s 
clinical state, environmental factors, or other concomitant medications or therapies 
administered. 
• Possibly Related: Follows a reasonable temporal sequence from administration and is 
unlikely to be attributed to the subject's clinical state or environmental factors or other 
therapies administered. 
• Definitely related:  Clear-cut temporal association with study drug administration with 
improvement on cessation of study drug AND cannot be readily attributed to other 
factors such as the subject’s clinical state, environmental factors, or other concomitant 
medications or therapies administered. 
10.9 Abnormal Test Findings 
When laboratory results are outside the normal range, a decision regarding whether the result is 
of clinical significance or not shall be made by the Investigator and shall be based, in part, upon 
the nature and degree of the observed abnormality. Abnormal evaluations may be repeated, to 
rule out lab error. 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE are as follows:  
• the test result is associated with accompanying symptoms, and/or; 
• the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or; 
• the test result is considered to be an AE by the investigator or Sponsor. 
• an abnormal test result, in the absence of any of the above conditions, does not constitute 
an AE. 
• any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
10.10 
Hospitalization 
AEs reported from the clinical study associated with subject hospitalization or prolongation of 
subject hospitalization, are considered serious. 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not an SAE.  Examples include:  
• Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (e.g., for work-up of 
persistent pre-treatment lab abnormality); 
• Social admission (e.g., subject has no place to sleep); 
• Administrative admission (e.g., for yearly physical exam); 
• Protocol-specified admission during a clinical study (e.g., for a procedure required by the 
study protocol); 
• Pre-planned or optional admission not associated with a precipitating clinical AE. 


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11 ASSESSMENT OF PHARMACOKINETICS 
11.1 Measurement of RSLV-132 Drug Levels 
RSLV-132 drug levels in subject serum samples will be quantitated by two different assays; a 
validated ELISA assay that directly measures RSLV-132 protein levels, and a catalytic activity 
assay that measures the RNase enzyme activity of RSLV-132. 
11.2 Pharmacokinetic Analysis 
Pharmacokinetic (PK) parameters will be calculated for each subject, whenever possible, based 
on the serum concentrations of RSLV-132. 


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12 STATISTICS 
A statistical analysis plan will be prepared after completion of the final protocol and will be 
finalized before database lock. The statistical analysis plan will include more details on the 
statistical analysis and presentation of the data.  The fundamentals of the analysis are listed 
below. 
 
12.1 Subject Population for Primary Endpoint Analysis 
The effect of RSLV-132 on blood cell gene expression and serum protein levels will be 
compared between the two arms.   Subjects who complete all treatment visits will be included in 
the primary analysis.  Randomized patients who receive the incorrect therapy from that intended 
will be summarized in the group according to the therapy actually received. In the unlikely event 
of a patient commencing one study therapy and crossing over to the other, the data for that 
patient will be included in summaries and analyses with the original group. 
 
12.2 Subject Population for Safety Analysis 
The safety of RSLV-132 will be compared between the two arms using the following safety 
parameters:  adverse events, previous and concomitant medications, previous and concomitant 
diseases and laboratory data. The safety population will include all patients who received 
treatment with either RSLV-132 or placebo. Randomized patients who receive the incorrect 
therapy from that intended will be summarized in the group according to the therapy actually 
received. Patients who are not randomized but who receive treatment or placebo will also be 
included in the safety population and summarized according to the therapy actually received. In 
the unlikely event of a patient commencing one study therapy and crossing over to the other, the 
data for that patient will be included in summaries and analyses with the original group. 
12.3 Sample Size 
The sample size chosen for this study was based upon precedent set by other studies of similar 
nature and is not based on any power calculation. 
 
 


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13 STUDY PROCEDURES 
13.1 Evaluations 
Evaluations are summarized in Appendix A. During the course of the study approximately 230 
mL of blood will be drawn.  Central laboratories will perform all evaluations with the exception 
of the urine pregnancy test at baseline. 
Every attempt will be made to perform evaluations on the scheduled day and time, as 
appropriate. Evaluations should be performed on the day of the scheduled visit as much as 
possible.  In any case, the visit should occur ± 2 days of the scheduled visit for visit days Day 8 
through Day 99 and ±5 days for Day 141. Telephone contacts scheduled for Days 176 and 211 
should occur +10 days of the scheduled contact.  All scheduled study visits or calls should occur 
on the specified number of days after Baseline, even if a preceding visit occurred off-schedule.  
In the event it should not be possible to adhere to the study schedule, the minimum interval 
between administrations of RSLV-132 during the 2-week dosing period is 10 calendar days.  
 
13.2 Screening Procedures 
The following Screening procedures will be performed for all potential subjects at a visit 
conducted within 60 days of study entry (prior to Baseline): 
• informed consent; 
• assess inclusion/exclusion criteria 
• demographics/weight/height; 
• hepatitis-B, C and HIV antibody tests; 
• FSH (when required to confirm menopause in female subjects) 
• whole blood for interferon signature analysis; 
• physical examination; 
• pregnancy test (serum); 
• complete medical and medication history; 
• vital signs (temperature, respiratory rate, blood pressure and pulse); 
• chem-21 (see Appendix B), CBC, and UA; 
• anti-Ro-52/Ro-60 autoantibodies; 
 


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13.3 Baseline (Day 1) Procedures 
Prior to study drug administration (pre-dose procedures): 
• inclusion/exclusion criteria re-evaluated 
• directed physical examination; 
• pregnancy test (urine); 
• interim medical/medication history; 
• vital signs (temperature, respiratory rate, blood pressure and pulse); 
• chem-21 (see Appendix B), CBC, and UA; 
• AE Assessment; 
• measure disease activity (ESSDAI, PGA); 
• stimulated and unstimulated salivary flow; 
• Schirmer’s test; 
• patient reported outcomes (ESSPRI, FACIT, Profile of fatigue, EQ-5D-L, Fatigue 
VAS, Neuropsychological analysis (at Newcastle University only)); 
• optional minor salivary gland biopsy (consented subjects); 
• serum for study drug concentration and RNase activity;  
• serum protein analysis; 
• whole blood for gene expression profile; 
• whole blood for ESR; 
• whole blood for DNA analysis; 
• serum for anti-Ro-52/Ro-60 autoantibodies; 
• serum for total immunoglobulins, C3 and C4; 
• serum for assessment of anti-RSLV-132 antibodies; 
After completion of above assessments: 
o study drug administration.  Subjects will remain under observation in the 
clinic for at least 2 hours following the first administration of study drug.  The 
clinic shall have resuscitation equipment available in close proximity to the 
infusion room. 
 


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13.4 Procedures on Days 8, 15, 43, and 71 
Prior to study drug administration (pre-dose procedures): 
- 
directed physical exam; 
- 
pregnancy test (urine); 
- 
interim medical/medication history; 
- 
vital signs (temperature, respiratory rate, blood pressure and pulse); 
- 
adverse event assessment; 
After completion of above assessments: 
o study drug administration 
 
13.5 Procedures on Days 29, 57, 85, and 99/Early Termination 
Prior to study drug administration (pre-dose procedures): 
- 
directed physical examination; 
- 
urine pregnancy test (except Day 99); 
- 
interim medical/medication history; 
- 
vital signs (temperature, respiratory rate, blood pressure and pulse); 
- 
chem-20 (see Appendix B), CBC, and UA; 
- 
adverse event assessment; 
- 
measure disease activity (ESSDAI, PGA, Schirmer’s, stimulated and unstimulated 
salivary flow); 
- 
patient reported outcomes (ESSPRI, FACIT, Profile of fatigue, EQ-5D-L, Fatigue 
VAS, Neuropsychological analysis (Day 99 only); 
- 
optional minor salivary gland biopsy (consented subjects) (Day 99 only); 
- 
serum for study drug concentration and RNase activity; 
- 
serum protein analysis; 
- 
whole blood for gene expression profile 
- 
whole blood for ESR; 
- 
serum for anti-Ro-52/Ro-60 autoantibodies 
- 
serum for total immunoglobulins, C3 and C4; 
- 
serum for anti-RSLV-132 antibodies (Day 29 only); 
After completion of above assessments: 
o study drug administration (except Day 99) 


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13.6  Procedures on Day 141  
The following procedures will be performed on Day 141: 
• directed physical examination; 
• pregnancy test (serum); 
• interim medical/medication history; 
• vital signs (temperature, respiratory rate, blood pressure and pulse); 
• adverse event assessment; 
• serum for study drug concentration and RNase activity; 
• serum for assessment of anti-RSLV-132 antibodies; 
 
13.7 Telephone Follow-up on Days 176 and 211 (End of Study) 
Subjects will be contacted via telephone at Day 176 and Day 211 to collect follow up 
information on any adverse events that were ongoing at Day 141,  and to determine if there are 
any new reportable adverse events (e.g. positive relationship to the investigational product). If 
new reportable adverse events are identified it will be requested that the subject return to the 
clinic for an unscheduled visit and assessment by the Principal Investigator.  
13.8 Vital Signs 
Vital signs, including temperature, respiratory rate, blood pressure and pulse will be obtained at 
each visit. Blood pressure and pulse will be measured after the subject has been seated for at 
least five minutes. 
13.9  Medical/Medication History 
Subjects arriving at the clinical unit for the Screening visit will have a complete medical history 
performed including the current and past medications the subject has been using.  At subsequent 
visits to the clinic only an interim medical/medication history shall be performed to determine if 
any changes to the subject’s symptoms and medications have taken place since the last visit.  
 
