A Study to Assess the Efficacy and Safety of Abatacept in Adults With Active Primary Sjögrens Syndrome

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy of abatacept compared to placebo in patients with Sjögren's Syndrome.

Official Title
-----------------
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Subcutaneous Abatacept in Adults With Active Primary Sjögrens Syndrome

Conditions
-----------------
Sjogrens Disease

Intervention / Treatment
-----------------
* Biological: Abatacept
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of at least 5 Positive anti-SS-A/Ro antibody at screening meet the 2016 American College of Rheumatology (ACR) / European League Against Rheumatism Classification Criteria for Sjögren's Syndrome (EULAR SS) Exclusion Criteria: Secondary Sjögrens syndrome Active life-threatening or organ-threatening complications of Sjögren's-syndrome Other medical condition associated with sicca syndrome Other protocol defined inclusion/exclusion criteria could apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abatacept<br>Abatacept for subcutaneous injection 125mg/mL in 1 mL pre-filled syringe for 6 months followed by Open-Label Abatacept for subcutaneous injection 125mg/mL in 1 mL pre-filled syringe for 6 months | Biological: Abatacept<br> <br> * Other names: Bristol-Myers Squibb (BMS)-188667;|
| Placebo Comparator: Placebo<br>Placebo for Abatacept for subcutaneous injection 125mg/mL in 1 mL pre-filled syringe for 6 months followed by Open-Label Abatacept for subcutaneous injection 125mg/mL in 1 mL pre-filled syringe for 6 months | Biological: Abatacept<br> <br> * Other names: Bristol-Myers Squibb (BMS)-188667;Other: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) | The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) total score is calculated as the sum of scores for activity level for each domain. The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) Scoring Algorithm. Domain: (Score) Constitutional: (No=0, Low=3, Moderate=6) Lymphadenopathy: (No=0, Low=4, Moderate=8, High=12) Glandular: (No=0, Low=2, Moderate=4) Articular: (No=0, Low=2, Moderate=4, High=6) Cutaneous: (No=0, Low=3, Moderate=6, High=9) Pulmonary: (No=0, Low=5, Moderate=10, High=15) Renal: (No=0, Low=5, Moderate=10, High=15) Muscular: (No=0, Low=6, Moderate=12, High=18) Peripheral Nervous System (PNS): (No=0, Low=5, Moderate=10, High=15) Central Nervous System (CNS): (No=0, Moderate=10, High=15) Haematological: (No=0, Low=2, Moderate=4, High=6) Biological: (No=0, Low=1, Moderate=2) (No = No Disease Activity (DA), Low = Low DA, Moderate = Moderate DA, High = High DA) Overall score, which can range from 0 to 123, a higher score indicates more disease activity | Day 169 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Inde (ESSPRI) | The total score EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is calculated as the mean of the 3 individual components. Total Score Range (0 = Best outcome and 10 = Worst Outcome) The scores for the ESSPRI individual components will be used as such reported by the participants and entered in the case report form (CRF), without any further calculations. It consists of 3 questions covering cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain. 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. | Day 169 | 
| Change From Baseline in the Stimulated Whole Salivary Flow | The mean change from baseline in the stimulated whole salivary flow at Day 169 | Day 169 | 
| Change From Baseline of DAS28-C-reactive Peptide (CRP): In The Full Population | The disease activity score DAS28-CRP is a continuous variable which is a composite of 4 variables: the 28 tender joint count (tender28), the 28 swollen joint count (swollen28), CRP and participant assessment of disease activity measure on a visual analogue scale (VAS) of 100mm. DAS28-CRP = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(hsCRP+1) + 0.014 * VAS + 0.96. (sqrt = Square root, ln = natural log) Positive Scores = Increased Disease Activity Negative Scores = Reduced Disease Activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline of DAS28-CRP: Tender Swollen Joint Count of at Least 3 | The disease activity score DAS28-CRP is a continuous variable which is a composite of 4 variables: the 28 tender joint count (tender28), the 28 swollen joint count (swollen28), CRP and participant assessment of disease activity measure on a visual analogue scale (VAS) of 100mm. DAS28-CRP = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(hsCRP+1) + 0.014 * VAS + 0.96. (sqrt = Square root, ln = natural log) Positive Scores = Increased Disease Activity Negative Scores = Reduced Disease Activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline of DAS28-CRP: Tender Swollen Joints Count Less Than 3 | The disease activity score DAS28-CRP is a continuous variable which is a composite of 4 variables: the 28 tender joint count (tender28), the 28 swollen joint count (swollen28), CRP and participant assessment of disease activity measure on a visual analogue scale (VAS) of 100mm. DAS28-CRP = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(hsCRP+1) + 0.014 * VAS + 0.96. (sqrt = Square root, ln = natural log) Positive Scores = Increased Disease Activity Negative Scores = Reduced Disease Activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the Joint Component of DAS28-CRP: In the Full Population | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. Tender Joint: Count 1-28 Swollen Joint: Count 1-28 Negative Scores = Reduced number of joints impacted Positive Scores = Increased number of joints impacted | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the CRP Component of DAS28-CRP: In the Full Population | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. CRP: measured lab value Positive Number = Increased level of CRP Negative Number = Reduced Level of CRP | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the Assessment of Disease Activity Component of DAS28-CRP: In the Full Population | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. Assesment of Disease Activity: 0-100 scale [100=Most severe] Positive Numbers = Increased Disease Activity Negative Numbers = Decreased Diseased activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the Joint Component of DAS28-CRP: Tender Swollen Joints of at Least 3 | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. Tender Joint: Count 1-28 Swollen Joint: Count 1-28 Negative Scores = Reduced number of joints impacted Positive Scores = Increased number of joints impacted | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the CRP Component of DAS28-CRP: Tender Swollen Joints of at Least 3 | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. CRP: measured lab value Positive Number = Increased level of CRP Negative Number = Reduced Level of CRP | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the Assessment of Disease Activity Component of DAS28-CRP: Tender Swollen Joints of at Least 3 | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. Assesment of Disease Activity: 0-100 scale [100=Most severe] Positive Numbers = Increased Disease Activity Negative Numbers = Decreased Diseased activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the Joint Component of DAS28-CRP: Tender Swollen Joint Count Less Than 3 | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. Tender Joint: Count 1-28 Swollen Joint: Count 1-28 Negative Scores = Reduced number of joints impacted Positive Scores = Increased number of joints impacted | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the CRP Component of DAS28-CRP: Tender Swollen Joint Count Less Than 3 | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. CRP: measured lab value Positive Number = Increased level of CRP Negative Number = Reduced Level of CRP | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in the Assessment of Disease Activity Component of DAS28-CRP: Tender Swollen Joint Count Less Than 3 | The mean change from baseline at all measured time points up to Day 169 in the individual components of DAS28-CRP. Assesment of Disease Activity: 0-100 scale [100=Most severe] Positive Numbers = Increased Disease Activity Negative Numbers = Decreased Diseased activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Participants Who Achieve Minimally Clinically Important Change in ESSDAI in at Least 3 Points | Proportion of participants who achieve a minimally clinically important change (of at least 3 points) in the ESSDAI at all measured time points up to Day 169. | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Participants Who Achieve Minimally Clinically Important Change in ESSDAI in at Least 5 Points | Proportion of participants who achieve a minimally clinically important change (of at least 5 points) in the ESSDAI at all measured time points up to Day 169. | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Participants Who Achieve Minimally Clinically Important Change in ESSPRI in at Least 1 Point | Proportion of participants who achieve a minimally clinically important change (of at least 1 point) in the ESSPRI at all measured time points up to Day 169. | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline at All Measured Time Points in the ESSDAI | The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) total score is calculated as the sum of scores for activity level for each domain. The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) Scoring Algorithm. Domain: (Score) Constitutional: (No=0, Low=3, Moderate=6) Lymphadenopathy: (No=0, Low=4, Moderate=8, High=12) Glandular: (No=0, Low=2, Moderate=4) Articular: (No=0, Low=2, Moderate=4, High=6) Cutaneous: (No=0, Low=3, Moderate=6, High=9) Pulmonary: (No=0, Low=5, Moderate=10, High=15) Renal: (No=0, Low=5, Moderate=10, High=15) Muscular: (No=0, Low=6, Moderate=12, High=18) Peripheral Nervous System (PNS): (No=0, Low=5, Moderate=10, High=15) Central Nervous System (CNS): (No=0, Moderate=10, High=15) Haematological: (No=0, Low=2, Moderate=4, High=6) Biological: (No=0, Low=1, Moderate=2) (No = No Disease Activity (DA), Low = Low DA, Moderate = Moderate DA, High = High DA) Overall score, which can range from 0 to 123, a higher score indicates more disease activity | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline at All Measured Time Points in the ESSPRI | The total score EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is calculated as the mean of the 3 individual components. Total Score Range (0 = Best outcome and 10 = Worst Outcome) The scores for the ESSPRI individual components will be used as such reported by the participants and entered in the case report form (CRF), without any further calculations. It consists of 3 questions covering cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain. 