Safety and Efficacy of VAY736 in Patients With Primary Sjogren's Syndrome (pSS)
- Conditions
- Primary Sjogren Syndrome
- Interventions
- Biological: VAY736Other: Placebo
- Registration Number
- NCT02962895
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study was to determine the dose-response relationship of VAY736 for key efficacy and safety parameters
- Detailed Description
This was a randomized, double-blind, placebo-controlled, multicenter, parallel-group trial that was divided into 4 study periods.
Period 1: A screening period of 4 weeks to assess patient eligibility. Patients could be re-screened only once, and no study-related re-screening procedure could be performed prior to written re-consent by the patient.
Period 2: A blinded treatment period of 24 weeks. At baseline, eligible patients were randomized to one of three ianalumab dose arms (VAY736 5 mg, 50 mg or 300 mg s.c.) or a placebo arm (placebo s.c.). Blinded study drug was administered every four weeks (q4w) for a 24-week period.
Except for Japan, randomization was stratified by baseline ESSDAI score (\<10 or ≥10 based on weighted scores). Separate blocks of randomization numbers were generated for patients in Japan versus the other countries participating to ensure that Japanese patients were equally distributed across all treatment groups in the study.
The primary endpoint was assessed at the end of Period 2 (Week 24). Treatment assignment in Period 2 remained double-blinded until the end of Period 3.
Period 3: An extended blinded treatment period of 28 weeks. After Week 24 assessments, patients in the ianalumab 300 mg arm were re-randomized in a 1:1 ratio to either continue on ianalumab 300 mg s.c. q4w or switch to matching placebo up to Week 52. Patients who received placebo during Period 2 were switched to ianalumab 150 mg s.c q4w up to Week 52. Patients who received 5 mg and 50 mg s.c. in Period 2 proceeded directly to safety follow-up (Period 4). Treatment assignment in Period 3 remained double-blinded.
Period 4: A post-treatment safety follow-up period. Patients who prematurely discontinued the study treatment at any time point or completed the treatment as planned entered the safety follow-up period. The minimum required duration of follow-up in the study was 20 weeks from the last administration of the study treatment (mandatory follow-up). The maximum duration of the follow-up was 2 years from the last dose of the study treatment, and it was defined by the level of recovery of CD19+ B-cells: conditional follow up (with reduced visit frequency) until CD19+ B-cell levels return to at least 80% of baseline or 50 cells/µL, whichever occurred first. Patients who had not yet recovered their B-cell counts two years after last ianalumab dosing were discharged from the study and had undergone their End of Study (EoS) visit. Patients who were treated with another immunomodulatory or immunosuppressive treatment (e.g., azathioprine, cyclophosphamide, high dose glucocorticosteroids) after completion of the minimum 20-week safety follow-up period were excluded from further safety follow-up.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 190
- Fulfilled revised American European Consensus Group criteria for pSS
- Seropositive at screening for anti-Ro/SSA antibodies
- Screening ESSDAI value >=6 scored from 7 domains: articular, cutaneous, glandular, lymphoadenopathy, constitutional, biologic and hematologic.
- Secondary Sjogren's syndrome
- Use of other investigational drugs
- Active viral, bacterial or other infections
- Positive hepatitis B, hepatitis C, HIV or tuberculosis test results at screening
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description VAY736 dose 1 - 5mg VAY736 VAY736 low VAY736 dose 2 - 50mg VAY736 VAY736 medium VAY736 dose 3 - 300 mg VAY736 VAY736 high Placebo Placebo Placebo control
- Primary Outcome Measures
Name Time Method Least Squares Mean Change From Baseline in ESSDAI Score at Week 24 Baseline, Week 24 The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) instrument 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 ranging 0-123. Higher scores on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scale are associated with poorer health states. A negative change from baseline indicates improvement in disease status.
- Secondary Outcome Measures
Name Time Method Least Squares Mean Change From Baseline in ESSDAI Score at Weeks 4, 8, 12, and 16 Baseline, Week 4, Week 8, Week 12, Week 16 The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) instrument 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 ranging 0-123. Higher scores on the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scale are associated with poorer health states. A negative change from baseline indicates improvement in disease status.
Least Squares Mean Change From Baseline in ESSPRI Score at Week 24 Baseline, Week 24 The EULAR Sjörgen's Syndrome Patient Reported Index (ESSPRI) is an established disease outcome measure for Sjögren's syndrome that is calculated by averaging the scales for pain, fatigue and dryness. The total score is the mean score of the 3 scales and ranges between 0 and 10 with higher values indicating more severity of symptoms. A negative change from baseline is a favorable outcome.
Least Squares Mean Change From Baseline in ESSPRI Score at Weeks 4, 8, 12 and 16 Baseline, Week 4, Week 8, Week 12, Week 16 The EULAR Sjörgen's Syndrome Patient Reported Index (ESSPRI) is an established disease outcome measure for Sjögren's syndrome that is calculated by averaging the scales for pain, fatigue and dryness. The total score is the mean score of the 3 scales and ranges between 0 and 10 with higher values indicating more severity of symptoms. A negative change from baseline is a favorable outcome.
Least Squares Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F) Score Over 24 Weeks Baseline, Week 24 The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the previous week. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The global score ranges between 0 and 52, with higher scores indicating less fatigue.
Least Squares Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-F) Score at Weeks 4, 8, 12 and 16 Baseline, Weeks 4, 8, 12 and 16 The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the previous week. The level of fatigue is measured on a four-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). The global score ranges between 0 and 52, with higher scores indicating less fatigue.
