Sjogren's Syndrome
Conditions
Brief summary
The primary objective of this study is to assess the efficacy of filgotinib, lanraplenib, and tirabrutinib in adults with active Sjogren's Syndrome (SjS).
Interventions
DRUGLanraplenib
1 x 30 mg tablet administered orally once daily
DRUGFilgotinib
1 x 200 mg tablet administered orally once daily
DRUGTirabrutinib
1 x 40 mg tablet administered orally once daily
1 x tablet administered orally once daily
1 x tablet administered orally once daily
DRUGTirabrutinib placebo
1 x tablet administered orally once daily
Sponsors
Galapagos NV
Ono Pharmaceutical Co. Ltd
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Diagnosed with primary or secondary SjS according to the 2002 American European Consensus Group (AECG) classification * Active SjS as defined by an European League Against Rheumatism (EULAR) Sjogren's syndrome disease activity index (ESSDAI) ≥ 5 * Seropositivity for antibodies to SjS-associated antigens A and/or B (anti-SSA or anti-SSB) Key
Exclusion criteria
* Concurrent treatment with any biologic disease modifying antirheumatic drug (bDMARD) (prior bDMARD treatment allowed with appropriate washout as per study protocol) Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline | Week 12 | Response was defined as: Improvement ≥ 20% in ≥ 3 of 5 participant-reported Sjogren's syndrome (SjS) related visual analogue score (VAS) measures (participant's assessment of global disease, pain, oral dryness, ocular dryness and fatigue), with no increase defined as \> 30 mm from baseline (Day 1) in any of the above 5 VAS measures, AND either ≥ 20% improvement in high sensitivity C-reactive protein (hsCRP) (if hsCRP ≥ 1.5 x upper limit of normal \[ULN\] on Day 1) or no increase in hsCRP to ≥ 1.5 x ULN (if hsCRP \< 1.5 x ULN on Day 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 | Baseline; Week 12 | The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement. |
| Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 | Baseline; Week 12 | The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement. |
| Change From Baseline in ESSDAI at Week 24 | Baseline; Week 24 | The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement. |
| Change From Baseline in ESSPRI at Week 24 | Baseline; Week 24 | The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement. |
Countries
Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States and Europe. The first participant was screened on 01 May 2017. The last study visit occurred on 02 October 2019.
Pre-assignment details
348 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Lanraplenib Lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for up to 49.4 weeks. | 37 |
| Filgotinib Filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet) orally once daily for up to 50.4 weeks. | 38 |
| Tirabrutinib Tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet) orally once daily for up to 50.3 weeks. | 39 |
| Placebo Participants received filgotinib placebo + lanraplenib placebo + tirabrutinib placebo tablets orally once daily for 24 weeks. At Week 24 Visit, participants were rerandomized 1:1:1, in a blinded fashion and received either of the three experimental study drugs orally once daily through Week 48:
* lanraplenib (1 x 30 mg tablet) + filgotinib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet)
* filgotinib (1 x 200 mg tablet) + lanraplenib placebo (1 x tablet) + tirabrutinib placebo (1 x tablet)
* tirabrutinib (1 x 40 mg tablet) + filgotinib placebo (1 x tablet) + lanraplenib placebo (1 x tablet) | 36 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Placebo Arm Re-Randomized | Withdrew Consent | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Randomized Treatment Period | Adverse Event | 5 | 2 | 1 | 0 | 0 | 0 | 0 |
| Randomized Treatment Period | Investigator's Discretion | 2 | 1 | 0 | 0 | 0 | 0 | 0 |
| Randomized Treatment Period | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Randomized Treatment Period | Protocol Violation | 0 | 1 | 1 | 1 | 0 | 0 | 0 |
| Randomized Treatment Period | Randomized but Didn't Receive Study Drug | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
| Randomized Treatment Period | Withdrew Consent | 4 | 5 | 3 | 3 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Filgotinib | Tirabrutinib | Lanraplenib | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 52.2 years STANDARD_DEVIATION 10.54 | 55.8 years STANDARD_DEVIATION 10.06 | 56.2 years STANDARD_DEVIATION 9.72 | 53.2 years STANDARD_DEVIATION 10.28 | 54.4 years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 6 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 38 Participants | 31 Participants | 30 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| EULAR Sjogren's syndrome patient reported index (ESSPRI) | 6.3 Score on a scale STANDARD_DEVIATION 2.31 | 5.9 Score on a scale STANDARD_DEVIATION 2.39 | 6.6 Score on a scale STANDARD_DEVIATION 1.9 | 5.9 Score on a scale STANDARD_DEVIATION 2.24 | 6.2 Score on a scale STANDARD_DEVIATION 2.22 |
| European League Against Rheumatism (EULAR) Sjogren's syndrome disease activity index (ESSDAI) | 10.2 Score on a scale STANDARD_DEVIATION 6.23 | 10.4 Score on a scale STANDARD_DEVIATION 5.36 | 10.5 Score on a scale STANDARD_DEVIATION 4.89 | 9.3 Score on a scale STANDARD_DEVIATION 3.96 | 10.1 Score on a scale STANDARD_DEVIATION 5.16 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 4 Participants | 5 Participants | 5 Participants | 19 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 32 Participants | 34 Participants | 31 Participants | 30 Participants | 127 Participants |
| Region of Enrollment Poland | 4 participants | 5 participants | 7 participants | 6 participants | 22 participants |
| Region of Enrollment Spain | 4 participants | 3 participants | 2 participants | 4 participants | 13 participants |
| Region of Enrollment United Kingdom | 3 participants | 1 participants | 2 participants | 3 participants | 9 participants |
| Region of Enrollment United States | 27 participants | 30 participants | 26 participants | 23 participants | 106 participants |
| Sex: Female, Male Female | 38 Participants | 37 Participants | 36 Participants | 35 Participants | 146 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 38 | 0 / 39 | 0 / 10 | 0 / 12 | 0 / 10 | 0 / 36 |
| other Total, other adverse events | 30 / 37 | 31 / 38 | 32 / 39 | 10 / 10 | 10 / 12 | 7 / 10 | 23 / 36 |
| serious Total, serious adverse events | 3 / 37 | 5 / 38 | 1 / 39 | 0 / 10 | 1 / 12 | 0 / 10 | 2 / 36 |
Outcome results
Primary
Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline
Response was defined as: Improvement ≥ 20% in ≥ 3 of 5 participant-reported Sjogren's syndrome (SjS) related visual analogue score (VAS) measures (participant's assessment of global disease, pain, oral dryness, ocular dryness and fatigue), with no increase defined as \> 30 mm from baseline (Day 1) in any of the above 5 VAS measures, AND either ≥ 20% improvement in high sensitivity C-reactive protein (hsCRP) (if hsCRP ≥ 1.5 x upper limit of normal \[ULN\] on Day 1) or no increase in hsCRP to ≥ 1.5 x ULN (if hsCRP \< 1.5 x ULN on Day 1).
