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NCT04035668: LOUiSSe

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

Terminated Phase 2 Results posted Last updated 30 January 2023
What this trial tests

Phase 2 trial testing Remibrutinib in Sjögren Syndrome in 73 participants. Terminated before completion.

Timeline
12 July 2019
Primary endpoint
23 November 2021
23 November 2021

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingtriple
Primary purposeother
Enrollment73
Start date12 July 2019
Primary completion23 November 2021
Estimated completion23 November 2021
Sites26 locations across Denmark, Belgium, Taiwan, United Kingdom, Germany, Hungary, Switzerland, Bulgaria

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 18 to 75, any sex, with Sjögren Syndrome. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) Total Score at Week 24 Primary · 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 activ

GroupValue95% CI
Remibrutinib 100 mg qd-4.70± 0.78
Remibrutinib 100 mg Bid-3.70± 0.80
Any Remibrutinib-4.20± 0.56
Placebo-1.34± 0.74
Change From Baseline in ESSDAI Total Score Over Time Secondary · 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 activ

Week 2
GroupValue95% CI
Remibrutinib 100 mg qd-1.68± 0.52
Remibrutinib 100 mg Bid-1.05± 0.52
Any Remibrutinib-1.37± 0.37
Placebo-0.37± 0.55
Week 4
GroupValue95% CI
Remibrutinib 100 mg qd-2.57± 0.60
Remibrutinib 100 mg Bid-2.54± 0.62
Any Remibrutinib-2.55± 0.43
Placebo-0.79± 0.61
Week 8
GroupValue95% CI
Remibrutinib 100 mg qd-2.74± 0.72
Remibrutinib 100 mg Bid-2.93± 0.71
Any Remibrutinib-2.83± 0.51
Placebo-2.36± 0.69
Week 12
GroupValue95% CI
Remibrutinib 100 mg qd-3.66± 0.74
Remibrutinib 100 mg Bid-2.56± 0.75
Any Remibrutinib-3.11± 0.53
Placebo-1.92± 0.73
Week 16
GroupValue95% CI
Remibrutinib 100 mg qd-4.02± 0.71
Remibrutinib 100 mg Bid-2.57± 0.74
Any Remibrutinib-3.29± 0.51
Placebo-2.16± 0.69
Week 20
GroupValue95% CI
Remibrutinib 100 mg qd-4.40± 0.73
Remibrutinib 100 mg Bid-3.26± 0.75
Any Remibrutinib-3.83± 0.52
Placebo-1.84± 0.69
Change From Baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) Total Score Over Time Secondary · 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 o

Week 2
GroupValue95% CI
Remibrutinib 100 mg qd-0.44± 0.26
Remibrutinib 100 mg Bid0.18± 0.26
Any Remibrutinib-0.13± 0.18
Placebo-0.09± 0.27
Week 4
GroupValue95% CI
Remibrutinib 100 mg qd-0.72± 0.30
Remibrutinib 100 mg Bid-0.14± 0.30
Any Remibrutinib-0.43± 0.21
Placebo-0.35± 0.30
Week 8
GroupValue95% CI
Remibrutinib 100 mg qd-0.83± 0.31
Remibrutinib 100 mg Bid-0.38± 0.31
Any Remibrutinib-0.60± 0.22
Placebo-0.57± 0.29
Week 12
GroupValue95% CI
Remibrutinib 100 mg qd-0.88± 0.31
Remibrutinib 100 mg Bid-0.32± 0.31
Any Remibrutinib-0.60± 0.22
Placebo-0.66± 0.29
Week 16
GroupValue95% CI
Remibrutinib 100 mg qd-0.77± 0.36
Remibrutinib 100 mg Bid-0.39± 0.37
Any Remibrutinib-0.58± 0.26
Placebo-0.71± 0.34
Week 20
GroupValue95% CI
Remibrutinib 100 mg qd-0.92± 0.38
Remibrutinib 100 mg Bid-0.74± 0.39
Any Remibrutinib-0.83± 0.27
Placebo-0.92± 0.36
Week 24
GroupValue95% CI
Remibrutinib 100 mg qd-1.17± 0.34
Remibrutinib 100 mg Bid-0.76± 0.35
Any Remibrutinib-0.96± 0.24
Placebo-1.13± 0.31
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Total Score Over Time Secondary · 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

