A Study to Assess the Efficacy of RO5459072 in Participants With Primary Sjogren's Syndrome

Study Overview
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Brief Summary
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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).

Official Title
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A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Phase 2A Study to Assess the Efficacy of RO5459072 in Patients With Primary Sjogren's Syndrome

Conditions
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Sjogren's Syndrome

Intervention / Treatment
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* Drug: Placebo
* Drug: RO5459072


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of primary Sjogren's syndrome according to the revised American-European Consensus Group (AECG) criteria ESSDAI score greater than or equal to (>/=) 5 ESSPRI score >/=5 Elevated serum titers of anti-Sjogren's-syndrome-related antigen A (anti-SSA) and/or anti-Sjogren's-syndrome-related antigen B (anti-SSB) antibodies at screening Negative pregnancy test at screening and baseline (for women only) Willing to comply with the study procedures and restrictions, including measures to prevent pregnancy and restrictions on sperm donation Exclusion Criteria: A diagnosis of secondary Sjogren's syndrome according to the revised AECG criteria Severe complications of Sjogren's syndrome Systemic immunosuppressant therapy, cyclophosphamide, or B-cell depleting therapy within 6 months prior to the screening visit Corticosteroid therapy exceeding 7.5 mg prednisone equivalents per day 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 screening A history suggesting reduced immune function or any other conditions predisposing participants to serious infection A history of lymphoma, myeloma or monoclonal gammopathy of unknown significance (MGUS), or any other malignancies within the past 5 years A diagnosis of fibromyalgia or significant depression Having any concomitant disease or condition that could interfere with the conduct of the study, or that would pose an unacceptable risk to the individual Participation in an investigational drug or device study within 3 months prior to screening Inability to comply with the study protocol for any other reason Women who are lactating, breastfeeding or planning to nurse 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching-placebo capsules will be administered orally, 2 times a day, for up to 12 weeks. | Drug: Placebo<br>* Matching-placebo capsules will be administered orally, 2 times a day with food.<br>|
| Experimental: RO5459072<br>RO5459072 at a dose of 100 milligrams (as capsules) will be administered orally, 2 times a day, for up to 12 weeks. | Drug: RO5459072<br>* RO5459072 at a dose of 100 milligrams (as capsules) will be administered orally, 2 times a day with food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Clinically Relevant Decrease in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Score | Percentage of participants with a clinically relevant decrease in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Score is defined as participants with absolute decrease of ≥ 3-points in ESSDAI score. ESSDAI is physician-assessed disease activity index developed by EULAR consortium consisting of 44 items in 12 organ-specific 'domains' (constitutional,lymphadenopathy, articular,muscular,cutaneous,glandular,pulmonary,renal,peripheral nervous system,central nervous system,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. Overall score is calculated as sum of all individual weighted domain scores (ranges from 0 (best) to 123 (worst activity). A score ≥ 5 is considered moderate or severe disease activity and a clinically relevant change in ESSDAI score is defined as absolute decrease of ≥ 3-points. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Clinically Relevant Decrease in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) Score | The efficacy of RO5459072 in patients with primary Sjogren's Syndrome Disease is evaluated in terms of the percentage of participants with a clinically relevant decrease in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) Score, where a clinically relevant decrease in ESSPRI score is defined as a decrease of ≥ 1 point. The ESSPRI is a patient-reported, subjective symptom index for primary Sjögren's syndrome developed by the EULAR consortium. It consists of 3 questions covering cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain (articular and/or muscular). Each domain scored on scale of 0-10 (0 =no symptom at all and 10 = worst symptom imaginable), and overall score is calculated as the mean of 3 individual domains where all domains carry same weight. | 12 weeks | 
| Change From Baseline in ESSDAI Score at Week 12 | Change from baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Score is defined as the change in score between baseline (Week -1) and Week 12. The ESSDAI is a physician-assessed disease activity index for primary Sjögren's syndrome developed by the EULAR consortium. 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, central nervous system, 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. Overall score is calculated as sum of all individual weighted domain scores (ranges from 0 (best) to 123 (worst activity). | Baseline (Week -1), Week 12 | 
