A Phase 2a, Randomized, Placebo Controlled, Study to Evaluate the Safety and Efficacy of AMG 557/MEDI5872 in Primary Sjögren's Syndrome

Study Overview
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Brief Summary
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A Phase 2a study to evaluate the efficacy and safety of AMG 557/MEDI5872 in Primary Sjögren's Syndrome

Detailed Description
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This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the clinical and biologic efficacy, as well as the safety of SC doses of AMG 557/MEDI5872 in adult subjects with Primary Sjögren's Syndrome.

Official Title
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A Phase 2a, Randomized, Placebo Controlled, Proof of Mechanism Study to Evaluate the Safety and Efficacy of AMG 557/MEDI5872 in Subjects With Primary Sjögren's Syndrome

Conditions
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Primary Sjögren's Syndrome

Intervention / Treatment
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* Biological: AMG 557/MEDI5872
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 through 75 years at the time of signing the ICF. Fulfill American-European Consensus Group (AECG) criteria for pSS ESSDAI score ≥ 6. Positive anti-SS-A and/or anti-SS-B autoantibodies and at least IgG > 13 g/L or RF level > upper limit of normal (ULN) or positive test for cryoglobulins Willingness to undergo protocol-required minor salivary gland biopsies. Negative TB test during screening Immunization up to date as determined by local standard of care. Exclusion Criteria: Previous treatment with AMG 557/MEDI5872. Evidence of signs or symptoms of a viral, bacterial, or fungal infection within 2 weeks (14 days) prior to randomization (Day 1) according to the assessment of the investigator; any infection requiring IV antibiotic or antiviral treatment within 8 weeks of randomization (Day 1); history of herpes zoster within 3 months prior to randomization (Day 1). Evidence of significant renal insufficiency Positive test at screening for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) antibody. Prior administration of any of the following: Belimumab in the past 6 months prior to randomization (Day 1); Rituximab in the past 12 months or CD19+ B cells < 5/µL if rituximab treatment was more than 12 months prior to randomization (Day 1); Abatacept in the past 6 months prior to randomization (Day 1); Tumor necrosis factor inhibitors (adalimumab, certolizumab, etanercept, golimumab, infliximab) in the past 3 months prior to randomization (Day 1); Tocilizumab in the past 3 months prior to randomization (Day 1); Cyclophosphamide (or any other alkylating agent) in the past 6 months prior to randomization (Day 1); cyclosporine (except for eye drops), tacrolimus, sirolimus, mycophenolate mofetil, azathioprine, or leflunomide in the past 3 months prior to randomization (Day 1). Receiving any of the following: Corticosteroids: > 10 mg/day oral prednisone (or equivalent); Any change or initiation of new dose within 4 weeks prior to signing the ICF through randomization (Day 1); Intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to signing the ICF through randomization (Day 1); Any change or initiation of new dose of topical corticosteroids within 2 weeks prior to signing the ICF through randomization (Day 1); Antimalarials: any increase or initiation of new dose of antimalarials (eg, chloroquine, hydroxychloroquine, quinacrine) within 12 weeks prior to signing the ICF through randomization (Day 1). Methotrexate: > 20 mg/week methotrexate; Any change or initiation of new dose of methotrexate within 4 weeks prior to signing the ICF through randomization (Day 1); Any change in route of administration. Any increase or initiation of new dose of regularly scheduled nonsteroidal anti inflammatory drugs (NSAIDs) within 2 weeks prior to signing the ICF through randomization (Day 1). Cevimeline or pilocarpine and cyclosporine eye drops (Restasis): any increase or initiation of new doses within 2 weeks prior to signing the ICF through randomization (Day 1).