Week 2
GroupValue95% CI
Remibrutinib 100 mg qd1.80± 1.32
Remibrutinib 100 mg Bid-0.51± 1.35
Any Remibrutinib0.64± 0.95
Placebo3.37± 1.43
Week 4
GroupValue95% CI
Remibrutinib 100 mg qd4.83± 1.50
Remibrutinib 100 mg Bid3.97± 1.57
Any Remibrutinib4.40± 1.09
Placebo3.51± 1.58
Week 8
GroupValue95% CI
Remibrutinib 100 mg qd4.00± 1.64
Remibrutinib 100 mg Bid3.79± 1.66
Any Remibrutinib3.90± 1.17
Placebo5.26± 1.60
Week 12
GroupValue95% CI
Remibrutinib 100 mg qd4.88± 1.80
Remibrutinib 100 mg Bid4.25± 1.86
Any Remibrutinib4.56± 1.30
Placebo7.30± 1.77
Week 16
GroupValue95% CI
Remibrutinib 100 mg qd4.40± 1.97
Remibrutinib 100 mg Bid3.29± 2.08
Any Remibrutinib3.84± 1.44
Placebo7.73± 1.98
Week 20
GroupValue95% CI
Remibrutinib 100 mg qd10.01± 2.20
Remibrutinib 100 mg Bid4.32± 2.30
Any Remibrutinib7.16± 1.60
Placebo5.77± 2.17
Week 24
GroupValue95% CI
Remibrutinib 100 mg qd8.17± 2.45
Remibrutinib 100 mg Bid4.64± 2.55
Any Remibrutinib6.40± 1.77
Placebo7.45± 2.32
Change From Baseline in EuroQual 5 Dimensions (EQ-5D) VAS Score Over Time Secondary · 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 cha

Week 2
GroupValue95% CI
Remibrutinib 100 mg qd-3.05± 3.11
Remibrutinib 100 mg Bid-2.86± 3.16
Any Remibrutinib-2.95± 2.22
Placebo-3.02± 3.28
Week 4
GroupValue95% CI
Remibrutinib 100 mg qd-1.74± 2.71
Remibrutinib 100 mg Bid-0.03± 2.86
Any Remibrutinib-0.88± 1.97
Placebo2.99± 2.87
Week 8
GroupValue95% CI
Remibrutinib 100 mg qd1.46± 3.20
Remibrutinib 100 mg Bid1.76± 3.20
Any Remibrutinib1.61± 2.26
Placebo3.44± 3.04
Week 12
GroupValue95% CI
Remibrutinib 100 mg qd-2.36± 2.71
Remibrutinib 100 mg Bid1.58± 2.82
Any Remibrutinib-0.39± 1.95
Placebo4.00± 2.64
Week 16
GroupValue95% CI
Remibrutinib 100 mg qd-0.44± 3.27
Remibrutinib 100 mg Bid4.27± 3.54
Any Remibrutinib1.92± 2.41
Placebo1.79± 3.28
Week 20
GroupValue95% CI
Remibrutinib 100 mg qd-0.91± 3.15
Remibrutinib 100 mg Bid5.37± 3.33
Any Remibrutinib2.23± 2.29
Placebo5.29± 3.01
Week 24
GroupValue95% CI
Remibrutinib 100 mg qd1.81± 3.47
Remibrutinib 100 mg Bid5.73± 3.65
Any Remibrutinib3.77± 2.52
Placebo2.07± 3.22
Change From Baseline in Physician Global Assessment Scale (PhGA) Score Over Time Secondary · 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 mode

Week 2
GroupValue95% CI
Remibrutinib 100 mg qd-4.21± 2.90
Remibrutinib 100 mg Bid-4.02± 2.85
Any Remibrutinib-4.12± 2.04
Placebo-4.82± 3.10
Week 4
GroupValue95% CI
Remibrutinib 100 mg qd-9.58± 2.89
Remibrutinib 100 mg Bid-8.93± 2.96
Any Remibrutinib-9.26± 2.08
Placebo-7.28± 2.95
Week 8
GroupValue95% CI
Remibrutinib 100 mg qd-13.68± 3.39
Remibrutinib 100 mg Bid-13.78± 3.28
Any Remibrutinib-13.73± 2.37
Placebo-13.23± 3.16
Week 12
GroupValue95% CI
Remibrutinib 100 mg qd-13.85± 3.63
Remibrutinib 100 mg Bid-9.45± 3.68
Any Remibrutinib-11.65± 2.60
Placebo-17.67± 3.52
Week 16
GroupValue95% CI
Remibrutinib 100 mg qd-19.37± 3.61
Remibrutinib 100 mg Bid-7.25± 3.74
Any Remibrutinib-13.31± 2.61
Placebo-15.90± 3.51
Week 20
GroupValue95% CI
Remibrutinib 100 mg qd-23.56± 3.43
Remibrutinib 100 mg Bid-17.31± 3.48
Any Remibrutinib-20.43± 2.45
Placebo-17.57± 3.20
Week 24
GroupValue95% CI
Remibrutinib 100 mg qd-21.25± 3.88
Remibrutinib 100 mg Bid-13.15± 3.95
Any Remibrutinib-17.20± 2.78
Placebo-20.15± 3.54
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs Secondary · 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.

TEAE
GroupValue95% CI
Remibrutinib 100 mg Bid22
Remibrutinib 100 mg qd21
Placebo20
Study drug-related TEAE
GroupValue95% CI
Remibrutinib 100 mg Bid10
Remibrutinib 100 mg qd8
Placebo9
Serious TEAE
GroupValue95% CI
Remibrutinib 100 mg Bid1
Remibrutinib 100 mg qd1
Placebo1
Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 4 Secondary · 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.