13.10 
 Minor Salivary Gland Biopsy 
Consented subjects will undergo an optional biopsy of the minor labial salivary glands.  The 
tissue will be examined microscopically to determine the degree of lymphocytic infiltration 
(Focus score).  RNA will be extracted from a portion of the salivary gland tissue and the level of 
interferon gene expression will be analyzed.  Additionally, the properties of cellular subtypes 
associated with the tissue, such as B-lymphocytes shall be analyzed by Newcastle University 
(Newcastle, UK). 


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13.11 
Study Drug Concentration 
Serum samples will be analyzed by ICON central laboratory (Farmingdale, NY) using a 
validated ELISA assay to determine the serum concentration of study drug at selected visits 
during the study. 
13.12 
Gene Expression Analysis 
Blood will be collected into PAXgene RNA collection tubes, RNA will be extracted and 
analyzed by Resolve Therapeutics (Seattle, WA) to measure the expression level of genes that 
are related to inflammatory pathways thought to be involved in primary Sjogren’s syndrome and 
to analyze the presence of various micro RNAs. 
13.13 
DNA Analysis 
Blood will be collected into PAXgene DNA collection tubes at Baseline, DNA will be prepared 
by Resolve Therapeutics (Seattle, WA) and stored for future pharmacogenomic analysis. 
  
13.14 
Serum Protein Analysis 
Serum samples will be obtained at various visits during the study and the level of circulating 
serum cytokines and other proteins that are thought to be related to the inflammation and 
autoimmunity process shall be measured by MyriadBRM (Austin, TX). 
 
13.15 
 Anti-Drug Antibodies 
Serum will be analyzed for the presence of anti-RSLV-132 antibodies by ICON central 
laboratory (Farmingdale, NY) using a validated immunoassay. Each positive serum sample will 
be evaluated for ADA specificity by repeating the immunoassay in the presence of an excess of 
RSLV-132. Confirmed positive samples will be tittered by serial dilution and a numerical titer 
will be assigned. 
13.16 
RNase Activity Assessments 
RSLV-132 RNase enzymatic activity in the serum of subjects will be determined by Resolve 
Therapeutics (Seattle, WA) using a qualified analytical procedure. 
13.17 
Autoantibody Profile 
Serum samples will be analyzed by ICON central laboratory (Farmingdale, NY) to measure 
complement components C3 and C4 and anti-Ro-52/60 autoantibodies will be analyzed by the 
University of Washington Medical Center, Clinical Immunology Lab (Seattle, WA). 


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14 STUDY ADMINISTRATION 
14.1 Protocol Amendments 
Protocol amendments that impact subject safety, change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IRB/IEC and submitted to the 
appropriate regulatory authorities before implementation of such study modification. 
14.2 Direct access to source data/documents 
The Investigators and clinical sites will permit trial related monitoring, audits, IRB/IEC review 
and regulatory inspections as requested by governmental authorities, Resolve Therapeutics or 
designee, including direct access to source data/documents (i.e., original paper or electronic 
medical records, laboratory reports, hospital documents, progress reports, signed informed 
consent forms, etc.) in addition to CRFs.  Source documents should be available to support all 
the data recorded in the eCRF, unless otherwise specified in the eCRF and data queries. 
 
14.3  Data Handling and Recordkeeping 
CRFs are the sole property of Resolve Therapeutics and should not be made available in any 
form to third parties, except for authorized representatives of Resolve Therapeutics or 
appropriate regulatory authorities, without written permission from Resolve Therapeutics. 
Investigators are required to prepare and maintain adequate and accurate case histories that 
record all observations and other data pertinent to the investigation on each individual 
administered the investigational drug or employed as a control in the investigation. Case histories 
include the case report forms and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes of the physician, the 
individual's hospital chart(s), and the nurses' notes. The case history for each individual shall 
document that informed consent was obtained prior to participation in the study 
 
The results from data collected during the study will be recorded in the subject’s CRF (either 
paper or electronic CRF). To maintain confidentiality, the subjects/patients will be identified 
only by numbers and/or initials.  The completed CRFs will be transferred to the Sponsor or 
designee. Copies of each CRF will be retained by the Investigator.  
 
14.4 Quality Control and Quality Assurance 
During the study, Resolve Therapeutics or its designee will conduct periodic monitoring visits to 
ensure that the protocol and current Good Clinical Practices (cGCPs) as defined by local 
regulations are being followed and to resolve data queries.  The monitors may review source 
documents to confirm that the data recorded on CRFs is accurate.  The investigator and 
institution will allow Resolve monitors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  Additionally, an unblinded monitor will 
periodically visit each site to evaluate drug compliance and accountability but will not be 
involved in the monitoring of any clinical data. 


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The study site may be subject to review by the institutional review board (IRB) / independent 
ethics committee (IEC), and/or to quality assurance audits performed by Resolve Therapeutics, 
and/or to inspection by appropriate regulatory authorities. 
It is important that the investigator(s) and their relevant personnel agree to cooperate and are 
available during the monitoring visits and possible audits or inspections and that sufficient time 
is devoted to the process. The Investigator is required to make all study documentation promptly 
available for inspection during these events and, in the event of an audit by a regulatory agency, 
to notify Resolve Therapeutics immediately. 
Findings and corrective actions of frequent findings will be distributed to all sites to ensure that 
mistakes are not repeated.   
14.5  Record Retention 
To enable evaluations and/or audits from regulatory authorities or Resolve Therapeutics, the 
investigator agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, e.g., CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, SAE forms, source documents, and detailed records of 
treatment disposition.  The records should be retained by the investigator according to local 
requirements which may include International Conference on Harmonization regulations, or 
other local requirements, whichever is longer. 
If the investigator relocates, retires, or for any reason withdraws from the study, Resolve 
Therapeutics should be prospectively notified.  The study records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to Resolve Therapeutics.  
The investigator must obtain Resolve's written permission before disposing of any records, even 
if retention requirements have been met. 
14.6 End of Study 
The end of the study is defined as the last study visit or telephone contact (whichever is later) for 
the last subject on study.  
14.7 Study Discontinuation or Suspension Criteria  
Premature discontinuation or suspension of this clinical study may occur because of a regulatory 
authority decision, change in opinion of the IRB/IEC, safety data, drug availability issues or at 
the discretion of Resolve Therapeutics.   
If this study is prematurely discontinued or suspended, Resolve Therapeutics will promptly 
notify all investigators.  In the event of discontinuation, each investigator must contact all 
subjects within 15 days.  As directed by Resolve Therapeutics, all study materials must be 
collected and all CRFs completed to the greatest extent possible.  The sponsor is committed to 
scientific integrity and proper dissemination of research results. 


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14.8 Publication of Study Results 
Publication of study results is addressed in the Clinical Study Agreement with participating 
investigators. 


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15 ETHICS 
15.1  Ethical Conduct of the Study 
The study will be performed in accordance with the protocol, International Conference on 
Harmonization Good Clinical Practice guidelines, and applicable local regulatory requirements 
and laws. 
15.2  Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the investigator to obtain prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, e.g., 
advertisements, if applicable, from the IRB/IEC.  All correspondence with the IRB/IEC should 
be retained in the Investigator File.  Copies of IRB/IEC approvals should be forwarded to 
Resolve Therapeutics or designee. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In that 
event, the investigator must notify the IRB/IEC and Resolve Therapeutics in writing within 5 
working days after the implementation. 
15.3 Subject Information and Informed Consent 
The informed consent form must be agreed to by Resolve Therapeutics and the IRB/IEC and 
must be in compliance with International Conference on Harmonization, cGCP, local regulatory 
requirements, and legal requirements. 
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  The investigator, or a 
person designated by the investigator, will obtain written informed consent from each subject in 
accordance with all local and national regulations.   
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Resolve Therapeutics before 
use.   
15.4  Sponsor Responsibilities 
Before subject enrollment, the Sponsor or designee is responsible for reviewing with study site 
staff the definitions, recording and reporting of AEs/SAEs, as well as monitoring instructions. 
The Sponsor or designee will notify all appropriate regulatory authorities of SAEs, as necessary, 
within the required time frames. The Sponsor’s Medical Monitor or designee will complete 
written safety reports with the information provided by the Investigator and study site staff, as 
needed, for submission to regulatory authorities. Expedited reporting requirements for Suspected 
Unexpected Serious Adverse Reactions (SUSARS) are detailed in section 10.4. 


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The Sponsor or designee is responsible for forwarding copies of documents that are submitted to 
regulatory authorities to the Investigator for submission to the local IRB/IEC, if applicable, and 
for inclusion in the study site files. 
15.5 Financing and Insurance 
Financing and insurance will be provided per the regulations of individual countries and are 
addressed in separate documents. 
 
15.6 Confidentiality 
The investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. Subjects should not be identified by their names, but by 
an identification code on e-CRFs or other documents submitted to the Sponsor. The investigator 
should keep a subject enrolment log showing codes, names and addresses. The investigator 
should maintain documents not for submission to Resolve Therapeutics, e.g., subjects’ written 
consent forms, in strict confidence. 
Every attempt will be made to keep subject participation in this research study confidential; 
however, absolute confidentiality cannot be guaranteed.  The Sponsor, representatives of the 
Sponsor, the medical institution, and regulatory health authorities may review subject research 
records.  Additionally, the respective IRBs or IECs that oversee the conduct of this study may 
review medical records of subjects enrolled by the respective institution.  
15.7 Disclosure 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential. The investigator agrees not to 
disclose such information in any way without prior written permission from the Sponsor. 
Any publication of the results, either in part or in total (articles in journals or newspapers, oral 
presentations, abstracts, etc.) by the Investigator(s) or their representative(s), shall require prior 
notification and review, within a reasonable time frame, by the Sponsor, and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights. 
 
