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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT04035668
Registration number
NCT04035668
Ethics application status
Date submitted
8/07/2019
Date registered
29/07/2019
Date last updated
30/01/2023
Titles & IDs
Public title
A Phase 2 Study to Evaluate the Safety and Efficacy of LOU064 in Patients With Moderate to Severe Sjögren's Syndrome
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Scientific title
An Adaptive Phase 2 Randomized Double-blind, Placebo-controlled Multi-center Study to Evaluate the Safety and Efficacy of Multiple LOU064 Doses in Patients With Moderate to Severe Sjögren's Syndrome (LOUiSSe)
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Secondary ID [1]
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2018-004387-54
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Secondary ID [2]
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CLOU064E12201
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Universal Trial Number (UTN)
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Trial acronym
LOUiSSe
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Sjögren Syndrome
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Condition category
Condition code
Inflammatory and Immune System
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Rheumatoid arthritis
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Musculoskeletal
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Other muscular and skeletal disorders
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Inflammatory and Immune System
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Autoimmune diseases
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Remibrutinib
Treatment: Drugs - Placebo
Experimental: Remibrutinib 100 mg bid - Remibrutinib 100 mg twice daily (bid)
Experimental: Remibrutinib 100 mg qd - Remibrutinib 100 mg once daily (qd)
Placebo Comparator: Placebo - Placebo group
Treatment: Drugs: Remibrutinib
Remibrutinib 100 mg was administered orally as two 50 mg hard gelatin capsules. Patients in the remibrutinib 100 mg bid dose group took 2 capsules of active medication in the morning and 2 capsules of active medication in the evening. Patients in the remibrutinib 100 mg qd dose group took 2 capsules of active medication in the morning and 2 capsules of the placebo in the evening.
Treatment: Drugs: Placebo
Placebo was administered orally as two hard gelatin capsules. Patients in the placebo dose group took 2 capsules of placebo in the morning and 2 capsules of placebo in the evening.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Change From Baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) Total Score at Week 24
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Assessment method [1]
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ESSDAI is a validated disease outcome measure for Sjögren's Syndrome. The instrument contains 12 organ-specific domains contributing to disease activity: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological and biological. For each domain, features of disease activity were scored according to their severity. These scores were summed across the 12 domains in a weighted manner to provide the total score. ESSDAI total score ranges from 0 to 123 with higher values indicating more disease activity. A negative change from baseline indicates improvement.
The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment.
A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSDAI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
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Timepoint [1]
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Baseline, Week 24
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Secondary outcome [1]
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Change From Baseline in ESSDAI Total Score Over Time
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Assessment method [1]
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ESSDAI is a validated disease outcome measure for Sjögren's Syndrome. The instrument contains 12 organ-specific domains contributing to disease activity: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological and biological. For each domain, features of disease activity were scored according to their severity. These scores were summed across the 12 domains in a weighted manner to provide the total score. ESSDAI total score ranges from 0 to 123 with higher values indicating more disease activity. A negative change from baseline indicates improvement.
The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment.
A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSDAI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
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Timepoint [1]
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Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20
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Secondary outcome [2]
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Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Total Score Over Time
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Assessment method [2]
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ESSPRI is an established disease outcome measure for Sjögren's Syndrome. It consists of three domains of dryness, pain, and fatigue. The patient can assess the severity of symptoms they experience on a single 0-10 numerical scale for each of the three domains. The ESSPRI score is defined as the mean of scores from the three scales: (dryness + pain +fatigue) /3. ESSPRI total score ranges from 0 to 10 with higher values indicating more disease symptoms. A negative change from baseline indicates improvement.
The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment.
A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSPRI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
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Timepoint [2]
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Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
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Secondary outcome [3]
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Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Total Score Over Time
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Assessment method [3]
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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 past week. The level of fatigue was measured on a 5-point Likert scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). FACIT-F total score ranges from 0 to 52 with higher values indicating higher quality of life (less fatigue). A positive change from baseline is a favorable outcome.
The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment.
