Sjogren's Syndrome
Conditions
Keywords
Sjogren's Syndrome, autoimmune, ESSDAI, ESSPRI, anti-CD40, CFZ533, iscalimab, TWINSS Extension
Brief summary
This study will evaluate the safety and tolerability of iscalimab at two dose levels in patients with Sjögren's Syndrome, who participated in the TWINSS core study, CCFZ533B2201 (NCT03905525). Additionally, this Extension study will further explore the pharmacokinetics (PK) and efficacy of iscalimab at two dose level.
Detailed description
This study was a continuation of the TWINSS core study CCFZ533B2201 (NCT03905525) that offered continuation of treatment for participants who completed the core study and were deemed by the Investigator to clinically benefit from continued iscalimab therapy based upon response to therapy at the end of the treatment period of the core study. The extension study was a 48-week treatment study, with a safety follow-up period of 12 weeks, to provide additional safety and tolerability information for iscalimab.At Week 60 of the TWINSS core study, eligible participants had the option to enroll in the extension study. Participants were classified as treatment responders or non-responder based on their European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) and EULAR Sjögren's syndrome patient reported index (ESSPRI) scores from predefined time points in the core study. In the extension study, participants were reassigned to either iscalimab 600 mg or 300 mg subcutaneously via prefilled syringes (PFS) based on their responder status and the iscalimab doses that they received in the core study All participants enrolled in the extension study received a weekly loading regimen at the start of the treatment period for the initial 3 weeks, followed by a subcutaneous maintenance regimen (600 or 300 mg subcutaneously every 2 weeks). Injections were performed at site or at home by site staff or participant/caregiver. Study blinding for the extension study was maintained until final database lock of the core study, upon which the participants and Investigators were unblinded, making it an open-label study through Week 120 (end of study visit).
Interventions
DRUGIscalimab
Iscalimab 600 mg or 300 mg was administered subcutaneously weekly for the first 3 weeks. Subsequently, iscalimab was administered subcutaneously bi-weekly (every other week or Q2W).
OTHERPlacebo
Placebo (1 injection of 2 ml) administered to participants in the iscalimab 300 mg arm to maintain blinding until the final database lock of the core study
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study was conducted as a double-blind treatment until the final database lock of the Core study (NCT03905525). During this period, participants, Investigator, site staff, and persons performing the assessments remained blinded to the identity of the treatment until the final database lock of Core study (NCT03905525)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Participants had to have participated in the TWINSS core study, CCFZ533B2201 (NCT03905525), and had to have completed the entire treatment period up to Week 48 and the follow-up period up to Week 60. 2. Signed informed consent had to be obtained prior to participation in the Extension study (i.e., before commencement of the Week 60 assessments of the core study). 3. In the judgment of the Investigator, participants had to be expected to clinically benefit from continued iscalimab therapy.
Exclusion criteria
1. Sjögren's Syndrome overlap syndromes where another autoimmune rheumatic disease constituted the principle illness, specifically: * Moderate-to-severe active systemic lupus erythematosus (SLE) with anti-dsDNA positivity and renal involvement, or other organ involvement that impeded on the ability to score ESSDAI domains * Active rheumatoid arthritis (RA) that impeded on the ability to score the ESSDAI articular domain * Systemic sclerosis * Any other concurrent connective tissue disease (e.g., lupus nephritis (LN), large vessel vasculitis (LVV), Sharp syndrome (mixed connective tissue disease) that was active and required immunosuppressive treatment outside the scope of this trial and would impede on Sjögren's Syndrome organ domain assessments 2. Use of other investigational drugs other than iscalimab during the core study 3. Active uncontrolled viral, bacterial or other infections requiring systemic treatment at the time of enrollment, or history of recurrent clinically significant infection or of bacterial infections with encapsulated organisms 4. Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human Chorionic Gonadotropin (hCG) laboratory test 5. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during dosing and for 14 weeks after stopping the investigational drug. 6. Missing ESSDAI (Cohort 1 and Cohort 2) or ESSPRI (Cohort 2) scores in the core study at Weeks 0 and 4 or Weeks 40 and 48.