 


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16 REFERENCES 
Bave U., Nordmark G, Lovgren T, Ronnelid J, Cajander S, Eloranta ML, Alm GV, Ronnblom L.  
2005.  Activation of the Type I Interferon System in Primary Sjogren's Syndrome.  Arth. & 
Rheum. 52: 1185-1195. 
 
Brkic Z, Maria NI, van Helden-Meeuwsen CG, van de Merwe JP, van Daele PL, Dalm VA, 
Wildenberg ME, Beumer W, Drexhage HA, Versnel MA.  2012.  Prevalence of interferon type I 
signature in CD14 monocytes of patients with Sjogrens syndrome and association with disease 
activity and BAFF gene expression.  Ann Rheum Dis 
 
Hall JC, Baer AN, Shah AA, Criswell LA, Shiboski H, Rosen A, Casciola-Rosen L. 2015.  
Molecular subsetting of interferon pathways in Sjogrens syndrome.  Arth & Rheum.  67, 2437-
2446. 
 
Lau, C.M., Broughton, C., Tabor, A.S., Akira, S., Flavell, R.A., Mamula, M.J., Christensen, 
S.R., Shlomchik, M.J., Viglianti, G.A., Rifkin, I.R., and Marshak-Rothstein, A.  2005.  RNA-
associated autoantigens activate B cells by combined B cell antigen/Toll-like receptor 7 
engagement.  J. Exp. Med. 202:1171-1177. 
 
Malladi AS, Sack KE, Shiboski C, Baer AN, et al.  2012.  Primary Sjogrens syndrome as a 
systemic disease: a study of participants enrolled in an international Sjogrens syndrome registry.  
Arthritis Care Res. 64: 911-918. 
 
Means, T.K., Latz, E., Hayashi, F., Murali, M.R., Golenbock, D.T., and Luster, A.D. 2005.  
Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and 
TLR9.  J. Clin. Invest. 115:407-417. 
 
Ramos-Casals M, Tzioufas AG, Font J.  2005.  Sjogrens syndrome: new clinical and therapeutic 
concepts.  Ann Rheum Dis.  64, 347-354. 
 
Skopouli FN, Dafni U, Ionnidis JP, Moutsopoulos HM.  2000.  Clinical evolution, and morbidity 
and mortality of primary Sjogrens syndrome. Semin. Arthritis Rheum.  29:296-304 
 
Theofilopoulos, A.N., Gonzalez-Quintial, R., Lawson, B.R., Koh, Y.T., Stern, M.E., Kono, D.H., 
Beutler, B., and Baccala, R.  2010.  Sensors of the innate immune system: their link to rheumatic 
diseases.  Nat.  Rev. Rheum. 6:146-156. 
 
 
 
 
 
 
 
 
 


 
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17 APPENDICES 
17.1 Appendix A:  Study Procedures 
 
Study Procedures 
Screen 
(-60 to -1) 
Baseline 
Day 1 
Day 
8  
Day 
15 
Day 
29 
Day 
43 
Day 
57 
Day 
71 
Day 
85 
Day 
99/ET 
Day 
141 
 
Day 
176  
Tel. FU 
Day 
211  
Tel. FU 
EOS 
Acceptable visit window (days)f 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 5 
±10 
±10 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics/weight/height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis, HIV tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FSH (female subjects only) g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for interferon signature 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
 
 
Pregnancy test 
Xb 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
 
Xb 
 
 
Medical/medication history 
X 
Xd  
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chem-20, CBC, UA 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
AE assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESSDAI, PGA, salivary flow, Schirmer’s test 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Patient reported outcomes 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Minor salivary gland biopsy (consented subjects)  
 
 X i 
 
 
 
 
 
 
 
X  
 
 
 
Serum for study drug concentration and RNase activity 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Serum for protein analysis 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Whole blood for gene expression 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Whole blood for ESR (performed by local laboratory) 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Whole blood for DNA analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for anti-Ro-52 and anti-Ro-60 autoantibodies 
X 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Serum for total immunoglobulins, C3 and C4 
 
X 
 
 
X 
 
X 
 
X 
X 
 
 
 
Serum for anti-RSLV-132 antibodies 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Study Drug administration 
 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
 
 
 
 
Abbreviations: ET = Early Termination, EOS = End of Study 


 
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Version 4 – 19 April 2017  
a directed physical exam. 
b serum pregnancy test 
c urine pregnancy test 
d interim medication/medical history only. 
e intravenous infusion of RSLV-132 (10 mg/kg) or placebo according to infusion rate in the Study Drug Reference Manual. 
f minimum interval between administrations of RSLV-132 during the 2 week dosing period is 10 calendar days.  
g to be collected when confirmation of menopause is required in female subjects  
h assessments to be performed for any subjects that terminate early 
i biopsies may be performed up to 14 days prior to the baseline visit and at or within 7 days prior to or after Day 99 
 


 
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17.2  Appendix B: Clinical Laboratory Evaluations 
 
Chemistry (Chem-21): 
Hematology (CBC): 
Other Tests: 
Albumin 
Alkaline Phosphatase 
ALT 
AST 
Bicarbonate 
Urea BUN 
Calcium 
Chloride 
Cholesterol 
Creatinine 
Creatine Kinase 
GGT 
Glucose 
LDH 
Phosphate 
Potassium 
Sodium 
Total Bilirubin 
Total Protein 
Triglycerides 
Uric acid 
Hematocrit 
hepatitis B and C 
HIV 
serum pregnancy test 
urine pregnancy test 
FSH 
DNA analysis  
ESR 
study drug concentration 
study drug RNase activity 
serum protein analysis 
anti-RSLV-132 antibodies 
anti-Ro-52 
anti-Ro-60 
C3, C4 
total immunoglobulins 
gene expression analysis 
 
 
Minor Salivary Gland 
Biopsy 
microscopy: Focus score 
RNA extraction for IFN 
gene expression 
cellular sub-type analysis 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count 
White blood cell differential 
 (Percent and Absolute): 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
 Bands 
 
Complete Urinalysis 
(UA): 
 
 
pH and Specific Gravity 
 
Bilirubin 
   
Glucose 
 
 
Ketones 
 
 
Leukocytes 
 
 
Nitrite 
  
 
Occult blood 
  
 
Protein 
 
 
Urobilinogen 
 
 
Microscopic (RBC, WBC) 
if necessary 
 
 
 


 
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17.3 Appendix C: Investigator Protocol Agreement Page 
 
By signing, I confirm that my staff and I have read and understand this protocol, and agree to 
comply with the conduct and terms of this study. My staff and I have agreed to abide by the 
following responsibilities: 
 To conduct the study in compliance with Sponsor agreements, this protocol, any future 
amendments, any conditions of the governing reviewing EC/IRB or regulatory agency, 
and with any other study conduct procedures implemented by Resolve Therapeutics. 
 To supervise all testing involving human subjects. 
 To abide by FDA or MHRA regulations, Good Clinical Practices (GCP), and all 
applicable regional regulations.  
 Ensure that the requirements for obtaining informed consent from each study participant 
or their legal representative are met. 
 To report any Serious Adverse Events to Resolve Therapeutics in a timely manner as 
required by the protocol. 
 To report any Serious Adverse Events to the IRB in a timely manner. 
 To report Non-Serious Adverse Events as required by the protocol. 
 To assure access by Resolve Therapeutics representatives to original source documents. 
 To maintain confidentiality and assure security of Resolve Therapeutics confidential 
documents that include but are not limited to: the protocol, case report forms, 
Investigator’s Brochure, final study documents, manuscript drafts, unpublished data, 
sponsor correspondence, etc. 
 To cooperate fully with any study related GCP audit as performed by the sponsor’s 
quality assurance group. 
 To cooperate fully with any regulatory agency audit. 
 
