Proof of Concept Study to Evaluate the Efficacy and Safety of BMS-931699 (Lulizumab) or BMS-986142 in Primary Sjögren's Syndrome

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of treatment with either lulizumab or BMS-986142 versus placebo in subjects with moderate to severe primary Sjögren's syndrome as measured by the change from baseline in ESSDAI at Week 12 between active treatment arms (lulizumab or BMS-986142, respectively) and the placebo arm.

Official Title
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A Phase II, Randomized, Multi-Center, Double-Blind, Placebo Controlled Study to Evaluate the Efficacy and Safety of BMS-931699 (Lulizumab) or BMS-986142 in Subjects With Moderate to Severe Primary Sjögren's Syndrome

Conditions
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Sjögren's Syndrome

Intervention / Treatment
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* Drug: BMS-931699
* Drug: BMS-986142
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Subjects diagnosed or classified as having moderate to severe primary Sjögren's Syndrome based on the 2016 ACR-EULAR Sjögren's Syndrome Classification Criteria for at least 16 weeks prior to screening ESSDAI ≥ 5 including disease activity (any score > 0) in at least one of the following domains: Glandular, Articular, Hematological, Biological, Lymphadenopathy Positive anti-SS-A/Ro and/or anti-SS-B/La autoantibody Unstimulated whole saliva secretion > 0.01 ml/min Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug and must not be pregnant or breastfeeding. Male and female subjects must be willing to adhere to protocol-mandated highly effective contraception for the duration of the study and for the protocol-specified follow up period. Hormone-based contraceptive methods are not permitted Exclusion Criteria: Secondary Sjögren's syndrome or the presence of any other systemic autoimmune disease (eg, RA, SLE, multiple sclerosis, vasculitis) Very severe primary Sjögren's syndrome or severe complications of primary Sjögren's syndrome at the time of the screening visit Active systemic or latent bacterial (including tuberculosis), viral or fungal infection, evidence of current or chronic Hepatitis B or C infection, or HIV infection Any significant concurrent medical condition at the time of screening or baseline visit Use of methotrexate, cyclophosphamide, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF) or leflunomide within 12 weeks of screening visit Previous treatment with biologics therapies either marketed or in development within 6 months prior to screening visit Treatment started or an unstable dose of hydroxychloroquine within 8 weeks of screening visit Oral corticosteroids > 10 mg/day within 14 days of dosing (Day 1), corticosteroid therapy ≥ 1 mg/kg during the 4 weeks preceding enrollment, or intravenous, intramuscular or intra-articular corticosteroids within 4 weeks of screening visit Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: BMS-931699<br>Subcutaneous weekly injection + daily oral placebo tablets | Drug: BMS-931699<br>* Specified dose on specified days<br>* Other names: lulizumab;Drug: Placebo<br>* Specified dose on specified days<br>|
| Experimental: BMS-986142<br>Daily oral tablets + subcutaneous placebo (weekly) injection | Drug: BMS-986142<br>* Specified dose on specified days<br>Drug: Placebo<br>* Specified dose on specified days<br>|
| Placebo Comparator: Placebo<br>Weekly subcutaneous placebo injection +daily oral placebo tablets | Drug: Placebo<br>* Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in ESSDAI | The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening | At baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in ESSDAI Scores at Week 4 and Week 8 | The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening | At baseline, week 4 and week 8 | 
| Mean Change From Baseline in ESSPRI Score at Week 4, Week 8, and Week 12. | ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains. | At baseline, week 4, week 8, and week 12 | 
| Proportion of Subjects With a > = 3 Point Improvement From Baseline in ESSDAI at Week 12 | The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening | At week 12 | 
| Proportion of Subjects With Both >= 3 Points Improvement in ESSDAI and >= 1 Point Improvement in ESSPRI From Baseline at Week 12 | The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of twelve organ-specific domains in 3 or 4 levels according to their severity. For example, for no disease activity the domain score equals 0 and for high disease activity the domain score equals 3 or 4. Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. The sum of the weighted domain scores is the overall score, which can range from 0 to 123. A higher score indicates more disease activity. Change from baseline was computed as the value at Week 24 minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening | At week 12 | 
| Proportions of Subjects With >=1 Point of Improvement From Baseline in ESSPRI | ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains | At week 12 | 
| Mean Change in Baseline in ESSPRI Individual Component of Dryness | ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains | At baseline, week 4, week 8, and week 12 | 
