Clinical trial NCT02701985
Conditions: Sjogren's Syndrome
Sponsor: Hoffmann-La Roche
Start date: 2016-07-05; Completion date: 2017-07-10
Enrollment: 75 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, two-treatment arm, parallel-group study designed to evaluate the effects of RO5459072 treatment on disease activity and symptoms of Sjogren's syndrome in adult participants with moderate to severe primary Sjogren's syndrome. The total duration of the study for each participant will be approximately 18 weeks (including screening).

Detailed description:

Arms: arm 1: Matching-placebo capsules will be administered orally, 2 times a day, for up to 12 weeks. arm 2: RO5459072 at a dose of 100 milligrams (as capsules) will be administered orally, 2 times a day, for up to 12 weeks.
Interventions: intervention 1: Placebo intervention 2: RO5459072
Intervention descriptions: intervention 1: Matching-placebo capsules will be administered orally, 2 times a day with food. intervention 2: RO5459072 at a dose of 100 milligrams (as capsules) will be administered orally, 2 times a day with food.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL GROUP PHASE 2A STUDY TO 
ASSESS THE EFFICACY OF RO5459072 IN PATIENTS WITH 
PRIMARY SJÖGREN’S SYNDROME 
NCT Number: 
NCT02701985 
Document Dates: 
Protocol Version 3: 30-Oct-2016 
 
 
 


 
Title
30-Oct-2016 15:40:47
Date and Time (UTC)
Translational Medicine Leader
Approver's Name
FINAL PROTOCOL APPROVAL 
 
 
 
 
CONFIDENTIAL STATEMENT 
 
The information contained in this document, especially any unpublished data, is the property of 
F.Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
RO5459072— F. Hoffmann-La Roche Ltd 
Protocol BP30037 Version 3 
PROTOCOL 
TITLE: 
A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL GROUP 
PHASE 2A STUDY TO ASSESS THE EFFICACY OF 
RO5459072 IN PATIENTS WITH PRIMARY 
SJÖGREN’S SYNDROME 
PROTOCOL NUMBER: BP30037 
VERSION: 
3 
EUDRACT NUMBER: 
2015-004476-30 
IND NUMBER: 
128528 
TEST PRODUCT: 
RO5459072 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1: 28 January 2016 
DATE AMENDED 
Version 2: 01 August 2016 
Version 3: See electronic date stamp below 


PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol BP30037 has been amended to incorporate the following changes to the 
protocol: 
Section 4.2.3: Implementation of changes to eligibility criteria 
 
 
. 
The eligibility criteria of the protocol have therefore been amended to mandate testing 
for tuberculosis and exclude patients with positive results. 
 the eligibility criteria have also been amended to exclude women 
who are breast-feeding or planning to nurse. 
The eligibility criteria have been amended to explicitly exclude patients who are using 
strong inhibitors of CYP3A4 and P-glycoprotein (P-gp), as well as compounds inducing 
CYP3A4. These medications were already specified as prohibited therapies. For 
consistency with changes to Section 4.5.2, patients using sensitive substrates of 
CYP3A4 with a narrow therapeutic window are also explicitly excluded.  
Section 4.5.2: Update on the use of prohibited therapy 
 
 
Explicit prohibition of the use of sensitive substrates of CYP3A4 with a narrow 
therapeutic index has been added to existing cautionary statements about the 
concomitant use of CYP3A4 substrates.  
Section 4.6.1.4: Addition of bicarbonate to laboratory test panel 
The European League against Rheumatism (EULAR) Sjögren's Syndrome Disease 
Activity Index (ESSDAI) assessment includes evaluation of renal acidosis. Measurement 
of bicarbonate is important for diagnosis of renal acidosis and has consequently been 
added to the laboratory test panel. 
Section 4.6.1.6: Addition of IgM to antibody titre measurements 
The ESSDAI assessment includes, among others, evaluation of 
hypergammaglobulinemia.  
Measurement of IgM is required for this assessment and hence total IgM has been 
added to the list of antibody titres to be measured. As samples for the above were not 
collected at all visits where ESSDAI was evaluated, additional assessment time points 
for cryoglobulin, IgG and IgM have been added to the Schedule of Assessment (SoA) 
RO5459072—F. Hoffmann-La Roche Ltd 
2/Protocol BP30037, Version 3 


tables and the complement C3/4 assessment has been moved to the blood biochemistry 
panel. 
Section 5.3.5.6: Liver Function Testing (LFTs) 
A section on interpretation and reporting of abnormal liver function tests has been 
inserted to provide more specific guidance for investigators. 
Section 6: Statistical Considerations and Analysis Plan 
The alpha level for any hypothesis testing has been clarified as 2-sided at the 0.05 level 
to align with the use of 95% confidence intervals (CIs). Additionally the primary analysis 
will use a non-responder approach for missing data and an exploratory analysis was pre-
specified adjusting for baseline ESSDAI score.  
Section 6.7: Pharmacodynamic Analyses 
This section has been modified to clarify that pharmacodynamic data will primarily be 
summarized and listed according to treatment actually received. Limited exploratory 
analyses employing methods used for efficacy endpoints on the mITT population may be 
carried out, but will be detailed in the statistical analysis plan. 
 
RO5459072—F. Hoffmann-La Roche Ltd 
3/Protocol BP30037, Version 3 


PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 3.2.6: Rationale for Pharmacodynamic Assessments 
Elevated circulating titers of a range of auto-antibodies are reported in patients with 
primary Sjögren’s syndrome (Tzioufas et al 2012), and as no single type is considered 
diagnostic, prognostic or predictive a panel including a representative cross-section will 
be measured, as well as total IgG, IgM and cryoglobulins (Quartuccio et al 2014). 
SECTION 4.2.3: Exclusion Criteria 
The exclusion criteria have been updated as follows: 
6. 
A positive test result for hepatitis B (HBV), hepatitis C (HCV), or human 
immunodeficiency virus (HIV), a history ofor tuberculosis, or any other active viral, 
fungal, yeast or bacterial infection at the screening visit. 
.... 
14. Women who are lactating. 
15. Use of other prohibited medication (moderate or potent inhibitors of CYP3A4; 
strong inducers of CYP3A4; strong inhibitors of the transporter P-glycoprotein 
[P-gp]; sensitive substrates of CYP3A4 with a narrow therapeutic index). 
 
SECTION 4.5.2: Prohibited Therapy 
Because RO5459072 is a substrate of CYP3A4 and P-gp, other prohibited medications 
are: 
• 
Moderate or potent inhibitors of CYP3A4 (e.g., itraconazole, erythromycin, 
nefazodone). 
• 
Strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine). 
• 
Sensitive substrates of CYP3A4 with a narrow therapeutic index (e.g., alfentanil, 
colchicine, ethosuxamide, fentanyl, and pimozide). 
• 
Strong inhibitors of the transporter P-glycoprotein (P-gp) (e.g., quinidine, 
clarithromycin). 
A full list of prohibited concomitant medications is provided in Appendix 4.  
RO5459072—F. Hoffmann-La Roche Ltd 
4/Protocol BP30037, Version 3 


SECTION 4.6.1.4: Laboratory Assessments 
• 
BloodSerum chemistry: Albumin, alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), bicarbonate, C-reactive 
protein (CRP), calcium, chloride, creatinine phosphokinase (CPK), gamma-glutamyl 
transferase (GGT), glucose, phosphate, potassium, creatinine, sodium, total bilirubin, 
total protein, troponin, urea, complement (C3 and C4), 
• 
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT) 
• 
Lipids: High-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein 
cholesterol (LDL-C), triglycerides, total cholesterol. 
• 
Urinalysis A midstream urine specimen will be collected for dipstick analysis of 
protein, blood, glucose, and pH. 
• 
At Screening only: HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), hepatitis C virus (HCV) antibody, tuberculosis testing. 
 
SECTION 4.6.1.6: Pharmacodynamic Assessments 
Auto-antibodies (anti-SSA/SSB) 
Serum will be collected for the determination of anti-SSA/SSB autoantibodies as 
indicated in the SoA (Appendix 1). These measurements will include anti-SSA, anti-SSB, 
ANA, and rheumatoid factor, as well as total IgG, IgM and cryoglobulins. 
…. 
Soluble Biomarker Assessments 
Plasma samples - Samples for measurement of biomarkers connected to Sjögren’s 
syndrome and extracellular matrix degradation will be collected at specified visits as 
indicated in the SoA (Appendix 1). Biomarkers to be measured will include complement 
(C3 and C4), β2-microglobulin, cytokines (including, but not limited to, BAFF, IL-4, IL-6 
and IL-10), beta-hydroxycholesterol and desmosine. 
SECTION 5.3.5.6: Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( >  3 ×  ULN) in combination with either an 
elevated total bilirubin ( >  2  ×  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST  >  3  ×  ULN in combination with total 
bilirubin  >  2  ×  ULN 
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• 
Treatment-emergent ALT or AST  >  3  ×  ULN in combination with clinical 
jaundice 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
SECTION 6.1: Determination of Sample Size 
A total of 70 patients will be randomized in a 1:1 ratio to RO5459072 or placebo 
(35 patients per treatment group). Assuming a maximum drop out rate of 15%, it is 
anticipated that enrollment of 70 patients would ensure at least 60 patients complete the 
study.
SeventySixty patients (350 per treatment group) will provide power in the range of at 
least 58 % to at least 80 % power to detect a 33% difference in ESSDAI response rates 
between treatment groups in the range of 25 % to 33 % (two-sided Chi-square test 
assuming alpha of 0.0515 and placebo rate ≤  25%). This sample size was determined by 
practical considerations. Seventyixty patients are also sufficient to provide 
approximately 8700% power to detect a difference of 3 points between treatment arms 
in change from baseline in ESSDAI score (t-test assuming two-sided alpha 0.015 and 
standard deviation of 5.0). 
Approximately 30 patients will be enrolled into the optional sub-study. It is anticipated 
that enrollment of a minimum of 30 patients should ensure at least 20 patients (10 per 
treatment group) complete the study and have biopsy samples taken at both baseline 
and Week 12, assuming a maximum drop-out rate of 15%.  This sample size was 
determined by practical consideration. 
SECTION 6.3.2: Pharmacodynamic Analysis Population 
All patients who have received at least one dose of the study medication and who have 
pharmacodynamic data available will be included in pharmacodynamic analyses. For 
these analyses, patients will primarily be grouped according to the treatment actually 
received; unless otherwise specified in the statistical analysis plan. 
Analyses of pharmacodynamic data will employ similar methods as used for continuous 
efficacy endpoints, i.e., analyses will employ the mITT population. 
SECTION 6.6.1:  Primary Efficacy Endpoint 
The primary endpoint is the proportion of patients who have ≥ 3 point reduction from 
baseline in ESSDAI score after 12 weeks of treatment. The proportion of subjects 
patients who have ≥ 3 point reduction from baseline in ESSDAI score after 12 weeks of 
treatment will be compared between the two treatment arms using a Pearson Chi-square 
RO5459072—F. Hoffmann-La Roche Ltd 
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RO5459072—F. Hoffmann-La Roche Ltd 
7/Protocol BP30037, Version 3 
test (two sided p-values, alpha 0.05). The difference in proportions Two sided p values 
will be reported. Absolute reduction in risk and corresponding 95% confidence interval 
(CI) will be provided. Patients with missing data at Week 12 will be treated as non
- responders in the analysisMissing data will be imputed by last observation carried 
forward (LOCF) method. 
Sensitivity analyses will be conducted if deemed necessary, including sensitivity 
analyses for imputational methodfor handling for missing data (e.g., ., 
completerscompleter’s analysis or last observation carried forward (LOCF) 
methodimputing non responders for missing observations). 
In addition; the proportion of patientsubjects who have  ≥  3 point reduction from 
baseline in ESSDAI score after 12 weeks of treatment will be analyzed using a logistic 
regression model, adjusting for baseline ESSDAI score. 
SECTION 6.6.2:  Secondary Efficacy Endpoint 
The denominator degrees of freedom will be estimated using the Kenward-
Roger.Satterthwaite’s approximation. 
SECTION 6.7: PHARMACODYNAMIC ANALYSES 
All pharmacodynamic parameters will be presented by listings and descriptive summary 
statistics separately by treatment group. 
Pharmacodynamic variables at each assessment time-point along with corresponding 
changes from baseline will be listed by individual and summarized using descriptive 
summary statistics. Descriptive summary statistics will include the calculation of 
arithmetic means, standard deviation, coefficient variation, median, and range, as 
appropriate. Graphical plots of individual and mean absolute and change from baseline 
versus time profiles will also be produced for each treatment. 
Analyses of pharmacodynamic data will employ similar methods as used for continuous 
efficacy endpoints, i.e., change from baseline at on treatment visits will be compared 
between the treatment groups using a MMRM approach in the mITT population. 
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol.  
 


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APPENDIX 4:  Prohibited Concomitant Medication 
MDR1 (P-gp) inhibitors 
Amiodarone, azithromycin, carvedilol, clarithromycin, dronedarone, erythromycin, 
fluvoxamine, indinavir, itraconazole, ketoconazole, lapatinib, propafenone, quercetin, 
quinidine, quinine, ranolazine, ritonavir (and ritonavir combinations), telaprevir, verapamil, 
vorapaxar. 
Sensitive substrates of CYP3A4 with a narrow therapeutic index 
Alfentanil, colchicine,ethosuxamide, fentanyl, pimozide. 
 
Various sections:  
Correction of minor inconsistencies between protocol sections and typographical errors 
has been done. Additional tuberculosis test at screening has been included. For clarity, 
tear and salivary flow assessments have been indicated in the SoA table (in line with 
salivary and tear sample collection time points), and additional biomarker sample 
collection time points (for the ESSDAI score) have been entered for the early 
termination/ follow-up visit in the SoA table. Furthermore, Figure 3 Study Design, was 
adjusted for improved clarity regarding the safety and follow-up visit. 
 
MASTER INFORMED CONSENT FORM 
The master Informed Consent Form been revised to reflect the changes to the protocol. 


 
TABLE OF CONTENTS 
SYNOPSIS OF PROTOCOL NUMBER BP30037.............................................. 15 
1. 
BACKGROUND AND RATIONALE............................................................. 26 
1.1 
Background on Disease......................................................... 26 
1.2 
Background on Cathepsin S.................................................. 27 
1.3 
Background on RO5459072 .................................................. 28 
1.3.1 
Previous Non-Clinical Studies ............................................... 28 
1.3.1.1 
Non-Clinical Pharmacology ................................................... 28 
1.3.1.2 
Non-Clinical Pharmacokinetics and Product 
Metabolism ............................................................................ 28 
1.3.1.3 
Toxicology and Safety Pharmacology ................................... 29 
1.3.2 
Previous Clinical Studies ....................................................... 30 
1.3.2.1 
Studies with RO5459072....................................................... 30 
1.3.2.2 
Studies with Other Cathepsin S Inhibitors ............................. 34 
1.4 
Study Rationale and Benefit–Risk Assessment..................... 34 
1.4.1 
Study Rationale ..................................................................... 34 
1.4.2 
Benefit-Risk Assessment....................................................... 35 
2. 
OBJECTIVES.............................................................................................. 36 
2.1 
Primary Objectives ................................................................ 36 
2.2 
Secondary Objectives............................................................ 37 
2.3 
Exploratory Objectives........................................................... 37 
2.4 
Optional Sub-study Objective ................................................ 37 
3. 
STUDY DESIGN ......................................................................................... 38 
3.1 
Description of Study .............................................................. 38 
3.1.1 
Overview of Study Design ..................................................... 38 
3.1.2 
End of Study.......................................................................... 39 
3.2 
Rationale for Study Design.................................................... 39 
3.2.1 
Rationale for Dosage Selection ............................................. 39 
3.2.2 
Rationale for Study Population .............................................. 40 
3.2.3 
Rationale for Control Group................................................... 41 
3.2.4 
Rationale for Design .............................................................. 42 
3.2.5 
Rationale for Efficacy Assessments ...................................... 42 
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3.2.6 
Rationale for Pharmacodynamic Assessments ..................... 43 
3.2.7 
Rationale for Pharmacokinetic Assessments......................... 44 
3.2.8 
Rationale for Safety Assessments......................................... 44 
3.2.9 
Rationale for Other Assessments.......................................... 44 
3.2.10 
Rationale for Biopsy Sub-study ............................................. 44 
3.3 
Outcome Measures ............................................................... 44 
3.3.1 
Efficacy Outcome Measures.................................................. 44 
3.3.2 
Pharmacodynamic Outcome Measures................................. 45 
3.3.3 
Pharmacokinetic Outcome Measures.................................... 45 
3.3.4 
Safety Outcome Measures .................................................... 45 
3.3.5 
Exploratory Outcome Measures ............................................ 46 
3.3.6 
Optional Sub-study Outcome Measures................................ 46 
4. 
MATERIALS AND METHODS .................................................................... 46 
4.1 
Centers.................................................................................. 46 
4.2 
Study Population ................................................................... 46 
4.2.1 
Recruitment Procedures........................................................ 47 
4.2.2 
Inclusion Criteria.................................................................... 47 
4.2.3 
Exclusion Criteria................................................................... 47 
4.3 
Method of Treatment Assignment and Blinding..................... 48 
4.3.1 
Treatment Assignment........................................................... 48 
4.3.2 
Blinding.................................................................................. 48 
4.3.3 
Emergency Unblinding........................................................... 48 
4.4 
Study Treatment.................................................................... 49 
4.4.1 
Formulation, Packaging, and Handling.................................. 49 
4.4.1.1 
RO5459072 and Placebo ...................................................... 49 
4.4.2 
Dosage, Administration, and Compliance.............................. 50 
4.4.2.1 
RO5459072 and Placebo ...................................................... 50 
4.4.3 
Investigational Medicinal Product Accountability ................... 50 
4.4.4 
Post-Trial Access to RO5459072 .......................................... 51 
4.5 
Concomitant Therapy and Food ............................................ 51 
4.5.1 
Permitted Therapy ................................................................. 51 
4.5.2 
Prohibited Therapy ................................................................ 52 
4.5.3 
Vaccination............................................................................ 53 
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4.5.4 
Food ...................................................................................... 53 
4.5.5 
Contraception ........................................................................ 53 
4.6 
Study Assessments ............................................................... 54 
4.6.1 
Description of Study Assessments ........................................ 54 
4.6.1.1 
Medical History and Demographic Data ................................ 54 
4.6.1.2 
Physical Examinations........................................................... 54 
4.6.1.3 
Disease-Specific Assessments.............................................. 55 
4.6.1.4 
Laboratory Assessments ....................................................... 56 
4.6.1.5 
Pharmacokinetic Assessments.............................................. 57 
4.6.1.6 
Pharmacodynamic Assessments........................................... 57 
4.6.1.7 
Clinical Genotyping................................................................ 59 
4.6.1.8 
Electrocardiograms................................................................ 59 
4.6.1.9 
Vital Signs.............................................................................. 60 
4.6.1.10 
Administering the SF36 and ESSPRI (Patient-
Reported Outcomes) ............................................................. 60 
4.6.1.11 
MSG Biopsies (Optional Sub-study) ...................................... 60 
4.6.1.12 
Timing of Assessments - Screening and 
Pretreatment Assessments.................................................... 61 
4.7 
Patient, Study, and Site Discontinuation................................ 61 
4.7.1 
Patient Discontinuation.......................................................... 61 
4.7.2 
Study and Site Discontinuation.............................................. 62 
5. 
ASSESSMENT OF SAFETY....................................................................... 62 
5.1 
Safety Parameters and Definitions ........................................ 62 
5.1.1 
Adverse Events ..................................................................... 63 
5.1.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 63 
5.1.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 64 
5.2 
Safety Plan ............................................................................ 64 
5.2.1 
Management of Specific Adverse Events .............................. 64 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 64 
5.3.1 
Adverse Event Reporting Period ........................................... 65 
5.3.2 
Eliciting Adverse Event Information ....................................... 65 
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5.3.3 
Assessment of Severity of Adverse Events ........................... 65 
5.3.4 
Assessment of Causality of Adverse Events ......................... 65 
5.3.5 
Procedures for Recording Adverse Events............................ 66 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 66 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 66 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 67 
5.3.5.4 
Abnormal Laboratory Values ................................................. 67 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 68 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 68 
5.3.5.7 
Deaths ................................................................................... 69 
5.3.5.8 
Preexisting Medical Conditions.............................................. 69 
5.3.5.9 
Hospitalization or Prolonged Hospitalization.......................... 69 
5.3.5.10 
Overdoses ............................................................................. 70 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 70 
5.4.1 
Emergency Medical Contacts................................................ 71 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 71 
5.4.3 
Reporting Requirements for Pregnancies.............................. 71 
5.4.3.1 
Pregnancies in Female Patients............................................ 71 
5.4.3.2 
Pregnancies in Female Partners of Male Patient................... 71 
5.4.3.3 
Abortions ............................................................................... 72 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 72 
5.5 
Follow-Up of Patients after Adverse Events .......................... 72 
5.5.1 
Investigator Follow-Up........................................................... 72 
5.5.2 
Sponsor Follow-Up ................................................................ 72 
5.6 
Post-Study Adverse Events................................................... 73 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 73 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 73 
6.1 
Determination of Sample Size ............................................... 74 
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6.2 
Summaries of Conduct of Study............................................ 74 
6.3 
Analysis Populations ............................................................. 74 
6.3.1 
Efficacy Analysis Population.................................................. 74 
6.3.2 
Pharmacodynamic Analysis Population................................. 74 
6.3.3 
Pharmacokinetic Analysis Population.................................... 75 
6.3.4 
Safety Analysis Population .................................................... 75 
6.4 
Summaries of Treatment Group Comparability ..................... 75 
6.5 
Safety Analyses..................................................................... 75 
6.5.1 
Adverse Events ..................................................................... 75 
6.5.2 
Clinical Laboratory Test Results............................................ 75 
6.5.2.1 
Standard Reference Ranges and Transformation 
of Data................................................................................... 76 
6.5.2.2 
Definition of Laboratory Abnormalities................................... 76 
6.5.3 
Vital Signs.............................................................................. 76 
6.5.4 
ECG Data Analysis................................................................ 76 
6.5.5 
Concomitant Medications ...................................................... 77 
6.6 
Efficacy Analyses .................................................................. 77 
6.6.1 
Primary Efficacy Endpoint...................................................... 77 
6.6.2 
Secondary Efficacy Endpoints............................................... 77 
6.7 
Pharmacodynamic Analyses ................................................. 78 
6.8 
Pharmacokinetic Analyses..................................................... 78 
6.9 
Exploratory Analyses............................................................. 78 
6.10 
Interim Analyses .................................................................... 78 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 78 
7.1 
Data Quality Assurance......................................................... 78 
7.2 
Electronic Case Report Forms............................................... 79 
7.3 
Patient-Reported Outcome Data ........................................... 79 
7.4 
Source Data Documentation.................................................. 79 
7.5 
Use of Computerized Systems .............................................. 80 
7.6 
Retention of Records............................................................. 80 
8. 
ETHICAL CONSIDERATIONS.................................................................... 80 
8.1 
Compliance with Laws and Regulations ................................ 80 
8.2 
Informed Consent .................................................................. 81 
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8.3 
Institutional Review Board or Ethics Committee.................... 82 
8.4 
Confidentiality........................................................................ 82 
8.5 
Financial Disclosure .............................................................. 82 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 83 
9.1 
Study Documentation ............................................................ 83 
9.2 
Site Inspections ..................................................................... 83 
9.3 
Administrative Structure......................................................... 83 
9.4 
Publication of Data and Protection of Trade 
Secrets .................................................................................. 83 
9.5 
Protocol Amendments ........................................................... 84 
10. REFERENCES ........................................................................................... 85 
 