 
 
 
 
Principal Investigator (printed name): 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator (signature): 
 
 
 
 
 
 
 
 
Date Signed (mm/dd/yyyy) 
 
 
 
 
 


 
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17.4 Appendix D – Summary of Changes 
 
 
From Version 3.0 to Version 4.0 
Overall 
1. Clarified that the strips used for the Schirmer’s test will not be retained. 
2. Removed plasma collection for the RNA analysis 
3. Clarified the neuropsychological tests will only be performed by the 
Newcastle site at Baseline and Day 99 
4. Corrected interferon signature inclusion criteria to > - 1 
5. Clarified any untoward event deemed directly related to a study 
procedure by the principal investigator will be recorded as an AE 
6. Added creatine kinase to chemistry panel and changed Chem-20 to 
Chem-21 
7. Clarified biopsies may be performed up to 14 days prior to the baseline 
visit and at or within 7 days prior to or after Day 99 
Section 
Detail of Changes 
Title Page 
Updated Version, Prior Version, Date of Publication  
Synopsis 
 
 
Secondary Study Endpoints : Clarified that neuropsychological analysis will 
only be performed at Newcastle University 
 
Section 1.8 #3: Corrected interferon signature metric to read > - 1  
Section 1.10:  
- 
Removed circulating RNA Analysis 
- 
Removed retention of Schirmer’s strips 
Section 1.11:  
- 
Screening and Baseline: Changed Chem-20 to Chem-21 
- 
Baseline and additional procedures: Removed plasma collection for 
circulating RNA analysis 
2 
Updated sections and page numbers based removal of RNA Analysis originally 
in section13.14 
Table 1 
Updated Chem-20 to Chem-21 
6.1 
Corrected interferon signature metric to read > - 1  
10.3 
Clarified any untoward event deemed directly related to a study procedure by 
the principal investigator will be recorded as an AE 
13.2 
Changed Chem-20 to Chem-21 
13.3 
- Changed Chem-20 to Chem-21 
- Removed retention of Schirmer’s strips 
- Clarified that neuropsychological analysis will only be performed at 
Newcastle University 
- Removed plasma collection for the RNA analysis 
13.5 
- Clarified neuropsychological analysis will only be performed on Day 99 
- Removed plasma collection for the RNA analysis 
13.14 
Removed plasma collection and RNA analysis 
17.1  
Appendix A 
- 
Clarified telephone contact is + or - 10 days 
- 
Removed RNA Analysis 


 
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- 
Added  footnote “i” clarifying biopsies may be performed up to 14 days 
prior to the baseline visit and at or within 7 days prior to or after Day 99 
17.2  
Appendix B 
Added Creatine Kinase and changed Chem-20 to Chem-21 
17.4 
Appendix D 
Updated Appendix D with Protocol changes. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Resolve Therapeutics, Inc. 
 
Final version 2.0 
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Statistical Analysis Plan 
 
Sponsor:   Resolve Therapeutics, Inc.    
Protocol Number: 132-04 
Protocol Version / Date:  2.0 / July 18th, 2018 
Protocol Title:  A Phase 2, Double-Blind, Placebo-Controlled Study of 
RSLV-132 in Subjects with Primary Sjogren’s Syndrome 
Author: Sharavi Peeramsetti, MS, Axio Research LLC 
Version / Date: 2.0 / July 18th, 2018 
 
 


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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...... 4 
2. 
INTRODUCTION .......................................................................... 6 
2.1. 
STUDY OBJECTIVES ........................................................................................................................ 6 
2.2. 
ENDPOINTS ..................................................................................................................................... 6 
2.2.1. 
Primary Study Endpoint .......................................................................................................... 6 
2.2.2. 
Secondary Study Endpoint ...................................................................................................... 6 
2.3. 
STUDY DESIGN ............................................................................................................................... 7 
2.3.1. 
Study Population ..................................................................................................................... 7 
2.3.2. 
Treatment Groups and Dosing ................................................................................................ 7 
2.3.3. 
Study Visits and Assessments .................................................................................................. 7 
2.3.4. 
Concomitant Medications ..................................................................................................... 11 
2.3.5. 
Subject Withdrawal ............................................................................................................... 11 
2.3.6. 
Randomization and Blinding ................................................................................................. 11 
2.3.7. 
Sample Size and Power ......................................................................................................... 12 
3. 
GENERAL CONSIDERATION FOR DATA ANALYSES .............. 12 
3.1. 
ANALYSIS SETS ............................................................................................................................ 12 
3.1.1. 
Intent-to-Treat Analysis Set ................................................................................................... 12 
3.1.2. 
Full Analysis Set .................................................................................................................... 12 
3.1.3. 
Safety Analysis Set ................................................................................................................. 13 
3.2. 
STATISTICAL ANALYSIS ISSUES ................................................................................................... 13 
3.2.1. 
Strata and Covariates ........................................................................................................... 13 
3.2.2. 
Examination of Subject Subsets ............................................................................................. 13 
3.2.3. 
Multiple Comparisons ........................................................................................................... 13 
3.2.4. 
Multi-center Studies .............................................................................................................. 13 
3.2.5. 
Missing Data and Outliers .................................................................................................... 13 
3.2.6. 
Data Conventions and Transformations ............................................................................... 14 
3.2.7. 
Study Baseline and Study Day ............................................................................................... 14 
3.2.8. 
Visit Windows ........................................................................................................................ 14 
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 14 
5. 
GENERAL ANALYSIS METHODS ............................................. 14 
6. 
SUBJECT DISPOSITION ........................................................... 15 
6.1. 
ENROLLMENT AND DISPOSITION OF SUBJECTS ............................................................................ 15 
6.2. 
EXTENT OF EXPOSURE .................................................................................................................. 16 
6.3. 
PROTOCOL DEVIATIONS ............................................................................................................... 16 
7. 
BASELINE DATA ....................................................................... 17 
7.1. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ...................................................................... 17 
7.2. 
MEDICAL HISTORY ....................................................................................................................... 17 


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8. 
PRIOR AND CONCOMITANT MEDICATIONS .......................... 17 
8.1. 
MEDICATIONS ............................................................................................................................... 17 
9. 
EFFICACY ANALYSES .............................................................. 18 
9.1. 
ANALYSIS OF PRIMARY EFFICACY ENDPOINTS ............................................................................ 18 
9.1.1. 
Blood Cell Gene Expression ................................................................................................. 18 
9.1.2. 
Serum Protein Level .............................................................................................................. 18 
9.2. 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS ....................................................................... 18 
9.2.1. 
ESSDAI .................................................................................................................................. 19 
9.2.2. 
PGA ....................................................................................................................................... 19 
9.2.3. 
Salivary Flow ........................................................................................................................ 19 
9.2.4. 
Schirmer’s test ....................................................................................................................... 20 
10. SAFETY ANALYSES .................................................................. 20 
10.1. 
ADVERSE EVENTS ..................................................................................................................... 21 
10.1.1. 
Overall Adverse Events ..................................................................................................... 21 
10.1.2. 
Incidence of Adverse Events .............................................................................................. 22 
10.1.3. 
Relationship of Adverse Event to Study Drug .................................................................... 22 
10.1.4. 
Severity of Adverse Event .................................................................................................. 22 
10.1.5. 
Serious Adverse Events ...................................................................................................... 22 
10.1.6. 
Adverse Events Leading to Hospitalization / Study Drug Discontinuation / Study 
Termination ......................................................................................................................................... 23 
10.2. 
LABORATORY AND OTHER SAFETY ASSESSMENTS .................................................................. 23 
10.2.1. 
Laboratory Blood and Urine Samples ............................................................................... 23 
10.2.2. 
Vital Signs .......................................................................................................................... 23 
10.2.3. 
Physical Exam ................................................................................................................... 24 
10.3. 
IMMUNOGENICITY ANALYSES .................................................................................................. 24 
11. PHARMACOKINETIC ANALYSES ............................................ 24 
12. REFERENCES ............................................................................ 25 
13. APPENDIX I:  FACIT-FATIQUE SCALE SAS SCORING ............ 26 
 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical Classification 
bpm 
Beats per minute 
°C 
Celsius  
CRF 
Case report form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
DBP 
Diastolic blood pressure 
eCRF 
Electronic case report form 
ESR 
erythrocyte sedimentation rate 
ESSDAI 
EULAR Sjogren’s syndrome disease activity index 
ESSPRI 
EULAR Sjogren’s syndrome patient reported index 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full analysis set 
HIV 
Human immunodeficiency virus 
ITT 
Intent-to-Treat analysis set 
IWRS 
Interactive Web Response System 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg 
 
Milligram 
mg/kg 
Milligram per kilogram 
mm 
Millimeter 
mm Hg 
Millimeter of mercury 
PGA 
Physician’s global assessment 
PK 
Pharmacokinetic 
pSS 
primary Sjogren's syndrome 


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PT 
Preferred term 
RNA 
Ribonucleic acid 
RR 
Respiratory rate 
SAP 
Statistical analysis plan 
SAS 
Safety analysis set 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment Emergent Adverse Event 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
This document presents the statistical analysis plan (SAP) for Resolve Therapeutics, Inc. 
based on protocol 132-04: A Phase 2, Double-Blind, Placebo-Controlled Study of RSLV-
132 in Subjects with Primary Sjogren’s Syndrome.  The analyses described in this 
document will be performed for the final clinical study report (CSR) after the database 
lock and unblinding.  Any deviations from the statistical analysis plan will be described 
and a justification given in the final CSR.   
All analyses will be conducted using SAS version 9.4 or higher.  
2.1. 
Study Objectives 
The present study will examine the role of circulating RNA complexed with 
autoantibodies and immune complexes and its role in activation of inflammatory 
pathways in patients with primary Sjogren’s syndrome. The study will be conducted in a 
subset of Sjogren’s patients who have elevated levels of SSA/Ro autoantibodies and a 
pattern of elevated interferon-stimulated gene expression in blood cells. Given the well-
established inflammatory properties of RNA, RSLV-132 will be administered to digest 
the RNA which is circulating bound to autoantibodies and thereby attenuate chronic 
activation of multiple inflammatory pathways. A number of biochemical and clinical 
parameters will be analyzed to determine the potential therapeutic utility of nuclease 
therapy in Sjogren’s syndrome. 
2.2. 
Endpoints 
2.2.1. 
Primary Study Endpoint 
The primary endpoint of the study is to assess the following biochemical parameters in 
the active versus control groups comparing Baseline (Day 1) with Day 99: 
• 
changes in blood cell gene expression or serum protein levels indicative of 
reduced inflammation. 
2.2.2. 
Secondary Study Endpoint 
The secondary endpoints of the study are to assess the following parameters in the active 
versus control groups comparing Baseline (Day 1) with Day 99: 
• 
safety and tolerability; 
• 
Ro 52/60 autoantibody levels (ICON); 
• 
total immunoglobulins (ICON); 
• 
erythrocyte sedimentation rate (ESR); 