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From start of extension study up to 14 weeks after last study-drug administration or end of study (whichever occurred earlier), assessed up to approximately 60 weeks | An AE was defined as any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant. TEAE included all AEs up to the last dose date plus 14 weeks or the end of the entire study (including the safety follow-up period), whichever occurred earlier. A patient with multiple severity ratings for an AE was only counted under the maximum rating. Additionally, a patient with multiple occurrences of an event was counted only once. The severity of AEs was assessed using the Common Terminology Criteria for Adverse Events, with the following grading system: Mild: usually transient in nature and generally not interfering with normal activities; Moderate: sufficiently discomforting to interfere with normal activities; Severe: prevented normal activities. A serious adverse event (SAE) was defined as any AE that required medical intervention, hospitalization, or results in death, disability, or a birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Free Iscalimab Concentration in Plasma | Predose at Day 1, 113, 225, 337 and 421 | Free iscalimab concentration in plasma during the treatment (Ctrough) and follow-up (up to end of study) periods. Blood sample was collected at the specified timepoints to assess the concentration of free iscalimab. The baseline assessment of this extension study (Day 1) was identical to the last timepoint (FUP3/Week 60) of the core study (CCFZ533B2201). |
| Incidence of Anti-iscalimab Antibodies in Plasma | 60 weeks | Number of participants with anti-iscalimab antibodies (ADA) in plasma at any time during the study. The baseline assessment of this extension study (Day 1) was identical to the last timepoint (FUP3/Week 60) of the core study (CCFZ533B2201). |
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
Participant flow
Recruitment details
Participants who completed the core study (CCFZ533B2201, NCT03905525) and were deemed by the Investigator to clinically benefit from continued iscalimab therapy based upon response to therapy at the end of the treatment period of the core study were enrolled in this study
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Iscalimab 600 mg Participants received 600 mg (2 injections of 300 mg/2 mL) of iscalimab subcutaneously weekly for the initial 3 weeks as loading doses, followed by a bi-weekly maintenance regimen at 600 mg (2 injections of 300 mg/2 mL). | 152 |
| Arm 2 - Iscalimab 300 mg Participants received one dose of 600 mg (2 injections of 300 mg/2 mL) of iscalimab subcutaneously on the first day of the extension study; then 300 mg weekly (1 injection of 300 mg/2 mL of iscalimab and 1 injection of 2 mL of placebo) for the next 2 weeks as loading doses. This was followed by a bi-weekly maintenance regimen of 300 mg (1 injection of 300 mg/2 mL of iscalimab and 1 injection of 2 mL of placebo). After the final database lock of the core study, participants underwent unblinding, leading to the discontinuation of placebo injections. | 54 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Safety Follow-up Period | Adverse Event | 2 | 1 |
| Safety Follow-up Period | Physician Decision | 1 | 0 |
| Safety Follow-up Period | Subject decision | 5 | 3 |
| Safety Follow-up Period | Withdrawal by Subject | 1 | 1 |
| Treatment Period | Adverse Event | 8 | 2 |
| Treatment Period | Physician Decision | 3 | 1 |
| Treatment Period | Subject decision | 7 | 4 |
| Treatment Period | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 1: Iscalimab 600 mg | Arm 2 - Iscalimab 300 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 9 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 126 Participants | 45 Participants | 171 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 16 Participants | 6 Participants | 22 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 2 Participants | 7 Participants |
| Race/Ethnicity, Customized Unknown | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 125 Participants | 45 Participants | 170 Participants |
| Sex: Female, Male Female | 148 Participants | 53 Participants | 201 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 152 | 0 / 54 |
| other Total, other adverse events | 102 / 152 | 38 / 54 |
| serious Total, serious adverse events | 13 / 152 | 2 / 54 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence (e.g., any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a participant. TEAE included all AEs up to the last dose date plus 14 weeks or the end of the entire study (including the safety follow-up period), whichever occurred earlier. A patient with multiple severity ratings for an AE was only counted under the maximum rating. Additionally, a patient with multiple occurrences of an event was counted only once. The severity of AEs was assessed using the Common Terminology Criteria for Adverse Events, with the following grading system: Mild: usually transient in nature and generally not interfering with normal activities; Moderate: sufficiently discomforting to interfere with normal activities; Severe: prevented normal activities. A serious adverse event (SAE) was defined as any AE that required medical intervention, hospitalization, or results in death, disability, or a birth defect.
