Primary Sjögren Syndrome
Conditions
Keywords
Primary Sjögren Syndrome, Sjögren Syndrome, Autoimmune Diseases, Rheumatic Diseases, Sicca Syndrome
Brief summary
This is a first exploration of GLPG3970 in participants with active primary Sjogren's Syndrome (pSS) to evaluate the efficacy, safety and tolerability and to determine its pharmacokinetics (PK) profile compared to placebo.
Interventions
DRUGGLPG3970
GLPG3970 film-coated tablet.
DRUGPlacebo
Placebo film-coated tablet.
Sponsors
Galapagos NV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Documented diagnosis of pSS for \<10 years prior to screening AND defined by the classification criteria \>=4 described by the American College of Rheumatology - European League Against Rheumatism (ACR-EULAR). 2. Participant has an ESSDAI score \>=5 assessed on 7 domains: constitutional, lymphadenopathy, glandular, articular, cutaneous, hematological, and biological. 3. Participant has an ESSPRI score \>=5. 4. Participant has stimulated whole salivary flow rate of \>=0.1 milliliter per minute (mL/min). 5. Participant has positive serum titers of anti-Sjögren's-syndrome-related antigen A (anti-SS-A)/Ro and/or anti-SS-B/La antibodies. 6. Participants already on treatment should be on stable standard of care (SoC) for at least 4 weeks prior to first investigational product (IP) dosing. The following SoC medications are permitted: * Corticosteroids \<=7.5 mg/day (prednisone or equivalent); AND/OR * Non-steroidal anti-inflammatory drugs (NSAIDs); AND/OR * One single antimalarial at a stable dose (hydroxychloroquine \<=400 mg/day; quinacrine 100 mg/kg/day, or chloroquine \<=250 mg/day); AND/OR * One single immunosuppressant at a stable dose (methotrexate \[MTX\] \<=10 mg/week or azathioprine \[AZA\] \<=2 mg/kg/day); AND/OR * One single cholinergic stimulant at a stable dose (e.g., pilocarpine, cevimeline). 7. Female participant of childbearing potential must have a negative highly sensitive (serum beta human chorionic gonadotropin or urine dipstick) pregnancy test. 8. Female participant of childbearing potential or male participant must agree to use highly effective contraception/preventive exposure measures. Key
Exclusion criteria
1. Secondary Sjögren's syndrome according to the ACR-EULAR (2016) classification. 2. History or presence of unstable condition not related to Sjögren's Syndrome that, in the opinion of the investigator, could constitute an unacceptable risk when taking the IP or interfere with the interpretation of data. 3. Participant has any active systemic infection within 2 weeks prior to first IP dosing, or poorly controlled chronic cardiac, pulmonary, or renal disease. 4. Participant has a known or suspected history of or a current immunosuppressive condition, or a history of opportunistic infections (e.g., human immunodeficiency virus \[HIV\] infection, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis). 5. Participant has a chronic hepatitis B virus (HBV) infection, as defined by persistent HBV surface antigen (HBsAg) positivity. Participant has hepatitis C virus (HCV) infection, as defined by positive HCV antibody at screening and detectable HCV viremia. Participants with positive HCV antibody must undergo reflex HCV ribonucleic acid (RNA) testing, and participants with HCV RNA positivity will be excluded. Participants with positive HCV antibody and negative HCV RNA are eligible. 6. Participant testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as detected at screening based on real time polymerase chain reaction (RT-PCR) or at baseline based on immunoglobulin M (IgM) immunoassay, or participants who have been in contact with SARS-CoV-2 infected individuals in the 2 weeks prior to first dosing of IP. Participants presenting any signs or symptoms of SARS-CoV-2 infection, as detected prior to first IP dosing following careful physical examination (e.g., cough, fever, headaches, fatigue, dyspnea, myalgia, anosmia, dysgeusia, anorexia, sore throat, etc). In addition, any other locally applicable standard diagnostic criteria may also apply to rule out SARS-CoV-2 infection. 7. Participant has taken any disallowed therapies: * Mycophenolate mofetil (MMF) within a week prior to screening. * Cyclosporine/Tacrolimus within a week prior to screening. * Cyclophosphamide within 6 months prior to screening. * Ocular medicines (e.g., topical cyclosporine, topical NSAIDs/ corticosteroids) for at least 4 weeks prior to screening, except for a sporadic use. * Biologics such as, but not limited to, rituximab, abatacept, and any other unapproved biologic within 6 months prior to screening. * Plasmapheresis within 12 weeks prior to screening. * Plasma exchange within 12 weeks prior to screening. * Intravenous immunoglobulin (IVIG) therapy within 24 weeks prior to screening. * Other prohibited medications within 2 weeks or 5 half-lives, whichever is longer, prior to first IP dosing. 