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• 
complement levels (C3 & C4) (ICON) 
• 
minor salivary gland histopathology (not summarized) 
• 
minor salivary gland interferon-stimulated gene expression (not summarized) 
• 
disease activity (ESSDAI or PGA, Schirmer’s test, stimulated and unstimulated 
salivary flow) (assessment worksheets provided in study regulatory binder); 
• 
patient-reported outcomes as measured by the following: ESSPRI, FACIT, Profile 
of fatigue, EQ-5D-L, Fatigue VAS, and Neuropsychological analysis scales (not 
summarized) (assessment worksheets provided in study regulatory binder); 
• 
Additional exploratory evaluations may be considered as driven by the evolving 
understanding of the mechanism of action, technical feasibility, and any other 
clinical or immunological information that may become available during the 
course of the clinical study. 
2.3. 
Study Design 
2.3.1. 
Study Population 
This is a multi-center, double-blind, placebo-controlled study to evaluate the impact of 8 
intravenous infusions of RSLV-132 in 28 patients enrolled at approximately 2-3 clinical 
centers in the United Kingdom with primary Sjogren’s syndrome (pSS). The study 
population will be 18 to 85 years male or female with pSS, elevated levels of anti Ro-52 
or anti Ro-60 antibodies, positive interferon signature and minimum weight of 45 kg. 
2.3.2. 
Treatment Groups and Dosing 
Following Baseline evaluations on Day 1 subjects will receive their first intravenous infusion 
of RSLV-132. Subjects will return to the research unit for additional visits as described in 
Table 1. The subjects will be randomized 3:1 (active: placebo) to receive 8 intravenous 
administrations of 10 mg/kg of study drug or placebo on days: 1, 8, 15, 29, 43, 57, 71, and 85.  
2.3.3. 
 Study Visits and Assessments 
Potential subjects will be screened to assess their eligibility to enter the study within 60 days 
prior to study entry (i.e., prior to Baseline visit). Following Baseline evaluations on Day 1, 
subjects will receive their first infusion of RSLV-132 or placebo. Subjects will return to the 
research unit for follow-up visits. A total of 9 post-baseline visits will occur; once weekly for 
two weeks, then every two weeks for 14 weeks, plus one further visit 8 weeks after the last 
study drug administration. There will then be two additional telephone contacts made to 
subjects at weeks 13 and 18 after the last dose, to monitor any potential late-emerging adverse 


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events. See Table 1 and the schedule of events for the specific procedures and collection time 
points.


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Table 1. Study Procedures 
Study Procedures 
Screen 
(-60 to -1) 
Baseline 
Day 1 
Day 
8 
Day 
15 
Day 
29 
Day 
43 
Day 
57 
Day 
71 
Day 
85 
Day 
99/
ET 
Day 
141 
Day 
176 
Tel. FU 
Day 
211 
Tel. FU 
EOS 
Acceptable visit window (days)f 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 5 
+ 10 
+ 10 
Informed consent 
X 
Inclusion/exclusion 
X 
X 
Demographics/weight/height 
X 
Hepatitis, HIV tests 
X 
FSH (female subjects only) g 
X 
Whole blood for interferon signature 
X 
Physical exam 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Pregnancy test 
Xb 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xc 
Xb 
Medical/medication history 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chem-20, CBC, UA 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESSDAI, PGA, salivary flow, Schirmer’s test 
X 
X 
X 
X 
X 
Patient reported outcomes 
X 
X 
X 
X 
X 
Minor salivary gland biopsy (consented 
subjects) 
X 
X 
Serum for study drug concentration and RNase 
activity 
X 
X 
X 
X 
X 
X 
Serum for protein analysis 
X 
X 
X 
X 
X 
Whole blood for gene expression 
X 
X 
X 
X 
X 


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Abbreviations: ET = Early Termination, EOS = End of Study 
a directed physical exam.  
b serum pregnancy test  
c urine pregnancy test  
d interim medication/medical history only.  
e intravenous infusion of RSLV-132 (10 mg/kg) or placebo according to infusion rate in the Study Drug Reference Manual.  
f minimum interval between administrations of RSLV-132 during the 2 week dosing period is 10 calendar days.  
g to be collected when confirmation of menopause is required in female subjects  
h assessments to be performed for any subjects that terminate early 
i biopsies may be performed up to 14 days prior to the baseline visit and at or within 7 days prior to or after Day 99 
 
 
 
 
 
Whole blood for ESR (performed by local) 
laboratory) 
X 
X 
X 
X 
X 
Whole blood for DNA analysis 
X 
Plasma for RNA analysis (selected subjects) 
X 
X 
Serum for anti-Ro-52 and anti-Ro-60 
autoantibodies 
X 
X 
X 
X 
X 
X 
Serum for total immunoglobulins, C3 and C4 
X 
X 
X 
X 
X 
Serum for anti-RSLV-132 antibodies 
X 
X 
X 
Study Drug administration 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 


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2.3.4. 
Concomitant Medications  
Subjects entering the study who had no changes to their medications used to treat pSS in the 
previous 30 days prior to the Baseline visit shall remain on the background medications at the 
same doses until Day 141 of the study. The use of pilocarpine or cevimeline during the trial is 
allowed, however subjects shall not use these medications within 12 hours prior to clinical 
disease activity measurements on days 1, 29, 57, 85, and 99 or use eye drops within 6 hours prior 
to clinical disease activity measurements on days 1, 29, 57, 85, and 99. 
No changes in Sjogren’s medications shall be permitted during the study with the exception of 
eye drops and analgesics. Medications prohibited prior to the study are listed in the exclusion 
criteria section of the protocol. The following medications are prohibited during the trial: 
hydroxychloroquine cyclophosphamide, belimumab, abatacept, TNF inhibitors, rituximab, and 
oral corticosteroids >10 mg/day. 
 
2.3.5. 
Subject Withdrawal 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. A subject should be discontinued from study drug treatment for any of the following 
reasons: AE which is either intolerable or poses safety concerns, pregnancy or disease 
worsening. The Investigator may also remove a subject from investigational treatment if, in the 
Investigator's opinion, it is not in the best interests of the subject to continue. Notification of 
discontinuation of investigational treatment will be made immediately to the Sponsor. In case of 
premature discontinuation of investigational treatment, efforts will be made to perform all 
protocol specified procedures for remaining study visit time points or at a minimum perform 
early termination assessments specified in Table 1. 
If a subject wishes to withdraw from the study, the site staff should confirm whether the subject 
is agreeable to continue the assessments without the investigational treatment or if they wish no 
further involvement in the study. In the latter case no further study-related evaluations will be 
performed and no additional data will be collected. 
The date and the reason for discontinuation of investigational treatment or withdrawal from the 
study will be recorded on the subject’s case report form (CRF). Subjects that withdraw after 
receiving study drug will not be replaced. 
2.3.6. 
Randomization and Blinding 
This will be a double-blind, placebo-controlled study.  As such, except for the specifically 
designated unblinded study site pharmacist, the investigator, sponsor, and remaining study site 
clinical staff will be blinded as to treatment.  Ongoing drug accountability will be monitored by 
an unblinded monitor. 


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A randomization code will be computer-generated by a contract research organization (CRO) 
Axio Research LLC.  Subjects meeting the study entry criteria will be randomized via an 
interactive web response system (IWRS).  Subjects will be randomized in a 3:1 ratio to either 
RSLV-132 or Placebo.  The randomization schedule will be generated by the randomization 
statistician at Axio Research (who is not on the project team) or designee and maintained in a 
secure and limited-access location separate from the study investigator and members of the 
project team.  The study subject, investigative staff, the Sponsor, the Sponsor study team 
(includes contractors and vendors), excluding the unblinded study site pharmacist and unblinded 
monitor mentioned above, will be blinded to treatment assignments during the study. 
Except in a medical emergency, the investigator or designee and blinded study site clinical staff 
will remain blinded during the conduct of the study and until such time that all discrepancies in 
the clinical database are resolved (i.e., at the time of the database lock). The date/initials and 
reason for the investigator and/or clinical staff removing the study blind will be documented. 
2.3.7. 
Sample Size and Power  
The sample size of approximately 28 subjects chosen for this study was based upon precedent set 
by other studies of similar nature and was not based on power calculations. Therefore no formal 
hypothesis testing will be performed. 
P-values obtained from the analyses, if they are generated, will be used for obtaining information 
only and will be evaluated at the two-sided alpha level of 0.05. 
3. 
GENERAL CONSIDERATION FOR DATA ANALYSES 
3.1. 
Analysis Sets 
3.1.1. 
Intent-to-Treat Analysis Set   
The Intent-to-Treat (ITT) Analysis Set is defined as all subjects who were randomized, 
regardless of whether the subject actually received any study drug (RSLV-132 or Placebo).  The 
subject will be included in the treatment group to which they were randomized. 
3.1.2. 
Full Analysis Set   
The Full Analysis Set (FAS) is a modified ITT and is defined as all subjects randomized who 
received at least one dose of study drug (RSLV-132 or Placebo).  The subject will be included in 
the treatment group to which they were randomized.  The Full Analysis Set is equivalent to the 
Efficacy Analysis Set defined in the study protocol and can be used interchangeably.  For the 
purpose of generating the summary tables and by subject listings under the description of this 
SAP, the term of Full Analysis Set will be used.  