GroupValue95% CI
Remibrutinib 100 mg Bid183± 82.5
Remibrutinib 100 mg qd225± 154
Maximum Observed Blood Concentration (Cmax) of Remibrutinib at Week 24 Secondary · 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.

GroupValue95% CI
Remibrutinib 100 mg Bid224± 202
Remibrutinib 100 mg qd169± 77.9
Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 4 Secondary · 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.

GroupValue95% CI
Remibrutinib 100 mg Bid1.000.500 – 3.00
Remibrutinib 100 mg qd1.000.500 – 4.00
Time to Reach Maximum Observed Blood Concentration (Tmax) of Remibrutinib at Week 24 Secondary · 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.

GroupValue95% CI
Remibrutinib 100 mg Bid1.000.500 – 3.00
Remibrutinib 100 mg qd1.000.500 – 3.08
Area Under the Blood Concentration-time Curve Within a Dosing Interval (Tau) at Steady-state (AUCtau) of Remibrutinib at Week 4 Secondary · 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 wa

GroupValue95% CI
Remibrutinib 100 mg Bid569± 311
Remibrutinib 100 mg qd1020± 700

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study treatment up 30 days after last dose (Week 29). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Remibrutinib 100 mg Bid
Serious: 1/24 (4%)
Deaths: 0/24
Remibrutinib 100 mg qd
Serious: 1/25 (4%)
Deaths: 0/25
Any Remibrutinib
Serious: 2/49 (4%)
Deaths: 0/49
Placebo
Serious: 1/24 (4%)
Deaths: 0/24
Total
Serious: 3/73 (4%)
Deaths: 0/73

Serious adverse events (3 terms)

ReactionSystemRemibrutinib 100 mg BidRemibrutinib 100 mg qdAny RemibrutinibPlaceboTotal
COVID-19 pneumoniaInfections and infestations
Herpes zosterInfections and infestations
PneumoniaInfections and infestations
Other adverse events (24 terms — click to expand)

ReactionSystemRemibrutinib 100 mg BidRemibrutinib 100 mg qdAny RemibrutinibPlaceboTotal
HeadacheNervous system disorders
NauseaGastrointestinal disorders
NasopharyngitisInfections and infestations
FatigueGeneral disorders
Upper respiratory tract infectionInfections and infestations
NeutropeniaBlood and lymphatic system disorders
Abdominal painGastrointestinal disorders
Urinary tract infectionInfections and infestations
ArthralgiaMusculoskeletal and connective tissue disorders
Back painMusculoskeletal and connective tissue disorders
LeukopeniaBlood and lymphatic system disorders
LymphopeniaBlood and lymphatic system disorders
DiarrhoeaGastrointestinal disorders
AstheniaGeneral disorders
White blood cell count decreasedInvestigations
MyalgiaMusculoskeletal and connective tissue disorders
Abdominal distensionGastrointestinal disorders
SinusitisInfections and infestations
FallInjury, poisoning and procedural complications
Blood immunoglobulin G increasedInvestigations
HypokalaemiaMetabolism and nutrition disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
Sjogren's syndromeMusculoskeletal and connective tissue disorders
PetechiaeSkin and subcutaneous tissue disorders

Most-reported serious reactions: COVID-19 pneumonia, Herpes zoster, Pneumonia.

Data from ClinicalTrials.gov NCT04035668 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Small Molecule NF-κB Pathway Inhibitors in Clinic.
    Ramadass V, Vaiyapuri T, Tergaonkar V. · · 2020 · cited 154× · PMID 32708302 · DOI 10.3390/ijms21145164
  2. Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy.
    Parisis D, Chivasso C, Perret J, Soyfoo MS, et al · · 2020 · cited 114× · PMID 32698400 · DOI 10.3390/jcm9072299
  3. Bruton's Tyrosine Kinase (BTK) Inhibitors and Autoimmune Diseases: Making Sense of BTK Inhibitor Specificity Profiles and Recent Clinical Trial Successes and Failures.
    Ringheim GE, Wampole M, Oberoi K. · · 2021 · cited 100× · PMID 34803999 · DOI 10.3389/fimmu.2021.662223
  4. Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial.
    Kaul M, End P, Cabanski M, Schuhler C, et al · · 2021 · cited 59× · PMID 33834628 · DOI 10.1111/cts.13005
  5. Targeting Bruton's Tyrosine Kinase in Inflammatory and Autoimmune Pathologies.
    Neys SFH, Hendriks RW, Corneth OBJ. · · 2021 · cited 53× · PMID 34150760 · DOI 10.3389/fcell.2021.668131
  6. Bruton's Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives.
    Robak E, Robak T. · · 2022 · cited 45× · PMID 35628931 · DOI 10.3390/jcm11102807
  7. Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases.
    Zhang D, Gong H, Meng F. · · 2021 · cited 45× · PMID 34443496 · DOI 10.3390/molecules26164907
  8. Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease.
    Neys SFH, Rip J, Hendriks RW, Corneth OBJ. · · 2021 · cited 41× · PMID 34609725 · DOI 10.1007/s40265-021-01592-0

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