| Change From Baseline in ESSPRI Score at Week 12 | Change from baseline in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) Score is defined as the change in score between baseline (Week -1) and Week 12. The ESSPRI is a patient-reported, subjective symptom index for primary Sjögren's syndrome developed by the EULAR consortium. 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 (0 =no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. | Baseline (Week -1), Week 12 | 
| Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Score at Week 12 | Change from baseline in Short Form-36 Health Survey (SF-36) Mental score is defined as the change in score between baseline (Week -1) and Week 12. The SF-36 was used to assess health-related quality of life at baseline and at on-treatment visits. The SF-36 consisted 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 scoring on a scale 0-100 (a score of 0 = maximum disability and a score of 100 = no disability). Reported here is the mental health domain score. | Baseline (Week -1), Week 12 | 
| Change From Baseline in SF-36 Physical Score at Week 12 | Change from baseline in Short Form-36 Health Survey (SF-36) Physical Score is defined as the change in score between baseline (Week -1) and Week 12. The SF-36 was used to assess health-related quality of life at baseline and at on-treatment visits. The SF-36 consisted 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 scoring on a scale 0-100. (a score of 0 = maximum disability and a score of 100 = no disability) | Baseline (Week -1), Week 12 | 
| Change From Baseline in ESSPRI Dryness Component Score at Week 12 | Change from baseline in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) dryness component score is defined as the change in score between baseline (Week -1) and Week 12. The Dryness Component score ranged from 0-10 (0 =no symptom at all and 10 = worst symptom imaginable). | Baseline (Week -1), Week 12 | 
| Change From Baseline in ESSPRI Fatigue Component Score at Week 12 | Change from baseline in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) fatigue component score is defined as the change in score between baseline (Week -1) and Week 12. The ESSPRI score 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 (0 =no symptom at all and 10 = worst symptom imaginable). | Baseline (Week -1), Week 12 | 
| Change From Baseline in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) Pain Component Score at Week 12 | Change from baseline in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) pain component score is defined as the change in score between baseline (Week -1) and Week 12. The ESSPRI score 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 (Each domain scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable). | Baseline (Week -1), Week 12 | 
| Change From Baseline in Tear Flow Rate at Weeks 2, 6, and 12 | Un-stimulated tear production rate was 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) was placed at the junction of the lateral and middle thirds of the lower eyelid of each eye. The maximum length of wetting along the strip at the end of the test period was measured. | Baseline, Week 2, Week 6, and Week 12 | 
| Change From Baseline in Mechanically Stimulated Salivary Flow Rate at Weeks 2, 6, and 12 | Change from baseline in mechanically stimulated salivary flow rate is defined as the change in flow (mL/min) between baseline (Week -1) and Week 2, Week 6 and Week 12. Using a mechanical stimulation method of a piece of neutral wax, paraffin, silicone, unflavored chewing gum, or similar chewable, unflavored, nonabsorbent material, patients were instructed to chew for a period of 5 minutes. The stimulated salivary flow rate was calculated assuming a specific gravity of 1 (i.e., 1 mL saliva = 1 g) and expressed in mL per minute. | Baseline, Week 2, Week 6, and Week 12 | 
| Change From Baseline in Anti-Sjögren's-Syndrome-Related Antigen A at Weeks 6, and 12 | Anti-Sjögren's-syndrome-related antigen A is a type of antibody found in the auto-antibody titers. | Baseline, Week 6, and Week 12 | 
| Change From Baseline in Anti-Sjögren's-Syndrome-Related Antigen B at Weeks 6, and 12 | Anti-Sjögren's-syndrome-related antigen B is a type of antibody found in the auto-antibody titers. | Baseline, Week 6, and Week 12 | 
| Change From Baseline in Rheumatoid Factor at Weeks 6, and 12 | Rheumatoid factor is a type of auto-antibody found in the auto-antibody titers. | Baseline, Week 6, and Week 12 | 
| Change From Baseline in Total Immunoglobulin G (IgG) at Weeks 6, and 12 | Total IgG is a type of auto-antibody found in the auto-antibody titers. | Baseline, Week 6, and Week 12 | 
| Change From Baseline in Total Immunoglobulin M (IgM) at Weeks 6, and 12 | Total IgM is a type of auto-antibody found in the auto-antibody titers. | Baseline, Week 6, and Week 12 | 
| Minimum Concentration (Cmin) of RO5459072 | Minimum observed plasma concentration (mass/volume) | Week 2, Week 6, and Week 12 | 
| Maximum Concentration (Cmax) of RO5459072 | Maximum observed plasma concentration (mass/volume) | Week 2, Week 6, and Week 12 | 
| Average Concentration (Caverage) of RO5459072 | Average observed plasma concentration (mass/volume) | Week 2, Week 6, and Week 12 | 
| Percentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Baseline up to Week 14 |