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3.1.3. 
Safety Analysis Set   
The Safety Analysis Set (SAS) is defined as all subjects who received any treatment with either 
RSLV-132 or placebo.  
Randomized subjects that receive the incorrect therapy from that intended will be summarized in 
the group according to the therapy actually received.  Subjects who are not randomized but who 
receive treatment or placebo will also be included and summarized according to the therapy 
actually received.  In the unlikely event of a subject commencing one study therapy and crossing 
over to the other, the data for that subject will be included in summaries and analyses with the 
original group. 
3.2. 
Statistical Analysis Issues 
3.2.1. 
Strata and Covariates 
There is no stratification and covariate analysis planned for this study.  However, if there is any 
stratification and covariate analysis performed in an ad hoc exploratory nature, it will be noted in 
the final CSR. 
3.2.2. 
Examination of Subject Subsets 
There is no subgroup analysis planned for this study.  However, if there is any subgroup analysis 
performed in an ad hoc exploratory nature, it will be noted in the final CSR. 
3.2.3. 
Multiple Comparisons 
No formal hypothesis testing and no multiple comparisons will be conducted for this study. 
3.2.4. 
Multi-center Studies 
The study will be conducted from 2-3 clinical centers in the United Kingdom. Randomization to 
the treatment groups will not be stratified by study site due to small sample size.  Subjects from 
all centers will be pooled for summaries. 
3.2.5. 
Missing Data and Outliers 
Every attempt will be made to capture all study data.  For subjects whose visit value is missing, 
the last observation will be carried forward (LOCF) for the efficacy analyses.  Any missing, 
unused, or spurious data will be noted in the final CSR.   


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3.2.6. 
Data Conventions and Transformations  
Laboratory numeric data may be recorded with a ‘<’ or ‘>’ sign (i.e. < 0.1 or > 0.1).  In order to 
summarize the data, the original value will be converted to 0.09 in the case of < 0.1 and to 0.11 
in the case of > 0.1.  The same principle will be used if the data has additional extended 
significant digits.  The actual values will be presented in the data listings.  
3.2.7. 
Study Baseline and Study Day 
Baseline is defined as the last assessment prior to the first dose of study drug (RSLV-132 or 
Placebo) at Day 1.  Measurements that are obtained after the first dose of study drug will be 
considered post-baseline values.  If a measurement of a variable is not made on a given subject 
prior to the first dose of study drug, then that subject will be considered not to have a baseline 
value for that variable.  Change from baseline is defined as post-baseline assessment minus 
baseline assessment.  
Study day for events on or after the date of the first dose will be defined as the number of days 
from the date of the first dose of study drug, plus 1 day, so that the date of the first dose will be 
defined as Day 1.  For events before the date of the first dose, study day will be calculated as the 
difference in days between the date of the first dose and the date of interest.  Thus, the day before 
the date of the first dose will be defined as Day -1. 
3.2.8. 
Visit Windows  
The case report form nominal visits and visit windows will be used in the summaries.  In general, 
unscheduled visits will not be summarized unless otherwise noted.  
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
There is no interim analysis and data monitoring committee planned for this study. 
5. 
GENERAL ANALYSIS METHODS 
Continuous variables will be summarized using descriptive statistics including number of 
subjects (n), mean, standard deviation (SD), median, minimum, and maximum.  Categorical 
variables will be summarized using frequencies and percentages.  Percentages will be calculated 
using the total number of subjects in each treatment group for each applicable population and/or 
subpopulation, unless otherwise noted. 
Number of subjects, minimums, and maximums will be calculated to the same number of 
decimal places as the source data.  Means, standard deviations and quartiles will be calculated to 


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one more decimal place than the source data.  Percentages will be calculated to one decimal 
place.  Zero count cells will be displayed as “0” with percentage of (0%).  Unless otherwise 
noted, summaries will be performed by the treatment group (Placebo and RSLV-132 10 mg/kg).  
If statistical tests are performed, the tests will be done at the two-sided, 5% significance level to 
compare Placebo vs. RSLV-132 10 mg/kg, unless otherwise specified.  The point estimate and 
95% confidence interval (CI) for the treatment differences may be displayed along with the p-
value for the treatment comparison.  P-values will be presented to three decimal places.  P-values 
< 0.0005 will be presented as < 0.001.  P-values greater than 0.9999 will be presented as > 0.999. 
In the absence of any predefined hypotheses in this study, the general strategy of the analysis 
will be to examine the data summaries for any trends amongst the treatment groups.  No formal 
hypothesis testing will be carried out.  P-values obtained from statistical testing of the analyses 
will be used for descriptive purposes only. 
All data collected in the clinical database will be included in the data listings, as appropriate. 
Subjects who were randomized and never treated will be accounted for in the data listings. 
6. 
SUBJECT DISPOSITION  
6.1. 
Enrollment and Disposition of Subjects 
Subjects’ enrollment and disposition will be summarized by treatment group on two different 
analysis sets.  The reasons for discontinuation will be listed in the order as they appear on the 
electronic case report form (eCRF). 
Summary based on the ITT analysis set will include all randomized subjects and will be 
summarize for the following.  The percentages will be calculated based on the number of 
subjects randomized in each of the treatment group.  
• Number and percentage of subjects randomized 
• Number and percentage of subjects randomized and discontinued prior to treatment 
• The reason for discontinuation prior to treatment 
Summary based on the FAS will include all randomized and treated subjects and will be 
summarize for the following.  The percentages will be calculated based on the number of 
subjects randomized and treated in each of the treatment group. 
• Number and percentage of subjects randomized and treated (Placebo or RSLV-132 10 
mg/kg) 
• Number and percentage of subjects randomized and treated who completed the study 


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• Number and percentage of subjects randomized and treated who discontinued from the 
study 
• The reasons for study discontinuation 
• Number and percentage of randomized and treated subjects included in each analysis set 
6.2. 
Extent of Exposure 
RSLV-132 or Placebo will be administered intravenously at 10 mg/kg at baseline, then weekly 
for two weeks and then once every 2 weeks for the next 10 weeks (in total 8 administrations) to 
subjects with pSS. These analyses will use the SAS population. 
Total duration of study drug dosing (days), total duration of infusion (Hours), total volume 
infused (mL) and total duration of study drug exposure will be summarized by treatment group.  
The number and percentage subjects with overall infusion status (completed, interrupted or 
terminated) during the treatment period and the reason for interrupted or terminated will be 
summarized by treatment group.  The percentages will be calculated based on the number of 
subjects in each treatment group. 
Total duration of study drug dosing will be calculated as the total number of days from the first 
dose date to the last dose date plus 1 regardless of temporarily dose interruptions.  Total duration 
of infusion will be calculated as the total minutes from each infusion segment (if the infusion 
was interrupted and then started again) start time to end time plus 1.   
Overall infusion completed is defined as a subject without any infusion interruptions or 
terminations during the study.  
 Total duration of study drug exposure (Days) is defined as the sum of (study Day 1 to the last 
visit date plus 1).  
6.3. 
Protocol Deviations 
Deviations from the protocol will be documented on an ongoing basis on the protocol deviations 
eCRF throughout the study.  Major protocol deviations will be determined prior to the database 
lock. The number and percentage of subjects within each major deviation category will be 
summarized by treatment group on the FAS.  The percentages will be calculated based on the 
number of subjects in each treatment group of the FAS.  The deviations collected on the eCRF 
will be listed.   
Inclusion and exclusion criteria data will be listed for all subjects. 


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7. 
 BASELINE DATA 
7.1. 
Demographic and Baseline Characteristics 
Demographic (age [years], gender, race, ethnicity, height [cm], weight [kg], BMI [kg/m2]) from 
screening visit and baseline characteristics from baseline Day 1 visit (complement levels (C3 & 
C4), ESR, ESSDAI, Schirmer’s Test, stimulated and unstimulated salivary flow, VAS, ESSPRI, 
FACIT, Profile of fatigue, EQ-5D-L) will be summarized descriptively by treatment group on 
the FAS.  For categorical parameters, the percentages will be calculated based on the number of 
subjects in each treatment group of the FAS. 
Age at Screening Visit will be calculated as (the informed consent date-birth date)/365.25.  
7.2. 
Medical History  
Number and percentage of subjects with medical history body system categories will be 
summarized by treatment group for the FAS. 
A subject with multiple occurrence of the same body system category will be counted only once.  
Medical history body system categories will be sorted alphabetically.  The percentages will be 
calculated based on the number of subjects in each treatment group of the FAS. 
8. 
PRIOR AND CONCOMITANT MEDICATIONS 
8.1. 
Medications  
Prior and concomitant medications will be coded using the World Health Organization (WHO) 
drug dictionary for anatomical therapeutic chemical classification (ATC) and preferred drug 
name.  The most current version of dictionary available will be used for the coding.  Number and 
percentage of subjects with each of the coded medications will be summarized by treatment 
group on the FAS.  A subject who used multiple medications will be counted only once for each 
ATC and preferred drug name.  ATC and preferred drug name within each ATC will be sorted 
alphabetically.  The percentages will be calculated based on the number of subjects in each 
treatment group of the FAS.  Prior and concomitant medications will be summarized separately.  
No inferential statistics will be performed. 
Prior medications are defined as any medications that started and stopped prior to the date of first 
dose of study drug (RSLV-132 or Placebo).  Concomitant medications are defined as any 
medications that started or were ongoing at or after the date of first dose of study drug (RSLV-
132 or Placebo).  Where a medication recorded with a partially or fully missing start/stop date or 