 
LIST OF TABLES 
Table 1 
Summary RO5459072 Pharmacokinetic Parameters at 
Steady-State after Administration with Food............................... 33 
Table 2 
Adverse Event Severity Grading Scale ....................................... 65 
 
 
LIST OF FIGURES 
Figure 1 
Mean Linear RO5459072 Plasma Concentration versus 
Time Profiles after a Single Dose and at Steady-State after 
Twice Daily Administration with Food ......................................... 32 
Figure 2 
Mean Change from Baseline in p10 Stimulation Index versus 
Time Profiles after a Single Oral Dose and after Repeat 
Dosing with Food ........................................................................ 33 
Figure 3 
Study Design............................................................................... 39 
Figure 4 
Simulation of cathepsin S enzyme inhibition over the dosing 
interval based on population pharmacokinetic/ 
pharmacodynamic model............................................................ 40 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments........................................................... 89 
Appendix 2 
Disease-Specific Assessments................................................... 91 
Appendix 3 
Dose-Equivalents of Systemic Corticosteroids............................ 93 
Appendix 4 
Prohibited Concomitant Medications........................................... 94 
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SYNOPSIS OF PROTOCOL NUMBER BP30037 
TITLE: 
A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, PARALLEL GROUP PHASE 2A STUDY TO 
ASSESS THE EFFICACY OF RO5459072 IN PATIENTS WITH 
PRIMARY SJÖGREN’S SYNDROME 
BP30037 
PROTOCOL NUMBER: 
3 
VERSION: 
EUDRACT NUMBER: 
2015-004476-30 
128528 
IND NUMBER: 
RO5459072 
TEST PRODUCT: 
PHASE: 
2A
Primary Sjögren’s Syndrome 
INDICATION: 
F. Hoffmann-La Roche Ltd 
SPONSOR: 
OBJECTIVES 
Primary Objective: 
• 
To investigate the effects of RO5459072 treatment on disease activity and symptoms of 
primary Sjögren’s syndrome. 
 
Secondary Objectives 
To investigate the effects of RO5459072 treatment on: 
• 
quality of life measures. 
• 
auto-antibody concentrations. 
• 
pharmacodynamic measures of exocrine gland function. 
Additionally: 
• 
To collect samples for population modelling of RO5459072 pharmacokinetics. 
• 
To investigate the safety and tolerability of RO5459072 treatment. 
 
Exploratory Objectives 
To investigate the effects of RO5459072 treatment on: 
• 
cathepsin S enzyme mass and activity. 
• 
sub-populations of circulating white blood cells. 
• 
biomarkers connected to Sjögren’s syndrome. 
• 
biomarkers of extracellular matrix degradation. 
Additionally: 
• 
To explore the influence of covariates on the effects of RO5459072 treatment. 
• 
To explore alternative composite endpoints as measures for evaluating effects of drug 
treatment. 
• 
To explore the effects of RO5459072 treatment on the use of concomitant medications. 
• 
To explore the occurrence of acute rebound phenomena on disease activity and 
symptoms following discontinuation of study drug treatment. 
RO5459072—F. Hoffmann-La Roche Ltd 
15/Protocol BP30037, Version 3 


 
Optional Sub-study 
The objective of the optional sub-study is: 
To investigate the effects of RO5459072 treatment on salivary gland structure, 
inflammation and the organization of inflammatory foci assessed by histology and 
immunohistochemistry of labial biopsy samples. 
STUDY DESIGN 
Description of Study 
Study BP30037 is a randomized, double-blind, placebo-controlled, two-treatment arm, 
parallel-group study designed to evaluate the effects of RO5459072 treatment on disease 
activity and symptoms of Sjögren’s syndrome in adult patients with moderate to severe 
primary Sjögren’s Syndrome. Patients will be randomized 1:1 to receive either 100 mg 
RO5459072 or placebo orally twice daily (b.i.d.). Patients will be treated for a maximum of 
12 weeks. 
Assessments of Sjögren’s syndrome disease activity, symptoms and quality of life will be 
made before, during the study treatment phase and upon completion in order to evaluate the 
efficacy of RO5459072 treatment. Patients should start study drug treatment one day after the 
baseline visit. In addition, patients will undergo pharmacodynamic assessments of exocrine 
gland function and provide samples for measurement of white blood cell numbers and levels 
of biomarkers associated with Sjögren’s syndrome or connected to the mechanism of action 
of RO5459072, as well as RO5459072 plasma concentrations. Safety and tolerability will be 
assessed throughout the study. 
At selected participating study centers, patients may also enroll into an optional sub-study in 
which consenting individuals will undergo minor salivary gland (MSG) biopsies for assessing 
histological changes in labial salivary glands. Biopsies will be taken at baseline and at the end 
of the study drug treatment period.  
Patients may concomitantly receive standard of care symptomatic treatment. Active or recent 
immunomodulatory therapy will not be allowed. 
NUMBER OF PATIENTS 
A total of 70 patients will be randomized in a 1:1 ratio to RO5459072 or placebo (35 patients 
per treatment group; approximately 30 patients will be enrolled into the optional sub-study).  
TARGET POPULATION 
Adults aged 18 to 75 years with moderate to severe primary Sjögren’s syndrome. 
INCLUSION/EXCLUSION CRITERIA 
Inclusion criteria: 
Patients must meet the following criteria for study entry: 
1. 
Males and females 18 to 75 years of age, inclusive. 
2. 
Patient willing to give written informed consent and to comply with the study procedures 
and restrictions. 
3. 
Primary Sjögren's syndrome diagnosed previously according to the revised American-
European Consensus Group (AECG) criteria. 
4. 
European League against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity 
Index (ESSDAI) score ≥ 5. 
5. 
EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score ≥ 5. 
6. 
Elevated serum titers of anti-Sjögren's-syndrome-related antigen A (anti-SSA) and/or 
anti-SSB antibodies at screening. 
7. 
Negative pregnancy test at screening and baseline (women only), and agreement to 
comply with measures to prevent pregnancy and restrictions on sperm donation (see 
Section 4.5.5). 
 
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Exclusion criteria: 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
A diagnosis of secondary Sjögren's syndrome according to the revised AECG criteria. 
2. 
Severe complications of Sjögren's syndrome, such as vasculitis with renal, neurologic or 
cardiac involvement; interstitial lung disease and severe myositis. 
3. 
Systemic immunosuppressant therapy (e.g., abatacept, azathioprine, ciclosporin, 
etanercept, tofacitinib), cyclophosphamide or B cell depleting therapy (e.g., rituximab 
anti-CD20 therapy) within 6 months prior to the screening visit. Low dose methotrexate 
treatment (i.e., oral doses ≤ 20 mg weekly) is, however, permitted. 
4. 
Corticosteroid therapy exceeding 7.5 mg prednisone equivalents per day. 
5. 
Mechanically stimulated whole salivary flow rate at baseline of < 0.1 mL/min. 
6. 
A positive test result for hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency 
virus (HIV), or tuberculosis, or any other active viral, fungal, yeast or bacterial infection at 
the screening visit. 
7. 
A history of recurring or chronic infections, any other indication of reduced immune 
function considered to be clinically significant by the Investigator, or any other underlying 
conditions which may further predispose patients to serious infection. 
8. 
A history of lymphoma, myeloma (monoclonal hypergammaglobulinemia) or monoclonal 
gammopathy of unknown significance (MGUS), or any other malignancies within the past 
5 years (except basal cell or squamous cell carcinoma of the skin that has been cured). 
9. 
A diagnosis of fibromyalgia, or a diagnosis of significant depression or anxiety that in the 
opinion of the investigator would confound the interpretation of the study results. 
10. Severe renal impairment (e.g., estimated glomerular filtration rate < 30 mL/min), moderate 
or severe hepatic impairment (e.g., Child-Pugh B or C) or other clinically significant hepatic 
disease (e.g., AST, ALT or GGT > 2x upper limit of normal). 
11. Current or a history of severe, progressive or uncontrolled hematologic, gastrointestinal, 
endocrine, pulmonary, cardiac, or neurologic disease, or any other concomitant disease or 
condition or any clinically significant finding at screening that could interfere with, or for 
which the treatment of might interfere with, the conduct of the study, or that would, in the 
opinion of the Investigator, pose an unacceptable risk to the individual in this study. 
12. Participation in an investigational drug or device study within 3 months prior to screening. 
13. Inability to comply with the study protocol for any other reason. 
14. Women who are lactating, breastfeeding or planning to nurse. 
15. Using other prohibited medication (moderate or potent inhibitors of CYP3A4; strong 
inducers of CYP3A4; strong inhibitors of the transporter P-glycoprotein [P-gp]; 
sensitive substrates of CYP3A4 with a narrow therapeutic index). 
LENGTH OF STUDY 
The total duration of the study for each patient will be approximately 18 weeks (screening visit 
to follow-up visit). For each subject the study will consist of: 
• 
Screening visit, up to 4 weeks before the first dose of study drug. 
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• 
Baseline visit, immediately preceding the first dose of study drug. 
• 
A 12-week double-blind treatment period, and including three study center visits. 
• 
A follow-up visit, 2 weeks after the last dose of study drug. 
 
END OF STUDY
The end of the study is defined as the date of the last study center visit of the last patient 
participating in the study (includes the safety follow-up visit). 
OUTCOME MEASURES
EFFICACY OUTCOME MEASURES 
Efficacy assessments will include the ESSDAI, ESSPRI, and Short Form-36 Health Survey 
(SF-36). ESSDAI and ESSPRI will also be measured at screening in order to assess eligibility 
for the study. 
The primary efficacy outcome for this study is: 
• 
Proportion of patients showing a clinically relevant decrease in ESSDAI score after 12 
weeks from baseline. 
where a clinically relevant decrease in ESSDAI score is defined as a decrease of ≥ 3 points. 
Secondary efficacy outcomes for this study are as follows: 
• 
Proportion of individuals showing a clinically relevant decrease in ESSPRI score after 
12 weeks where a clinically relevant decrease in ESSPRI score is defined as a decrease 
of ≥ 1 point. 
• 
Change from baseline in ESSDAI, ESSPRI and SF-36 scores after 12 weeks. 
• 
Change from baseline in each of the individual components of the ESSPRI (dryness, 
fatigue and pain) after 12 weeks. 
 
PHARMACODYNAMIC OUTCOME MEASURES 
The pharmacodynamics outcome measures for this study include: 
• 
Tear flow rate using the Schirmer’s test will be measured to assess the change from 
baseline. 
• 
Mechanically stimulated salivary flow rate will be measured to assess the change from 
baseline. 
• 
Measurement of serum auto-antibody titers from baseline which will include anti-SSA, 
anti-SSB, anti-nuclear antibodies, and rheumatoid factor, as well as total IgG, IgM and 
cryoglobulins. Auto-antibody titers (anti-SSA, anti-SSB) will also be measured at 
screening in order to assess eligibility for the study. 
• 
Erythrocyte sedimentation test (ESR) will be measured to assess the change from 
baseline. 
• 
Change from baseline in cathepsin S mass and activity in plasma, tears and saliva. 
• 
The collection and measurement of circulating numbers of sub-populations of white blood 
cells from baseline, which will be counted by fluorescence-activated cell sorting (FACS) 
immunophenotyping of cell surface markers and may include TBNK/monocytes, TH and 
TFH cells and B cells. 
• 
Biomarkers connected to Sjögren’s syndrome and extracellular matrix degradation will be 
measured to assess the change from baseline in biomarker concentrations. Biomarkers 
to be measured will include complement (C3 and C4), β2-microglobulin, cytokines 
(including - but not limited to - BAFF, IL-4, IL-6 and IL-10), beta-hydroxycholesterol 
and desmosine.  
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SAFETY OUTCOME MEASURES 
Safety assessments will include recording of adverse events (AEs) and concomitant 
medication use throughout the study, measurement of vital signs and triplicate 12-lead ECGs 
and laboratory safety testing. 
Laboratory safety tests will include: 
• 
Hematology: Hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, mean 
corpuscular volume, absolute reticulocyte count, total and differential leucocyte (WBC) 
absolute count (neutrophils, eosinophils, lymphocytes, monocytes and basophils).  
• 
Blood chemistry: Albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), 
bicarbonate, aspartate aminotransferase (AST), C-reactive protein (CRP), calcium, 
chloride, creatinine phosphokinase (CPK), gamma-glutamyl transferase (GGT), glucose, 
phosphate, potassium, creatinine, sodium, total bilirubin, total protein, troponin, urea, 
complement (C3 and C4). 
• 
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT)  
• 
Lipids: High-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein cholesterol 
(LDL-C), triglycerides, total cholesterol. 
• 
Urinalysis: A midstream urine specimen will be collected for dipstick analysis of protein, 
blood, glucose, and pH. 
 
The safety outcome measures for this study are as follows: 
• 
The incidence and severity of AEs. 
• 
The incidence of SAEs or withdrawals because of AEs. 
• 
The incidence of out-of-reference-range values for vital signs and ECGs, and laboratory 
tests. 
• 
Change from baseline in vital signs and ECGs, and laboratory tests by visit. 
PHARMACOKINETIC OUTCOME MEASURES 
RO5459072 plasma concentration data will be pooled with data from other studies 
(Study WP29542 and Study BP29772) for population pharmacokinetic modelling. 
 
EXPLORATORY OUTCOME MEASURES 
Exploratory assessments will include collection of samples for genotyping, including human 
leukocyte antigen (HLA) haplotyping, at baseline. 
The exploratory outcomes for this study are as follows: 
• 
Comparisons of the performance of alternative composite endpoints (e.g., Sjögren’s 
response index [Sjögren’s syndromeRI-30]) as predictive markers of drug treatment 
response. 
• 
Change from Week 12 to follow-up for ESSDAI, ESSPRI and SF-36 scores in each 
treatment group. 
• 
Comparisons of drug treatment effects between genotypes. 
• 
Patterns of use of selected concomitant medications. 
 
OPTIONAL SUB-STUDY OUTCOME MEASURES 
Patients consenting to also participate in the optional sub-study will undergo minor salivary 
gland (MSG) biopsies at baseline and Week 12. Biopsy samples will be processed for 
histological examination. 
The outcomes for the optional sub-study are as follows: 
• 
Change from baseline in focus score (number of lymphocytes per 4 mm2). 
• 
Change from baseline in numbers of defined sub-populations of infiltrating lymphocytes. 
• 
Subjective evaluation of changes from baseline in minor salivary gland (MSG) structure. 
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Other exploratory analyses may include, but not be limited to, changes in leukocyte and 
stromal subpopulation numbers and degree of activation. 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The investigational medicinal products in this study are:  
• 
RO5459072 50 mg capsules for oral administration (Formulation F03)  
• 
Placebo capsules for oral administration (Formulation F04). 
 
