PD of VAY736 in Patients With Primary Sjögren's Syndrome

Study Overview
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Brief Summary
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This study was designed to evaluate the safety, tolerability, pharmacokinetics and therapeutic efficacy of a single intravenous infusion of VAY7346 monoclonal antibody in pSS patients

Detailed Description
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Patients were enrolled in 2 sequential cohorts: Cohort 1: 6 patients received 3 mg/kg or Placebo (2:1 ratio) Cohort 2: 21 patients received 10 mg/kg, 3 mg/kg or Placebo (6:1:3 ratio) At week 24 the blind was broken to assess continuation in the trial: If a patient received VAY736 and their B cell recovery was demonstrated at Week 24, then patients completed the trial. If a patient received VAY736 and their B cell recovery was NOT demonstrated at Week 24, then patients were followed up until B cell recovery was demonstrated If a patient received placebo, they were offered the option of receiving open-label VAY736 (10 mg/kg) in a separate treatment arm.

Official Title
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A Single Dose, Double-blind, Placebo-controlled, Parallel Study to Assess the Pharmacodynamics, Pharmacokinetics and Safety and Tolerability of VAY736 in Patients With Primary Sjögren's Syndrome

Conditions
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Primary Sjögren's Syndrome

Intervention / Treatment
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* Drug: VAY736
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Fulfilled revised European US consensus criteria for pSS ESSDAI value ≥ 6 Elevated serum titers at screening of ANA (≥ 1:160) Seropositive at screening for anti-SSA and/or anti-SSB antibodies Stimulated whole salivary flow rate at screening of > 0 mL/min EXCLUSION CRITERIA: - Prior or previous use of (specific dosages and intervals prior to study start may apply): B-cell depleting therapy (e.g., rituximab), Prednisone, anti-BAFF mAb, CTLA4-Fc Ig (abatacept), anti-TNF-α mAb, cyclophosphamide, azathioprine and medications known to cause dry mouth. Hydroxychloroquine or methotrexate in a consistent dose for ≥ 3 months prior to randomization is allowed Active or recent history of clinically significant infection Vaccination within 2 month prior to study History of primary or secondary immunodeficiency

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VAY736 3 mg/kg<br>single dose iv of VAY736 at a dose of 3mg/kg | Drug: VAY736<br> <br> |
| Experimental: VAY736 10 mg/kg<br>single dose iv of VAY736 at a dose of 10mg/kg | Drug: VAY736<br> <br> |
| Placebo Comparator: Placebo<br>single dose iv of Placebo. At Week 24 patients were offered to receive open label VAY736 10 mg/kg. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) | The effect of VAY736 on clinical disease activity was measured by the change in ESSDAI (EULAR Sjögren's syndrome disease activity index) between baseline and week 12. The instrument contains 12 organ-specific domains contributing to disease activity. For each domain, features of disease activity are scored in 3 or 4 levels according to their severity. These scores are then summed across the 12 domains in a weighted manner to provide the total score (range 0-123). A reduction from baseline indicates improvement in patients. | Baseline, week 12 | 
| Overall Incidence of Adverse Events | Number of subjects with Adverse Events during the double blind treatment period. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EULAR Sjögren's Syndrome Patient Response Index (ESSPRI) | The ESSPRI is a patient self-reported outcome measure to assess dryness, limb pain, fatigue and mental fatigue, where each of the domains normally reported as 0 (not at all) to 10 (extremely severe). The final ESSPRI score is the average of three: dryness, pain and fatigue. A reduction from baseline indicates the improvement of symptoms. During the study all individual scores were reported as 1 to 10 instead. A linear transformation was reported to map the scores to the range of 0-10. | Baseline, week 12 | 
| Change in Short Form (36) Health Survey (SF-36) | The SF-36 is a 36-item, patient self-reported outcome measure (questionnaires) of patient health. The outcome of the questionnaires in eight scales results in two summary scores, physical component and mental component, both ranging from 0 - 100. An increase from baseline in either component summary score indicates reduced disease burden. | Baseline, week 12 | 
| Change in Multidimensional Fatigue Inventory (MFI) | The MFI is a patient self-reported outcome measure (questionnaires) to assess fatigue covering the following dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. Each dimension has a posible range from 4-20. A reduction from baseline in MFI indicates improvement. | Baseline, week 12 | 
| Change in the Physician's Global Assessment of Overall Disease Activity by Means of Visual Analog Scale (VAS) | The visual analogue scale used is a 100 mm VAS ranging from no disease (0 mm) to maximal disease activity (100 mm). | Baseline, week 12 | 
| Change in the Patient's Global Assessment of Overall Disease Activity by Means of Visual Analog Scale (VAS) | The visual analogue scale used is a 100 mm VAS ranging from no disease (0 mm) to maximal disease activity (100 mm). | Baseline, week 12 | 
| VAY736 Serum Concentration - AUCinf | The area under the serum concentration-time curve from time zero to infinity [mass × time / volume]. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 
| VAY736 Serum Concentration - AUClast | The area under the serum concentration-time curve from time zero to the time of the last quantifiable concentration [mass × time / volume]. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 
| VAY736 Serum Concentration - CL | The systemic (or total body) clearance from serum following intravenous administration [volume / time]. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 
| VAY736 Serum Concentration - Cmax | The observed maximum serum concentration following drug administration [mass / volume]. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 
| VAY736 Serum Concentration - T1/2 | Apparent terminal half-life, determined as the ln2/lambda_z or 0.693/lambda_z. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 
| VAY736 Serum Concentration - Tmax | The time to reach the maximum concentration after drug administration [time]. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 
| VAY736 Serum Concentration - Vz | The volume of distribution during the terminal elimination phase following intravenous administration [volume]. The concentration of VAY736 was measured in the serum. | 0, 1, 2, 3, 6, 9, 12, 16, 20, 24 and approximately 52 weeks. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary Sjögren's syndrome, pharmacodynamics