Study of Pharmacodynamic Effects of VAY736 in Patients With Primary Sjögren's Syndrome

Study Overview
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Brief Summary
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This study consists of three consecutive parts. Part 1 in primary Sjögren's syndrome (pSS) patients (n=2-6) and Part 2 in healthy voluteers (n=3) are feasibility studies to assess if the selected [Zr-89]-rituximab PET/CT method is a valid method to assess B cells in salivary glands of pSS patients. In Part 1 and Part 2 no IMP will be applied to the subjects. In Part 3, pSS patients (n=12) will receive the IMP, VAY736. Posted information will be focused on Part 3. The overarching purpose of this study is to test a new drug (VAY736) for the treatment of pSS. In pSS, the salivary glands (the glands that produce saliva) and other organs are affected by inflammation. A certain type of white blood cells called B cells prominently infiltrate the salivary glands in pSS, whereas they are not present in healthy salivary glands. Scientific evidence suggests that B cells may be involved in the disease process in pSS and that eliminating B cells may benefit patients with pSS. This study will test a new imaging method and a new treatment for pSS. Both the imaging method and the treatment are specific for B cells.

Official Title
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A Three-part, Partially Open Label and Double-blind, Randomized Study to Assess the Pharmacodynamic Effects, Safety, Tolerability and Preliminary Efficacy of VAY736 in Patients With Primary Sjögren's Syndrome Using [Zr-89]-Rituximab PET/CT

Conditions
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Primary Sjögren's Syndrome

Intervention / Treatment
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* Drug: VAY736 lower dose
* Drug: VAY736 higher dose


Participation Criteria
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Eligibility Criteria
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Part 1 and 3: Inclusion Criteria: Fullfilled consensus criteria for primary Sjögren's syndrome Patients must have elevated serum levels for some Sögren Syndorme specific parameters such as antinuclear antibodies (ANA), rheumatoid factor (RF) etc. Exclusion Criteria: Patients that are suffering from Secondary Sjögren's syndrome. Patients previously treated with monoclonal antibody treatments such as rituximab, infliximab, adalimumab, etc. Part 2 Inclusion criteria: - healthy male and female people 18-75 years of age Exclusion criteria: Use of other investigational drugs at the time of enrollment Exposure to a sizeable degree of radiation (≥ 5 mSv) in an investigational research study in the past year prior to this study
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: VAY736 lower dose<br>12 evaluable patients will be enrolled and randomized (at a ratio of 1:1) to receive either a lower dose or a higher dose of the study drug (VAY736) | Drug: VAY736 lower dose<br>* Patients will receive a total number of 3 monthly subcutaneous injections with the lower dose of VAY736<br>|
| Experimental: VA736 higher dose<br>12 evaluable patients will be enrolled and randomized (at a ratio of 1:1) to receive either a lower dose or a higher dose of the study drug (VAY736) | Drug: VAY736 higher dose<br>* Patients will receive a total number of 3 monthly subcutaneous injections with the higher dose of VAY736<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: To determine the feasibility of measuring major salivary gland infiltrating B cells in pSS patients using [Zr- 89]rituximab PET/CT imaging | Part 1: PET/CT imaging of pSS major salivary gland 3, 6 and 9 days after i.v. injection with [Zr- 89]rituximab | Part 1: 4 weeks | 
| Part 2: To define the normal range of PET/CT imaging values for major salivary gland tissue, cervical lymph nodes and spleen in healthy volunteers with [Zr-89]-rituximab | Part 2: PET/CT imaging of healthy volunteers' major salivary gland, cervical lymph nodes and spleen on optimal time point after i.v. injection with [Zr-89]-rituximab (e.g. 3 days after injection) | Part 2: 4 weeks | 
| Part 3: To compare the effect of two different VAY736 s.c. dose regimes on salivary gland-infiltrating B cells in pSS patients, using [Zr-89]-rituximab PET/CT imaging | Part 3: PET/CT imaging of pSS tissues on optimal time point after i.v. injection with [Zr-89]-rituximab, at baseline and 12 weeks after the start of VAY736 treatment | Part 3: 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of multiple s.c. dosing of VAY736 in pSS patients as measured by safety assessments | AEs, vital signs, ECGs, safety laboratory parameters (Hematology, Biochmistry, Urinalysis) | 12 weeks | 
| To asses the pharmacokinetiks of VAY736 in pSS patients | Multiple s.c. dose VAY736 PK parameter - Area under the curve (AUC) | 12 weeks | 
| To assess the pharmacokinetiks of VAY736 in pSS patients | Multiple s.c. dose VAY736 PK parameter - Trough concentrations after multiple dose | 12 weeks | 
| Assess the pharmacodynamic effect of VAY736 on circulating CD19+ B-cells in pSS | Multiple s.c. dose VAY736 PD parameter - depletion of B cells | 12 weeks | 
| Asses effect of two different VAY736 dose levels on target tissue structure and function in pSS | Assess size of spleen and cervical lyph nodes by PET/CT imaging and ultrasound-aided size measurements | 12 weeks | 
| Asses effect of two different VAY736 dose levels on target tissue structure and function in pSS | Assess salivary glands size and echostructure by ultrasound | 12 weeks | 
| Asses effect of two different VAY736 dose levels on target tissue structure and function in pSS | Assess salivary gland function (quantitative) by salivary flow (stimulated and unstimulated) | 12 weeks | 
| Asses effect of two different VAY736 dose levels on target tissue structure and function in pSS | Assess lacrimal gland function by Schirmer's test | 12 weeks | 
| To evaluate the effect of two different VAY736 dose levels (s.c. q4w) on pSS disease activity | Assess the change in the EULAR Sjögren'sSyndrome Disease Activity Index (ESSDAI). | 12 weeks | 
| To evaluate the effect of on self-reported outcomes in pSS patients | Multidimensional Fatigue Inventory (MFI-20); the short form 36 health Survey (SF-36); EULAR Sjögren's Syndorm Patient Reported Intensity (ESSPRI) | 12 weeks | 
| To evaluate the change in the physician global assessment of patients's overall disease activity | Physician's visual anaglog scale (VAS) | 12 weeks | 
| To evaluate the change in the patients global assessment of their disease activity | Patient's visual analogue scale (VAS) | 12 weeks | 
| To assess the immunogenicity of VAY736 | Anti-VAY736 antibodies | 12 weeks | 
| To assess the immunogenicity of a micodose of rituximab | Anti-rituximab antibodies | 25 weeks | 
| To asses the pharmacokinetiks of VAY736 in pSS patients | Multiple s.c. dose VAY736 PK parameter - Cmax | 12 weeks | 
| To asses the pharmacokinetiks of VAY736 in pSS patients | Multiple s.c. dose VAY736 PK parameter - tmax | 12 weeks | 
| To asses the pharmacokinetiks of VAY736 in pSS patients | Multiple s.c. dose VAY736 PK parameter - half live (t1/2) | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Sjögren's syndrome, Sicca syndrome, Salivary glands, Positron Emission Tomography, B cell depletion