| Mean Change in Baseline in ESSPRI Individual Component of Fatigue | ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains | At baseline, week 4, week 8, and week 12 | 
| Mean Change in Baseline in ESSPRI Individual Component of Pain | ESSPRI, also known as EULAR Sjogren's Syndrome Patient Reported Index, measures subjective symptoms of dryness, pain and fatigue. It uses 0-10 numerical scales, one for each domain. The weight of the domains is identical, and the final score is the mean score of the 3 domains | At baseline, week 4, week 8, and week 12 | 
| Mean Change From Baseline in Unstimulated Salivary Flow Rate | Serum and saliva biomarkers (collected from samples obtained during unstimulated and stimulated salivary flow assessments) were measured to determine the potential PD effect of BMS-931699 and BMS-986142 on disease-related protein analytes. These assessments included, but were not limited to, the detection of cytokines and other protein analytes by immunoassays and/or mass spectrometry proteomic profiling. | At baseline, week 4, week 8, and week 12 | 
| Mean Change From Baseline in Stimulated Salivary Flow Rate | Serum and saliva biomarkers (collected from samples obtained during unstimulated and stimulated salivary flow assessments) were measured to determine the potential PD effect of BMS-931699 and BMS-986142 on disease-related protein analytes. These assessments included, but were not limited to, the detection of cytokines and other protein analytes by immunoassays and/or mass spectrometry proteomic profiling. | At baseline, week 4, week 8, and week 12 | 
| Mean Change From Baseline in Ocular Surface Staining | The test was performed by instillation of fluorescein dye and either lissamine green or Rose bengal dye to stain the cornea and conjunctiva, respectively. After instilling the dye, the ocular surface was examined through a slit lamp (biomicroscope). | At baseline, week 4, week 8, and week 12 | 
| Mean Change From Baseline in Schrimer's Test | The test (without anaesthesia) was performed by placing a narrow calibrated filter-paper strip in the inferior cul-de-sac of each eye. Aqueous tear production was measured by the length in millimeters that the strip wets during the 5 minute test period | At baseline, week 4, week 8, and week 12 | 
| Mean Change From Baseline in the Tear Break-up Time Test | Determined by instilling fluorescein dye and evaluating the stability of the pre-corneal tear film. After several blinks, the tear film is examined using a broad beam of the slit-lamp (biomicroscope) with a cobalt blue filter. The TBUT, defined as the time in seconds between the subjects's last blink and the first appearance of a random dry spot on the corneal surface, is measured 3 times and the mean value is recorded. | At baseline, week 4, week 8, and week 12 | 
| Mean Change From Baseline in Numeric Rating Scale (NRS) for Mouth, Eye and Vaginal Dryness | The Numeric Rating Scale (NRS-11) is an 11-point scale for patient self-reporting of pain. 0 = No Pain, 1-3 = Mild Pain(nagging, annoying, interfering little with ADLs), 4-6 = Moderate Pain (interferes significantly with ADLs), 7-10 = Severe Pain (disabling; unable to perform ADLs) | At baseline, at week 2, week 4, week 6, week 8, week 10, week 12, and week 18 | 
| Mean Change From Baseline in Subject Global Assessment of Disease Activity (SubGDA) | The subjects overall assessment of disease activity from 0-10 cm VAS scale with 0 being no disease and 10 cm being most severe disease | At baseline, week 2, week 4, week 6, week 8, week 10, week 12, and week 18 | 
| Mean Change Form Baseline in Physician Global Assessment of Disease Activity (phyGDA) | The investigator's or physician's overall assessment of disease activity from 0-10 cm VAS scale with 0 being no disease and 10 cm being most severe disease. | At baseline, week 2, week 4, week 6, week 8, week 10, week 12, and week 18 | 
| Mean Change From Baseline in Short Form-36 (SF-36) | First, precoded numeric values are recoded per the scoring key given in Table 1. Note that all items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the percentage of total possible score achieved. In step 2, items in the same scale are averaged together to create the 8 scale scores. Table 2 lists the items averaged together to create each scale. Items that are left blank(missing data) are not taken into account when calculating the scale scores. Hence, scale scores represent the average for all items in the scale that the respondent answered | At baseline, week 4, week 8, week 12, and week 18 | 
| Mean Change From Baseline in Female Sexual Function Index (FSFI) | The Female Sexual Function Index (FSFI), a 19-item questionnaire, has been developed as a brief, multidimensional self-report instrument for assessing the key dimensions of sexual function in women | At baseline, week 4, week 8, week 12, and week 18 | 
| Mean Change From Baseline in Work Participation and Activity Impairment Questionnaire (WPAI) | Affords calculation of 4 scales to measure the impact of IBD on different domains of impairment in work or other activities: absenteeism, presenteeism (impairment at work), productivity loss (overall work impairment), activity impairment | At baseline, week 4, week 8, week 12, and week 18 |