Study of Safety and Efficacy of Multiple Doses of CFZ533 in Two Distinct Populations of Patients With Sjogren's Syndrome

Study Overview
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Brief Summary
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This study will evaluate safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple doses of CFZ533 (iscalimab) in patients with Sjögren's Syndrome.

Detailed Description
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This is a double-blind, randomized, placebo-controlled, multicenter study of CFZ533 in 2 distinct populations (cohorts) of patients with Sjögren's Syndrome: 1) moderate-to-severe disease (systemic and symptomatic involvement) and; 2) low systemic involvement but high symptom burden. The study includes up to 6 weeks screening period, 48 weeks of treatment (divided into treatment periods of 24 weeks each) and 12 weeks follow up. Study treatment will be administered as bi-weekly subcutaneous injections.

Official Title
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A 48-week, 6-arm, Randomized, Double-blind, Placebo-controlled Multicenter Trial to Assess the Safety and Efficacy of Multiple CFZ533 Doses Administered Subcutaneously in Two Distinct Populations of Patients With Sjogren's Syndrome (TWINSS)

Conditions
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Sjögren Syndrome

Intervention / Treatment
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* Drug: CFZ533
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Male or female patient ≥ 18 years of age Classification of Sjögren's Syndrome according to ACR/EULAR 2016 criteria (Shiboski et al 2017) Seropositive for anti-Ro/SSA antibodies Stimulated whole salivary flow rate of ≥ 0.1 mL/min Inclusion criteria specific for Cohort 1: ESSDAI ≥ 5 within the 8 predefined organ domains ESSPRI score of ≥5 Inclusion criteria specific for Cohort 2: ESSDAI < 5 within 8 domains scored for inclusion criterion for Cohort 1 ESSPRI fatigue subscore ≥ 5 or ESSPRI dryness subscore ≥ 5 Exclusion Criteria: Sjögren's Syndrome overlap syndromes where another autoimmune rheumatic disease constitutes the principle illness Use of other investigational drugs Prior use of B cell depleting therapies, abatacept or any other immunosuppressants unless specifically allowed be the protocol. Use of steroids at dose >10 mg/day. Uncontrolled ocular rosacea (affecting the eye adnexa), posterior blepharitis or Meibomian gland disease (this criterion applies only to patients considered for Cohort 2) Active viral, bacterial or other infections requiring systemic treatment Receipt of live/attenuated vaccine within a 2-month period prior to randomization. Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Evidence of active tuberculosis (TB) infection.

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Patients will be screened and enrolled into one of the 2 study Cohorts: Cohort 1: At baseline subjects will be randomized in ratio 1:1:1:1 into one of three CFZ533 (iscalimab) arms (A, B or C) or to placebo (Arm D). After completion of 24 weeks of treatment (Period 1) placebo patients (Arm D) will be switched to active treatment (Arm D1) for the subsequent 24 weeks (Period 2). Cohort 2: At baseline subjects will be randomized in ratio 1:1 to iscalimab (Arm E) or to placebo (Arm F). After completion of 24 weeks of treatment (Period 1), placebo patients (Arm F) will be switched to iscalimab active treatment (Arm F1) for the subsequent 24 weeks (Period 2). All patients treated with iscalimab (Arms A,B,C,and E) in Period 1 will continue the same study treatment in Period 2.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 /Arm A<br>CFZ533 dose 1 | Drug: CFZ533<br>* Biological<br>* Other names: iscalimab;|
| Experimental: Cohort 1/Arm B<br>CFZ533 dose 2 | Drug: CFZ533<br>* Biological<br>* Other names: iscalimab;|
| Experimental: Cohort 1/Arm C<br>CFZ533 dose 3 | Drug: CFZ533<br>* Biological<br>* Other names: iscalimab;|
| Placebo Comparator: Cohort 1/Arm D<br>Placebo dose (up to week 24) | Other: Placebo<br>* liquid placebo for injections<br>|
| Experimental: Cohort 1/Arm D1<br>CFZ533 dose 1 (from week 24) | Drug: CFZ533<br>* Biological<br>* Other names: iscalimab;|
| Experimental: Cohort 2/Arm E<br>CFZ533 dose 1 | Drug: CFZ533<br>* Biological<br>* Other names: iscalimab;|
| Placebo Comparator: Cohort 2/Arm F<br>Placebo dose (up to week 24) | Other: Placebo<br>* liquid placebo for injections<br>|
| Experimental: Cohort 2/Arm F1<br>CFZ533 dose 2 (from week 24) | Drug: CFZ533<br>* Biological<br>* Other names: iscalimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) score from baseline at 24 weeks as compared to placebo | Cohort 1 - Efficacy | 24 weeks | 
| Change in EULAR Sjögren Syndrome Patient Reported Index (ESSPRI) score from baseline at 24 weeks as compared to placebo. | Cohort 2 - Efficacy | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in ESSPRI at Week 24 | Cohort 1 - Efficacy (Patient Reported Outcomes) | 24 weeks | 
| Change from baseline in score of Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) questionnaire at Week 24 | Cohort 1&2 - Efficacy (Patient Reported Outcomes) | 24 weeks | 
| Change from baseline in Physician Global Assessment (PhGA) at Week 24 | Cohort 1&2 - Efficacy (Clinical Outcome Measures) | 24 weeks | 
| Change from baseline in ESSDAI at Week 24 | Cohort 2 - Efficacy (Clinical Outcome Measures) | 24 weeks | 
| Proportion of subjects with at least 12 points improvement measured by score of Impact of Dry Eye on Everyday Life (IDEEL) questionnaire symptom bother module at Week 24. | Cohort 2 - Efficacy (Patient Reported Outcomes) | 24 weeks | 
| Incidence of adverse events (AEs), serious adverse events (SAEs) from baseline to Week 24 and from week 24 to the end of study | Cohort 1&2 - Safety | 60 weeks | 
| Serum Free Light Chain (FLC) levels at analysis visit up to end of study | Cohort 1&2 - Biomarkers (1) | 60 weeks | 
| Immunoglobulin IgG and IgM levels at analysis visits up to end of study | Cohort 1&2 - Biomarkers (2) | 60 weeks | 
| Percent change from baseline in plasma CXCL-13 levels at analysis visits up to end of study | Cohort 1&2 - Biomarkers (3) Chemokine (C-X-C motif) ligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1), is a protein ligand that in humans is encoded by the CXCL13 gene. | 60 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sjögren, fatigue, dryness, anti-CD40, CFZ533, iscalimab, TWINSS, autoimmune