All IMPs will be supplied and packaged by the Sponsor. 
Study drugs are to be taken orally twice daily (b.i.d.) with food, i.e., with breakfast in the 
morning and a meal in the evening, for 12 weeks. Capsules should be swallowed whole. 
Patients will be randomly assigned to one of two possible blinded study drug treatments: 
• 
100 mg RO5459072 (2 x F03 capsules) b.i.d. with food for 12 weeks (Weeks 1 to 12). 
• 
Placebo (2 x F04 capsules) b.i.d. with food for 12 weeks (Weeks 1 to 12). 
PROCEDURES 
A Schedule of Assessments (SoA) is provided (see Appendix 1). 
STATISTICAL METHODS 
EFFICACY ANALYSES 
Efficacy analyses will include modified intent-to-treat (mITT) population which is defined as all 
randomized patients who received at least one dose of double-blind study medication and 
have evaluable measurement of the parameter of interest at baseline and at least at one 
post-baseline visit. 
The proportion of patients who have ≥ 3-point reduction from baseline in ESSDAI score after 
12 weeks of treatment will be compared between the two treatment arms using a Pearson 
Chi-square test (two-sided p-values, alpha 0.05). The difference in proportions and 
corresponding 95% CI will be provided. Supportive analyses will be conducted if deemed 
necessary. Patients with missing data at Week 12 will be treated as non-responders in the 
analysis. Other methods of imputation for missing data will be described in the protocol and 
statistical analyses plan. 
Secondary endpoints that are binary will be analyzed using similar methods used for 
analyzing the primary endpoint. 
Continuous secondary endpoints will be analyzed using a Mixed Model for Repeated 
Measures (MMRM) approach incorporating all observed data up to 12 weeks of treatment. 
The MMRM will include the absolute change from baseline as the dependent variable. The 
fixed effects in the model will include treatment, visit (week), treatment-by-visit (weeks) 
interaction, along with baseline score as continuous covariates. An unstructured 
variance-covariance structure will be applied to the model. 
Additional exploratory analyses will be conducted if deemed appropriate. 
PHARMACODYNAMIC ANALYSES 
All pharmacodynamic parameters will be presented by listings and descriptive summary 
statistics separately by treatment group. 
 
PHARMACOKINETIC ANALYSES 
The population methods used for modelling of plasma concentration data will be described 
separately. 
 
SAFETY ANALYSES 
Safety data presentations will include all subjects who received at least one dose of the study 
medication. For these analyses, patients will be grouped according to the treatment actually 
received. 
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SAMPLE SIZE JUSTIFICATION 
A total of 70 patients will be randomized in a 1:1 ratio to RO5459072 or placebo treatment 
groups. 
 
A total of 70 patients (35 per treatment group) will provide a power in the range of at least 58 
% to 80 % to detect a difference in ESSDAI response rates between treatment groups in the 
range of 25 % to 33 %(two-sided Chi-square test assuming alpha of 0. 05 and placebo 
response rate ≤ 25%). This sample size was determined by practical considerations. Seventy 
patients also provides approximately 70% power to detect a difference of 3-points between 
treatment groups in change from baseline in ESSDAI score (t test assuming two-sided alpha 
of 0.05 and standard deviation of 5.0). 
Approximately 30 patients will be enrolled into the optional sub-study. It is anticipated that 
enrollment of 30 patients should ensure at least 20 patients (10 per treatment group) 
complete the study and have biopsy samples taken at both baseline and Week 12, assuming 
a maximum drop-out rate of 15%. 
CONCOMITANT MEDICATIONS 
In addition to the study drug treatment, patients may continue to concomitantly use existing 
treatments for Sjögren’s syndrome.  
Prohibited therapies are: 
• 
Corticosteroid therapy exceeding 7.5 mg prednisone equivalent per day. 
• 
Anti-CD20 therapy (e.g., rituximab) or other B cell-depleting therapy within 6 months of 
screening. 
• 
Immunosuppressant therapy (e.g., abatacept, azathioprine, ciclosporin, etanercept, 
tofacitinib). Low dose methotrexate treatment (oral doses ≤ 20 mg weekly) is, however, 
permitted. 
• 
Cyclophosphamide. 
Systemic immunomodulatory therapy (e.g, hydroxychloroquine), low dose corticosteroids, or low 
dose methotrexate, or topically administered immunosuppressive agents (e.g., cyclosporine eye 
drops) are permissible providing the patient has been on a stable dose for ≥ 2 months prior to 
screening and the dose remains unchanged during the study. Similarly patients on non-steroidal 
anti-inflammatory drugs (NSAIDs), antidepressants, or pilocarpine must have been on a stable 
dose for 4 weeks prior to screening and expected to remain on this dose throughout the study. If 
any of these drugs have been discontinued recently, patients must be off drug for at least 8 
weeks before screening. 
Pilocarpine or drugs with similar pharmacological action should not be used within 12 hours of 
the assessment visit. 
Other prohibited medications are: 
• 
Moderate or potent inhibitors of CYP3A4 (e.g., itraconazole, erythromycin, nefazodone). 
• 
Strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine). 
• 
Sensitive substrates of CYP3A4 with a narrow therapeutic index (e.g., alfentanil, 
colchicine, ethosuxamide, fentanyl, and pimozide). 
• 
Strong inhibitors of the transporter P-glycoprotein (P-gp) (e.g., quinidine, clarithromycin). 
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CONTRACEPTION 
Women of childbearing potential and men with female partners of childbearing potential must 
agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods 
that result in a failure rate of  < 1% per year throughout the treatment period and for a specified 
period after the last dose of study treatment. Men with female partners of childbearing potential, 
or pregnant female partners, must remain abstinent or use contraceptive measures throughout 
the treatment period and for a specified period after the last dose of study treatment. Men must 
also refrain from donating sperm for specified periods. Women of childbearing potential will be 
required to undergo urine and serum pregnancy testing at each study center visit as defined in 
the SoA (see Section 4.5.5 and Appendix 1). 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AECG 
American-European Consensus Group 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BP 
Blood pressure 
CNS 
Central nervous system 
CRO 
Contract research organization 
CSAP 
Clinical statistical analysis plan 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
DMARDs 
Disease-modifying anti-rheumatic drugs 
DNA 
Deoxyribonucleic acid 
DRF 
Dose-range-finding 
EC 
Ethics Committee 
ECG 
Electrocardiograms 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ePRO 
Electronic patient-reported outcome 
EFD 
Embryo-fetal development 
ESF 
Eligibility screening form 
ESR 
Erythrocyte sedimentary test 
ESSDAI 
European League against Rheumatism (EULAR) 
Sjögren's Syndrome Disease Activity Index 
ESSPRI 
EULAR Sjögren’s Syndrome Patient Reported Index 
EU 
European Union 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
Human Ether-à-go-go-Related Gene 
hERG 
HBsAG 
Hepatitis B surface antigen 
HBcAb 
Total hepatitis B core antibody 
HCV 
Hepatitis C 
HDL 
High-density lipoproteins 
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Abbreviation 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
IxRS 
Interactive (voice/web) response system 
LC-MS/MS 
Liquid chromatography coupled to tandem mass 
spectrometry 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoproteins 
LOCF 
Last observation carried forward 
LPLV 
Last patient, last visit 
LSLO 
Last study subject, last observation 
MAD 
Multiple-ascending doses 
MD 
Multiple-doses 
MHC 
Major histocompatibility complex 
mITT 
Modified intent-to-treat 
MMRM 
Mixed model for repeated measures 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MSG 
Minor salivary gland 
NOAEL 
No-observed-adverse-effect level 
OTC 
Over-the-counter 
PNS 
Peripheral nervous system 
PRO 
Patient-reported outcome 
PT 
Prothrombin time 
QRS 
QRS Complex 
QT 
QT Interval 
QTc 
QT Corrected for heart rate 
QTcF 
QT Corrected for heart rate using the Fridericia’s 
correction factor 
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Abbreviation 
Definition 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SoA 
Schedule of assessments 
SPA 
Statistical Programmer 
ULN 
Upper limit of normal 
WBC 
White blood cell 
 
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1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND ON DISEASE 
Sjögren’s syndrome is one of the most common rheumatic autoimmune disorders (Fox 
et al 2000). The estimated prevalence, which differs considerably depending on type of 
study, diagnostic criteria and other variables between countries ranges from 0.2 to 2.7% 
(Patel et al 2014). It is a chronic systemic autoimmune disease in which immune-
mediated inflammation, characterized by lymphocytic infiltration of exocrine glands and 
epithelia, causes secretory gland dysfunction leading to dryness of the main mucosal 
surfaces. It is characterized by considerable heterogeneity and its spectrum extends 
from only secretory gland dysfunction to systemic involvement with extra-glandular 
manifestations in as many as 50% of patients. Thus, symptoms may vary considerably 
from mild sicca symptoms, pain, fatigue and arthralgia to more severe systemic 
symptoms such as arthritis, vasculitis or glomerulonephritis. Systemic disease manifests 
chiefly as rheumatologic, neurologic, pulmonary, hematologic, and renal disorders 
(Kassan et al 2004). Sjögren’s syndrome can occur in a primary form (primary Sjögren’s 
syndrome) or in conjunction with an underlying autoimmune condition (secondary 
Sjögren’s syndrome), such as rheumatoid arthritis or systemic lupus erythematosus 
(Patel et al 2014). Sjögren’s syndrome is also associated with a significantly increased 
risk of non-Hodgkin B cell lymphoma (Liang et al 2014).  
As for other autoimmune disorders, Sjögren’s syndrome is more prevalent in women 
(incidence 10 to 20 times that of men) and the age of onset is generally between 40-50 
years of age. The cause of primary Sjögren’s syndrome is unknown. It is rare in children 
(de Souza et al 2012). It is believed that, in addition to gender (sex hormones), the 
combination of genetic and environmental factors play a role in the development of the 
disease. In addition to a strong association with genes encoding several human 
leukocyte antigen (HLA) molecules, association with several genes involved in both the 
innate and adaptive immune responses have been identified in primary Sjögren’s 
syndrome (Lessard et al 2013). Viral infection or reactivation of latent viruses have been 
suggested to be involved in the onset, triggering and/or perpetuation of primary 
Sjögren’s syndrome in genetically-susceptible individuals (Lucchesi et al 2014). 
Hallmarks of primary Sjögren’s syndrome are mononuclear cell infiltration of the lacrimal 
and salivary glands with mainly CD4 helper T cells, and to a lesser extent B cells and 
CD8 cytotoxic T cells, increased cytokine production, abnormal B cell hyperactivity and 
autoantibody production. Evidence of the involvement of the innate immunity, especially 
the type 1 interferon (IFN) system, has also been well-established (Ambrosi and 
Wahren-Herlenius 2015). 
The mononuclear cell infiltration of the exocrine glands with CD4 T cells and the strong 
association of primary Sjögren’s syndrome with HLA locus highlight the importance of 
antigen presentation to T cells. Through the production of cytokines and the 
maintenance of B cell-mediated responses, T cells contribute to tissue damage and 
systemic manifestations of the disease. Target tissue epithelial cells, through the 
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secretion of cytokines, are thought to contribute to the local initiation and/or maintenance 
of the innate and adaptive immune responses and to the formation of ectopic lymphoid 
structures (Ambrosi and Wahren-Herlenius 2015). It has also been suggested that, by 
providing auto-antigens, they contribute to the activation of autoreactive B cells and the 
formation of plasmacytoid dendritic cells-activating immune complexes in the target 
tissue. 
No therapy has been demonstrated to affect the course of the disease. Treatment is 
generally symptomatic and supportive, that is, by using stimulators and substitutes of 
tears and saliva secretion (such as cholinergic agents, e.g., cevimeline and pilocarpine 
[Gottenberg et al 2014]) to manage ocular and oral symptoms, as well as supportive 
surgical procedures, intensive oral hygiene, and prevention and treatment of oral 
infections (Mavragani and Moutsopoulos 2010). Non-steroidal anti-inflammatory drugs 
may be used to treat musculoskeletal symptoms and corticosteroids or 
immunosuppressive drugs may be prescribed for severe systemic complications. 
Traditional disease-modifying anti-rheumatic drugs (DMARDs) have limited effects in 
primary Sjögren’s syndrome. Hydroxychloroquine, an immunomodulating agent, is 
widely used in the treatment of Sjögren’s syndrome; however, a recent clinical trial has 
shown limited efficacy (Gottenberg et al 2014). No biological agent has yet been 
approved for primary Sjögren’s syndrome treatment.  
For further details on the background of Sjögren’s Syndrome, please see Section 2.1 of 
the Investigator’s Brochure (IB). 
1.2 
BACKGROUND ON CATHEPSIN S 
Cathepsin S is a cysteine protease of the papain family that is found within the 
lysosomes/endosomes of cells, but is also secreted (Gupta et al 2008). It is expressed in 
the spleen, lymph, heart and lung but, the main expression in normal tissue is in 
antigen-presenting cells (APCs), including macrophages, B cells and dendritic cells 
(Hsing and Rudensky 2005). Within APCs, cathepsin S has an integral role in major 
histocompatibility complex class II (MHC-II) antigen peptide complex formation during 
antigen presentation (Gupta et al 2008; Hsing and Rudsensky 2005). CD74 (also known 
as the MHC-II invariant chain or Ii) acts as a chaperone during MHC-II maturation and is 
degraded in several steps; cleavage of a 10 kDa intermediate fragment (“p10”) is 
catalyzed by cathepsin S. Inhibition of cathepsin S activity leads to accumulation of p10, 
reduced expression of MHC-II at the cell surface, and potentially results in reduced 
antigen-presenting capacity. Additionally, cathepsin S also catalyzes degradation of all 
major components of the extracellular matrix (collagen, elastin, proteoglycan). It is 
hypothesized that cathepsin S participates in extracellular matrix remodeling (Gupta et al 
2008). 
Cathepsin S is thought to be involved in a number of autoimmune and allergic conditions, 
and diseases involving inflammation and matrix remodeling. Cathepsin S is highly 
up-regulated in injured tissue of patients with auto-immune and metabolic diseases. 
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Cathepsin S-deficient mice have lower susceptibility to a number of experimentally-
induced disease conditions and cathepsin S inhibitors have been shown to be effective 
in a variety of animal models of autoimmunity and/or local tissue destruction. Therefore, 
inhibition of cathepsin S is believed to be a possible therapeutic approach for treatment 
of a number of diseases, including autoimmune diseases such as celiac disease, lupus 
nephritis and Sjögren’s syndrome. 
1.3 
BACKGROUND ON RO5459072 
RO5459072 is a covalent, reversible, selective and potent competitive inhibitor of 
cathepsin S being developed for the treatment of Sjögren’s syndrome. The inhibition of 
cathepsin S by RO5459072 is expected to reduce MHC class II-mediated antigen 
presentation, attenuate the activation of CD4+ T cells, suppress T cell-dependent 
auto-antibody production, and neutralize the tissue damage caused by activated 
macrophages and neutrophils. RO5459072 may therefore represent an important new 
targeted therapy in Sjögren’s syndrome and other autoimmune diseases. 
1.3.1 
Previous Non-Clinical Studies 
For more detailed information, please refer to the Non-clinical Studies section (Section 4) 
of the IB. 
1.3.1.1 
Non-Clinical Pharmacology 
In human primary B cells, increasing concentrations of RO5459072 resulted in 
dose-dependent accumulation of p10, which is cleaved by cathepsin S and therefore, 
provides an indirect measure of intracellular cathepsin S inhibition. Inhibition of p10 
cleavage interferes with maturation of MHC class II molecules in APCs. In human 
peripheral blood mononuclear cells (PBMCs), RO5459072 reduced the amount of 
pro-inflammatory cytokines produced (e.g., interleukin-2 [IL-2] and interferon-gamma). In 
C57/Bl6 mice, increasing concentrations of RO5459072 were shown to 
dose-dependently increase the levels of the p10 fragment in splenocytes. Similarly, in 
cynomolgus monkeys, RO5459072 treatment increased concentrations of the p10 
fragment in circulating B cells. In a spontaneous mouse model of lupus nephritis 
(MRL/Faslpr/lpr mice), a reduction in activated T cells, B cells and plasma cells was 
observed in the spleen. In addition, a significant attenuation in total immunoglobulin (Ig) 
G1, IgG2a and anti-double stranded DNA (anti-dsDNA) auto-antibody levels was 
observed after 8 weeks of treatment (by food admix) with 10 mg/kg RO5459072. In a 
chronic atherosclerosis model in mice, increased accumulation of p10 correlated with 
decreased plasma levels of pro-inflammatory IL-2 and reduced arterial lipid 
accumulation. 
1.3.1.2 
Non-Clinical Pharmacokinetics and Product Metabolism 
The pharmacokinetics of RO5459072 were investigated in rats, dogs, and monkeys. In 
all species, RO5459072 showed a low blood clearance (6-11% of the hepatic blood 
flow), and a moderate volume of distribution (0.6-1.4 L/kg) and half-life (3.5-4.5 hours). 
RO5459072—F. Hoffmann-La Roche Ltd 
28/Protocol BP30037, Version 3 
 