A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in FACIT-F for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
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Timepoint [3]
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Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
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Secondary outcome [4]
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Change From Baseline in EuroQual 5 Dimensions (EQ-5D) VAS Score Over Time
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Assessment method [4]
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EQ-5D is a standardized instrument that measures the health-related quality of life. The EQ-5D consists of a descriptive system and a visual analog scale (VAS).The EQ-5D VAS records the patient's self-rated health on a vertical visual analogue scale with 0 representing 'Worst imaginable Health State' and 100 'Best imaginable Health State'. A positive change from baseline is a favorable outcome.
The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment.
A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in EQ-5D VAS score for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
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Timepoint [4]
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Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
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Secondary outcome [5]
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Change From Baseline in Physician Global Assessment Scale (PhGA) Score Over Time
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Assessment method [5]
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The physician's global assessment scale was used for the Investigator to rate the disease activity of their patient using 100 mm visual analog scale (VAS) ranging from "no disease activity" (0) to "maximal disease activity" (100). A negative change from baseline indicates improvement.
The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment.
A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in PhGA score for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
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Timepoint [5]
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Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
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Secondary outcome [6]
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Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
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Assessment method [6]
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Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as TEAEs. TEAEs are defined as adverse events that started after the first dose of study medications or adverse events present prior to start of double-blind treatment but increased in severity.
The number of participants in each category is reported in the table.
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Timepoint [6]
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From first dose of study treatment up 30 days after last dose (Week 29)
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Secondary outcome [7]
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Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 4
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Assessment method [7]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Cmax is defined as the maximum (peak) observed blood concentration following a dose.
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Timepoint [7]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
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Secondary outcome [8]
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Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 24
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Assessment method [8]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Cmax is defined as the maximum (peak) observed blood concentration following a dose.
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Timepoint [8]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
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Secondary outcome [9]
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Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 4
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Assessment method [9]
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Remibrutinib was determined in whole blood by a validated LC-MS/MS method with a LLOQ of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Tmax is defined as the time to reach maximum (peak) blood concentration following a dose.
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Timepoint [9]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
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Secondary outcome [10]
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Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 24
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Assessment method [10]
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Remibrutinib was determined in whole blood by a validated LC-MS/MS method with a LLOQ of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Tmax is defined as the time to reach maximum (peak) blood concentration following a dose.
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Timepoint [10]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
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Secondary outcome [11]
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Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 4
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Assessment method [11]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUCtau is defined as the area under the blood concentration-time curve calculated/extrapolated to the end of a dosing interval (tau) at steady-state. Tau was 24 hours for the qd dosing group and 12 hours for the bid dosing group. For the calculation of AUCtau, the pre-dose concentrations at Week 4 and Week 24 were duplicated as 24 hours and 12 hours concentrations for the qd and bid groups, respectively. The linear trapezoidal method was used for AUCtau calculation.
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Timepoint [11]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
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Secondary outcome [12]
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Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 24
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Assessment method [12]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUCtau is defined as the area under the blood concentration-time curve calculated/extrapolated to the end of a dosing interval (tau) at steady-state. Tau was 24 hours for the qd dosing group and 12 hours for the bid dosing group. For the calculation of AUCtau, the pre-dose concentrations at Week 4 and Week 24 were duplicated as 24 hours and 12 hours concentrations for the qd and bid groups, respectively. The linear trapezoidal method was used for AUCtau calculation.
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Timepoint [12]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
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Secondary outcome [13]
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Area Under the Blood Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4h) of Remibrutinib at Week 4
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Assessment method [13]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUC0-4h is defined as the area under the blood concentration-time curve from time zero to 4 hours post-dose, which was the last sampling time. The linear trapezoidal method was used for AUC0-4h calculation.
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Timepoint [13]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
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Secondary outcome [14]
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Area Under the Blood Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4h) of Remibrutinib at Week 24
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Assessment method [14]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUC0-4h is defined as the area under the blood concentration-time curve from time zero to 4 hours post-dose, which was the last sampling time. The linear trapezoidal method was used for AUC0-4h calculation.
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Timepoint [14]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
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Secondary outcome [15]
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Elimination Half-life (T1/2) of Remibrutinib at Week 4
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Assessment method [15]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. T1/2 is defined as the time taken for the blood concentration, as well as the amount of the drug in the body, to fall by one-half.
