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

Novartis Pharmaceuticals273 enrolled

Overview

This study was to evaluate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple doses of CFZ533 (iscalimab) in patients with Sjögren's Syndrome (SjS).

This study consisted of a 6-week screening, 2 treatment periods of 24 weeks each, and a follow-up period of 12 weeks. In Periods 1 and 2, thirteen (13) treatment administration visits were planned, including a weekly loading regimen (2 visits) at the start of each treatment period. One administration equaled to two subcutaneous (s.c.) injections. This study included two distinct cohorts termed Cohort 1 and Cohort 2. * Cohort 1: subjects with moderate-to-severe systemic and symptomatic disease involvement. * Cohort 2: subjects with low systemic disease involvement but high symptom burden.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

273

Conditions

Sjögren Syndrome

Interventions

CFZ533DRUG

Biological

PlaceboOTHER

liquid placebo for injections

Eligibility

Sex: ALLMin age: 18 YearsMax age: 100 Years

Medical Language ↔ Plain English

Inclusion Criteria: Both cohorts must have met all the following criteria: 1. Signed informed consent must be obtained prior to participation in the study 2. Male or female patient \>= 18 years of age 3. Classification of Sjögren's Syndrome according to ACR/EULAR 2016 criteria (Shiboski et al 2016) 4. Seropositive for anti-Ro/SSA antibodies 5. Stimulated whole salivary flow rate of \>= 0.1 mL/min 6. Able to communicate well with the Investigator to understand and comply with the requirements of the study Inclusion criteria specific for Cohort 1: 7. Screening ESSDAI value \>= 5 within the following 8 organ domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, renal, hematologic and biologic * Patients with involvement of one or more of the remaining 4 domains are eligible but scores of these domains will not contribute to the assessment for eligibility for Cohort 1 * At selected sites participating in Cohort 2, patients who based on the above criterion 7, do not qualify for Cohort 1, should be further evaluated for Cohort 2 8. Screening ESSPRI score of \>= 5 Inclusion criteria specific for Cohort 2: 9. Screening ESSDAI value \< 5 within 8 domains scored for inclusion criterion #7 Cohort 1 10. Screening ESSPRI fatigue subscore \>= 5 or ESSPRI dryness subscore \>= 5 11. Hypergammaglobulinemia defined by IgG greater than upper limit of normal (ULN) or lymphocytopenia (less than lower limit of normal (LLN)) or hypocomplementemia (low C3, or low C4 - when considered due to disease activity and not due to genetic factors) 12. Score of \>= 30 on IDEEL symptom bother questionnaire at Screening Exclusion Criteria: 1. Sjögren's Syndrome overlap syndromes where another autoimmune rheumatic disease constitutes the principal illness 2. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days whichever is longer, or longer if required by local regulations 3. Prior treatment with any of the following within 6 months prior to randomization: * B-cell depletors (e.g. rituximab, ianalumab) unless CD19+ B cell count have returned to ≥ 50 cells/µL * abatacept * anti-tumor necrosis factor alpha monoclonal anti-body * intravenous/subcutaneous Ig; plasmapheresis; i.v. or oral cyclophosphamide * i.v. or oral cyclosporine A * any other immunosuppressants unless explicitly allowed in criterion #5 4. Use of steroids (predniso(lo)ne or equivalent corticosteroid) at dose \> 10 mg/day 5. Use of steroids and synthetic DMARDS at inconsistent dose and within 3 months prior to randomization

Locations (71)

Outcomes

Primary Outcomes

Cohort 1: Change in EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) Score From Baseline at 24 Weeks as Compared to Placebo

ESSDAI is a validated disease outcome measure for SjS that 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. The domains (weights) are as follows: constitutional (3), lymphadenopathy (4), glandular (2), articular (2), cutaneous (3), pulmonary (5), renal (5), muscular (6), peripheral nervous system (PNS) (5), central nervous system (CNS) (5), hematological (2) and biological (1). The total score may vary between 0-123. It is considered low activity an ESSDAI \< 5; moderate activity 5-13, and high activity if ESSDAI is \>= 14.

Time frame: Baseline, Week 24

Cohort 2: Change in EULAR Sjögren Syndrome Patient Reported Index (ESSPRI) Score From Baseline at 24 Weeks as Compared to Placebo.

