A Phase 2 Study to Evaluate the Safety and Efficacy of LOU064 in Patients With Moderate to Severe Sjögren's Syndrome (LOUiSSe)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Sjögren Syndrome
• Intervention / Treatment: Drug: Remibrutinib; Drug: Placebo

Detailed Description

This study was planned as an adaptive Phase 2 randomized, double-blind, placebo-controlled, multi-center, integrated dose-ranging study to evaluate the safety and efficacy of multiple remibrutinib doses in patients with moderate to severe Sjögren's Syndrome.

Of the initially planned two parts, only Part 1 of the study was conducted. In Part 1, the highest expected biologically active single dose of remibrutinib (100 mg) was tested in two different dosing regimens, a once daily dose (qd) or twice daily dose (bid), and compared to the placebo group. Each patient in Part 1 of the study underwent a screening period of up to 6 weeks, a treatment period of 24 weeks, and a follow-up period of 30 days post-treatment before the End of Study (EOS) visit. The total duration for each patient in the study, including Screening, was up to 35 weeks. For the treatment period, patients were randomized in a 1:1:1 ratio to one of the 3 treatment groups: remibrutinib 100 mg bid, remibrutinib 100 mg qd and placebo.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Woodville, South Australia, Australia, 5011
      • Novartis Investigative Site
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Novartis Investigative Site
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
• Belgium
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Bulgaria
  • Sofia, Bulgaria, 1612
    • Novartis Investigative Site
• China
  • Anhui
    • Hefei, Anhui, China, 230001
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210008
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
• Denmark
  • Glostrup, Denmark, 2600
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 10117
    • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Barcelona
    • Sabadell, Barcelona, Spain, 08208
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46010
      • Novartis Investigative Site
  • Pontevedra
    • Vigo, Pontevedra, Spain, 36200
      • Novartis Investigative Site
• Switzerland
  • Basel, Switzerland, 4031
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1011
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 81346
    • Novartis Investigative Site
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Taichung, Taiwan, 40705
    • Novartis Investigative Site
  • Taiwan ROC
    • Taichung, Taiwan ROC, Taiwan, 40201
      • Novartis Investigative Site
• United Kingdom
  • Liverpool, United Kingdom, L9 7AL
    • Novartis Investigative Site
  • Swindon, United Kingdom, SN3 6BB
    • Novartis Investigative Site
  • Tyne And Wear, United Kingdom, NE29 8NH
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo group	Drug: 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.
Experimental: Remibrutinib 100 mg bid; Remibrutinib 100 mg twice daily (bid)	Drug: 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.; Other Names: LOU064
Experimental: Remibrutinib 100 mg qd; Remibrutinib 100 mg once daily (qd)	Drug: 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.; Other Names: LOU064; Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) Total Score at Week 24	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.	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in ESSDAI Total Score Over Time	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.	Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20
Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Total Score Over Time	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.	Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Total Score Over Time	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.	Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
Change From Baseline in EuroQual 5 Dimensions (EQ-5D) VAS Score Over Time	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.	Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
Change From Baseline in Physician Global Assessment Scale (PhGA) Score Over Time	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.	Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	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.	From first dose of study treatment up 30 days after last dose (Week 29)
Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 4	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 24	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 4	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 24	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 4	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 24	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
Area Under the Blood Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4h) of Remibrutinib at Week 4	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
Area Under the Blood Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4h) of Remibrutinib at Week 24	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
Elimination Half-life (T1/2) of Remibrutinib at Week 4	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
Elimination Half-life (T1/2) of Remibrutinib at Week 24	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.	pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2019
• Primary Completion (Actual): November 23, 2021
• Study Completion (Actual): November 23, 2021

Study Registration Dates

• First Submitted: July 8, 2019
• First Submitted That Met QC Criteria: July 24, 2019
• First Posted (Actual): July 29, 2019

Study Record Updates

• Last Update Posted (Estimate): January 30, 2023
• Last Update Submitted That Met QC Criteria: January 27, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Arthritis; Immune System Diseases; Eye Diseases; Connective Tissue Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Xerostomia; Dry Eye Syndromes; Stomatognathic Diseases; Lacrimal Apparatus Diseases; Sjogren Syndrome; remibrutinib; LOU064; Mouth Diseases; Pathological Processes; Salivary Gland Diseases
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Eye Diseases; Disease; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Stomatognathic Diseases; Mouth Diseases; Lacrimal Apparatus Diseases; Arthritis, Rheumatoid; Xerostomia; Salivary Gland Diseases; Dry Eye Syndromes; Syndrome; Sjogren's Syndrome
• Other Study ID Numbers: CLOU064E12201; 2018-004387-54 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No