8. Concurrent use of anticholinergic agents or any other medication known to cause dry mouth/dry eyes that, in the opinion of the investigator, are a contributing factor to the participant's dryness and/or use of anticholinergic agents not contributing to this dryness, if not stable at least 4 weeks prior to screening. 9. Participant has a history of tuberculosis (TB) diagnosis or evidence of active or latent infection with Mycobacterium tuberculosis. 10. Participant has a history of lymphoma or any malignancy within the past 5 years prior to screening with the exception of excised and curatively treated non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of cervix which is considered cured with minimal risk of recurrence. 11. Participant has severe organ manifestation or life-threatening condition, or has planned a surgery during the study. Note: Other protocol-defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) Score at Week 12 | Baseline, Week 12 | The ESSDAI is a systemic disease activity index to assess 12 domains (organ systems: constitutional, lymphadenopathy and lymphoma, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, CNS, hematological, biological) in participants with pSS. Each of the domains was assessed for activity level (no, low, moderate, and high). Each domain score was obtained by multiplying the activity level with the domain weight, ranged from 1 to 6, and assigned a numerical score based on pre-determined weighting of each individual domain. The sum of all individual weighted domain scores was the overall score, ranged from 0 (best) to 123 (worst activity). A higher score indicated more disease activity. A clinically meaningful reduction from baseline (≥3 points) indicated the improvement of symptoms. Least squares (LS) mean was calculated using mixed models for repeated measures (MMRM). |
| Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | From first dose of study drug up to 30 days after last dose of study drug (maximum duration=16 weeks) | An adverse event (AE) was any untoward medical occurrence in a participant administered study drug and which did not necessarily have a causal relationship with study drug. The severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE) current version at the time of assessment. The maximum intensity of the AE were Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). A TEAE was any AE with an onset date on or after the first dose of GLPG3970 and no later than 30 days after last dose of GLPG3970, or any worsening of any AE on or after the GLPG3970 start date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Baseline, Weeks 4, 8, and 12 | The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain was scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score was calculated as the mean of the 3 individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A higher score indicates worst symptom. A clinically significant reduction from baseline of the ESSPRI score (at least one point or 15% of the baseline value) indicated the improvement of symptoms. |
| Change From Baseline in ESSDAI Score at Weeks 4, 8, and 12 | Baseline, Weeks 4, 8, and 12 | The ESSDAI is a systemic disease activity index to assess 12 domains (organ systems: constitutional, lymphadenopathy and lymphoma, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, CNS, hematological, biological) in participants with pSS. Each of the domains was assessed for activity level (no, low, moderate, and high). Each domain score was obtained by multiplying the activity level with the domain weight, ranged from 1 to 6, and assigned a numerical score based on pre-determined weighting of each individual domain. The sum of all individual weighted domain scores was the overall score, ranged from 0 (best) to 123 (worst activity). A higher score indicated more disease activity. A clinically meaningful reduction from baseline (≥3 points) indicated the improvement of symptoms. Results of Week 12 is presented in primary outcome measure 1. |
| Observed Pre-dose Plasma Concentration (Ctrough) of GLPG3970 | Pre-dose (within 30 minutes prior to dosing) on Weeks 1, 4, 8, and 12 | Plasma concentration of GLPG3970 observed at pre-dose in nanogram per milliliter (ng/mL), obtained directly from the observed concentration versus time data. |
Countries
Germany, Greece, Hungary, Poland, Ukraine
Participant flow
Recruitment details
Participants were enrolled at 10 clinical study sites across 5 countries (1 in Germany, 1 in Greece, 1 in Hungary, 6 in Poland, and 1 in Ukraine).