 
After oral dosing, RO5459072 reached maximum concentration between 1 and 7 hours 
(tmax). Oral bioavailability was active pharmaceutical ingredient (API)-form and 
formulation-dependent. Following multiple oral doses of amorphous RO5459072 in rats, 
exposure increased approximately dose-proportionally from 5 to 100 mg/kg/day. In 
monkeys, exposure increased in a nearly dose-proportional manner with the crystalline 
API at doses between 5 and 20 mg/kg/day and less than dose-proportional at higher 
dose levels. In rabbits, exposure increased in a more than dose-proportional manner 
with the amorphous API whereas, it increased in a less than dose-proportional manner 
with the crystalline API. In all species, the compound did not accumulate with dose or 
time and no sex-specific differences were observed for the exposure. 
In human plasma, RO5459072 was moderately bound to plasma proteins (15% 
free-fraction) and mainly to albumin, and in mammalian species tested the free-fraction 
was between 12% and 35%. Whole blood distribution occurred mainly to the plasma 
compartment in animal species, but also to erythrocytes in humans. In vitro metabolism 
was low to moderate in microsomes and low in hepatocytes across species, consistent 
with in vivo clearance. In microsomes, the major metabolite observed was M1 
(N-demethylation); M2 (oxygenation) was only detected in low amounts in the mouse. In 
hepatocytes, M1 was the only metabolite observed in all tested species. Furthermore, in 
vitro cytochrome P450 (CYP)-selective inhibition data showed that M1 was formed via 
CYP3A4. Urine analysis in rats, dogs, and monkeys revealed that only a small amount of 
unchanged compound was recovered (≤ 3.6%), indicating that renal elimination does not 
play a major role in the clearance of RO5459072 in these species. 
RO5459072 did not inhibit the metabolism of CYP1A2-, 2B6-, 2C8-, 2C9-, 2C19-, 2D6- 
and 3A4/5-mediated reactions up to 50 μM and did not show potential for 
time-dependent inhibition of CYP3A4. RO5459072 induced CYP3A4, 2B6, and to a 
lesser extent, 1A2 messenger ribonucleic acid (mRNA) and enzymatic activity in human 
liver. For CYP3A4 and 2B6, mRNA EC50 was 19.2 μM and 39.7 μM, respectively. 
RO5459072 was found to be a strong P-glycoprotein (P-gp) substrate while also 
showing good passive membrane permeability. Furthermore, the compound inhibited the 
transport of substrates of multi-drug resistance protein 1 (MDR1), organic 
anion-transporting polypeptide (OATP) 1B1, OATP1B3, multidrug and toxin extrusion 
protein 1 (MATE1) and MATE2-K with IC50 values of ≥ 9.5 μM. However, the transport of 
substrates of OAT1 and OAT3, and organic cation transporter 2 (OCT2) was not 
inhibited in the presence of RO5459072. 
1.3.1.3 
Toxicology and Safety Pharmacology 
Oral administration of RO5459072 was well-tolerated in rats and cynomolgus monkeys 
in repeat-dose toxicity studies up to 13 weeks. Based on the non-clinical safety 
information available to date, the no-observed-adverse-effect level (NOAEL) following 
repeated dosing is at least 100 mg/kg/day in rats and 200 mg/kg/day in the cynomolgus 
monkey, the highest doses tested in 13-week good laboratory practice (GLP) toxicity 
studies. Mean plasma exposures at the NOAELs were 683 μg • h/mL (AUC0-24h) and 
RO5459072—F. Hoffmann-La Roche Ltd 
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59.20 μg/mL (Cmax) in the rat, and 99.40 μg • h/mL and 5.44 μg/mL in the cynomolgus 
monkey for AUC0-24h and Cmax, respectively. The no-observed-effect level (NOEL) for 
cardiovascular effects in the monkey is considered to be at least 600 mg/kg/day, the 
highest dose tested in the single-dose telemetry study in the monkey. 
Target organs of toxicity were only identified at very high exposures during the 
dose-range finding (DRF) studies, in which the amorphous API form was used. In the rat 
DRF study, the liver and the heart were identified as possible target organs of toxicity; in 
the cynomolgus monkey, the liver and the kidney were target organs of toxicity. The 
heart finding observed in the rat DRF study is considered incidental as it was not 
observed in the 13-week GLP study at similar exposures. Exposures associated with 
adverse findings were 815/736 μg • h/mL in male and female rats, and 
470/289 μg • h/mL in male and female cynomolgus monkeys, respectively. 
Embryo-fetal development (EFD) studies revealed a teratogenic potential of RO5459072 
in the rat and a RO5459072-related disturbance in axial skeletal development in both the 
rat and rabbit. Evidence of teratogenicity, characterized by cardiovascular malformations, 
was observed in the rat at 7-times the predicted human efficacious AUC(0-24h). The 
NOAEL for teratogenicity in the rat was established at 115 mg • h/mL (AUC) and the 
NOAEL for embryotoxicity was 13 mg • h/mL in the rat and 54 mg • h/mL in the rabbit. 
In a single-dose modified Irwin test and a respiratory study, no effects on the central 
nervous system or respiratory function were observed in rats up to the highest dose 
tested (100 mg/kg oral). 
RO5459072 interacted weakly with human ether-à-go-go-related gene (hERG) channels 
in vitro (IC20 = 41.46 μM or 25 μg/mL). In a single-dose telemetry study in cynomolgus 
monkeys, cardiovascular parameters were not changed in animals dosed up to 
300 mg/kg RO5459072 twice daily (b.i.d.). This dose resulted in a Cmax of 8.7 μg/mL at 
10 hours post-dose. 
In vitro and in vivo genotoxicity studies revealed no indication for a mutagenic, 
clastogenic or aneugenic potential of RO5459072. 
1.3.2 
Previous Clinical Studies 
1.3.2.1 
Studies with RO5459072 
RO5459072 has been administered to humans in two previously completed studies 
(Study WP29542 and Study BP29772). A detailed description of the design and results 
of both studies are presented in the IB (Effects in Humans, Section 5). 
Study WP29542 was a single-center, randomized, double-blind, placebo-controlled, 
single-ascending dose (SAD) study to evaluate the safety, tolerability, pharmacokinetic 
and pharmacodynamic effects of single oral doses of RO5459072 in healthy male and 
female volunteers. The study employed an interleaved cohort (“leapfrog”) cross-over 
RO5459072—F. Hoffmann-La Roche Ltd 
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design. Subjects were recruited in two cohorts of eight subjects (Cohorts A and B) and 
dosing alternated between two cohorts, with a minimum of 7 days between each dosing 
period. Study drug and placebo were administered in a total of eight treatment periods, 
four periods for each cohort. In each period, subjects received a single oral dose of 
RO5459072 or placebo, with treatments assigned in a 6:2 ratio, i.e., within each cohort 
of eight subjects in any period, six subjects received active treatment and two received 
placebo. Hence, for each individual within a cohort, the study was a randomized, 
placebo-controlled, four-treatment, four-period, four-way cross-over. 
Nine treatments were investigated in the study: single 1, 3, 10, 30, 100, 300, and 600 mg 
doses of RO5459072 administered while fasted, a single 100 mg dose of RO5459072 
administered with a high-fat meal, and placebo. A total of 17 healthy volunteers aged 21-
59 years were enrolled in the study. Fifteen subjects completed the study as planned 
and without major protocol violations.  
Study BP29772 was a randomized, double-blind, placebo-controlled, parallel group, 
ascending-dose design in healthy male and female volunteers with adaptive dose and 
dosing regimen; the study is clinically completed with the report in progress. The main 
goal was to investigate the effects of RO5459072 on pharmacodynamic measures of 
cathepsin S activity and immune function. Other objectives included investigation of the 
safety and tolerability of one week of dosing with RO5459072 and characterization of the 
steady-state pharmacokinetics of RO5459072. Four cohorts of nine subjects (Cohorts A 
to D) were to be recruited, although because of an unexpectedly high screen failure rate 
only six subjects were recruited in Cohort D. Within each cohort, subjects were assigned 
to receive active and placebo treatments in a 2:1 ratio, i.e., within each cohort of nine 
subjects, six subjects received active treatment and three received placebo. After 
baseline assessments (Day -1), each subject received a single oral dose of RO5459072 
or placebo with food (Day 1) followed by the same dose of RO5459072 or placebo once 
or twice daily (o.d. or b.i.d.) with food for 7 days (Day 3 to Day 9). In addition, each 
subject received intra-dermal administration of four recall antigens and a negative 
control at screening and during treatment for assessment of delayed-type 
hypersensitivity responses. Five treatments were investigated in the study: 50, 100, and 
200 mg doses of RO5459072 administered twice daily with food, a 100 mg dose of 
RO5459072 administered once daily with food, and placebo administered once or twice 
daily with food. A total of 33 healthy volunteers aged 18-60 years were enrolled in the 
study. All 33 subjects completed the study as planned and without major protocol 
violations. 
Safety 
The incidence of adverse events (AEs) was low in both studies: a total of 
77 treatment-emergent AEs were recorded in 15 subjects in Study WP29542 and a total 
of 54 treatment-emergent AEs were recorded in 20 subjects in Study BP29772. There 
were no deaths or serious adverse events (SAEs), no withdrawals because of AEs and 
no dose-limiting AEs were identified. There was no apparent relationship to RO5459072 
RO5459072—F. Hoffmann-La Roche Ltd 
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dose or treatment in the pattern or incidence of AEs. All AEs were considered to be mild 
in intensity except for five moderate events (influenza in three subjects, vomiting in one 
subject and muscle strain in one subject) in Study WP29542. Only application site 
irritation and hypersensitivity (due to ECG electrodes), pollakiuria, headache, 
disturbance in attention, dizziness, influenza and back pain occurred in more than one 
subject at any dose of RO5459072 in either study but did not show any apparent 
relationship with dose. 
Mean and mean changes from baseline in vital signs, ECG and safety laboratory 
parameters showed no apparent dose-related trends or differences compared with 
placebo. 
Pharmacokinetics 
RO5459072 pharmacokinetics are both dose- and time-dependent (Figure 1 and 
Table 1). Exposure was not dose-proportional across dose ranges tested; in particular 
there was a less-than-dose-proportional increase in exposure at doses above 100 mg 
(Table 1). 
Steady-state was achieved by the third day of dosing. Steady-state exposures were 2-4-
fold higher than corresponding single dose exposures, and were ~50% greater than 
predicted from single-dose data. 
Variability in exposure was small and did not appear to change over the dose-range 
tested (e.g. CV% 17-19% in Cmax and 12-20% in AUCtau). There were no obvious 
differences in RO5459072 exposure between men and women or between age groups. 
Figure 1 Mean Linear RO5459072 Plasma Concentration versus Time 
Profiles after a Single Dose and at Steady-State after Twice Daily 
Administration with Food 
 
Arithmetic means. Error bars indicate standard deviation. 
 
RO5459072—F. Hoffmann-La Roche Ltd 
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Table 1 
Summary RO5459072 Pharmacokinetic Parameters at 
Steady-State after Administration with Food 
Parameters 
(Units) 
50 mg b.i.d 
N = 6 
100 mg b.i.d. 
N = 6 
200 mg b.i.d. 
N = 4 
AUC0-12h (ng • h/mL) 
9650 (12%) 
21500 (14%) 
26900 (20%) 
Cmax (ng/mL) 
1110 (19%) 
2340 (19%) 
2950 (18%) 
Tmax (h) 
4.5 (0.0-6.0) 
4.0 (3.0-6.0) 
2.0 (0.0-6.0) 
Pharmacokinetic parameters are presented as geometric mean (CV%), except for Tmax which is 
shown as median (range). 
 
Dosing with food increased RO5459072 exposure. Average peak and total exposure 
were 83% and 21% greater, respectively, when a 100 mg dose was administered in fed 
as compared to fasted state. 
Pharmacodynamics 
Pharmacodynamic effects were assessed from relative concentrations of 10kDa CD74 
intermediate (p10) using a method based on fluorescence-activated cell sorting (FACS) 
of PBMC preparations. p10 is a substrate for cathepsin S and is therefore, a marker of 
cathepsin S activity. 
Changes in p10 levels in circulating B cells after a single dose (Day 1) and after one 
week of repeated dosing (Day 9) are shown in Figure 2 . 
Figure 2 Mean Change from Baseline in p10 Stimulation Index versus 
Time Profiles after a Single Oral Dose and after Repeat Dosing 
with Food 
 
Arithmetic means of change from baseline in p10 after a single oral dose (left graph) and 
repetitive dosing with food (right graph). Error bars indicate standard deviation. 
 
RO5459072 treatment produced dose-dependent increase in p10 levels in circulating 
B cells. There were detectable responses to higher doses in all individuals, and 
RO5459072—F. Hoffmann-La Roche Ltd 
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responses were maintained throughout dosing interval after repeat dosing. There was no 
effect on p10 levels in monocytes. 
FACS analysis of PBMCs also indicated that expression of MHC-II (HLA-DR) at the 
B cell surface was transiently reduced following RO5459072 treatment. 
RO5459072 treatment had no apparent effects on delayed type hypersensitivity 
responses to intradermal recall antigen challenges. 
1.3.2.2 
Studies with Other Cathepsin S Inhibitors 
There is one published report of a clinical study involving dosing of a cathepsin S 
inhibitor to humans (Payne et al 2014) and the Sponsor has previously conducted a 
clinical study with another cathepsin S inhibitor structurally related to RO5459072. There 
were no notable safety findings in either study. 
1.4 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
1.4.1 
Study Rationale 
Auto-immune disorders are characterized by an aberrant immunological response to 
antigens. Sjögren’s syndrome is a chronic systemic autoimmune disease in which an 
aberrant immune response to self-antigens causes secretory gland dysfunction and 
systemic symptoms. There is no approved, effective treatment for Sjögren’s syndrome 
with the exception of products used for managing symptoms of the disorder. Sjögren’s 
syndrome is characterized by mononuclear cell infiltration of the lacrimal and salivary 
glands (mainly CD4 helper T cells and to a lesser extent B cells) as well as the presence 
of circulating autoantibodies. In addition, Sjögren's syndrome is considered a 
prototypical germinal center auto-immune disorder. Germinal centers in lymphoid tissues 
are central to B cell development and antibody production in response to antigens, and 
antigen presentation by B cells to TFH cells plays a significant role in the germinal center 
reaction. There are multiple lines of evidence that germinal centers are important in 
Sjögren’s syndrome, including the observation of ectopic "germinal center-like" 
structures in the salivary glands of approximately 25% of patients. Whilst the exact 
causes of Sjögren’s syndrome are currently undetermined, together these data indicate 
the importance of MHC-II antigen presentation as a pathogenic mechanism. Cathepsin S 
inhibitors have been shown to be effective in non-clinical experimental models of 
auto-immune disorders including Sjögren’s syndrome (Rupanaqudi et al 2015; 
Katunuma et al 2003). This study is therefore being conducted with the principal aim of 
investigating the effects of RO5459072 treatment on disease activity and symptoms of 
Sjögren’s syndrome. However, because this is an early study in the clinical development 
of a compound with a novel immunomodulatory mechanism of action, there is a need to 
profile the pharmacological effects of RO5459072 treatment. The study is, therefore, 
also intended to characterize the effects of RO5459072 on immune functioning through 
appraisal of a variety of relevant pharmacodynamic measures and biomarkers. 
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1.4.2 
Benefit-Risk Assessment 
Sjögren’s syndrome is a chronic systemic auto-immune disease in which an aberrant 
immune response to self-antigens causes secretory gland dysfunction and systemic 
symptoms. There is no approved, effective treatment for Sjögren’s syndrome. There is, 
therefore, a reasonable expectation that RO5459072 treatment might ameliorate the 
signs and symptoms of Sjögren’s syndrome. However, this is the first study to test the 
effects of a cathepsin S inhibitor in patients with Sjögren’s syndrome; there are no 
clinical data to prove that individuals will derive any benefit from RO5459072 treatment. 
Furthermore, as this is a placebo-controlled study, patients who are randomized to 
placebo will not derive direct benefit from participation in the study. 
The risks of study participation are primarily those associated with adverse reactions to 
the study drug, although there may also be some discomfort from collection of blood 
samples and other study procedures. Participants in the optional sub-study will also 
have additional discomfort and risk of sequelae from the biopsy procedure. 
Study BP30037 is the fourth study involving dosing of RO5459072 to humans but the 
first involving dosing in patients with Sjögren’s syndrome. Data from two previously 
completed clinical studies performed in healthy subjects (Studies WP29542 and 
BP29772) show a very good tolerability profile over the dose-range tested. There were 
no notable safety findings either from single doses up to 600 mg or from repeat dosing 
up to 200 mg b.i.d. administered for one week.  
Available data on administration of cathepsin S inhibitors to humans do not indicate any 
acute safety risks associated with RO5459072 dosing or the mechanism of action. 
Studies WP29542 and BP29772, and a published report of a single-dose study of a 
structurally unrelated cathepsin S inhibitor (Payne et al 2014), demonstrate that 
short-term inhibition of cathepsin S enzyme activity is well-tolerated. Similarly, mice 
lacking cathepsin S activity (Ctss “knockout” mice) have an ostensibly normal phenotype, 
suggesting that there are no specific risks associated with inhibition of cathepsin S 
activity. Therefore, repeat-dose non-clinical toxicology studies are the principal guide to 
potential adverse drug reactions from long-term dosing with RO5459072. Those studies 
did not reveal any findings of particular concern for dosing patients at the proposed dose 
of 100 mg b.i.d. RO5459072 up to 12 weeks. The RO5459072 exposures from 100 mg 
b.i.d. dosing are anticipated to be 2-fold below the corresponding exposures at NOAEL 
in the cynomolgus monkey and 16-fold below the NOAEL in the rat 13-week study. 
The potential for clinically relevant drug-drug interactions between RO5459072 and 
other concomitant medications is believed to be minimal. Where there is the theoretical 
potential for pharmacokinetic interactions to occur, specific guidance is given to minimize 
the potential risk to individuals (e.g., prohibition of potent CYP3A4 inhibitors). 
All study participants will undergo safety assessments at intervals throughout the study. 
Although there were no adverse findings in GLP toxicology studies, effects on the liver 
RO5459072—F. Hoffmann-La Roche Ltd 
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and kidney observed at higher exposures in a non-GLP dose-range finding study in 
cynomolgus monkeys are considered to be monitorable through a standard battery of 
laboratory safety tests. The cardiac findings observed in a non-GLP DRF study in rats 
were not seen in the 13-week GLP toxicity study at similar exposures and are therefore 
considered incidental. Despite the involvement of cathepsin S in antigen presentation, 
non-clinical studies and available clinical data reveal no evidence suggesting a risk of 
clinically important immunosuppression and special measures to monitor immune 
function are not considered to be necessary. Nevertheless, individuals who are 
immunosuppressed or are at increased risk of infection will not be enrolled. 
Based on the observation that cathepsin S enzyme expression is increased after 
treatment with a cathepsin S inhibitor, there is a theoretical possibility acute rebound 
phenomena (i.e., re-emergence of symptoms at a severity worse than at baseline) may 
occur following discontinuation of RO5459072 treatment. However, because cathepsin S 
enzyme expression should return to normal soon after discontinuation of RO5459072, 
any pharmacodynamic rebound should be transient and is considered unlikely to 
manifest as changes in disease activity or symptoms. 
Patients who choose to participate in the optional sub-study will have labial salivary 
gland biopsies performed at the beginning and end of the study. Labial biopsies are 
minimally invasive, routinely used for clinical diagnostic purposes (Vitali et al 2002) and 
have potential utility as an outcome measure in clinical studies (Fisher et al 2015). 
Nevertheless, there is a risk of sequelae from the biopsy procedure: the incidence of 
permanent neurological damage is estimated to be ~0.17% (Varela Centelles et al 2014). 
Therefore, biopsies will only be performed on consenting individuals at selected study 
centers with experience of performing biopsies, i.e., centers where biopsies are routinely 
performed as part of normal clinical practice by experienced practitioners. 
In summary, non-clinical data provide the necessary rationale that RO5459072 may 
provide a treatment benefit for patients with Sjögren’s syndrome. No significant safety 
concerns have been identified about the use of RO5459072 in patients with Sjögren’s 
syndrome. Where theoretical risks from RO5459072 treatment have been identified from 
non-clinical studies, appropriate clinical safety monitoring measures are implemented. 
Hence, the risks to participants in this study are considered acceptable. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVES 
The primary objective of this study is: 
• 
To investigate the effects of RO5459072 treatment on disease activity and 
symptoms of primary Sjögren’s syndrome. 
 
RO5459072—F. Hoffmann-La Roche Ltd 
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2.2 
SECONDARY OBJECTIVES 
To investigate the effects of RO5459072 treatment on: 
• 
quality of life measures. 
• 
auto-antibody concentrations. 
• 
pharmacodynamic measures of exocrine gland function. 
Additionally: 
• 
To collect samples for population modelling of RO5459072 pharmacokinetics. 
• 
To investigate the safety and tolerability of RO5459072 treatment. 
 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
To investigate the effects of RO5459072 treatment on: 
• 
cathepsin S enzyme mass and activity. 
• 
sub-populations of circulating white blood cells. 
• 
biomarkers connected to Sjögren’s syndrome. 
• 
biomarkers of extracellular matrix degradation. 
Additionally: 
• 
To explore the influence of covariates on the effects of RO5459072 treatment. 
• 
To explore alternative composite endpoints as measures for evaluating effects of 
drug treatment. 
• 
To explore the effects of RO5459072 treatment on the use of concomitant 
medications. 
• 
To explore the occurrence of acute rebound phenomena on disease activity and 
symptoms following discontinuation of study drug treatment. 
 
