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

• ClinicalTrials.gov Identifier: NCT04035668
• Recruitment Status: Terminated
• First Posted: July 29, 2019
• Results First Posted: December 20, 2022
• Last Update Posted: January 30, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Sjögren Syndrome	Drug: Remibrutinib; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official 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)
• Actual Study Start Date: July 12, 2019
• Actual Primary Completion Date: November 23, 2021
• Actual Study Completion Date: November 23, 2021

Arms and Interventions

Arm	Intervention/treatment
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 Name: 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 Name: 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.
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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Change From Baseline in ESSDAI Total Score Over Time [ Time Frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20 ]

   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.

2. Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Total Score Over Time [ Time Frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24 ]

   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.

3. Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Total Score Over Time [ Time Frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24 ]

   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.

4. Change From Baseline in EuroQual 5 Dimensions (EQ-5D) VAS Score Over Time [ Time Frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24 ]

   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.

5. Change From Baseline in Physician Global Assessment Scale (PhGA) Score Over Time [ Time Frame: Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24 ]

   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.

6. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: From first dose of study treatment up 30 days after last dose (Week 29) ]

   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.

7. Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 4 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
8. Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 24 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
9. Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 4 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
10. Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 24 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
11. Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 4 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
12. Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 24 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
13. Area Under the Blood Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4h) of Remibrutinib at Week 4 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
14. Area Under the Blood Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4h) of Remibrutinib at Week 24 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
15. Elimination Half-life (T1/2) of Remibrutinib at Week 4 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.
16. Elimination Half-life (T1/2) of Remibrutinib at Week 24 [ Time Frame: pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose 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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Novartis Investigative Site

Boston, Massachusetts, United States, 02111

Australia, South Australia

Novartis Investigative Site

Woodville, South Australia, Australia, 5011

Australia, Tasmania

Novartis Investigative Site

Hobart, Tasmania, Australia, 7000

Australia, Victoria

Novartis Investigative Site

Clayton, Victoria, Australia, 3168

Belgium

Novartis Investigative Site

Gent, Belgium, 9000

Bulgaria

Novartis Investigative Site

Sofia, Bulgaria, 1612

China, Anhui

Novartis Investigative Site

Hefei, Anhui, China, 230001

China, Jiangsu

Novartis Investigative Site

Nanjing, Jiangsu, China, 210008

China, Sichuan

Novartis Investigative Site

Chengdu, Sichuan, China, 610041

Denmark

Novartis Investigative Site

Glostrup, Denmark, 2600

Germany

Novartis Investigative Site

Berlin, Germany, 10117

Hungary

Novartis Investigative Site

Debrecen, Hungary, 4032

Spain

Novartis Investigative Site

Sabadell, Barcelona, Spain, 08208

Novartis Investigative Site

Valencia, Comunidad Valenciana, Spain, 46010

Novartis Investigative Site

Vigo, Pontevedra, Spain, 36200

Novartis Investigative Site

Barcelona, Spain, 08041

Novartis Investigative Site

Madrid, Spain, 28041

Switzerland

Novartis Investigative Site

Basel, Switzerland, 4031

Novartis Investigative Site

Lausanne, Switzerland, 1011

Taiwan

Novartis Investigative Site

Taichung, Taiwan ROC, Taiwan, 40201

Novartis Investigative Site

Kaohsiung, Taiwan, 81346

Novartis Investigative Site

Taichung, Taiwan, 40447

Novartis Investigative Site

Taichung, Taiwan, 40705

United Kingdom

Novartis Investigative Site

Liverpool, United Kingdom, L9 7AL

Novartis Investigative Site

Swindon, United Kingdom, SN3 6BB

Novartis Investigative Site

Tyne And Wear, United Kingdom, NE29 8NH

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):

Study Protocol  [PDF] February 12, 2021

Statistical Analysis Plan  [PDF] February 2, 2022

More Information

Additional Information:

A Plain Language Trial Summary is available on novctrd.com 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04035668
• Other Study ID Numbers: CLOU064E12201; 2018-004387-54 ( EudraCT Number )
• First Posted: July 29, 2019
• Results First Posted: December 20, 2022
• Last Update Posted: January 30, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

LOU064; remibrutinib; Sjogren Syndrome; Dry Eye Syndromes; Pathological Processes; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Xerostomia; Salivary Gland Diseases; Mouth Diseases; Stomatognathic Diseases; Lacrimal Apparatus Diseases; Eye Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Additional relevant MeSH terms:

Sjogren's Syndrome; Syndrome; Disease; Pathologic Processes; Arthritis, Rheumatoid; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Xerostomia; Salivary Gland Diseases; Mouth Diseases; Stomatognathic Diseases; Dry Eye Syndromes; Lacrimal Apparatus Diseases; Eye Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Remibrutinib; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action