Sjögren Syndrome
Conditions
Keywords
Sjögren Syndrome (SjS), sicca syndrome, dryness, fatigue, autoimmune disease, European League Against Rheumatism (EULAR), EULAR Sjögren syndrome disease activity index (ESSDAI), EULAR Sjögren syndrome patient reported index (ESSPRI), monoclonal antibody, anti-CD40, iscalimab (CFZ533), TWINSS
Brief summary
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).
Detailed description
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.
Interventions
DRUGCFZ533
Biological
OTHERPlacebo
liquid placebo for injections
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Patients, investigator staff, persons performing the assessments, were blinded to the identity of the treatment within each cohort from the time of randomization until end of the study visit (week 60)
Intervention model description
Patients were screened and enrolled into one of the 2 study Cohorts: Cohort 1: At baseline subjects were 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 were 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 continued the same study treatment in Period 2.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Change in EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) Score From Baseline at 24 Weeks as Compared to Placebo | Baseline, 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 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. |
| Cohort 2: Change in EULAR Sjögren Syndrome Patient Reported Index (ESSPRI) Score From Baseline at 24 Weeks as Compared to Placebo. | Baseline, Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort 1: Change From Baseline in ESSPRI at Week 24 | Baseline, Week 24 | 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. |
| Cohort 1: Change From Baseline in Score of Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Questionnaire at Week 24 | Baseline, 24 weeks | 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. |
| Cohort 1: Change From Baseline in Physician Global Assessment (PhGA) at Week 24 | Baseline, 24 weeks | 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. |
| Cohort 2: Change From Baseline in Score of Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Questionnaire at Week 24 | Baseline, 24 weeks | 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. |
| Cohort 2: Change From Baseline in Physician Global Assessment (PhGA) at Week 24 | Baseline, 24 weeks | 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. |
| Cohort 2: Change From Baseline in ESSDAI at Week 24 | Baseline, 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. |
| 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. | Baseline, 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. |
| Cohort 1: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) up to Week 24 | 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. |
| Cohort 1: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) in All Study Periods | up to 14 weeks following the last dose of study treatment, up to maximum Week 60 | 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. |
| Cohort 2: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) up to Week 24 | Up to Week 24 | 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) 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 and placebo. |
| Cohort 2: Incidence of Adverse Events (AEs), Serious Adverse Events (SAEs) in All Study Periods | up to 14 weeks following the last dose of study treatment, up to maximum Week 60 | 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. |
| Cohort 1: Change From Baseline in Serum Free Light Kappa (FLCκ) Chains Levels | 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) | Serum samples for free light kappa (FLCκ) chains were collected and analyzed. |
| Cohort 2: Change From Baseline in Serum Free Light Kappa (FLCκ) Chains Levels | 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) | Serum samples for free light kappa (FLCκ) chains were collected and analyzed. |
| Cohort 1: Change From Baseline in Immunoglobulin G (IgG) Levels | 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) | Plasma samples for Immunoglobulin G (IgG) were collected and analyzed. |
| Cohort 2: Change From Baseline in Immunoglobulin G (IgG) Levels | 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) | Plasma samples for Immunoglobulin G (IgG) were collected and analyzed. |
| Cohort 1: Change From Baseline in Immunoglobulin M (IgM) Levels | 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) | Plasma samples for Immunoglobulin M (IgM) were collected and analyzed. |
| Cohort 2: Change From Baseline in Immunoglobulin M (IgM) Levels | 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) | Plasma samples for Immunoglobulin M (IgM) were collected and analyzed. |
| Cohort 1: Change From Baseline in Plasma CXCL-13 Levels | Baseline, Week 4, Week 12, Week 24 (End Treatment Period 1), Week 32, Week 48 (End Treatment Period 2), FUP 3 (Week 60) | 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. |
| Cohort 2: Change From Baseline in Plasma CXCL-13 Levels | Baseline, Week 4, Week 12, Week 24 (End Treatment Period 1), Week 32, Week 48 (End Treatment Period 2), FUP 3 (Week 60) | 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. |
Countries
Argentina, Australia, Austria, Brazil, Canada, Chile, Colombia, France, Germany, Greece, Hungary, Israel, Italy, Japan, Netherlands, Portugal, Romania, Russia, South Korea, Sweden, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORStudy Director Novartis Pharmaceuticals
Novartis Pharmaceuticals
Participant flow
Recruitment details
The study was conducted at 71 sites in 23 countries. Argentina (2), Australia (1), Austria (2), Brazil (3), Canada (3), Chile (5), Colombia (3), France (5), Germany (4), Greece (1), Hungary (3), Israel (3), Italy (3), Japan (5), Republic of Korea (1), Netherlands (2), Portugal (4), Romania (2), Russia (6), Sweden (1), Turkey (1), United Kingdom (3), United States (8).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 53.3 Years STANDARD_DEVIATION 9.55 |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 31 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 220 Participants |
| Sex: Female, Male Female | 41 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 41 | 0 / 44 | 1 / 42 | 0 / 44 | 0 / 50 | 0 / 44 | 1 / 50 |
| other Total, other adverse events | 18 / 43 | 28 / 41 | 33 / 44 | 34 / 42 | 34 / 44 | 27 / 50 | 32 / 44 | 41 / 50 |
| serious Total, serious adverse events | 1 / 43 | 4 / 41 | 6 / 44 | 6 / 42 | 6 / 44 | 2 / 50 | 5 / 44 | 6 / 50 |
Outcome results
None listed