Pre-assignment details
A total of 69 participants were screened. Of these, 31 participants were randomized and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| GLPG3970 Participants received GLPG3970 400 mg (2 \*200 mg tablet), orally, once daily for 12 weeks. | 20 |
| Placebo Participants received placebo matched to GLPG3970 tablet, orally, once daily for 12 weeks. | 11 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Other than specified | 1 | 0 |
| Overall Study | Study terminated by sponsor | 5 | 3 |
Baseline characteristics
| Characteristic | GLPG3970 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants | 10 Participants | 29 Participants |
| ESSDAI Score | 12.5 score on a scale STANDARD_DEVIATION 6.6 | 8.3 score on a scale STANDARD_DEVIATION 2.4 | 11.0 score on a scale STANDARD_DEVIATION 5.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 11 Participants | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 11 Participants | 31 Participants |
| Sex: Female, Male Female | 19 Participants | 10 Participants | 29 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 11 |
| other Total, other adverse events | 10 / 20 | 7 / 11 |
| serious Total, serious adverse events | 2 / 20 | 0 / 11 |
Outcome results
Primary
Change From Baseline in European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) Score at Week 12
The ESSDAI is a systemic disease activity index to assess 12 domains (organ systems: constitutional, lymphadenopathy and lymphoma, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, CNS, hematological, biological) in participants with pSS. Each of the domains was assessed for activity level (no, low, moderate, and high). Each domain score was obtained by multiplying the activity level with the domain weight, ranged from 1 to 6, and assigned a numerical score based on pre-determined weighting of each individual domain. The sum of all individual weighted domain scores was the overall score, ranged from 0 (best) to 123 (worst activity). A higher score indicated more disease activity. A clinically meaningful reduction from baseline (≥3 points) indicated the improvement of symptoms. Least squares (LS) mean was calculated using mixed models for repeated measures (MMRM).
Time frame: Baseline, Week 12
Population: Participants in the full analysis set (FAS: all randomized participants who received at least one dose of study drug) with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GLPG3970 | Change From Baseline in European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) Score at Week 12 | -4.4 score on a scale | Standard Error 1.56 |
| Placebo | Change From Baseline in European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) Score at Week 12 | -3.0 score on a scale | Standard Error 2.03 |
p-value: 0.61790% CI: [-6.2, 3.4]Mixed Models Analysis
Primary
Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity
An adverse event (AE) was any untoward medical occurrence in a participant administered study drug and which did not necessarily have a causal relationship with study drug. The severity of AEs was graded using the Common Terminology Criteria for Adverse Events (CTCAE) current version at the time of assessment. The maximum intensity of the AE were Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). A TEAE was any AE with an onset date on or after the first dose of GLPG3970 and no later than 30 days after last dose of GLPG3970, or any worsening of any AE on or after the GLPG3970 start date.
Time frame: From first dose of study drug up to 30 days after last dose of study drug (maximum duration=16 weeks)
Population: The safety analysis set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GLPG3970 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate | 5 participants |
| GLPG3970 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Life-threatening | 0 participants |
| GLPG3970 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Severe | 3 participants |
| GLPG3970 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Death | 0 participants |
| GLPG3970 | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Mild | 3 participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Death | 0 participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Mild | 4 participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate | 3 participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Severe | 0 participants |
| Placebo | Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) by Severity | Life-threatening | 0 participants |
Secondary
Change From Baseline in ESSDAI Score at Weeks 4, 8, and 12
The ESSDAI is a systemic disease activity index to assess 12 domains (organ systems: constitutional, lymphadenopathy and lymphoma, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, CNS, hematological, biological) in participants with pSS. Each of the domains was assessed for activity level (no, low, moderate, and high). Each domain score was obtained by multiplying the activity level with the domain weight, ranged from 1 to 6, and assigned a numerical score based on pre-determined weighting of each individual domain. The sum of all individual weighted domain scores was the overall score, ranged from 0 (best) to 123 (worst activity). A higher score indicated more disease activity. A clinically meaningful reduction from baseline (≥3 points) indicated the improvement of symptoms. Results of Week 12 is presented in primary outcome measure 1.