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Timepoint [15]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
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Secondary outcome [16]
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Elimination Half-life (T1/2) of Remibrutinib at Week 24
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Assessment method [16]
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Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. T1/2 is defined as the time taken for the blood concentration, as well as the amount of the drug in the body, to fall by one-half.
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Timepoint [16]
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pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
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Eligibility
Key inclusion criteria
- Diagnosis of SjS according to the 2016 ACR/EULAR criteria
- Screening ESSDAI (based on weighted score) = 5 derived from 8 domains
- Screening ESSPRI = 5
- Seropositive for anti-Ro/SSA antibodies at or within 3 months prior to screening
- Unstimulated salivary flow > 0 mL/min.
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Minimum age
18
Years
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Maximum age
75
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Sjögren's Syndrome overlap syndromes with another autoimmune disease as primary
illness
- DMARDs or kinase inhibitors within 3 months prior to baseline above certain doses OR
maintained during study
- Rituximab or other B cell depleting drug within 12 months of Screening .
- Current use of prednisone or equivalent > 15mg/d or dose change within 2 weeks prior
to Screening
- Use of medication known to cause, as a major side effect, dry mouth / eyes
- HIV, Hepatitis C, Hepatitis B, known or suspected history of an ongoing, chronic or
recurrent infectious disease such as tuberculosis
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Study design
Purpose of the study
Other
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
12/07/2019
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
23/11/2021
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Sample size
Target
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Accrual to date
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Final
73
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Recruitment in Australia
Recruitment state(s)
SA,TAS,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - Woodville
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Recruitment hospital [2]
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Novartis Investigative Site - Hobart
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Recruitment hospital [3]
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Novartis Investigative Site - Clayton
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Recruitment postcode(s) [1]
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5011 - Woodville
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Recruitment postcode(s) [2]
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7000 - Hobart
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Recruitment postcode(s) [3]
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3168 - Clayton
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Recruitment outside Australia
Country [1]
0
0
United States of America
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State/province [1]
0
0
Massachusetts
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Country [2]
0
0
Belgium
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State/province [2]
0
0
Gent
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Country [3]
0
0
Bulgaria
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State/province [3]
0
0
Sofia
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Country [4]
0
0
China
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State/province [4]
0
0
Anhui
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Country [5]
0
0
China
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State/province [5]
0
0
Jiangsu
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Country [6]
0
0
China
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State/province [6]
0
0
Sichuan
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Country [7]
0
0
Denmark
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State/province [7]
0
0
Glostrup
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Country [8]
0
0
Germany
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State/province [8]
0
0
Berlin
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Country [9]
0
0
Hungary
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State/province [9]
0
0
Debrecen
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Country [10]
0
0
Spain
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State/province [10]
0
0
Barcelona
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Country [11]
0
0
Spain
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State/province [11]
0
0
Comunidad Valenciana
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Country [12]
0
0
Spain
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State/province [12]
0
0
Pontevedra
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Country [13]
0
0
Spain
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State/province [13]
0
0
Madrid
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Country [14]
0
0
Switzerland
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State/province [14]
0
0
Basel
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Country [15]
0
0
Switzerland
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State/province [15]
0
0
Lausanne
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Country [16]
0
0
Taiwan
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State/province [16]
0
0
Taiwan ROC
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Country [17]
0
0
Taiwan
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State/province [17]
0
0
Kaohsiung
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Country [18]
0
0
Taiwan
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State/province [18]
0
0
Taichung
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Country [19]
0
0
United Kingdom
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State/province [19]
0
0
Liverpool
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Country [20]
0
0
United Kingdom
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State/province [20]
0
0
Swindon
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Country [21]
0
0
United Kingdom
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State/province [21]
0
0
Tyne And Wear
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This was an adaptive design phase 2 study to establish safety and efficacy; and to
characterize the dose-response of LOU064 in subjects with moderate to severe Sjögren's
syndrome. LOU064 is an oral Bruton's tyrosine kinase (BTK) inhibitor.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT04035668
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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0
Novartis Pharmaceuticals
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Address
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0
Novartis Pharmaceuticals
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Country
0
0
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Phone
0
0
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Fax
0
0
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Email
0
0
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Contact person for public queries
Name
0
0
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Address
0
0
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Country
0
0
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Phone
0
0
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Fax
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0
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Email
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0
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT04035668
Download to PDF