Least Squares Mean Change From Baseline in 36-Item Short Form Health Survey (SF-36) Physical Component (PCS) and Mental Component (MCS) Over 24 Weeks Baseline, Week 24 The SF36 includes 8 scale scores (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) and two summary scores, the physical and mental component scores. The first four and last four scales comprise physical and mental component scores, respectively. The range of scores of the physical component (PCS) and mental component (MCS) is 0 (lowest or worst possible level of functioning) to 100 (highest or best possible level of functioning).
Least Squares Mean Change From Baseline in 36-Item Short Form Health Survey (SF-36) Physical Component (PCS) and Mental Component (MCS) at Weeks 4, 8, 12 and 16 Baseline, Weeks 4, 8, 12 and 16 The SF36 includes 8 scale scores (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) and two summary scores, the physical and mental component scores. The first four and last four scales comprise physical and mental component scores, respectively. The range of scores of the physical component (PCS) and mental component (MCS) is 0 (lowest or worst possible level of functioning) to 100 (highest or best possible level of functioning).
Least Squares Mean Change From Baseline in Physician's Global Assessment (PhGA) of Patient's Overall Disease Activity Using Patient Visual Analog Scale (VAS) Over 24 Weeks Baseline, 24 weeks Physician global assessment of overall disease activity (PhGA) was performed using a 100 mm visual analogue scale (VAS) ranging from no disease activity (score 0) to maximal disease activity (score 100), after the question "Considering all the ways the disease affects your patient, draw a line on the scale for how well his or her condition is today". A negative change from baseline is a favourable outcome.
Least Squares Mean Change From Baseline in Physician's Global Assessment (PhGA) of Patient's Overall Disease Activity Using Patient Visual Analog Scale (VAS) at Weeks 4, 8, 12 and 16 Baseline, Weeks 4, 8, 12 and 16 Physician global assessment of overall disease activity (PhGA) was performed using a 100 mm visual analogue scale (VAS) ranging from no disease activity (score 0) to maximal disease activity (score 100), after the question "Considering all the ways the disease affects your patient, draw a line on the scale for how well his or her condition is today". A negative change from baseline is a favourable outcome.
Patient's Global Assessment (PaGA) Score at Weeks 4, 8, 12, 16 and 24 Weeks 4, 8, 12, 16 and 24 The PaGA of disease activity was performed using a 100 mm Visual Analog Scale (VAS) ranging from 0 (no disease activity) to 100 (maximal disease activity), in response to the question "Considering all the ways Sjögren's syndrome affects you, please draw a line on the scale to indicate how well you are doing today". A negative change from baseline is a favourable outcome.
Least Squares Mean Change From Baseline in Salivary Flow Rate at Week 24 Baseline, 24 weeks Change from baseline in salivary flow rate (unstimulated and stimulated) at 24 weeks as compared to placebo.
Unstimulated saliva is a mix of serous and mucous secretions coming primarily from the submandibular and minor salivary glands. The parotid gland produces the largest volume of stimulated saliva. Stimulated saliva accounts for 80-90% of daily salivary production.Percent Change From Baseline in Whole Blood CD19+ B-cell Counts. Baseline, Week 24, Week 28 B-cell counts were measured before, during and after treatment with VAY736. After stopping VAY736 treatment they were used to monitor patients for time to recovery of adequate CD19+ B cell counts prior to discharge from the study. Change from baseline in B-cell counts before, during and after treatment with VAY736 as well as the time to recover to baseline like values (defined as at least 80% of baseline counts or \>= 50 cells/μL) were analyzed by descriptive statistics.
Baseline was defined as the last assessment performed on or prior to the date of administration of the first dose of study treatment.Kaplan-Meier Analysis for Time to Recovery to Baseline Like Values for B-cell Counts Up to two years from last dose patient received. B-cell counts were measured before, during and after treatment with VAY736. After stopping VAY736 treatment they were used to monitor patients for time to recovery of adequate CD19+ B cell counts prior to discharge from the study. Change from baseline in B-cell counts before, during and after treatment with VAY736 as well as the time to recover to baseline like values (defined as at least 80% of baseline counts or \>= 50 cells/μL) were analyzed by descriptive statistics.
Baseline was defined as the last assessment performed on or prior to the date of administration of the first dose of study treatment.Peak Serum Concentration of VAY736 baseline to week 24, then week 28 Pharmacokinetic Concentrations
This outcome only applies to patients who received at least one dose of VAY739 (so not applicable to placebo)
Trial Locations
- Locations (10)
Indiana Univ School of Dentistry
🇺🇸Indianapolis, Indiana, United States
The John Hopkins Jerome L Greene Sjogren
🇺🇸Baltimore, Maryland, United States
Tufts School of Dental Medicine
🇺🇸Boston, Massachusetts, United States
AAIR Research Center
🇺🇸Rochester, New York, United States
UPMC
🇺🇸Pittsburgh, Pennsylvania, United States
Advanced Rheumatology and Arthritis Wellness Center
🇺🇸Wexford, Pennsylvania, United States
Baylor College Of Medicine
🇺🇸Houston, Texas, United States
First Outpatient Research Unit
🇺🇸San Antonio, Texas, United States
Integral Rheumatology and Immunology Specialists IRIS
🇺🇸Plantation, Florida, United States
Novartis Investigative Site
🇬🇧Southend, United Kingdom