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time, and it is unclear as to whether the medication is concomitant, it will be assumed that it is 
concomitant. 
9. 
EFFICACY ANALYSES 
Efficacy analyses include assessing changes in disease activity using blood cell gene expression, 
serum protein level, ESSDAI, PGA, stimulated and unstimulated salivary flow, and Schirmer’s 
test. 
Each assessment will be summarized descriptively by treatment group on the FAS for all study 
visits at which the data were collected.  No statistical testing will be performed, unless otherwise 
specified. 
If the data are collected at the Screening Visit and are not collected at the Baseline (Day 1), the 
Screening values will be used as the baseline.   
All data will be listed. 
9.1. 
Analysis of Primary Efficacy Endpoints 
The primary endpoint is to assess changes in blood cell gene expression and serum protein level 
as surrogate endpoints in the active versus control groups comparing Baseline with Day 99 
among FAS population.   
9.1.1. 
Blood Cell Gene Expression 
Blood will be collected into PAX gene RNA collection tubes, RNA will be extracted and 
analyzed by Resolve Therapeutics (Seattle, WA) to measure the expression level of genes that 
are related to inflammatory pathways thought to be involved in primary Sjogren’s syndrome and 
to analyze the presence of various micro RNAs. The analysis of gene expression profiles will not 
be a part of this SAP. 
9.1.2. 
Serum Protein Level 
Serum samples will be obtained at various visits during the study and the level of circulating 
serum cytokines and other proteins that are thought to be related to the inflammation and 
autoimmunity process shall be measured by MyriadBRM (Austin, TX). The analysis of serum 
protein level will not be a part of this SAP. 
9.2. 
Analysis of Secondary Efficacy Endpoints 
The following measurements will be used to assess efficacy:ESSDAI, PGA, stimulated and unstimulated 
salivary flow, and Schirmer’s test. Patient reported outcomes such as ESSPRI, FACIT, Profile of 


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fatigue, EQ-5D-L, and Fatigue VAS are also summarized as a part of secondary measures. 
9.2.1. 
ESSDAI 
European League Against Rheumatism (EULAR) Sjögren’s syndrome disease activity index 
(ESSDAI) will be performed for each subject at Baseline (Day1), Day 29, Day 57, Day 85 and 
Day 99 to determine the pSS disease activity for each subject at the visit.  The total score will be 
summarized.  The improvements from Baseline (Day 1) to Day 99 in ESSDAI total scores will 
be evaluated as part of the efficacy endpoints.  Lower score represents less disease activity. 
Summary of observed values: Observed values and the change from baseline, including percent 
change from baseline at each scheduled visit will be summarized.  No statistical testing will be 
performed. 
Summary of imputed values: Imputed values and the change from Baseline (Day 1) in the 
ESSDAI total score at each scheduled visit will also be analyzed.  The two-sample t-test will be 
used for the treatment group comparison for descriptive purposes.  LOCF will be used to impute 
missing values on the FAS. 
9.2.2. 
PGA 
Physicians Global Assessment (PGA) will be performed for each subject at Baseline (Day1), 
Day 29, Day 57, Day 85 and Day 99 to determine the pSS disease activity for each subject at the 
visit.  The assessment is measured on a 0 to 100 Millimeter (mm) scale with score 0 to be No 
Disease Activity and score 100 to be the most Severe Disease Activity.  The improvements from 
Baseline (Day 1) to Day 99 in PGA scores will be evaluated as part of the efficacy endpoints. 
Summary of observed values: Observed values and the change from baseline at each scheduled 
visit will be summarized.  No statistical testing will be performed. 
Summary of imputed values: Imputed values and the change from Baseline (Day 1) in the PGA 
score at each scheduled visit will also be analyzed.  The two-sample t-test will be used for the 
treatment group comparison for descriptive purposes.  LOCF will be used to impute missing 
values on the FAS. 
9.2.3. 
Salivary Flow 
Stimulated and unstimulated salivary flow will be measured by each subject at Baseline (Day1), 
Day 29, Day 57, Day 85 and Day 99 for each subject at the visit.  The changes from Baseline 
(Day 1) to Day 99 in two total weights (grams) of stimulated and unstimulated salivary flow will 
be evaluated as part of the efficacy endpoints. 


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Summary of observed values: Observed values and the change from baseline at each scheduled 
visit will be summarized.  No statistical testing will be performed. 
Summary of imputed values: Imputed values and the change from Baseline (Day 1) in the 
stimulated and unstimulated salivary flow total weights at each scheduled visit will also be 
analyzed.  The two-sample t-test will be used for the treatment group comparison for descriptive 
purposes.  LOCF will be used to impute missing values on the FAS. 
9.2.4. 
Schirmer’s test 
Schirmer’s test will be performed by each subject at Baseline (Day1), Day 29, Day 57, Day 85 
and Day 99 for each subject at the visit.  The changes from Baseline (Day 1) to Day 99 in the 
wetting measurement (mm) of left and right eyes will be evaluated as part of the efficacy 
endpoints. 
Summary of observed values: Observed values and the change from baseline at each scheduled 
visit will be summarized.  No statistical testing will be performed. 
Summary of imputed values: Imputed values and the change from Baseline (Day 1) in the 
wetting measurement (mm) of left and right eyes at each scheduled visit will also be analyzed.  
The two-sample t-test will be used for the treatment group comparison for descriptive purposes.  
LOCF will be used to impute missing values on the FAS. 
9.2.5. 
Patient Reported Outcomes (EULAR Sjogren’s syndrome patient reported index 
(ESSPRI), Functional Assessment of Chronic Illness Therapy (FACIT), Profile 
of fatigue, EQ-5D-5L, Fatigue Visual Analog Scale (VAS))  
Patient reported outcomes will be performed by each subject at Baseline (Day1), Day 29, Day 
57, Day 85 and Day 99 for each subject at the visit. 
Summary of observed values: Observed values and the change from baseline at each scheduled 
visit will be summarized.  No statistical testing will be performed. Specifically, ESSPRI will also 
include summaries of percent change from baseline at each scheduled visit.  
Regarding FACIT, the composite scores at each time point will be summarized.  
10. 
SAFETY ANALYSES 
The safety assessment of the treatment will be compared between the two groups by adverse 
events and laboratory results as well as any physical findings that have changed from baseline.  
The safety analysis will include adverse events, concomitant medications, laboratory data, vital 
signs and immunogenicity of RSLV-132.   


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Sponsor will clean all the data and lock the database once the last subject completes the day 99 
visit.  Once all the subjects have completed day 211 sponsor will clean any pending data queries, 
and plan to compile the complete safety data set. 
All data will be summarized as observed and no data imputation will be used. 
10.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
version 20.0 or higher) adverse event dictionary.  If a subject experiences multiple events that 
map to a single preferred term, the greatest severity and strongest investigator assessment of 
relationship to study drug will be reported for the applicable summaries.  
Treatment-emergent adverse events (TEAE) are defined as events for which the date of onset is 
on or after the date of first dose of study drug (RSLV-132 or Placebo).  Where an adverse event 
(AE) collected after the date of first dose with a partially or fully missing start date or time, and it 
is unclear as to whether the AE is treatment emergent, it will be assumed that it is treatment 
emergent. 
The number and percentage of subjects with adverse events will be summarized by treatment 
group.  The percentages will be calculated based on the number of subjects in each treatment 
group of the SAS.  System organ class (SOC) and preferred term (PT) within each SOC will be 
presented in descending frequency of RSLV-132 group.  Subjects will be counted only once for 
each SOC and PT. 
All adverse events (treatment-emergent and non-treatment-emergent) will be listed.  
10.1.1. 
 Overall Adverse Events 
The number and percentage of subjects with at least one adverse event will be summarized for 
the following:  
• Subjects with any treatment-emergent adverse event 
• Subjects with severe  treatment-emergent adverse event 
• Subjects with any study drug related treatment-emergent adverse event  
• Any treatment-emergent adverse event leading to study drug discontinuation / study 
termination    
• Subjects with any treatment-emergent serious adverse event 
• Subjects with any study drug related treatment-emergent serious adverse event 
• Subjects with outcome of death 


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10.1.2. 
 Incidence of Adverse Events 
Subjects with at least one treatment-emergent adverse event will be summarized by SOC, PT, 
and by treatment group.  
Treatment-emergent adverse event summary by PT with descending order of frequency in the 
RSLV-132 group will also be presented by treatment group.   
10.1.3. 
Relationship of Adverse Event to Study Drug 
Treatment-emergent adverse events with closest relationship to study drug according to the 
categories specified in the protocol (Not Related, Possibly Related and Definitely Related) will 
be summarized for related events by SOC, PT, and treatment group. 
A study drug related AE is defined as any AE that is assessed by the investigator with the 
relationships of “Possibly Related” and “Definitely Related”.  Study drug non-related AE is 
defined as any AE that assessed by investigator with the relationships of “Not-Related”. 
Any treatment-emergent AEs that have a missing relationship will be presented in the summary 
table as “Related” but will be presented in the data listing with a missing relationship. 
10.1.4. 
Severity of Adverse Event 
Treatment-emergent adverse events with maximum investigator-reported severity (Mild, 
Moderate, Severe, Life Threatening and Fatal) will be summarized by SOC, PT, and treatment 
group. 
Any treatment-emergent AEs that have a missing severity will be presented in the summary table 
with the worst severity but will be presented in the data listing with a missing severity. 
10.1.5. 
Serious Adverse Events 
All treatment-emergent serious adverse events (SAEs) will be summarized by SOC, PT, and by 
treatment group.   
A summary of study drug related treatment-emergent SAEs by SOC, PT, and treatment group 
will also be presented. 