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEDI5872 210 mg<br>Participants will receive a fixed SC dose of 210 mg MEDI5872 every week (QW) from Days 1 to 15 and then every 2 weeks (Q2W) from Days 29 to 85 in double-blind period. In open-label period, participants will continue dosing of MEDI5872 210mg Q2W from Days 99 to 183 and will receive an additional dose of blinded placebo on Day 106. | Biological: AMG 557/MEDI5872<br>* Participants will receive a fixed SC dose of 210 mg MEDI5872 (AMG 557/MEDI5872) QW for 3 weeks (Days 1 to 15) and then Q2W for 9 weeks (Days 29 to 85) in double-blind period of the study. In open-label period, all participants from double-blind period will receive a fixed SC dose of 210 mg MEDI5872 from Day 99 to Day 183 (QW from Days 99 to 113 for participants from Placebo arm and on Days 99 and 113 for participants from MEDI5872 210 mg arm; and Q2W from Days 127 to 183 for participants from both arms).<br>|
| Placebo Comparator: Placebo/MEDI5872 210 mg<br>Participants will receive a SC dose of placebo matching with MEDI5872 QW on Days 1, 8, and 15 and then Q2W from Days 29 to 85 in double-blind period. In open-label period, participants will receive a fixed SC dose of 210 mg MEDI5872 QW (Days 99 to 113) and Q2W (Days 127 to 183) in open-label period. | Other: Placebo<br>* The SC dose of placebo every week for 3 weeks (Days 1 to 15) and then every 2 weeks for 9 weeks (Days 29 to 85) in double-blind period of the study. In open-label period, an additional dose of blinded placebo will be administered on Day 106 for participants who will receive MEDI5872 210mg in double-blinded period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) Score at Day 99 | The European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI) is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of 12 organ-specific domains (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, and biological). Each domain is assessed for activity level in 3 or 4 levels (i.e., no, low, moderate, high) according to their severity (no disease activity equals to 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. Overall score is calculated as sum of all individual weighted domain scores (ranges from 0 (best) to 123 (worst activity). A higher score indicates worsening of the disease. Adjusted mean change and standard error are presented. | Baseline (Day 1 predose) and Day 99 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio to Baseline in Peripheral Blood Biomarkers at Day 99 | The peripheral blood biomarkers included total plasma cell levels (including plasma blast levels) and T follicular helper (TFH) cells. Adjusted geometric mean ratio to baseline and standard error (log) are presented. | Baseline (Day 1 predose) and Day 99 | 
| Ratio to Baseline in Minor Salivary Gland Tissue Biomarkers at Day 99 | The minor salivary gland biopsy biomarkers included total plasma cell levels, CD4/ inducible T-cell costimulator (ICOS) TFH cells, and PD-1/ICOS TFH cells. Adjusted geometric mean ratio to baseline and standard error (log) are presented. | Baseline (Day 1 predose) and Day 99 | 
| Ratio to Baseline in Focus Score at Day 99 | The focus score is a semi-quantitative assessment of focal lymphocytic sialoadenitis, which is defined as the presence of >= 1 dense aggregate of 50 or more lymphocytes in a 4 mm2 area. Higher numbers are associated with more inflammation. | Baseline (Day 1 predose) and Day 99 | 
| Change From Baseline in European League Against Rheumatism Sjogren's Syndrome Patient Reported Index (ESSPRI) Score at Day 99 | The European League Against Rheumatism Sjogren's Syndrome Patient Reported Index (ESSPRI) is a patient-reported, subjective symptom index for primary Sjögren's syndrome. 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. Adjusted mean change and standard error are presented. | Baseline (Day 1 predose) and Day 99 | 
| Percentage of ESSDAI Responders at Day 99 | The ESSDAI is a clinical index that measures Sjogren's syndrome disease activity. A physician scores the disease activity level of 12 organ-specific domains (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, and biological). Each domain is assessed for activity level in 3 or 4 levels (no, low, moderate, high) according to their severity (0=no disease activity and ¾ = high disease activity of the domain). Each domain is assigned a weight between 1 and 6, and the domain score is multiplied by the domain weight. Overall score is calculated as sum of all individual weighted domain scores (ranges from 0 [best] to 123 [worst activity]). Participants are considered to be an ESSDAI[x] responder as they achieved a reduction of x points or more in ESSDAI score, did not prematurely discontinue the study drug, and did not receive prohibited concomitant medications. | Baseline (Day 1 predose) and Day 99 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were collected from Day 1 (postdose) until Day 99 for 'Placebo' arm and Day 296 for 'Any MEDI5872 210 mg' arm that were absent before treatment or that worsened relative to pre-treatment state. | Placebo arm: Day 1 (postdose) through Day 99 (predose); Any MEDI5872 210 mg arm: Day 1 (postdose) through Day 296 for MEDI5872 210 mg arm, and Day 99 (postdose) through Day 296 for participants who received placebo at double-blind period | 
| Number of Participants With Adverse Events of Special Interest (AESIs) | An AESI (serious or non-serious) was one of scientific and medical interest specific to understanding of study drug and may have required close monitoring and rapid communication by investigator to the sponsor. The AESIs for this study were hepatic function abnormality meeting the definition of Hy's law, new or reactivated tuberculosis infection, malignancy, and hypersensitivity and anaphylactic reactions. Treatment-emergent AESIs were collected from Day 1 (postdose) until Day 99 for 'Placebo' arm and Day 296 for 'Any MEDI5872 210 mg' arm. | Placebo arm: Day 1 (postdose) through Day 99 (predose); Any MEDI5872 210 mg arm: Day 1 (postdose) through Day 296 for MEDI5872 210 mg arm, and Day 99 (postdose) through Day 296 for participants who received placebo at double-blind period |