2.4 
OPTIONAL SUB-STUDY OBJECTIVE 
The objective of the optional sub-study is: 
• 
To investigate the effects of RO5459072 treatment on salivary gland structure, 
inflammation and the organization of inflammatory foci assessed by histology and 
immunohistochemistry of labial biopsy samples. 
RO5459072—F. Hoffmann-La Roche Ltd 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
Study BP30037 is a randomized, double-blind, placebo-controlled, two-treatment arm, 
parallel-group study designed to evaluate the effects of RO5459072 treatment on 
disease activity and symptoms of Sjögren’s syndrome in adult patients with moderate to 
severe primary Sjögren’s syndrome. Patients will be randomized 1:1 to receive either 
100 mg RO5459072 or placebo orally twice daily (b.i.d.) and will be treated for a 
maximum of 12 weeks. Based on the Investigator judgment, patients may be 
re-screened and enrolled if the patient meets all of the eligibility criteria at a later 
time-point. 
Assessments of Sjögren’s syndrome disease activity, symptoms and quality of life will be 
made before (baseline [Week -1]), during the study treatment phase, upon completion 
and, at the early termination visit and at the safety and follow-up visit in order to evaluate 
the efficacy of RO5459072 treatment. Patients will start study drug treatment one day 
after the last baseline assessment. In addition, patients will undergo pharmacodynamic 
assessments of exocrine gland function and provide samples for measurement of white 
blood cell numbers and levels of biomarkers associated with Sjögren’s syndrome or 
connected to the mechanism of action of RO5459072, as well as RO5459072 plasma 
concentrations. Safety and tolerability will be assessed throughout the study. 
At selected participating study centers, patients may also enroll into an optional 
sub-study in which consenting individuals will undergo minor salivary gland (MSG) 
biopsies for assessing histological changes in labial salivary glands. Biopsies will be 
taken at baseline (Week -1) and at the end of the study drug treatment period 
(Week 12, ± 1 week). The data from the sub-study will be analyzed and reported 
separately. 
Patients may concomitantly receive standard of care symptomatic treatment (see 
Section 4.5.1). 
RO5459072—F. Hoffmann-La Roche Ltd 
38/Protocol BP30037, Version 3 
 


 
Figure 3 Study Design 
 
The total duration of the study for each patient will be (up to) 18 weeks: 
• 
Screening visit: Up to 28 days prior to 1st dose. 
• 
Baseline visit (BL): Up to 7 days prior to 1st dose. 
• 
Treatment period: Up to 12 weeks (Days 1 to 84). 
• 
Follow-up visit: 14 days after last dose. 
 
3.1.2 
End of Study 
The end of the study is defined as the date of the last study center visit of the last patient 
participating in the study (includes the safety follow-up visit). 
3.2 
RATIONALE FOR STUDY DESIGN 
3.2.1 
Rationale for Dosage Selection 
A RO5459072 dose of 100 mg b.i.d. has been selected for this study based on 
pharmacokinetic, pharmacodynamics and safety data from previous clinical studies in 
healthy volunteers (Studies WP29542 and BP29772; Figure 4). 
RO5459072—F. Hoffmann-La Roche Ltd 
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Figure 4 Simulation of cathepsin S enzyme inhibition over the dosing 
interval based on population pharmacokinetic/ 
pharmacodynamic model. 
 
The dose of 100 mg has been well-tolerated when administered as a single-dose under 
both fasted and fed conditions and in a b.i.d. regimen administered under fed conditions 
for one week. It also produced robust and sustained effect on a mechanistic marker of 
intracellular cathepsin S activity (p10 concentrations in circulating B cells). 
Pharmacokinetic/pharmacodynamic modelling indicate that a 100 mg b.i.d. dose taken 
with food will maintain ≥ 95% enzyme inhibition throughout the dosing interval and 
thereby, maximize the potential for producing functional effects on MHC-II-mediated 
antigen presentation and immune responses. In turn, this is anticipated to maximize the 
likelihood to produce treatment benefit on the signs and symptoms of Sjögren’s 
syndrome in a 12-week “proof-of-concept” study. This approach is supported by data 
from the use of cathepsin S inhibitors in non-clinical experimental models: maximal 
effects on relevant endpoints are seen at doses which achieve maximal inhibition of 
intracellular enzyme activity (Investigator’s Brochure). 
A 100 mg b.i.d. dosing regimen is predicted to result in exposures lower than those 
observed NOAEL doses in non-clinical toxicology studies. The average steady-state 
exposures observed at 100 mg b.i.d. dosing in Study BP29772 (2.34 μg/mL and 
21.48 μg • h/mL for Cmax and AUC0-12h, respectively) is 2.3-fold lower than the 
corresponding exposure at the NOAEL in the most sensitive species in 13-week GLP 
toxicology studies (cynomolgus monkeys: 5.44 μg/mL and 99.40 μg • h/mL for Cmax and 
AUC0-24h, respectively) based on AUC0-24h.  
3.2.2 
Rationale for Study Population 
This trial will enroll adult patients with primary Sjögren’s syndrome who present with 
moderate to severe disease activity and symptoms. This patient population is considered 
potentially most likely to receive benefit from study drug treatment (Carrubi et al 2013). 
RO5459072—F. Hoffmann-La Roche Ltd 
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Study entry requires a diagnosis of primary Sjögren’s syndrome according to the 
American-European Consensus Group (AECG) diagnostic criteria (Vitali et al 2002); 
these internationally-recognized consensus criteria based on a combination of subjective 
and objective measures, are currently considered to be the most appropriate means by 
which to diagnose Sjögren’s syndrome. However, because one of the study aims is to 
characterize the treatment effects on immune processes, patients are specifically 
required to have detectable circulating concentrations of anti-Sjögren's-syndrome-related 
antigen A (anti-SSA) or anti-SSB antibodies. These auto-antibodies are common among 
patients with Sjögren’s syndrome and are considered as a surrogate marker of ongoing 
germinal center reactions. 
It is also required that disease activity and symptoms are considered moderate to severe 
at the time of enrollment, and therefore, the qualifying participant would be considered a 
suitable candidate for immunomodulatory pharmacotherapy as part of normal clinical 
management of the disease. Severity is judged using validated consensus indices which 
are currently considered as “gold standard” instruments for assessing disease activity 
and the cardinal symptoms of Sjögren’s syndrome (European League against 
Rheumatism [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] and EULAR 
Sjögren’s Syndrome Patient Reported Index [ESSPRI], respectively. See Section 3.2.5). 
Patients who are less likely to benefit from treatment, and those with confounding factors 
that might mask a drug effect, will not be enrolled. Patients for whom dry eye or 
xerostomia symptoms are secondary manifestations of other autoimmune disorders 
(i.e., secondary Sjögren’s syndrome) or can be attributed to other causes (e.g., previous 
radiotherapy or concomitant drug use) will be excluded. Fibromyalgia, significant 
depression or anxiety are also not permissible, while patients who are using, or have 
recently used, immunotherapy or immunosuppressive therapy will also not be enrolled. 
Similarly, although there is no restriction on the length of time a participant has had 
Sjögren’s syndrome, the study will not enroll patients who have no residual salivary 
gland function because of the expectation that profound salivary gland damage will not 
be modifiable by drug treatment. 
Finally, individuals who may theoretically be placed at additional risk by participating in 
the study will be excluded. Specific examples are patients with a history of lymphoma, 
and those who are immunosuppressed or otherwise predisposed to serious infection. 
Overall, the entry criteria are consistent with other recently completed and ongoing 
clinical studies of pharmacological therapies in this patient population (Brown et al 2014). 
3.2.3 
Rationale for Control Group 
Study BP30037 is a placebo-controlled study, and patients will be allocated to 
RO5459072 and placebo treatment groups in a 1:1 ratio. Study drug treatment will be 
given on top of the existing symptomatic treatments for Sjögren’s syndrome, 
i.e., patients will be able to continue to use their existing medications. The use of a 
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placebo comparator is justified because there are currently no approved, effective 
treatments for Sjögren’s syndrome. Furthermore, allocation of equal numbers of patients 
to the active and placebo groups is considered necessary because of the relative paucity 
of clinical trial or other longitudinal data available in the public domain for this indication; 
there is a need to generate an adequate within-study comparator dataset to allow proper 
evaluation of the magnitude of any treatment effects. 
3.2.4 
Rationale for Design 
The study will employ a parallel group design in which patients will receive either 
RO5459072 or placebo treatment for 12 weeks. Although maximal inhibition of 
cathepsin S enzyme activity should occur during the first days of dosing, it is anticipated 
that any effects on functional pharmacodynamic parameters and clinical endpoints will 
take weeks or months to become manifest. Similar studies with immunosuppressant 
compounds (e.g., abatacept, rituximab) suggest that while drug effects may become 
apparent within 4 to 6 weeks of the start of treatment, full effects only become apparent 
with longer treatment (Meiners et al 2014, Devauchelle-Pensec et al 2014, Carubbi et al 
2013). The maximum duration of study drug treatment is, however, limited by the 
duration of completed GLP toxicology studies (i.e., 13 weeks). 
3.2.5 
Rationale for Efficacy Assessments 
The primary efficacy outcome for this study is based on assessment of changes in 
disease activity using the ESSDAI instrument. The ESSDAI is a physician-assessed 
disease activity index for primary Sjögren’s syndrome developed by the EULAR 
consortium from a worldwide, multicenter study (Seror et al 2010). The ESSDAI has 
been validated and shows good correlation with a “gold standard” physician global 
assessment (Seror et al 2015), and has been used in many recent clinical studies 
(Vissink et al 2012). A score ≥ 5 is considered to represent moderate or severe disease 
activity and a clinically relevant change in ESSDAI score is defined as an absolute 
decrease of ≥ 3-points (Seror et al 2014). Disease activity and symptoms are 
independent aspects of Sjögren’s syndrome, and the ESSPRI and ESSDAI scores do 
not correlate (Seror et al 2013). The ESSDAI has been selected as primary measure 
because it is a physician-rated index and potentially a more objective and sensitive 
measure of drug treatment effects. 
Secondary efficacy endpoints include assessment of changes in core symptoms of 
Sjögren’s syndrome using the ESSPRI instrument. The ESSPRI is a patient-reported, 
subjective symptom index for primary Sjögren’s syndrome developed by the EULAR 
consortium from a worldwide, multicenter study (Seror et al 2011). It has also been 
validated and shows good correlation with a “gold standard” patient global assessment 
(Seror et al 2015). A score ≥ 5 is considered to represent moderate or severe symptoms 
and a clinically relevant change in ESSPRI score is defined as an absolute decrease of 
≥1-point (Seror et al 2014). 
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In addition to the disease activity and symptoms specific to Sjögren’s syndrome, overall 
quality of life will be assessed using the SF-36 questionnaire. The SF-36 is a 
questionnaire developed to evaluate health-related quality of life in individuals with 
medical disorders (Ware et al 1993). The SF-36 is widely used and validated in a 
number of different populations and there are existing literature data on use in Sjögren’s 
syndrome as well as other auto-immune disorders: patients with primary Sjögren’s 
syndrome score appreciably worse than matched controls on all domains (Segal et al 
2009). 
Efficacy and pharmacodynamic assessments will be made at baseline and intervals 
during the treatment period, thereby allowing changes from baseline in each individual 
and the speed of onset of any treatment effect to be evaluated. In addition, efficacy 
assessments will also be made at the follow-up visit in order to explore the occurrence of 
acute rebound phenomena following discontinuation of study drug treatment. Rebound 
phenomena (i.e., re-emergence of symptoms at a severity worse than at baseline) are a 
theoretical possibility based on the observation that cathepsin S enzyme expression is 
increased after treatment with a cathepsin S inhibitor (Payne et al 2014). 
3.2.6 
Rationale for Pharmacodynamic Assessments 
A range of pharmacodynamic assessments are included in the study in order to profile 
treatment effects on exocrine gland function, immune function, and other biomarkers 
connected to Sjögren’s syndrome. Impaired tear and saliva production is characteristic 
of Sjögren’s syndrome and production rates will be measured using simple, 
well-precedented and non-invasive methods. Elevated circulating titers of a range of 
auto-antibodies are reported in patients with primary Sjögren’s syndrome (Tzioufas et al 
2012), and as no single type is considered diagnostic, prognostic or predictive a panel 
including a representative cross-section will be measured, as well as total IgG, IgM and 
cryoglobulins (Quartuccio et al 2014). FACS immunophenotyping of cell surface markers 
will be used to determine numbers of cells in defined white blood cell sub-populations of 
interest and may include TBNK/monocytes, T helper cells and T follicular helper cells 
and B cells (Szabo et al 2013; Szabo et al 2016 ). Immunophenotyping will focus on 
those sub-populations which are reported to be altered in patients with Sjögren’s 
syndrome or which might be expected to change with treatment based on the 
mechanism of action of RO5459072. Biomarkers to be measured will include erythrocyte 
sedimentation test (ESR), complement components and β2-microglobulin, which are all 
reported to be altered in patients with Sjögren’s syndrome (Pertovaara and Korpela 
2014), along with potentially relevant cytokines (e.g., BAFF, IL-4, IL-6 and IL-10; Pollard 
et al 2013). Gene expression changes related to interferon response including but not 
limited to MxA will be measured (Maria et al, 2014). 
In addition, markers directly linked to the mechanism of action of RO5459072 will also 
be measured to quantify the primary and secondary pharmacological effects. These will 
include cathepsin S mass and activity in plasma, tears and saliva (Hamm-Alvarez et al 
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2014), and desmosine as a marker of extracellular matrix degradation (Schenke-Layland 
2008). 
3.2.7 
Rationale for Pharmacokinetic Assessments 
The plasma concentration data will be pooled with data from other studies (WP29542 
and BP29772) for population pharmacokinetic and pharmacokinetic/pharmacodynamic 
modelling. 
3.2.8 
Rationale for Safety Assessments 
The available clinical and non-clinical data do not indicate any particular safety concerns 
associated with RO5459072 treatment at the dose proposed and do not suggest any 
risks that would require specific monitoring. Patients will come to the study center for 
regular ambulatory visits to undergo standard safety assessments alongside other 
assessments. Adverse events (AEs) will be collected throughout the study and clinical 
laboratory assessments, vital signs and triplicate 12-lead ECGs will be monitored as part 
of a typical approach to evaluating safety in early clinical development studies. 
Although inhibition of cathepsin S has the potential to reduce antigen-presenting 
capacity, non-clinical studies did not reveal any evidence of a risk of clinically important 
immunosuppression. Therefore, while any infections reported will be carefully evaluated, 
specific tests of immune function are not considered to be warranted. 
3.2.9 
Rationale for Other Assessments 
It has been reported that the effects of cathepsin S deficiency on MHC-II antigen 
presentation may be influenced by HLA haplotype and therefore, samples will be 
collected for genotyping of loci encoding HLAs, along with the cathepsin S gene (CTss). 
The data will then be used to explore how genotype and haplotype may influence drug 
effects.  
3.2.10 
Rationale for Biopsy Sub-study 
The study will include an optional sub-study to collect MSG biopsy samples. MSG 
biopsies are routinely used for clinical diagnostic purposes (Vitali et al 2002) and have 
potential utility as an outcome measure in clinical studies (Fisher et al 2015). For 
example, it has been reported that long-term rituximab treatment reduces ectopic 
lymphoid structures and germinal center-like structures in MSG biopsies (Carubbi et al 
2013). For recruitment reasons, the MSG biopsies are optional and non-participation in 
the sub-study will not preclude the inclusion of the patient into the main study. 
3.3 
OUTCOME MEASURES 
3.3.1 
Efficacy Outcome Measures 
Efficacy assessments will include the ESSDAI, ESSPRI, and the SF-36. ESSDAI and 
ESSPRI will also be measured at screening in order to assess eligibility for the study. 
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The primary efficacy outcome for this study is: 
• 
Proportion of patients showing a clinically relevant decrease in ESSDAI score from 
baseline after 12 weeks.  
where a clinically relevant decrease in ESSDAI score is defined as a decrease of 
≥ 3 points. 
Secondary efficacy outcomes for this study are as follows: 
• 
Proportion of individuals showing a clinically relevant decrease in ESSPRI score 
after 12 weeks where a clinically relevant decrease in ESSPRI score is defined as a 
decrease of ≥ 1 point. 
• 
Change from baseline in ESSDAI, ESSPRI and SF-36 scores after 12 weeks. 
• 
Change from baseline in each of the individual components of the ESSPRI (dryness, 
fatigue and pain) after 12 weeks. 
where a clinically relevant decrease in ESSPRI score is defined as a decrease 
of ≥ 1 point. 
3.3.2 
Pharmacodynamic Outcome Measures 
The pharmacodynamic outcome measures for this study are as follows: 
• 
Change from baseline in tear flow rate. 
• 
Change from baseline in salivary flow rate. 
• 
Change from baseline in auto-antibody titres. 
• 
Change from baseline in erythrocyte sedimentation test (ESR). 
• 
Change from baseline in cathepsin S mass and activity in plasma, tears and saliva. 
• 
Change from baseline in circulating numbers of defined sub-populations of white 
blood cells. 
• 
Change from baseline in biomarker concentrations. 
 
3.3.3 
Pharmacokinetic Outcome Measures 
RO5459072 plasma concentration data will be pooled with data from other studies 
(Study WP29542 and Study BP29772) for population pharmacokinetic modelling. The 
modelling results will be reported separately. 
3.3.4 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
The incidence and severity of AEs. 
• 
The incidence of SAEs or withdrawals because of AEs. 
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• 
The incidence of out-of-reference-range values for vital signs and ECGs, and 
laboratory tests. 
• 
Change from baseline in vital signs and ECGs, and laboratory tests by visit. 
 
3.3.5 
Exploratory Outcome Measures 
The exploratory outcomes for this study are as follows: 
• 
Comparisons of the performance of alternative composite endpoints (e.g., Sjögren’s 
response index [SSRI-30]) as predictive markers of drug treatment response. 
• 
Change from Week 12 to follow-up for ESSDAI, ESSPRI and SF-36 scores in each 
treatment group. 
• 
Comparisons of drug treatment effects between genotypes. 
• 
Patterns of use of selected concomitant medications. 
 
3.3.6 
Optional Sub-study Outcome Measures 
Patients consenting to also participate in the optional sub-study will undergo MSG 
biopsies at baseline and Week 12. Biopsy samples will be processed for histological 
examination. 
The outcomes for the optional sub-study are as follows: 
• 
Change from baseline in focus score (number of lymphocytes per 4 mm2).  
• 
Change from baseline in numbers of defined sub-populations of infiltrating 
lymphocytes. 
• 
Subjective evaluation of changes from baseline in minor salivary gland (MSG) 
structure. 
Other exploratory analyses may include, but not be limited to, changes in leukocyte and 
stromal subpopulation numbers and degree of activation. 
 