The ESSPRI is a self-evaluation index for measuring symptoms including pain, fatigue and dryness. Each symptom was measured with a single 0 (no symptoms) to 10 (severe symptoms) numerical scale and the final ESSPRI score is calculated by averaging these domains with a maximum severity score of 10.

Time frame: Baseline, Week 24

Secondary Outcomes

Cohort 1: Change From Baseline in ESSPRI at Week 24

Time frame: Baseline, Week 24

Cohort 1: Change From Baseline in Score of Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Questionnaire at Week 24

The FACIT F (Functional Assessment of Chronic Illness Therapy-Fatigue) is a validated 13 item patient reported outcome measure assessing fatigue and its impact on daily functioning over the past 7 days, with total scores ranging from 0 to 52, where higher scores indicate less fatigue.

Data from ClinicalTrials.gov

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North GA Rheumatology Group PC

Suwanee, Georgia, United States

Indiana Univ School of Dentistry

Indianapolis, Indiana, United States

Ochsner Health System

Baton Rouge, Louisiana, United States

The John Hopkins Jerome L Greene Sjogren

Baltimore, Maryland, United States

Tufts School of Dental Medicine

Boston, Massachusetts, United States

Winthrop University Hospital

Mineola, New York, United States

Perelman School of Medicine

Philadelphia, Pennsylvania, United States

Uni Wisconsin School Med Pub Health

Madison, Wisconsin, United States

Novartis Investigative Site

Buenos Aires, Argentina

Novartis Investigative Site

CABA, Argentina

...and 61 more locations

Time frame: Baseline, 24 weeks

Cohort 1: Change From Baseline in Physician Global Assessment (PhGA) at Week 24

Physician's global assessment (PhGA) of disease activity was performed using a Visual Analog Scale (VAS) - an unnumbered 100 mm horizontal line ranging from "no disease activity" (score 0) to "maximal disease activity" (score 100). The assessment of patient's condition on the day is made by placing a vertical mark across the line.

Time frame: Baseline, 24 weeks

Cohort 2: Change From Baseline in Score of Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Questionnaire at Week 24

Time frame: Baseline, 24 weeks

Cohort 2: Change From Baseline in Physician Global Assessment (PhGA) at Week 24

Time frame: Baseline, 24 weeks

Cohort 2: Change From Baseline in ESSDAI at Week 24

ESSDAI is a validated disease outcome measure for SjS that 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. The domains (weights) are as follows: constitutional (3), lymphadenopathy (4), glandular (2), articular (2), cutaneous (3), pulmonary (5), renal (5), muscular (6), peripheral nervous system (PNS) (5), central nervous system (CNS) (5), hematological (2) and biological (1). The final score may vary between 0-123. It is considered low activity an ESSDAI \< 5; moderate activity 5-13, and high activity if ESSDAI is \>= 14.

Time frame: Baseline, week 24

Cohort 2: 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.

The Impact of Dry Eye on Everyday Life (IDEEL) questionnaire is a comprehensive dry eye specific questionnaire to evaluate treatment satisfaction, symptom-related bother and impact on daily life in a population with dry eye. This study only utilized the Dry Eye Symptom-Bother module. The Dry Eye Symptom-Bother module of IDEEL is composed of a single dimension (20 items). A 4-point Likert-like scale is used: from "not at all" to "very much". Patients could also answer "I did not have this symptom / Not applicable". One item is scored on a 5-point Likert-like scale from "none of the time" to "all of the time". The range for the symptom-bother score is 0 to 100, with higher scores indicating greater symptom bother.

Time frame: Baseline, Week 24

Cohort 1: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) up to Week 24

The distribution of adverse events in Treatment Period 1 was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Analyses of data in the Safety Set (SAF) up to Week 24 (Period 1) is presented by actual treatment during Period 1, with data from separate cohort for the CFZ533 600mg and for the Placebo groups: CFZ533 600 mg, CFZ533 300 mg, CFZ533 150 mg and placebo.