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. | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in Components of ESSDAI | The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) total score is calculated as the sum of scores for activity level for each domain. The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) Scoring Algorithm. Domain: (Score for activity level) Constitutional: (No=0, Low=3, Moderate=6) Lymphadenopathy: (No=0, Low=4, Moderate=8, High=12) Glandular: (No=0, Low=2, Moderate=4) Articular: (No=0, Low=2, Moderate=4, High=6) Cutaneous: (No=0, Low=3, Moderate=6, High=9) Pulmonary: (No=0, Low=5, Moderate=10, High=15) Renal: (No=0, Low=5, Moderate=10, High=15) Muscular: (No=0, Low=6, Moderate=12, High=18) Peripheral Nervous System (PNS): (No=0, Low=5, Moderate=10, High=15) Central Nervous System (CNS): (No=0, Moderate=10, High=15) Haematological: (No=0, Low=2, Moderate=4, High=6) Biological: (No=0, Low=1, Moderate=2) (No = No Disease Activity, Low = Low Disease Activity, Moderate = Moderate Disease Activity, High = High Disease Activity) | Day 29, Day 57, Day 85, Day 113, Day 141 and Day 169 | 
| Change From Baseline in ESSPRI Components | The total score EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) is calculated as the mean of the 3 individual components. Total Score Range (0 = Best outcome and 10 = Worst Outcome) The scores for the ESSPRI individual components will be used as such reported by the participants and entered in the case report form (CRF), without any further calculations. It consists of 3 questions covering cardinal symptoms of Sjögren's syndrome: dryness, fatigue and pain. 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. | Day 29, Day 57, Day 85, Day 113, Day 141, Day 169 | 
| Change From Baseline in Schirmer's Test | The Mean change from baseline in Schirmer's Test at all measured time points up to day 169 The length in millimeters that the strip wets during the 5 minute test period for each eye. Collection is done separately for each eye. | Day 85, Day 169 | 
| Change From Baseline in the Ocular Staining Score (OSS) | The Mean change from baseline in OSS at all measured time points up to day 169 Score of 0 = No Staining Score of 12 = diffuse staining The total score will be calculated as the sum of the score for these parameters for each eye. Medial Nasal Bulbar Conjunctiva (MNBC) [score scale: 0 - 3], Corneal (CORN) Staining of Punctate Epithelial Erosions (PEE) [score scale: 0 - 3], Lateral Temporal Bulbar Conjunctiva (LTBC) [score scale: 0 - 3], Patches of Confluent Staining (CONF) [score scale: 0 - 1], PEE observed in the pupil region, i.e. central 4mm diameter portion of the cornea (PUPL) [score scale: 0 - 1], one of more filaments seen anywhere on the cornea (FILA) [score scale: 0 - 1] | Day 85, Day 169 | 
| Change From Baseline in Tear Break-up Time | The Mean change from baseline in Tear Break-up Time at all measured time points up to day 169 The CRF collects the time in seconds to first appearance of a random dry spot on the corneal surface for 3 repetitions in each eye. The average time will calculated for each eye averaging the 3 measurements for each eye separately. In case only 2 measurements are available, the average of the 2 measurements will be calculated. In case there is only 1 measurement, that measurement will be used for the analysis. | Day 85, Day 169 | 
| Change From Baseline in Unstimulated Salivary Flow | The mean change from baseline in unstimulated whole salivary flow at all measured time points up to Day 169. | Day 85, Day 169 | 
| Change From Baseline in Stimulated Salivary Flow | The mean change from baseline in Stimulated whole salivary flow at all measured time points up to Day 169. | Day 85, Day 169 | 
| Change From Baseline in Numeric Rating Scale for Mouth Dryness | The mean change from baseline in participant symptoms using the Numeric Rating Scale (NRS) for mouth dryness at all measured time points up to Day 169. The oral and ocular dryness are each assessed by the patients with numeric rating scales from 0 to 10 with 0 representing no dryness and 10 representing maximal dryness | Day 1, 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in Numeric Rating Scale for Eye Dryness | The mean change from baseline in patient symptoms using the Numeric Rating Scale (NRS) for eye dryness at all measured time points up to Day 169. The oral and ocular dryness are each assessed by the patients with numeric rating scales from 0 to 10 with 0 representing no dryness and 10 representing maximal dryness | Day 1, 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in Participant Assessment of Disease Activity | The participant global assessment of disease activity are assessed with visual analog scales. The participant marks a vertical line through a horizontal line, where the beginning of the horizontal line represents the best situation, and the end of the horizontal line represents the very worst situation. The CRF collects the distance in millimeters from the