4. 
MATERIALS AND METHODS 
4.1 
CENTERS 
This is a multi-center, multi-country study to be conducted in the US and Europe. 
Additional sites may be included for back-up purposes and may be activated if needed. 
Administrative and Contact Information, and List of Investigators are provided separately. 
4.2 
STUDY POPULATION 
Patients with primary Sjögren’s Syndrome will be enrolled into this study. Adults between 
18 and 75 years old, diagnosed according to AECG criteria, with moderate to severe 
disease activity and symptoms based on ESSDAI and ESSPRI score can be enrolled in 
the study. The study will require approximately 70 patients. 
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Approximately 30 patients will be enrolled in the optional sub-study. 
4.2.1 
Recruitment Procedures 
Patients will be identified for potential recruitment per site-specific recruitment plans. 
4.2.2 
Inclusion Criteria 
Patients must meet all of the following criteria for study entry: 
1. Males and females 18 to 75 years of age, inclusive. 
2. Patient willing to give written informed consent and to comply with the study 
procedures and restrictions. 
3. Primary Sjögren's syndrome diagnosed previously according to the revised 
American-European Consensus Group (AECG) criteria. 
4. European League against Rheumatism (EULAR) Sjögren's Syndrome Disease 
Activity Index (ESSDAI) score ≥ 5. 
5. EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score ≥ 5. 
6. Elevated serum titers at screening of anti-Sjögren's-syndrome-related antigen A 
(anti-SSA) and/or anti-SSB antibodies at screening. 
7. Negative pregnancy test at screening and baseline (women only), and 
agreement to comply with measures to prevent pregnancy and restrictions on 
sperm donation (see Section 4.5.5). 
 
4.2.3 
Exclusion Criteria 
1. A diagnosis of secondary Sjögren's syndrome according to the revised AECG 
criteria. 
2. Severe complications of Sjögren's syndrome, such as vasculitis with renal, 
neurologic or cardiac involvement; interstitial lung disease and severe myositis, 
3. Systemic immunosuppressant therapy (e.g., abatacept, azathioprine, ciclosporin, 
etanercept, tofacitinib), cyclophosphamide or B cell depleting therapy (e.g., 
rituximab anti-CD20 therapy) within 6 months prior to the screening visit. Low 
dose methotrexate treatment (i.e., oral doses ≤ 20 mg weekly) is, however, 
permitted.  
4. Corticosteroid therapy exceeding 7.5 mg prednisone equivalents per day. 
5. Mechanically stimulated whole salivary flow rate at baseline of < 0.1 mL/min. 
6. A positive test result for hepatitis B (HBV), hepatitis C (HCV), or human 
immunodeficiency virus (HIV), or tuberculosis, or any other active viral, fungal, 
yeast or bacterial infection at the screening visit. 
7. A history of recurring or chronic infections, any other indication of reduced 
immune function considered to be clinically significant by the Investigator, or any 
other underlying conditions which may further predispose patients to serious 
infection. 
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8. A history of lymphoma, myeloma (monoclonal hypergammaglobulinemia) or 
monoclonal gammopathy of unknown significance (MGUS), or any other 
malignancies within the past 5 years (except basal cell or squamous cell 
carcinoma of the skin that has been cured). 
9. A diagnosis of fibromyalgia, or a diagnosis of significant depression or anxiety 
that in the opinion of the investigator would confound the interpretation of the 
study results. 
10. Severe renal impairment (e.g., estimated glomerular filtration rate < 30 mL/min), 
moderate or severe hepatic impairment (e.g., Child-Pugh B or C) or other 
clinically significant hepatic disease (e.g., AST, ALT or GGT > 2x upper limit of 
normal). 
11. Current or a history of severe, progressive or uncontrolled hematologic, 
gastrointestinal, endocrine, pulmonary, cardiac, or neurologic disease, or any 
other concomitant disease or condition or any clinically significant finding at 
screening that could interfere with, or for which the treatment of might interfere 
with, the conduct of the study, or that would, in the opinion of the Investigator, 
pose an unacceptable risk to the individual in this study. 
12. Participation in an investigational drug or device study within 3 months prior to 
screening. 
13. Inability to comply with the study protocol for any other reason. 
14. Women who are lactating, breastfeeding or planning to nurse. 
15. Using other prohibited medication (moderate or potent inhibitors of CYP3A4; 
strong inducers of CYP3A4; strong inhibitors of the transporter P-glycoprotein 
[P-gp]; sensitive substrates of CYP3A4 with a narrow therapeutic index). 
 
4.3 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.3.1 
Treatment Assignment 
Subjects will be randomly assigned to RO5459072 or placebo treatment groups in a 
1:1 ratio using interactive voice/web-based response system IxRS (IvRS and IwRS). 
4.3.2 
Blinding 
This is a double-blind study. Blinding to study treatment allocation will be achieved 
through use of matching-placebo capsules. Neither the patient, nor the Investigator, nor 
the Sponsor will be aware of the treatment allocation. The randomization list will, 
however, be made available to the staff at bioanalytical laboratories, to the Sponsor 
personnel responsible for pharmacokinetic and pharmacodynamic bioanalysis and to 
programmers. 
4.3.3 
Emergency Unblinding 
In the event of an emergency, the treatment code for an individual patient will be readily 
available to the Investigator and Sponsor through the IxRS. If unblinding is necessary for 
patient management (in the case of a serious adverse event), the Investigator will be 
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able to break the treatment code by contacting the IxRS. Treatment codes should not be 
broken except in emergency situations. If the Investigator wishes to know the identity of 
the study drug for any other reason, he or she should contact the Medical Monitor 
directly. The Investigator should document and provide an explanation for any premature 
unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event). 
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected serious adverse events (see Section 5.1) that are considered by 
the Investigator to be related to study drug. 
Whenever disclosure of the identity of the study drug is necessary, adequate procedures 
will be in place to ensure integrity of the data. Any unblinding, at the investigating site 
end, will be documented in the study report with date, reason for identifying the drug and 
the name of all the person(s) who had to be unblinded. 
4.4 
STUDY TREATMENT 
4.4.1 
Formulation, Packaging, and Handling 
4.4.1.1 
RO5459072 and Placebo 
The investigational medicinal products (IMPs) in this study are:  
• 
RO5459072 50 mg capsules for oral administration (Formulation F03). 
• 
Placebo capsules for oral administration (Formulation F04). 
 
All IMPs will be supplied and packaged by the Sponsor. 
Reddish brown, hard gelatin capsules for oral administration will be provided. The 
capsule fill consists of RO5459072 drug substance only. Matching-placebo capsules are 
also provided. The capsule fill for the matching-placebo consists only of the inactive 
ingredient lactose monohydrate of compendial grade. 
Study drug packaging will be overseen by the Roche clinical trial supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification and dosage. Capsules of RO5459072/Placebo should be stored according 
to the details on the product label (“Do not store above 25°C, protected from light, keep 
container tightly closed”; see Pharmacy Manual for further details). 
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations. 
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature 
conditions, and report any deviations or product complaints to the monitor upon 
discovery.  
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For further details, see the Investigator’s Brochure (Section 3.2). 
4.4.2 
Dosage, Administration, and Compliance 
4.4.2.1 
RO5459072 and Placebo 
Patients will be randomly assigned to one of two possible blinded study drug treatments: 
• 
100 mg RO5459072 (2 x F03 capsules) b.i.d. with food for 12 weeks. 
• 
Placebo (2 x F04 capsules) b.i.d. with food for 12 weeks. 
 
Study drugs are to be taken orally twice daily (b.i.d.) with food, i.e., with breakfast in the 
morning and a meal in the evening, for 12 weeks. Patients should start study drug 
treatment one day after the baseline visit. Capsules should be swallowed whole.  
The qualified individual responsible for dispensing the study drug will allocate drug 
supplies according to the assigned patient randomization number. This individual will 
write the date dispensed and subject number on the Drug Dispensing Form. This 
individual will also record the study drug MEDNO received by each subject during the 
study. 
Accountability and subject compliance will be assessed by maintaining adequate study 
drug dispensing records. The Investigator is responsible for ensuring that dosing is 
administered in compliance with the protocol. Delegation of this task must be clearly 
documented and approved by the Investigator. 
4.4.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (RO5459072 and placebo) will be provided 
by the Sponsor. The investigational site will acknowledge receipt of IMPs, to confirm the 
shipment condition and content. Any damaged shipments will be replaced. 
The Investigator is responsible for the control of drugs under investigation. Adequate 
records of the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing 
Log) of the study drug must be maintained. The Drug Dispensing Log must be kept 
current and should contain the following information: 
• 
The identification of the patient to whom the study drug was dispensed (for example 
patient initials and date of birth). 
• 
The date(s), quantity of the study drug dispensed to the patient. 
• 
The date(s) and quantity of the study drug returned by the patient. 
• 
All records and drug supplies must be available for inspection by the Roche Monitor 
at every monitoring visit. 
 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
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Sponsor. Local or institutional regulations may require immediate destruction of used 
investigational medicinal product for safety reasons. In these cases, it may be 
acceptable for investigational study site staff to destroy dispensed investigational 
product before a monitoring inspection provided that source document verification is 
performed on the remaining inventory and reconciled against the documentation of 
quantity shipped, dispensed, returned, destroyed and provided that adequate storage 
and integrity of drug has been confirmed. 
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Written documentation of destruction must contain the following: 
• 
Identity medication number (MEDNO) of investigational product[s] destroyed. 
• 
Quantity of investigational product[s] destroyed. 
• 
Date of destruction. 
• 
Method of destruction. 
• 
Name and signature of responsible person [or company] who destroyed 
investigational product[s]. 
 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.4.4 
Post-Trial Access to RO5459072 
RO5459072 will not be provided to participants after conclusion of the study. 
4.5 
CONCOMITANT THERAPY AND FOOD 
4.5.1 
Permitted Therapy 
In addition to the study drug treatment, patients may continue to concomitantly use 
existing treatments for Sjögren’s syndrome. With exception of the prohibited therapies 
described in Section 4.5.2, systemic immunomodulatory therapy (e.g., 
hydroxychloroquine), low dose corticosteroids ( ≤  7.5 mg prednisone equivalent dose per 
day), or low dose methotrexate, or topically administered immunosuppressive agents 
(e.g., cyclosporine eye drops) are permissible provided the patient has been on a stable 
dose for ≥ 2 months prior to screening and the dose is expected to remain unchanged 
during the study. Similarly patients on non-steroidal anti-inflammatory drugs (NSAIDs), 
antidepressants, or pilocarpine must also have been on a stable dose for 4 weeks prior 
to screening and be expected to remain on this dose throughout the study. If any of 
these drugs have been discontinued recently, patients must be off drug for at least 8 
weeks before screening. 
All medications (prescription and over-the-counter [OTC]) taken within 30 days of study 
screening visit, until the follow-up visit, will be recorded on the appropriate eCRF. The 
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dose and/or frequency of use of selected medications commonly prescribed to patients 
with Sjögren’s syndrome will be specifically captured in the eCRF. 
4.5.2 
Prohibited Therapy 
Use of concomitant therapies which systemically suppress the immune system are not 
permitted during the study. Prohibited therapies are: 
• 
Corticosteroid therapy exceeding 7.5 mg prednisone equivalent per day (see 
Appendix 3). 
• 
Anti-CD20 therapy (e.g., rituximab) or other B cell-depleting therapy within 6 months 
of screening. 
• 
Immunosuppressant therapy (e.g., abatacept, azathioprine, ciclosporin, etanercept, 
tofacitinib). Low dose methotrexate treatment (oral doses ≤ 20 mg weekly) is, 
however, permitted. 
• 
Cyclophosphamide. 
 
Pilocarpine or drugs with similar pharmacological action should not be used within 
12 hours prior to an assessment visit. 
Because RO5459072 is a substrate of CYP3A4 and P-gp, other prohibited medications 
are: 
• 
Moderate or potent inhibitors of CYP3A4 (e.g., itraconazole, erythromycin, 
nefazodone). 
• 
Strong inducers of CYP3A4 (e.g., rifampicin, carbamazepine). 
• 
Sensitive substrates of CYP3A4 with a narrow therapeutic index (e.g., alfentanil, 
colchicine, ethosuxamide, fentanyl, and pimozide). 
• 
Strong inhibitors of the transporter P-glycoprotein (P-gp) (e.g., quinidine, 
clarithromycin). 
 
A full list of prohibited concomitant medications is provided in Appendix 4.  
RO5459072 weakly induces CYP3A4 activity in vitro. RO5459072 treatment therefore 
has the theoretical potential to cause a small decrease in exposure of concomitantly 
administered CYP3A4 substrates. For this reason, caution is advised when initiating 
study drug treatment in individuals already established on a stable dose of a CYP3A4 
substrate, or starting dosing with a CYP3A4 substrate in individuals receiving study drug 
treatment. See Section 4.2.2 regarding use of hormonal contraception. 
In vitro data indicate that RO5459072 weakly inhibits the transport of substrates of 
MDR1 (P-gp), OATP1B1 and MATE2-K transporters. The potential for RO5459072 to 
alter the pharmacokinetics of substrates of these transporters (e.g., digoxin, pravastatin, 
metformin, etc) in vivo cannot be entirely discounted. Therefore, caution is advised when 
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administering study drug treatment together with medications known to be substrates of 
these transporters. 
RO5459072 was found to induce CYP2B6 expression and enzyme activity in vitro but its 
M1 metabolite was also found to be a moderate inhibitor of CYP2B6 in vitro. It is 
therefore possible that RO5459072 treatment may lead to changes in exposure of 
concomitant medications which are predominantly metabolized by CYP2B6. For this 
reason, caution is advised when administering RO5459072 treatment together with 
medications known to be sensitive substrates of CYP2B6 (e.g., efavirenz, bupropion). 
4.5.3 
Vaccination 
Investigators should be aware of the theoretical potential for study drug treatment to 
impair vaccine efficacy. Investigators should therefore follow local guidelines and 
standards of care for immunization of individuals receiving immunosuppressant 
therapies. The use of live vaccines is not recommended. 
4.5.4 
Food 
Study drugs are to be taken with food. Food and beverages containing grapefruit or 
grapefruit juice should be avoided during the study because of the potential effects on 
CYP3A4 activity. 
4.5.5 
Contraception 
Embryo-fetal development studies identified a teratogenic potential of RO5459072. 
Enrolment in the study is therefore contingent on agreement to comply with measures to 
prevent pregnancy. All women are required to have a negative pregnancy test at 
screening and baseline and any woman who becomes pregnant should be immediately 
withdrawn from the study (see Sections 4.7.1 and 5.4.3). 
Women of childbearing potential must agree to remain abstinent (refrain from 
heterosexual intercourse) or use a contraception method that results in a failure rate 
of  <  1% per year, during the treatment period and for at least 28 days after the last dose 
of study drug. 
• 
Examples of non-hormonal contraceptive methods with a failure rate of  <  1% per 
year include bilateral tubal ligation, male sterilization, and copper intra uterine 
devices.  
• 
Examples of hormonal contraceptive methods with a failure rate of  <  1% per year 
include established, proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intra-uterine devices. However, because of the theoretical 
potential for drug-drug interactions which might impair the efficacy of hormonal 
contraception, these must be supplemented with a barrier method such as male or 
female condom with spermicide. 
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A woman is considered not to be of childbearing potential if she is post-menopausal 
( ≥  12 months of non−therapy-induced amenorrhea, with no identified cause other than 
menopause) or has undergone surgical sterilization (removal of ovaries and/or uterus). 
Men with female partners of childbearing potential or pregnant female partners, men 
must remain abstinent (refrain from heterosexual intercourse) or use a condom during 
the treatment period and for at least 28 days after the last dose of study drug to avoid 
exposing the embryo. All men must refrain from donating sperm during the treatment 
period and for at least 28 days after the last dose of study drug.  
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
4.6 
STUDY ASSESSMENTS 
4.6.1 
Description of Study Assessments 
All examinations listed below will be performed according to the schedule of 
assessments outlined in Appendix 1. Instruction manuals and supply kits will be provided 
for all central laboratory assessments. 
4.6.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, all surgeries, reproductive status, 
smoking history, use of alcohol and drugs of abuse and all concomitant medications 
(e.g., prescription drugs, OTCs, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 30 days prior to the screening visit. 
Demographic data will include age, sex, and self‑reported race/ethnicity. 
4.6.1.2 
Physical Examinations 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in patient’s notes. New or worsened clinically significant abnormalities should 
be recorded as adverse events on the Adverse Event eCRF. 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, throat, neck and lymph nodes, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems. 
A physical examination will include careful attention to areas of known and possible 
malignancy. 
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4.6.1.3 
Disease-Specific Assessments 
4.6.1.3.1 
ESSDAI 
EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) will be employed to 
assess disease activity at baseline and during the treatment phase. The ESSDAI is a 
physician-assessed disease activity index for primary Sjögren’s syndrome developed by 
the EULAR consortium (Seror et al 2010; Seror et al 2015). It consists of 44 items in 
12 organ-specific ‘domains’ contributing to disease activity (constitutional, 
lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, 
peripheral nervous system [PNS], central nervous system [CNS], hematological, 
biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and 
assigned a numerical score based on pre-determined weighting of each individual 
domain. An overall score is then calculated as the sum of all individual weighted domain 
scores. 
4.6.1.3.2 
ESSPRI 
EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) will be used to assess 
Sjögren’s syndrome symptom severity at baseline and during the treatment phase. The 
ESSPRI is a patient-reported, subjective symptom index for primary Sjögren’s syndrome 
developed by the EULAR consortium (Seror et al 2011, Seror et al 2015). It consists of 
three questions covering the cardinal symptoms of Sjögren’s syndrome: dryness, fatigue 
and pain (articular and/or muscular). Each domain scored on scale of 0-10, and an 
overall score is calculated as the mean of the three individual domains where all 
domains carry the same weight.  
A clinically relevant change in ESSPRI score is defined as an absolute decrease of 
≥ 1 point (Seror et al 2014). 
4.6.1.3.3 
SF-36 V2 (Acute Version) 
The Short Form 36 Health Survey (SF-36 V2) will be used to assess health-related 
quality of life at baseline and at on-treatment visits. The SF-36 consists of 36 questions 
covering 8 domains (general health, physical functioning, role-functioning physical, 
bodily pain, social functioning, role-functioning emotional, mental health and vitality), with 
each domain scored on a scale 0-100 (Ware et al 1993). The acute version has a 1-
week recall period, asking patients to consider the past week in responding to questions. 
4.6.1.3.4 
Salivary and lacrimal gland function 
• 
Mechanically Stimulated Salivary Flow 
Stimulated salivary flow will be measured at baseline and at on-treatment visits using a 
mechanical stimulation method. The test should be performed at a similar time of day at 
each visit and conducted under standard conditions; patients should refrain from oral 
hygiene procedures, smoking, eating and drinking for at least 2 hours before the test and 
be seated in an upright position. Patients will be provided with a piece of neutral wax, 
paraffin, silicone, unflavored chewing gum, or similar chewable, unflavored, non-
absorbent material and instructed to chew for a period of 5 minutes. Saliva will be 
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collected into a pre-weighed collecting container. The container is then re-weighed to 
determine the weight of saliva. The stimulated salivary flow rate is calculated assuming a 
specific gravity of 1 (i.e., 1 mL saliva = 1 g) and expressed in mL per minute. The sample 
will be used for biomarker measurements. The samples can be frozen (for further 
details, see the Laboratory Manual).  
• 
Tear production 
Un-stimulated tear production rate will be measured from both eyes (without the use of 
analgesics/ anesthetic drops) at baseline and at on-treatment visits using the Schirmer 
method. A thin strip of filter paper (Schirmer strip, e.g., 35 x 5 mm) will be placed at the 
junction of the lateral and middle thirds of the lower eyelid of each eye and the eyes 
should be gently closed. The strips will be left in place for 5 minutes so that tear fluid is 
absorbed. The maximum length of wetting along the strip at the end of the test period 
will be measured and recorded in millimeters. The sample will be used for biomarker 
assessments too. 
4.6.1.4 
Laboratory Assessments 
Laboratory safety tests shall be collected at visits specified in the Schedule of 
Assessments (Appendix 1). On each occasion patients must have fasted for at least 4 h 
before sampling. 
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor patient’s safety. Where the clinical significance of abnormal 
lab results is considered uncertain, screening lab tests may be repeated before 
randomization to confirm eligibility. If there is an alternative explanation for a positive 
urine or blood test for drugs of abuse, e.g., previous occasional intake of a medication or 
food containing for example codeine, benzodiazepines or opiates, the test could be 
repeated to confirm washout. 
In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found. Results of 
clinical laboratory testing will be recorded on the eCRF or be received as electronically 
produced laboratory reports submitted directly from the central laboratory. Situations 
may arise when local laboratories are utilized such as for safety labs. In these cases, 
reference ranges must be submitted where applicable. 
With the exception of the urine pregnancy and ESR tests, which will be locally assessed, 
the samples for the following laboratory tests will be sent to the central laboratory for 
analysis: 
• 
Hematology: Hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, 
mean corpuscular volume, absolute reticulocyte count, total and differential 
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leucocyte (WBC) absolute count (neutrophils, eosinophils, lymphocytes, monocytes 
and basophils). 
• 
Blood chemistry: Albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), bicarbonate, C-reactive protein (CRP), 
calcium, chloride, creatinine phosphokinase (CPK), gamma-glutamyl transferase 
(GGT), glucose, phosphate, potassium, creatinine, sodium, total bilirubin, total 
protein, troponin, urea, complement (C3 and C4). 
• 
Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT) 
• 
Lipids: High-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein 
cholesterol (LDL-C), triglycerides, total cholesterol. 
• 
Urinalysis A midstream urine specimen will be collected for dipstick analysis of 
protein, blood, glucose, and pH. 
• 
At Screening only: HIV (specific tests HIV-1 antibody, HIV-1/2 antibody, HIV-2 
antibody), hepatitis B surface antigen (HBsAg), total hepatitis B core antibody 
(HBcAb), hepatitis C virus (HCV) antibody, tuberculosis testing. 
• 
Pregnancy test: All women (including those who have had a tubal ligation) will 
have a serum pregnancy test at screening and at baseline. A urine pregnancy test 
will also be done at baseline prior to randomization. Women of childbearing potential 
will have serum and urine pregnancy tests at all subsequent visits (see SoA table, 
Appendix 1). 
 