Time frame: Up to Week 24

Cohort 1: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) in All Study Periods

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Analyses of data in the Safety Set (SAF) for period 2/3 or overall study is presented by actual treatment sequence during periods 1 and 2, where the CFZ533 600 mg - CFZ533 600 mg sequence included data from patients in separate cohort. CFZ533 600 mg 24 Weeks arm includes only patients from Placebo - CFZ533 600 mg arm, who took at least one CFZ533 600 mg dose in Period 2 (Patients who received Placebo in Period 1 and discontinued before Week 24 are not included). CFZ533 600 mg 48 Weeks arm includes all subjects from CFZ533 600 mg - CFZ533 600 mg arm, and subjects from CFZ533 150 mg - CFZ533 150 mg and CFZ533 300 mg - CFZ533 300 mg arms but only took the first or the first two loading dose(s) in period 1.

Time frame: up to 14 weeks following the last dose of study treatment, up to maximum Week 60

Cohort 2: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) up to Week 24

Time frame: Up to Week 24

Cohort 2: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) in All Study Periods

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters. Analyses of data in the Safety Set (SAF) for period 2/3 or overall study is presented by actual treatment sequence during periods 1 and 2, where the CFZ533 600 mg - CFZ533 600 mg sequence included data from patients in separate cohort. CFZ533 300 mg 24 Weeks includes only patients from Placebo - CFZ533 300 mg arm, who received Placebo in Period 1, and either took CFZ533 600 mg loading dose + at least two CFZ533 300 mg subsequent doses in Period 2 or missed CFZ533 600 mg loading dose and took at least one CFZ533 300 mg dose in Period 2 (Patients who received Placebo in Period 1 and discontinued before Week24 are not included). CFZ533 600 mg 48 Weeks arm includes all subjects from CFZ533 600 mg - CFZ533 600 mg arm.

Time frame: up to 14 weeks following the last dose of study treatment, up to maximum Week 60

Cohort 1: Change From Baseline in Serum Free Light Kappa (FLCκ) Chains Levels

Serum samples for free light kappa (FLCκ) chains were collected and analyzed.

Time frame: Baseline, Week 4, Week 12, Week 24 (End Treatment Period 1), Week 32, Week 40, Week 48 (End Treatment Period 2), FUP2 (Week 56), FUP 3 (Week 60)

Cohort 2: Change From Baseline in Serum Free Light Kappa (FLCκ) Chains Levels

Serum samples for free light kappa (FLCκ) chains were collected and analyzed.

Time frame: Baseline, Week 4, Week 12, Week 24 (End Treatment Period 1), Week 32, Week 40, Week 48 (End Treatment Period 2), FUP2 (Week 56), FUP 3 (Week 60)

Cohort 1: Change From Baseline in Immunoglobulin G (IgG) Levels

Plasma samples for Immunoglobulin G (IgG) were collected and analyzed.

Time frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24 (End Treatment Period 1), Week 28, Week 32, Week 40, Week 48 (End Treatment Period 2), FUP1 (Week 52), FUP2 (Week 56), FUP 3 (Week 60)

Cohort 2: Change From Baseline in Immunoglobulin G (IgG) Levels

Plasma samples for Immunoglobulin G (IgG) were collected and analyzed.

Cohort 1: Change From Baseline in Immunoglobulin M (IgM) Levels

Plasma samples for Immunoglobulin M (IgM) were collected and analyzed.

Cohort 2: Change From Baseline in Immunoglobulin M (IgM) Levels

Plasma samples for Immunoglobulin M (IgM) were collected and analyzed.

Cohort 1: Change From Baseline in Plasma CXCL-13 Levels

Plasma samples for Chemokine (C-X-C motif) ligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1) were collected and analyzed.

Time frame: Baseline, Week 4, Week 12, Week 24 (End Treatment Period 1), Week 32, Week 48 (End Treatment Period 2), FUP 3 (Week 60)

Cohort 2: Change From Baseline in Plasma CXCL-13 Levels

Plasma samples for Chemokine (C-X-C motif) ligand 13 (CXCL13), also known as B lymphocyte chemoattractant (BLC) or B cell-attracting chemokine 1 (BCA-1) were collected and analyzed.

Time frame: Baseline, Week 4, Week 12, Week 24 (End Treatment Period 1), Week 32, Week 48 (End Treatment Period 2), FUP 3 (Week 60)