Time frame: From start of extension study up to 14 weeks after last study-drug administration or end of study (whichever occurred earlier), assessed up to approximately 60 weeks
Population: The Safety Set (SAF) included all participants who received at least one dose of study treatment. Participants were analyzed according to the actual treatment received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event- Mild | 57 Participants |
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event- Severe | 8 Participants |
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse event (all severities) | 127 Participants |
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious Adverse Event | 13 Participants |
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event- Moderate | 62 Participants |
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event leading to study medication discontinuation | 8 Participants |
| Arm 1: Iscalimab 600 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event leading to study medication discontinuation | 2 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Death | 0 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse event (all severities) | 43 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event- Mild | 24 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event- Moderate | 17 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Adverse Event- Severe | 2 Participants |
| Arm 2 - Iscalimab 300 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious Adverse Event | 2 Participants |
Secondary
Free Iscalimab Concentration in Plasma
Free iscalimab concentration in plasma during the treatment (Ctrough) and follow-up (up to end of study) periods. Blood sample was collected at the specified timepoints to assess the concentration of free iscalimab. The baseline assessment of this extension study (Day 1) was identical to the last timepoint (FUP3/Week 60) of the core study (CCFZ533B2201).
Time frame: Predose at Day 1, 113, 225, 337 and 421
Population: The pharmacokinetic set (PKS) included all participants who received at least one dose of iscalimab treatment and had quantifiable PK measurements of iscalimab. Number analysed refers to the number of participants with a quantifiable PK measurement at the specified time point
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: Iscalimab 600 mg | Free Iscalimab Concentration in Plasma | Day 113 | 125 microgram / mililiter | Geometric Coefficient of Variation 62.7 |
| Arm 1: Iscalimab 600 mg | Free Iscalimab Concentration in Plasma | Day 337 | 138 microgram / mililiter | Geometric Coefficient of Variation 69.3 |
| Arm 1: Iscalimab 600 mg | Free Iscalimab Concentration in Plasma | Day 225 | 126 microgram / mililiter | Geometric Coefficient of Variation 104.7 |
| Arm 1: Iscalimab 600 mg | Free Iscalimab Concentration in Plasma | Day 421 | 4.47 microgram / mililiter | Geometric Coefficient of Variation 533.7 |
| Arm 1: Iscalimab 600 mg | Free Iscalimab Concentration in Plasma | Day 1 | 3.56 microgram / mililiter | Geometric Coefficient of Variation 372.2 |
| Arm 2 - Iscalimab 300 mg | Free Iscalimab Concentration in Plasma | Day 421 | 350.4 microgram / mililiter | Geometric Coefficient of Variation 0.336 |
| Arm 2 - Iscalimab 300 mg | Free Iscalimab Concentration in Plasma | Day 1 | 451.8 microgram / mililiter | Geometric Coefficient of Variation 0.751 |
| Arm 2 - Iscalimab 300 mg | Free Iscalimab Concentration in Plasma | Day 113 | 56.9 microgram / mililiter | Geometric Coefficient of Variation 54 |
| Arm 2 - Iscalimab 300 mg | Free Iscalimab Concentration in Plasma | Day 225 | 50.3 microgram / mililiter | Geometric Coefficient of Variation 57 |
| Arm 2 - Iscalimab 300 mg | Free Iscalimab Concentration in Plasma | Day 337 | 62.6 microgram / mililiter | Geometric Coefficient of Variation 63.3 |
Secondary
Incidence of Anti-iscalimab Antibodies in Plasma
Number of participants with anti-iscalimab antibodies (ADA) in plasma at any time during the study. The baseline assessment of this extension study (Day 1) was identical to the last timepoint (FUP3/Week 60) of the core study (CCFZ533B2201).
Time frame: 60 weeks
Population: The immunogenicity Set (IMS) included all subjects who received at least one dose of iscalimab treatment and had quantifiable immunogenicity measurements of iscalimab.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1: Iscalimab 600 mg | Incidence of Anti-iscalimab Antibodies in Plasma | 1 Participants |
| Arm 2 - Iscalimab 300 mg | Incidence of Anti-iscalimab Antibodies in Plasma | 2 Participants |