Time frame: Baseline, Weeks 4, 8, and 12
Population: Participants in the FAS with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| GLPG3970 | Change From Baseline in ESSDAI Score at Weeks 4, 8, and 12 | Change at Week 4 | -1.7 score on a scale | Standard Error 1.17 |
| GLPG3970 | Change From Baseline in ESSDAI Score at Weeks 4, 8, and 12 | Change at Week 8 | -3.5 score on a scale | Standard Error 1.28 |
| Placebo | Change From Baseline in ESSDAI Score at Weeks 4, 8, and 12 | Change at Week 4 | -1.4 score on a scale | Standard Error 1.32 |
| Placebo | Change From Baseline in ESSDAI Score at Weeks 4, 8, and 12 | Change at Week 8 | -4.0 score on a scale | Standard Error 2.02 |
Comparison: Week 4p-value: 0.85990% CI: [-3.6, 2.9]Mixed Models Analysis
Comparison: Week 8p-value: 0.83790% CI: [-3.8, 4.8]Mixed Models Analysis
Secondary
Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12
The ESSPRI is a participant-reported questionnaire to assess subjective participant symptoms and includes 3 domains (dryness, pain, and fatigue). Each domain was scored on scale of 0-10 (0 = no symptom at all and 10 = worst symptom imaginable), and an overall score was calculated as the mean of the 3 individual domains where all domains carry the same weight. Minimum score can be 0 and maximum score can be 10. A higher score indicates worst symptom. A clinically significant reduction from baseline of the ESSPRI score (at least one point or 15% of the baseline value) indicated the improvement of symptoms.
Time frame: Baseline, Weeks 4, 8, and 12
Population: Participants in the FAS with available data were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| GLPG3970 | Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Change at Week 4 | -1.25 score on a scale | Standard Error 0.37 |
| GLPG3970 | Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Change at Week 8 | -2.05 score on a scale | Standard Error 0.41 |
| GLPG3970 | Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Change at Week 12 | -2.15 score on a scale | Standard Error 0.59 |
| Placebo | Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Change at Week 4 | -0.60 score on a scale | Standard Error 0.49 |
| Placebo | Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Change at Week 8 | -1.28 score on a scale | Standard Error 0.56 |
| Placebo | Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Score at Weeks 4, 8, and 12 | Change at Week 12 | -1.79 score on a scale | Standard Error 0.7 |
Comparison: Week 4p-value: 0.308990% CI: [-1.7, 0.41]Mixed Models Analysis
Comparison: Week 8p-value: 0.283490% CI: [-1.97, 0.43]Mixed Models Analysis
Comparison: Week 12p-value: 0.710990% CI: [-2.02, 1.3]Mixed Models Analysis
Secondary
Observed Pre-dose Plasma Concentration (Ctrough) of GLPG3970
Plasma concentration of GLPG3970 observed at pre-dose in nanogram per milliliter (ng/mL), obtained directly from the observed concentration versus time data.
Time frame: Pre-dose (within 30 minutes prior to dosing) on Weeks 1, 4, 8, and 12
Population: Participants in the pharmacokinetic (PK) analysis set (all randomized participant who received at least 1 dose of study drug and for which plasma concentration data were available) with available data were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| GLPG3970 | Observed Pre-dose Plasma Concentration (Ctrough) of GLPG3970 | Week 1 | 77.6 ng/mL | Geometric Coefficient of Variation 64.7 |
| GLPG3970 | Observed Pre-dose Plasma Concentration (Ctrough) of GLPG3970 | Week 4 | 70.4 ng/mL | Geometric Coefficient of Variation 108 |
| GLPG3970 | Observed Pre-dose Plasma Concentration (Ctrough) of GLPG3970 | Week 8 | 65 ng/mL | Geometric Coefficient of Variation 265 |
| GLPG3970 | Observed Pre-dose Plasma Concentration (Ctrough) of GLPG3970 | Week 12 | 66 ng/mL | Geometric Coefficient of Variation 219 |