4.6.1.5 
Pharmacokinetic Assessments 
Blood samples for measurement of plasma concentrations of RO5459072 using a 
validated assay (and its metabolites as appropriate, in an exploratory manner) will be 
collected at visits specified in the SoA (Appendix 1). Samples will be sent to a central 
laboratory for analysis. The date and time of each sample collection will be recorded in 
the eCRF. 
Plasma concentrations of RO5459072 will be measured by a specific and validated 
liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Metabolites 
may also be measured in exploratory manner using qualified analytical methods. 
The plasma concentration data will be pooled with data from other studies (e.g., 
WP29542 and BP29772) for population pharmacokinetic and 
pharmacokinetic/pharmacodynamic modelling. The results of that population modelling 
will be reported separately. 
4.6.1.6 
Pharmacodynamic Assessments 
Samples for the pharmacodynamics assessments will be either locally analyzed, sent to 
one or several central laboratories or to the Sponsor for analysis. 
Pharmacodynamic assessments will include the measurement of tear flow rate using the 
Schirmer’s test, stimulated salivary flow rate, serum auto-antibody titers, ESR, collection 
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of samples for measurement of circulating numbers of sub-populations of white blood 
cells, biomarkers connected to Sjögren’s syndrome and extracellular matrix degradation 
Cathepsin S mass and activity will be measured in plasma, tears and saliva samples 
(please see SoA, Appendix 1). Auto-antibody titers will also be measured at screening in 
order to assess eligibility for the study.  
Based on continuous analysis of the data in this study from the samples collected, 
samples not considered to be critical for safety may be amended or stopped during 
study conduct. 
Auto-antibodies (anti-SSA/SSB) 
Serum will be collected for the determination of anti-SSA/SSB autoantibodies as 
indicated in the SoA (Appendix 1). These measurements will include anti-SSA, anti-SSB, 
ANA, and rheumatoid factor, as well as total IgG, IgM and cryoglobulins. 
Immunophenotyping 
Whole blood samples will be collected to quantify white blood cell counts by flow 
cytometry (CD4+ T cells and follicular T helper cells, B cell subsets and natural killer 
[NK] cells) at the visits indicated in the SoA (Appendix 1). Sub-populations of white blood 
cells will be counted by FACS immunophenotyping of cell surface markers and may 
include TBNK/monocytes, TH and TFH cells and B cells. 
Soluble Biomarker Assessments 
Plasma samples - Samples for measurement of biomarkers connected to Sjögren’s 
syndrome and extracellular matrix degradation will be collected at specified visits as 
indicated in the SoA (Appendix 1). Biomarkers to be measured will include β2-
microglobulin, cytokines (including - but not limited to - BAFF, IL-4, IL-6 and IL-10), beta-
hydroxycholesterol and desmosine. 
For sampling procedures, storage conditions, and shipment instructions, refer to the 
separate central laboratory documentation. 
Cathepsin S Mass and Activity 
Plasma samples - Samples for measurement of cathepsin S mass and activity will be 
collected at specified visits as indicated in the SoA (Appendix 1). 
Saliva and tear samples – Cathepsin S mass and activity will be measured in saliva 
and tear fluids collected as part of pharmacodynamic assessments of salivary and 
lacrimal gland flow (see Section 4.6.1.3). 
Erythrocyte Sedimentation Ratio 
Samples for determining the ESR value and inflammation related to Sjögren’s syndrome 
will be collected at specified visits as indicated in the SoA (Appendix 1). 
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mRNA Sampling 
A whole blood sample will be collected for mRNA extraction as indicated in the SoA 
(Appendix 1). The mRNA may be used to measure gene expression changes related to 
interferon response including, but not limited, to MxA. 
4.6.1.7 
Clinical Genotyping 
A whole blood sample will be collected for DNA extraction, as indicated in the SoA 
(Appendix 1). The DNA may be used for genotyping of alleles in genes encoding 
transporters and drug metabolizing enzymes (e.g., CYP3A4, CYP3A5) and transporters 
(e.g., MDR1), human leukocyte antigens (i.e., HLA gene family) and cathepsin S (CTSS). 
The DNA will be destroyed after analysis and the data arising from clinical genotyping 
will be subject to the confidentiality standards described in Section 8.4. 
4.6.1.8 
Electrocardiograms 
Triplicate 12-lead ECG recordings (i.e., three useful ECGs without artifacts) will be 
obtained within approximately 2-5 minutes at each specified visits. The average of the 
three readings will be used to determine ECG intervals (e.g., PR, QRS, QT). Additional 
unscheduled ECGs should be performed in case of abnormalities and if clinical 
symptoms occur. Whenever possible, the same brand/model of a standard high-quality, 
high-fidelity electrocardiograph machine equipped with computer-based interval 
measurements should be used for each patient. The conditions should be as close as 
possible to the baseline ECG; this includes, but is not limited to, food intake, activity level, 
stressors and room temperature. 
To minimize variability, it is important that patients be in a resting position 
(semi-recumbent) for ≥ 10 minutes prior to each ECG evaluation. Body position should 
be consistently maintained for each ECG evaluation to prevent changes in heart rate. 
Environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre‑ECG resting period and during ECG recording. In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality. 
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the patient’s 
permanent study file at the site. If considered appropriate by Roche, ECGs may be 
analyzed retrospectively at a central laboratory. 
ECG characteristics, including heart rate, QRS duration, and PR, and QT intervals, will 
be recorded on the eCRF. QTcF (Fridericia’s correction) and RR will be calculated by 
the Sponsor/recorded on the eCRF. Changes in T-wave and U-wave morphology and 
overall ECG interpretation will be documented on the eCRF. T-wave information will be 
captured as normal or abnormal, U-wave information will be captured in two categories: 
absent/normal or abnormal. 
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4.6.1.9 
Vital Signs 
Vital signs will include resting blood pressure (BP), heart rate, respiratory rate and body 
temperature and will be recorded at the visits specified in the Schedule of Assessments 
(Appendix 1). 
Blood pressure, heart rate and respiratory rate should be obtained in a quiet room at a 
comfortable temperature, with the patient's arm unconstrained by clothing or other 
material. All measurements will be obtained from the same arm and, with the same cuff 
size, using a well-calibrated automatic instrument with a digital readout, throughout the 
study (the “ideal” cuff should have a bladder length that is 80% and a width that is at 
least 40% of arm circumference [a length-to-width ratio of 2:1]). The automatic cuff 
should be placed on the designated arm prior to the patient being in a resting position. 
The patient should be asked to remove all clothing that covers the location of cuff 
placement. The individual should be comfortably seated, with the legs uncrossed, and 
the back and arm supported, such that the middle of the cuff on the upper arm is at the 
level of the right atrium (the mid-point of the sternum). After the patient has been resting 
in semi-recumbent position for ≥ 10 minutes, blood pressure, heart rate and respiratory 
rate will be obtained. 
4.6.1.10 
Administering the SF36 and ESSPRI (Patient-Reported 
Outcomes) 
The SF36 & ESSPRI are PRO instruments which will be completed by patients in this 
study to more fully characterize the clinical profile of RO5459072. The PRO instruments, 
translated as required in the local language, will be distributed in paper PRO booklet 
format by the Investigator staff and completed in their entirety by the patient at specified 
visits during the study. 
Entries should be reviewed for completeness by the site staff during the visit and the 
patient/caregiver should be requested to complete any blank items. Changes to the form 
should not be made once the patient/caregiver has left the site for that visit. 
The paper PRO booklets are part of the source documentation. A visit-specific paper 
PRO booklet, containing the PRO assessments for that study day, will be provided. 
Patients should complete the PRO booklets at the beginning of each study visit, prior to 
other study assessments or discussion of health status. 
4.6.1.11 
MSG Biopsies (Optional Sub-study) 
At selected participating study centers, patients may also enroll into an optional 
sub-study in which consenting individuals will undergo labial (MSG) biopsies for 
assessing histological and structural changes in labial salivary glands using, 
e.g., immunohistochemistry. 
Biopsies will be taken using a minimally invasive technique according to standard 
practice at each study center, e.g., multiple 2-3mm incisions on the buccal side of the lip 
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to collect the glandular tissue using forceps. Biopsy sample handling and shipment 
instructions will be provided in a separate laboratory manual. Histology and 
immunohistochemistry methods will be described and reported separately. 
4.6.1.12 
Timing of Assessments - Screening and Pretreatment 
Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled patient and for patients who are not subsequently enrolled will be maintained 
at the study site.  
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that patients meet all eligibility criteria. The Investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure. Based on the Investigator judgment, patients may be re-screened 
and enrolled if the patient meets all of the eligibility criteria at a later time-point. 
An Eligibility Screening Form (ESF) documenting the Investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site. 
Screening and pre-treatment assessments will be performed within 28 days prior to first 
dose of study drug treatment, unless otherwise specified. After the study 
completion/early termination visit, adverse events should be followed as outlined in 
Sections 5.5, 5.4.3 and 5.6. 
For assessments, and timing of assessments, please see the SoA table (Appendix 1). 
4.7 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
Patient Discontinuation 
The Investigator has the right to discontinue a patient from RO5459072 or withdraw a 
patient from the study at any time. In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason. Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following: 
• 
Patient withdrawal of consent at any time. 
• 
Pregnancy. 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study. 
• 
Investigator or Sponsor determines it is in the best interest of the patient. 
• 
The patient requires corticosteroid therapy exceeding 7.5 mg prednisone equivalent 
per day, or the dose of existing corticosteroid therapy is increased during the study 
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treatment period (see Section 4.5.2 and Appendix 3), or institution of any other 
immunosuppressive therapy, or an increase in dose of existing therapy. 
 
Every effort should be made to obtain information on patients who withdraw from the 
study. The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. 
Patients will not be followed for any reason after consent has been withdrawn. Patients 
who withdraw from the study will not be replaced. 
Under no circumstances will patients who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study. 
4.7.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program. 
The Sponsor has the right to replace a site at any time. Reasons for replacing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment. 
• 
Poor protocol adherence. 
• 
Inaccurate or incomplete data recording. 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice. 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest; 
measurement of protocol‑specified safety laboratory assessments; measurement of 
protocol-specified vital signs, ECGs; and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4
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5.1.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An adverse event can therefore 
be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition). 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X‑ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies). 
 
5.1.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria:
• 
Fatal (i.e., the adverse event actually causes or leads to death). 
• 
Life-threatening (i.e., the adverse event, in the view of the Investigator, places the 
patient at immediate risk of death). 
This does not include any adverse event that had it occurred in a more severe form or 
was allowed to continue might have caused death. 
• 
Requires or prolongs in-patient hospitalization (see Section 5.3.5.9). 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions). 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug. 
• 
Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, see Section 5.3.3); the event itself 
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may be of relatively minor medical significance (such as severe headache without any 
further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.1.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2 for reporting instructions). Adverse events of special interest for 
this study include the following: 
• 
Cases of elevated transaminases (ALT or AST) in combination with either an 
elevated bilirubin or clinical jaundice.  
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only 
when a contamination of the study drug is suspected. 
 
5.2 
SAFETY PLAN 
5.2.1 
Management of Specific Adverse Events  
No dosage modifications or interruptions are planned for patients participating in this 
study. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The Investigator is responsible for ensuring that all adverse events (see Section 5.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4-5.6 . 
For each adverse event recorded on the Adverse Event eCRF, the Investigator will make 
an assessment of seriousness (see Section 5.1.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
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5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact. All adverse 
events, whether reported by the patient or noted by study personnel, will be recorded in 
the patient’s medical record. Adverse events will then be reported on the Adverse Event 
eCRF as follows: 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies). Any 
other adverse event should not be reported. 
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 28 days after the last dose of study drug. No additional active 
monitoring is required after the follow-up visit. 
After a period of 28 days from the last dose of study drug, investigators should report 
any deaths, serious adverse events, or other adverse events of concern that are 
believed to be related to prior treatment with study drug (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time-points. Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 2 below provides guidance for assessing adverse event severity. 
Table 2 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity. 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity. 
Severe 
Incapacitating with inability to work or to perform normal daily activity. 
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see Section 5.1.2). 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
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not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly. The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug. 
• 
Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study drug, or reintroduction of study drug. 
• 
Known association of the event with the study drug or with similar treatments. 
• 
Known association of the event with the disease under study. 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event. 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
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• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time-points. Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this. 
A recurrent adverse event is one that resolves between patient evaluation time-points 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy. 
• 
Clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5-times the upper limit of normal (ULN) 
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
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characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation). 
• 
Results in a medical intervention or a change in concomitant therapy. 
• 
Clinically significant in the Investigator’s judgment. 
 
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( >  3  ×  ULN) in combination with either an 
elevated total bilirubin ( >  2  ×  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, investigators must report as an adverse event the occurrence of either of the 
following: 
• 
Treatment-emergent ALT or AST  >  3  ×  ULN in combination with total 
bilirubin  >  2  ×  ULN 
• 
Treatment-emergent ALT or AST  >  3  ×  ULN in combination with clinical 
jaundice 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be reported. 
The term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without 
preexisting heart disease, within one hour of the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and stable. 
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
“unexplained death” should be recorded on the Adverse Event eCRF. If the cause of 
death later becomes available (e.g., after autopsy), “unexplained death” should be 
replaced by the established cause of death. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.9 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Section 5.3.5.9), except as outlined below. 
The following hospitalization scenarios are not considered to be serious adverse events: 
• 
Hospitalization for respite care. 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
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The hospitalization was planned prior to the study. 
The patient has not suffered an adverse event. 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available. 
 
5.3.5.10 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an adverse event unless it results in untoward medical effects. 
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF. 
All adverse events associated with an overdose or incorrect administration of study drug 
should be recorded on the Adverse Event eCRF. If the associated adverse event fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2). 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events. 
• 
Non-serious adverse events of special interest. 
• 
Pregnancies. 
 