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10.1.6. 
Adverse Events Leading to Hospitalization / Study Drug Discontinuation / Study 
Termination 
All treatment-emergent adverse events that lead to either required or prolonged inpatient 
hospitalization or study drug discontinuation or study termination will be summarized by SOC, 
PT, and by treatment group. 
10.2. 
Laboratory and Other Safety Assessments 
Each assessment will be summarized descriptively by treatment groups on the SAS.  For 
assessments not measured at Baseline (Day 1) pre-dose, Screening Visit value will be used as the 
baseline.  No missing data imputation will be used. 
All data will be listed.  
10.2.1. 
Laboratory Blood and Urine Samples 
Laboratory hematology, serum chemistry and urinalysis samples will be collected for each 
subject at scheduled visits for safety evaluations.  The laboratory test parameters are listed in the 
Protocol Appendix B.  The samples are analyzed by a central laboratory. 
Observed values and the change from Baseline (Day 1) at each visit will be summarized for the 
continuous values.  Number and percentage of subjects in each category will be summarized for 
the categorical values.  In addition, the number and percentage of subjects who have the lab 
results that are noted to be “clinically significant” by the investigator will be summarized.  The 
number and percentage of subjects who have Grade 3 or higher lab toxicity (based on 
Rheumatology CTC Grade System) during the study will also be summarized.  The percentages 
will be calculated based on the number of subjects in each treatment group of the SAS.   
Serum and urine pregnancy tests are for women of childbearing potential only.  Serum 
pregnancy test will be performed at Screening Visit and Day 141 (EOS).  The samples are 
analyzed by a central laboratory.  The urine pregnancy test will be done at Baseline (Day 1) only 
and will be performed at each study site.  Serum and urine pregnancy test data will be listed only. 
10.2.2. 
Vital Signs 
Vital signs will be evaluated for each subject at scheduled visits for systolic and diastolic blood 
pressure (SBP and DBP, mmHg), pulse rate (beats per minute [bpm]), respiratory rate (RR, 
bpm), and oral temperature (Celsius °C).   
Observed values and the change from Baseline (Day 1) at each visit will be summarized using 
descriptive statistics.   


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10.2.3. 
Physical Exam 
Physical exam will be performed according to the Study Procedures indicated in the Protocol 
Appendix B. 
The number and percentage of subjects with clinically significant abnormality in each body 
system will be summarized for each visit.  The percentages will be calculated based on the actual 
number of subjects at each visit in each treatment group of the SAS. 
10.3. 
Immunogenicity Analyses 
Serum will be analyzed for the presence of anti-RSLV 132 antibodies using a validated 
immunoassay.  Each positive serum sample will be evaluated for anti-drug antibodies (ADA) 
specificity by repeating the immunoassay in the presence of an excess of RSLV-132.  Confirmed 
positive, specific serum samples will be titered by serial dilution and a numerical titer will be 
assigned.  The immunogenicity of RSLV-132 as measured by the presence of RSLV-132 
antibodies will be evaluated as part of the safety endpoints. 
The serum samples for evaluating ADA will be collected for each subject at scheduled visits.  To 
assess immunogenicity, the number and percent of positive and negative results will be 
summarized descriptively by treatment groups on the SAS.  The percentages will be calculated 
based on the number of subjects in each treatment group with samples available at each visit. 
11. 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic (PK) parameters will be calculated for each subject, whenever possible, based 
on the serum concentrations of RSLV-132.  RSLV-132 drug concentration levels will be 
summarized if it is available. 


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12. 
REFERENCES 
 
 
 


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13. 
APPENDIX I:  FACIT-FATIQUE SCALE SAS SCORING 
*======================================================================== * 
* FACIT-Fatigue subscale Version 4 Scoring Program (Unweighted)           * 
* SAS codes written for all platforms (DOS, Windows, and UNIX)            * 
* (c) Copyright, 1995-1998, Chih-Hung Chang & David Cella                 * 
* All rights reserved                                                     * 
*                                                                         * 
* Version 4                                                               * 
*                                                                         * 
* Permission is granted for use and non-profit distribution of these SAS  * 
* codes providing that all copyright notices remain intact. The right to  * 
* distribute any portion of this program for profit or as part of any     * 
* commercial product is specifically reserved for the authors of that     * 
* portion.                                                                * 
*                                                                         * 
* SAS Programmer: Jennifer Beaumont 
 
                             * 
*======================================================================== * 
 
*======================================================================== * 
* Note1: Data may be input via CARDS statement or from an external file   * 
* with an INFILE statement                                                * 
*======================================================================== *; 
 
DATA fatigue; 
  INPUT id_code $ hi7 hi12 an1-an5 an7 an8 an12 an14-an16; 
  CARDS; 
A 0 0 0 2 2 2 1 1 0 0 1 2 3 
B 2 0 4 4 0 4 1 2 2 2 0 9 9 
C 0 0 4 4 1 3 4 2 1 1 0 9 9 
D 1 0 0 3 3 3 2 3 3 9 1 1 1 
E 0 0 4 4 0 4 4 4 3 3 1 2 3 
F 3 1 1 1 0 2 1 0 0 1 0 9 9 
G 0 2 2 4 4 4 4 4 2 3 0 9 9 
H 0 0 4 4 0 4 4 4 3 3 0 9 9 
I 0 0 4 4 0 4 4 3 1 1 0 9 9 
 ; 
 
DATA SCORING; 
  SET fatigue; 
 
  ARRAY ITEM {13} hi7 hi12 an1-an5 an7 an8 an12 an14-an16; 
 
  DO I=1 TO 13; 
    IF ITEM(I)=8 OR ITEM(I)=9 THEN ITEM(I)=.; 
  END; 
 
*======================================================================== * 
* SCORE REVERSALS FOR FACIT-Fatigue subscale.                             * 
*======================================================================== *; 
      
     HI7=4-HI7; 
     HI12=4-HI12; 
     AN1=4-AN1; 
     AN2=4-AN2; 


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     AN3=4-AN3; 
     AN4=4-AN4; 
     AN8=4-AN8; 
     AN12=4-AN12; 
     AN14=4-AN14; 
     AN15=4-AN15; 
     AN16=4-AN16; 
 
*======================================================================== * 
* NUMBERS OF ITEMS ANSWERED.                                              * 
*======================================================================== *; 
 
          FAT_N = N(OF HI7 HI12 AN1-AN5 AN7 AN8 AN12 AN14-AN16); 
           
*======================================================================== * 
* PRORATED SUBSCALE SCORE =                                               * 
*  [SUM OF ITEM SCORES]x[N OF ITEMS IN SUBSCALE]/[N OF ITEMS ANSWERED]    * 
*                                                                         * 
* WHEN THERE ARE MISSING DATA, PRORATING BY SUBSCALE IN THIS WAY IS       * 
* ACCEPTABLE AS LONG AS MORE THAN 50% OF THE ITEMS WERE ANSWERED.         * 
* THE TOTAL SCORE IS CALCULATED AS THE SUM OF THE PRORATED SUBSCALE       * 
* SCORES.                                                                 * 
* THE FACT SCALE IS CONSIDERED TO BE AN ACCEPTABLE INDICATOR OF PATIENT   * 
* QUALITY OF LIFE AS LONG AS OVERALL ITEM RESPONSE RATE IS GREATER THAN   * 
* 80%.                                                                    * 
*======================================================================== *; 
 
*======================================================================= * 
* FATIGUE SUBSCALE SCORE                        
 
 
      * 
*======================================================================= *; 
 
IF (FAT_N/13 > .50) THEN 
    Fatigue = SUM(OF HI7 HI12 AN1-AN5 AN7 AN8 AN12 AN14-AN16)*13/(FAT_N); 
 
RUN; 
 
PROC MEANS DATA=SCORING; 
  VAR Fatigue; 
  TITLE 'FACIT-Fatigue subscale UNIVARIATE STATISTICS'; 
  RUN; 
 
 


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Signature Page 
 
Reviewed and Accepted by: 
 
 
 
 
 
 
James Posada, PhD, Chief Executive Officer 
Resolve Therapeutics, LLC 
 
Date 
 
 
 
 
 
 
Daniel J. Burge, MD, Study Physician 
Resolve Therapeutics, LLC 
 
Date 
 
 
 
 
 
 
Anna Leonen, Director, Clinical Data Operations 
Axio Research, LLC 
 
Date 
 
Prepared by: 
 
 
 
 
 
 
Sharavi Peeramsetti, Project Director/Biostatistician 
Axio Research, LLC 
 
Date 
 
02Oct2018