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

Novartis Pharmaceuticals

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Conditions

Primary Sjögren's Syndrome

Interventions

Eligibility

Sex: ALL

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: 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)

Time frame: 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

Time frame: Part 3: 12 weeks

Secondary Outcomes

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)

Time frame: 12 weeks

To asses the pharmacokinetiks of VAY736 in pSS patients

Multiple s.c. dose VAY736 PK parameter - Area under the curve (AUC)

Time frame: 12 weeks

To assess the pharmacokinetiks of VAY736 in pSS patients

Multiple s.c. dose VAY736 PK parameter - Trough concentrations after multiple dose

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: 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).

Time frame: 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)

Time frame: 12 weeks

To evaluate the change in the physician global assessment of patients's overall disease activity

Physician's visual anaglog scale (VAS)

Time frame: 12 weeks

To evaluate the change in the patients global assessment of their disease activity

Patient's visual analogue scale (VAS)

Time frame: 12 weeks

To assess the immunogenicity of VAY736

Anti-VAY736 antibodies

Time frame: 12 weeks

To assess the immunogenicity of a micodose of rituximab

Anti-rituximab antibodies

Time frame: 25 weeks

To asses the pharmacokinetiks of VAY736 in pSS patients

Multiple s.c. dose VAY736 PK parameter - Cmax

Time frame: 12 weeks

To asses the pharmacokinetiks of VAY736 in pSS patients

Multiple s.c. dose VAY736 PK parameter - tmax

Time frame: 12 weeks

To asses the pharmacokinetiks of VAY736 in pSS patients

Multiple s.c. dose VAY736 PK parameter - half live (t1/2)

Time frame: 12 weeks