Time frame: Week 12
Population: The Full Analysis Set included all randomized participants who received at least one dose of study drug. Included participants with available data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lanraplenib | Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline | 42.9 percentage of participants |
| Filgotinib | Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline | 43.2 percentage of participants |
| Tirabrutinib | Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline | 35.1 percentage of participants |
| Placebo | Percentage of Participants Fulfilling Protocol-Specified Response Criteria at Week 12, as Compared to Baseline | 26.5 percentage of participants |
p-value: 0.159795% CI: [-6.3, 37.6]Cochran-Mantel-Haenszel
p-value: 0.169495% CI: [-5.1, 38.3]Cochran-Mantel-Haenszel
p-value: 0.330995% CI: [-13.2, 29.4]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in ESSDAI at Week 24
The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement.
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanraplenib | Change From Baseline in ESSDAI at Week 24 | -4.3 score on a scale | Standard Error 0.81 |
| Filgotinib | Change From Baseline in ESSDAI at Week 24 | -5.4 score on a scale | Standard Error 0.75 |
| Tirabrutinib | Change From Baseline in ESSDAI at Week 24 | -4.0 score on a scale | Standard Error 0.75 |
| Placebo | Change From Baseline in ESSDAI at Week 24 | -4.2 score on a scale | Standard Error 0.78 |
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.956495% CI: [-2.2, 2.1]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.278895% CI: [-3.3, 0.9]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.804795% CI: [-1.8, 2.3]MMRM
Secondary
Change From Baseline in ESSPRI at Week 24
The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement.
Time frame: Baseline; Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanraplenib | Change From Baseline in ESSPRI at Week 24 | -1.1 score on a scale | Standard Error 0.34 |
| Filgotinib | Change From Baseline in ESSPRI at Week 24 | -0.8 score on a scale | Standard Error 0.31 |
| Tirabrutinib | Change From Baseline in ESSPRI at Week 24 | -1.2 score on a scale | Standard Error 0.31 |
| Placebo | Change From Baseline in ESSPRI at Week 24 | -0.9 score on a scale | Standard Error 0.33 |
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.678295% CI: [-1.1, 0.7]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.917195% CI: [-0.8, 0.9]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.464195% CI: [-1.2, 0.5]MMRM
Secondary
Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12
The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain is scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A negative change from baseline value indicates improvement.
Time frame: Baseline; Week 12
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanraplenib | Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 | -1.0 score on a scale | Standard Error 0.34 |
| Filgotinib | Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 | -1.4 score on a scale | Standard Error 0.33 |
| Tirabrutinib | Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 | -1.4 score on a scale | Standard Error 0.33 |
| Placebo | Change From Baseline in EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) at Week 12 | -1.0 score on a scale | Standard Error 0.34 |
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.944695% CI: [-0.9, 1]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.397795% CI: [-1.3, 0.5]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.496695% CI: [-1.2, 0.6]MMRM
Secondary
Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12
The ESSDAI is a physician-administered tool designed to measure disease activity. It consists of 12 organ-specific 'domains' contributing to disease activity associated with the participant's Sjogren's Syndrome only (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system, central nervous system, hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. Overall score (ranges from 0 (no activity) to 123 (worst activity)) is calculated as sum of all individual weighted domain scores. A negative change from baseline value indicates improvement.
Time frame: Baseline; Week 12
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lanraplenib | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 | -2.5 score on a scale | Standard Error 0.76 |
| Filgotinib | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 | -4.7 score on a scale | Standard Error 0.72 |
| Tirabrutinib | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 | -3.2 score on a scale | Standard Error 0.73 |
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) at Week 12 | -3.9 score on a scale | Standard Error 0.76 |
Comparison: Least Squares (LS) Means, 95% confidence interval (CI), and P-values were obtained from Mixed Effects Model for Repeated Measures (MMRM) with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.206695% CI: [-0.7, 3.4]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.399895% CI: [-2.9, 1.2]MMRM
Comparison: LS Means, 95% CI, and P-values were obtained from MMRM with the terms for baseline value, treatment, stratification factors, visit, and treatment-by-visit interaction.p-value: 0.511395% CI: [-1.4, 2.7]MMRM