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis. 
• 
Significant new diagnostic test results. 
• 
Change in causality based on new information. 
• 
Change in the event’s outcome, including recovery. 
• 
Additional narrative information on the clinical course of the event. 
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Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical monitors is available 
24 hours a day 7 days a week.  
Medical monitors contact details are listed in the “Protocol Administrative and Contact 
Information & List of Investigators”. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest 
(see Sections 5.1.2 and 5.1.3), investigators should record all case details that can be 
gathered on the Serious Adverse Reporting Form and forward this form to the SAE 
Responsible within 24 hours. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug. A Clinical Trial Pregnancy Reporting Form should be completed by 
the Investigator and submitted to the Sponsor within 24 hours after learning of the 
pregnancy. Pregnancy should not be recorded on the Adverse Event eCRF. The 
Investigator should discontinue study drug and counsel the patient, discussing the risks 
of the pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy. 
5.4.3.2 
Pregnancies in Female Partners of Male Patient 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
28 days after the last dose of study drug. A Clinical Trial Pregnancy Reporting Form 
should be completed by the Investigator and submitted to the Sponsor within 24 hours 
after learning of the pregnancy. Attempts should be made to collect and report details of 
the course and outcome of any pregnancy in the partner of a male patient exposed to 
study drug. The pregnant partner will need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy. 
Once the authorization has been signed, the Investigator will update the Clinical Trial 
Pregnancy Reporting Form with additional information on the course and outcome of the 
pregnancy. An Investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
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5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5.4.2). 
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form. 
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the Investigator, the patient 
is lost to follow-up, or the patient withdraws consent. Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF. 
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 5.4.3. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious adverse events of special interest, and 
pregnancies, the Sponsor or a designee may follow up by telephone, fax, electronic mail, 
and/or a monitoring visit to obtain additional case details and outcome information 
(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
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5.6 
POST-STUDY ADVERSE EVENTS 
The Investigator is not required to actively monitor patients for adverse events after the 
end of the adverse event reporting period (defined as 28 days after the last dose of 
study drug). However, the Sponsor should be notified if the Investigator becomes aware 
of any death or any other serious adverse event occurring after the end of the adverse 
event reporting period (either by faxing, or by scanning and emailing, the Serious 
Adverse Event Reporting Form using the fax number or email address provided to the 
investigators), if the event is believed to be related to prior study drug treatment. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
events of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IRBs, ECs, and 
applicable Health Authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
RO5459072 Investigator's Brochure 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The database will be cleaned and frozen when all patients have completed the study or 
discontinued. The treatment assignment will then be unblinded and analyses will be 
performed on all data.  
All efficacy outcomes will be analyzed using modified intent-to-treat population (mITT) 
which is defined as all randomized subjects who received any study medication and 
have evaluable measurement of the parameter of interest at baseline and at least one 
post-baseline visit. For all efficacy analyses, the treatment groups will be based on the 
treatment assigned at randomization. 
All safety analyses will include all randomized patients who have received any study 
drug. For these analyses, patients will be grouped according to the treatment actually 
received. 
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There will be no adjustment made for any multiple comparisons. To aid the interpretation 
from the formal hypothesis testing, two-sided 95% confidence intervals will be provided.  
Descriptive summaries will include mean, standard deviation, median and range for 
continuous variables and counts and percentages for categorical variables. 
Details of statistical analyses will be provided in the statistical analysis plan. 
6.1 
DETERMINATION OF SAMPLE SIZE 
A total of 70 patients will be randomized in a 1:1 ratio to RO5459072 or placebo 
(35 patients per treatment group). 
Seventy patients (35 per treatment group) will provide power in the range of at least 58 
% to 80 % to detect a  difference in ESSDAI response rates between treatment groups 
in the range of 25 % to 33 % (two-sided Chi-square test assuming alpha of 0.05 and 
placebo rate ≤  25%). This sample size was determined by practical considerations. 
Seventy patients are also sufficient to provide approximately 70% power to detect a 
difference of 3 points between treatment arms in change from baseline in ESSDAI score 
(t-test assuming two-sided alpha 0.05 and standard deviation of 5.0). 
Approximately 30 patients will be enrolled into the optional sub-study. It is anticipated 
that enrollment of a minimum of 30 patients should ensure at least 20 patients (10 per 
treatment group) complete the study and have biopsy samples taken at both baseline 
and Week 12, assuming a maximum drop-out rate of 15%. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Protocol deviations will be listed. The number of patients who were randomized, 
discontinued or completed the study will be summarized by treatment groups.  
6.3 
ANALYSIS POPULATIONS 
6.3.1 
Efficacy Analysis Population 
All efficacy outcomes will be analyzed according to the mITT principle. The mITT 
population will comprise of all patients who are randomized, received study drug and 
have evaluable measurement of the parameter of interest at baseline and at least one 
post-baseline visit. For all efficacy analyses, the treatment groups will be based on the 
treatment assigned at randomization. 
6.3.2 
Pharmacodynamic Analysis Population 
All patients who have received at least one dose of the study medication and who have 
pharmacodynamic data available will be included in pharmacodynamic analyses. For 
these analyses, patients will primarily be grouped according to the treatment actually 
received; unless otherwise specified in the statistical analysis plan. 
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6.3.3 
Pharmacokinetic Analysis Population 
The population methods used for modelling of plasma concentration data will be 
described separately. 
6.3.4 
Safety Analysis Population 
All patients who have received at least one dose of the study medication will be included 
in the safety analysis population. For these analyses, patients will be grouped according 
to the treatment actually received.  
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, race, gender, ESSPRI score, 
ESSDAI score, salivary flow rate, etc. will be summarized for all randomized patients by 
treatment group. 
6.5 
SAFETY ANALYSES 
Safety analysis will be performed for all patients in the safety analysis population. All 
safety parameters will be listed by patient and summarized in tables. Safety will be 
determined by AEs, laboratory tests, vital signs, ECGs and physical examinations.  
There will be no formal statistical analyses of safety data; data will be presented using 
appropriate summary statistics and graphical plots as appropriate. 
Exposure to study medication will be summarized by total duration of study medication 
and cumulative dose using descriptive statistics. No statistical testing is planned for 
safety analyses. Dose modifications, interruptions and the reasons will be presented. 
6.5.1 
Adverse Events 
The original terms recorded on the eCRF by the Investigator for adverse events will be 
standardized by the Sponsor. 
AE data will be reported in listings and presented in frequency tables by MedDRA terms. 
AEs will be summarized by mapped term and appropriate thesaurus level. If applicable, 
summaries of AE by seriousness and relationship to study treatment will be presented, 
as well as summaries of AEs leading to death, premature withdrawal from study 
treatment. 
6.5.2 
Clinical Laboratory Test Results 
All clinical laboratory data will be stored on the database in the units in which they were 
reported. Patients’ listings and summary statistics at each assessment time will be 
presented using the International System of Units (SI units; Système International 
d’Unités). Laboratory data not reported in SI units will be converted to SI units before 
processing. 
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Laboratory test values will be presented by individual listings with flagging of values 
outside the normal ranges. Summary tables of change from baseline over time based on 
SI (Standard International) units will be displayed. Shifts in grade from baseline to the 
worst grade observed during treatment will be presented for selected laboratory 
parameters. 
6.5.2.1 
Standard Reference Ranges and Transformation of Data 
Roche standard reference ranges, rather than the reference ranges of the central 
lab/Investigator, as applicable, will be used. For most parameters, the measured 
laboratory test result will be assessed directly using the Roche standard reference 
range. Certain laboratory parameters will be transformed to Roche’s standard reference 
ranges. 
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges (if applicable), 
e.g., enzyme tests that include AST, ALT, and alkaline phosphatase and total bilirubin. 
Since the standard reference ranges for these parameters have a lower limit of zero, 
only the upper limits of the ranges will be used in transforming the data. 
6.5.2.2 
Definition of Laboratory Abnormalities 
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in patient listings of laboratory data. 
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a patient, the midpoint of the standard reference range will be used as the 
patient’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the patient listings as 
“HH” for very high or “LL” for very low. 
6.5.3 
Vital Signs 
Vital signs data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, tabular summaries will 
be used, as appropriate. 
6.5.4 
ECG Data Analysis 
ECG data will be presented by individual listings with flagging of values outside the 
normal ranges and flagging of marked abnormalities. In addition, the 12-lead triplicates 
will be averaged out. All analyses of QT data will be based on averages of the triplicate 
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measures at each scheduled time-point. These averages will be derived prior to any 
further data manipulation. Tabular summaries will be used, as appropriate. 
6.5.5 
Concomitant Medications 
The original terms recorded on the patient’s eCRF by the Investigator for concomitant 
medications will be standardized by the Sponsor by assigning preferred terms. 
Concomitant medications will be presented in summary tables and listings. The dose 
and/or frequency of use of selected medications commonly prescribed to patients with 
Sjögren’s syndrome will also be summarized. 
6.6 
EFFICACY ANALYSES 
6.6.1 
Primary Efficacy Endpoint 
The primary endpoint is the proportion of patients who have ≥ 3 point reduction from 
baseline in ESSDAI score after 12 weeks of treatment. The proportion of patients who 
have ≥ 3 point reduction from baseline in ESSDAI score after 12 weeks of treatment will 
be compared between the two treatment arms using a Pearson Chi-square test (two 
sided p-values, alpha 0.05). The difference in proportions and corresponding 95% 
confidence interval (CI) will be provided. Patients with missing data at Week 12 will be 
treated as non-responders in the analysis. 
Sensitivity analyses will be conducted if deemed necessary, including sensitivity 
analyses for handling missing data (e.g., completer’s analysis or last observation 
carried forward (LOCF) method for missing observations). 
In addition; the proportion of patient who have ≥ 3 point reduction from baseline in 
ESSDAI score after 12 weeks of treatment will be analyzed using a logistic regression 
model, adjusting for baseline ESSDAI score. 
6.6.2 
Secondary Efficacy Endpoints 
Secondary endpoints that are binary will be analyzed using similar methods used for 
analyzing the primary endpoint. 
Continuous secondary endpoints will be analyzed using a Mixed Model for Repeated 
Measures (MMRM) approach incorporating all observed data up to 12 weeks of 
treatment. The MMRM will include the absolute change from baseline as the dependent 
variable. The fixed effects in the model will include treatment, visit (week), 
treatment-by-visit (weeks) interaction, along with baseline score as continuous 
covariates. An unstructured variance-covariance structure will be applied to model the 
within-patient errors, and the restricted maximum likelihood method will be used for 
estimating the variance components. The denominator degrees of freedom will be 
estimated using the Kenward-Roger approximation. 
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The least squares mean of change from baseline for each treatment group together with 
a 95% CI will be calculated from the MMRM model for each visit. At Week 12, the 
placebo-corrected difference will be estimated from the same MMRM model and will be 
used to test the null hypothesis of zero difference. 
6.7 
PHARMACODYNAMIC ANALYSES 
All pharmacodynamic parameters will be presented by listings and descriptive summary 
statistics separately by treatment group.
Pharmacodynamic variables at each assessment time-point along with corresponding 
changes from baseline will be listed by individual and summarized using descriptive 
summary statistics. Descriptive summary statistics will include the calculation of 
arithmetic means, standard deviation, coefficient variation, median, and range, as 
appropriate. Graphical plots of individual and mean absolute and change from baseline 
versus time profiles will also be produced for each treatment. 
6.8 
PHARMACOKINETIC ANALYSES 
The population methods used for modelling of plasma concentration data will be 
described separately in the modelling report. 
6.9 
EXPLORATORY ANALYSES 
Exploratory analyses will be conducted as deemed appropriate. 
6.10 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the Electronic Data 
Capture (EDC) system. 
A comprehensive validation check program will verify the data. Discrepancies will be 
generated automatically in the system at the point of entry or added manually for 
resolution by the Investigator. 
The Sponsor will produce a Data Handling Manual that describes the quality checking to 
be performed on the data. Laboratory electronic data will be sent directly to the Sponsor, 
using the Sponsor’s standard procedures to handle and process the electronic transfer 
of these data. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
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The Sponsor will be responsible for data management of this study, including quality 
checking of the data. Sites will be responsible for data entry into the EDC system. In the 
event of discrepant data, the CRO will request data clarification from the sites, which the 
sites will resolve electronically in the EDC system. 
7.2 
ELECTRONIC CASE REPORT FORMS 
Data for this study will be captured via an on line EDC system. The data collected in the 
source documents is entered onto the study eCRF. An audit trail will maintain a record of 
initial entries and changes made; reasons for change; time and date of entry; and user 
name of person authorizing entry or change. For each patient enrolled, an eCRF must 
be completed and electronically signed by the Principal Investigator or authorized 
delegate from the study staff. If a patient withdraws from the study, the reason must be 
noted on the eCRF. If a patient is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document 
the outcome. 
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the Sponsor/CRO in the eCRFs and in all required reports. 
eCRFs will be submitted electronically to the Sponsor/CRO and should be handled in 
accordance with instructions from the Sponsor/CRO. 
At the end of the study, the Investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records. 
Acknowledgement of receipt of the compact disc is required. 
7.3 
PATIENT-REPORTED OUTCOME DATA 
Data from paper PRO questionnaires will be entered into the EDC system by site staff. 
Paper PRO questionnaires are source data and should be handled according to 
Section 7.4. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
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Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, ePRO data (if applicable), informed consent forms, laboratory 
test results, and medication inventory records, must be retained by the Principal 
Investigator for at least 15 years after completion or discontinuation of the study, or for 
the length of time required by relevant national or local Health Authorities, whichever is 
longer. After that period of time, the documents may be destroyed, subject to local 
regulations. No records may be disposed of without the written approval of the Sponsor. 
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
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applicable local, state, and federal laws. Studies conducted in the EU/EEA will comply 
with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form will be provided to each site. If applicable, 
it will be provided in a certified translation of the local language. The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample 
Informed Consent Forms or any alternate consent forms proposed by the site 
(collectively, the “Consent Forms”) before IRB/EC submission. The final IRB/EC‑
approved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for Health Authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative. All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
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8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated. In 
addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC. Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local Health Authority and IRB/EC. Investigators may receive written IND safety reports 
or other safety‑related communications from the Sponsor. Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with Health 
Authority requirements, and the policies and procedures established by their IRB/EC, 
and archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local Health Authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., LPLV). 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. In 
addition, at the end of the study, the Investigator will receive the patient data, which 
includes an audit trail containing a complete record of all changes to data. 
Roche shall also submit a Development Update Safety Report (DSUR) once a year to 
the IRB/EC and Health Authorities according to local regulatory requirements and 
timelines of each country participating in the study. 
It is the understanding of the Sponsor that this protocol (and any modifications) as well 
as appropriate consent procedures and advertisements, will be reviewed and approved 
by an IRB/EC. This board must operate in accordance with the current Federal 
Regulations and/or in accordance with Good Clinical Practice. The Sponsor will be sent 
a letter or certificate of approval prior to initiation of the study, and also whenever 
subsequent amendments/modifications are made to the protocol.  
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
The Sponsor of the trial is F. Hoffmann-La Roche Ltd. The Sponsor is responsible for the 
study management (monitoring), data management, statistical analysis and medical 
writing for this clinical study report. A clinical study report will be written and distributed 
to Health Authorities as required by applicable regulatory requirements. 
The protocol will be submitted to country/ institutional ethics committees. 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission. This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the Investigator. 
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The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement. 
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements. 
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10. 
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Biomarker for Sjögren's Syndrome. Arthritis Rheum. 2014;66:1872-1881. 
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Katunuma N, Matsunaga Y, Himeno K, et al. Insights into the roles of cathepsins in 
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Mavragani CP, Moutsopoulos HM. The geoepidemiology of Sjögren's syndrome. 
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Seror R, et al. European League Against Rheumatism Sjögren's Syndrome Disease 
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Patient-Reported Index: a complete picture of primary Sjögren's syndrome 
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Seror R, Bootsma H, Saraux A, et al. Defining disease activity states and clinically 
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Appendix 1  
Schedule of Assessments 
 
Visit8
Screening Baseline1
Week 2
Week 6
Week 9
Week 12
Follow‐Up Visit
Early 
Termination 
Visit
Days
‐28 to ‐8
‐7 to ‐1
14 (± 7)
42 (± 7)
63 (± 7)
84 (± 7)
98 (± 7)
(NA)
Informed Consent
x
Randomization
x
Study drug dispensing
x
x
x
Study drug return
x
x
Entry criteria
x
x
Demography
x
Medical History
x
Physical Examination2
x
x
x
Pregnancy testing3
x
x
x
x
x
x
x
x
Tuberculosis testing
x
HIV, HBV and HCV testing
x
Clinical Genotyping
x
ESSDAI score
x
x
x
x
x
x
ESSPRI score
x
x
x
x
x
x
x
x
SF-36 
x
x
x
Salivary samples4
x
x
x
x
Saliva flow assessment
x
x
x
x
Tear samples4
x
x
x
x
Tear flow assessment
x
x
x
x
mRNA sample
x
x
x
x
Autoantibodies
x
x
x
x
x
5
x
5
Soluble biomarkers
x
x
x
x
Immunophenotyping
x
x
x
x
Cathepsin S activity/ mass
x
x
x
x
ESR test
x
x
x
x
PK sample
x
x
x
Safety laboratory 
assessments6
x
x
x
x
x
x
x
x
ECG - 12 Lead
x
x
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
x
MSG biopsy (optional sub-
study only)
x
x7
Adverse Event or 
Intercurrent Illness
Previous and Concomitant 
Treatments
Treatment Period
x
x
 
 
 
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Appendix 1  
Schedule of Assessments (cont.) 
 
1 
First study drug administration should be one day after the last baseline 
assessment. 
2 
Physical examination includes weight, heart and respiratory rate, and body 
temperature. 
3 
All women will have serum pregnancy tests performed at screening and 
baseline. A urine pregnancy test will also be done at baseline prior to 
randomization. All women of childbearing potential will have serum and 
urine pregnancy tests at each subsequent visit.  
4 
The same salivary or tear sample is used for volume and biomarker 
assessments (see Section 4.6.1.3.4.). 
5 
Only markers required for ESSDAI scoring will be collected. 
6 
Safety laboratory assessment consists of hematology, blood chemistry, 
coagulation, lipids and urinalysis.  
7 
MSG biopsies procedures for the optional substudy may be performed at 
separate study center visits providing the procedures are carried out within 
the windows specified for the main study. 
8 
Screening, baseline and on-treatment visit schedules are all relative to the 
first day of study drug administration (Day 1). The follow-up visit is 
scheduled relative to the Week 12 end-of-treatment visit (+14 days after the 
end-of-treatment visit [± 7 days]). 
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Appendix 2  
Disease-Specific Assessments 
ESSDAI 
 
ESSPRI 
 
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Appendix 2  
Disease-Specific Assessments (cont.)  
AECG 
16. 
Primary Sjögren's syndrome diagnosed according to the revised American-
European Consensus Group (AECG) criteria i.e. presence of any 4 of the 6 items 
below, with a least items d and f, or presence of any 3 of items c, d, e and f: 
a) Ocular dryness symptoms. 
b) Oral dryness symptoms. 
c) Schirmer’s test  ≤ 5 mm/5min. 
d) Focus score ≥ 1 focus/4 mm2 on minor salivary gland biopsy. 
e) Unstimulated whole salivary flow ≤ 0.1 mL/min. 
f) Positive anti-SSA or SSB antibodies.  
 
 
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Appendix 3  
Dose-Equivalents of Systemic Corticosteroids 
 
Relative Glucocorticoid 
Activity 
Approximate Equivalent 
Dose* (mg) 
Short-acting 
Hydrocortisone 
1 
30 
Cortisone 
0.8 
37.5 
Intermediate-acting 
Prednisone 
4 
7.5 
Prednisolone 
4 
7.5 
Methylprednisolone 
5 
6 
Triamcinolone 
5 
6 
Dexamethasone 
30 
1 
Betamethasone 
30 
1 
*Equivalent dose shown is for oral or IV administration. 
 
Table adapted from: 
Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of 
the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 
2013;9(1):30. 
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Appendix 4  
Prohibited Concomitant Medications 
Corticosteriods for systemic use (ATC H02) 
(Note that prednisone or prednisone equivalent of ≤ 7.5mg is permitted.) 
Aldosterone, betamethasone, cloprednol, cortisone, cortivazol, deflazacort, 
desoxycortone, dexamethasone, fludrocortisone, fluocortolone, hydrocortisone, 
meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, 
prednylidene, rimexolone, triamcinolone, trilostane. 
Immunosuppressants (ATC L04A) 
(Note  that low dose methotrexate ≤ 20 mg is permitted as per Section 4.5.2 , Prohibited 
Therapy.) 
Abatacept, abetimus, adalimumab, afelimomab, alefacept, alemtuzumab, anakinra, 
anti-lymphocyte immunoglobulin, apremilast, azathioprine, basiliximab, belatacept, 
belimumab, briakinumab, canakinumab, certolizumab pegol, ciclosporin, daclizumab, 
eculizumab, efalizumab, etanercept, everolimus, fingolimod, golimumab, gusperimus, 
infliximab, leflunomide, lenalidomide, mepolizumab, methotrexate, muromonab-CD3, 
mycophenolic acid, natalizumab, pirfenidone, pomalidomide, rilonacept, secukinumab, 
siltuximab, sirolimus, tacrolimus, teriflunomide, thalidomide, tocilizumab, tofacitinib, 
ustekinumab, vedolizumab, voclosporin. 
CYP3A4 inducers 
Barbiturates, carbamazepine, efavirenz, systemic glucocorticoids, modafinil, nevirapine, 
oxcarbazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort 
(hyperforin). 
CYP3A4 inhibitors 
Aprepitant, clarithromycin, diltiazem, erythromycin, fluconazole, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, verapamil. 
 
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Appendix 4  
Prohibited Concomitant Medications (cont.)  
MDR1 (P-gp) inhibitors 
Amiodarone, azithromycin, carvedilol, clarithromycin, dronedarone, erythromycin, 
fluvoxamine, indinavir, itraconazole, ketoconazole, lapatinib, propafenone, quercetin, 
quinidine, quinine, ranolazine, ritonavir (and ritonavir combinations), telaprevir, verapamil, 
vorapaxar. 
Sensitive substrates of CYP3A4 with a narrow therapeutic index 
Alfentanil, colchicine,ethosuxamide, fentanyl, pimozide. 
RO5459072—F. Hoffmann-La Roche Ltd 
95/Protocol BP30037, Version 3