start of the scale that is marked as well as the length of the scale in millimeters. In cases that the length of the scale is in less or more than 100 millimeters, then the participants measurement will be rescaled to the equivalent of 100 millimeters using the formula below: Rescale Measurement in mm = (measurement as reported on CRF in mm/length of the line on CRF in mm) * 100mm A negative score = participant assessment of disease activity has improved A positive score = participant assessment of disease activity has worsened | Day 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in Physician Global Assessment of Disease Activity | The physician global assessment of disease activity are assessed with visual analog scales. The physician marks a vertical line through a horizontal line, where the beginning of the horizontal line represents the best situation, and the end of the horizontal line represents the very worst situation. The CRF collects the distance in millimeters from the start of the scale that is marked as well as the length of the scale in millimeters. In cases that the length of the scale is in less or more than 100 millimeters, then the participants measurement will be rescaled to the equivalent of 100 millimeters using the formula below: Rescale Measurement in mm = (measurement as reported on CRF in mm/length of the line on CRF in mm) * 100mm A negative score = physician assessment of disease activity has improved A positive score = physician assessment of disease activity has worsened | Day 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in Patient Fatigue | The mean change from baseline in patient fatigue using Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue assessment of disease activity at all measured time points up to Day 169. PROMIS Fatigue instruments 10 Questions ranging from a score 0 to 40. Sum of the values gives you the raw sum. The raw is inputted into this formula to give you the raw score: Raw Score = (Raw sum*number of items on the short form)/(Number of items that were actually answered) Raw score is translated to a T-Score using a table. T-Score is used as the final score. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. The standardized T-score is reported as the final score for each participant. A negative T Score = Better Prognosis A positive T Score = Worse prognosis | Day 29, 57, 85, 113, 141, 169 | 
| Change From Baseline in Female Sexual Function Using the Female Sexual Function Index (FSFI) | For the FSFI, is a 19 item instrument used for assessing key dimensions of female sexual function over the past 4 weeks with 6 domains being analyzed. The specific domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) analyzed in the FSFI are scored on a scale ranging from 0 to 5, with higher scores indicating better performance. Domain scores are calculated by summing the scores of the individual questions that make up the domain and multiplying the sum by the factor in the table below. The full scale score is the sum of the six domain scores. Full Scale Score range: 2.0(minimum score) - 36.0 (maximum score) Negative Score = Reduced functioning Positive Score = Improved functioning | Day 85, Day 169 | 
| Change From Baseline in 36-item Short Form Health Survey (SF-36) | The SF-36 determines participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Scores on each item are summed and averaged (range: 0=worst to 100=best). Increases from baseline indicate improvement | Day 85, Day 169 | 
| Geometric Mean of Trough Concentration (Cmin) of Abatacept | Geometric mean of trough concentration (Cmin) of abatacept at all measured time points. | Day 29, 85, 113, 141, 169 | 
| Percentage of Participants With a Positive Antibody Response | Percentage of participants with at least one positive immunogenicity response up to Day 169 and during 3 months follow up (for participants who discontinue during the 6-months double-blind). | Day 85 db, day 169 db, post treatment day 85 | 
| Summary of Adverse Events: Double Blind Period | Percentage of participants with adverse events, deaths, serious adverse events and adverse events leading to discontinuation | Day 1 up to first dose of Open Label Treatment Period (OLTP) abatacept or up to 56 post last dose in double -blind for those not in OL. | 
| Laboratory Marked Abnormalities: Double Blind Period | Laboratory values meeting the marked abnormality criteria | Day 1 up to first dose of OL abatacept or up to 56 post last dose in double -blind for those not in OL. | 
| Percentage of Participants With a Positive Antibody Response in the Cumulative Abatacept Period | Percentage of participants with at least one positive immunogenicity response On Day 365 (end of Open label treatment period) and day 85 post open label follow up period. | Day 365, post open label treatment day 85 | 
| Summary of Adverse Events: Cumulative Abatacept Period | Percentage of participants with adverse events, deaths, serious adverse events and adverse events leading to discontinuation | Day 365 and 3 months of follow up approximately 450 Days | 
| Laboratory Marked Abnormalities: Cumulative Abatacept Period | Laboratory values meeting the marked abnormality criteria | Day 365 and 3 months of follow up approximately 450 Days |