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    Clinical Trial Results:
    A phase IIa efficacy and safety trial with intravenous S95011 in primary Sjögren’s Syndrome patients. An international, multicentre, randomised, double-blind, placebo-controlled study

    Summary
    EudraCT number
    2020-001526-59
    Trial protocol
    GB   HU   DE  
    Global end of trial date
    02 May 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-95011-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04605978
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier (I.R.I.S.)
    Sponsor organisation address
    50 rue Carnot, Suresnes Cedex, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155 72 43 66, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of multiple intravenous infusions of 750 mg of S95011 compared to placebo after 13 weeks of treatment in reducing disease activity using European League Against Rheumatism (EULAR) Sjögren Syndrome Disease Activity Index (ESSDAI)
    Protection of trial subjects
    The study was conducted in accordance with the protocol and with the following: Consensus ethical principles derived from international guidelines including the Declaration of Helsinki, 1964, as revised in Fortaleza, 2013; Applicable Good Clinical Practice (GCP) guidelines; Applicable laws and regulations. The study was initiated only after the Ethics Committee's approval, in accordance with the local regulations in each of the countries. Patients were to give freely their written informed consent (by signing the main study ICF [or screening ICF]) before the start of the screening process of the study.
    Background therapy
    Those patients who were receiving permitted medications for pSS [oral corticosteroids (prednisone or equivalent), anti-malarials, methotrexate, NSAIDs, artificial tears and artificial saliva/salivary stimulants (e.g. cevimeline, pilocarpine), cyclosporine eye drops and lifitegrast], must be maintained on a stable regimen throughout the treatment period compared to baseline. These treatments are considered “usual” background therapy in the absence of recognized standard of care.
    Evidence for comparator
    Matching placebo
    Actual start date of recruitment
    03 Aug 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 13
    Worldwide total number of subjects
    48
    EEA total number of subjects
    35
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    38
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 19 centers in 7 countries recruited patients.

    Pre-assignment
    Screening details
    The target population is male or female patients suffering from primary Sjögren’s Syndrome with moderate to high activity disease level (ie, systemic manifestations): adults, male or female, diagnosed with primary Sjögren’s Syndrome (pSS based) on 2016 American College of Rheumatology-EULAR criteria who fulfilled inclusion criteria of the study.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This is a double-blind, placebo-controlled study. The appearance and form of S95011 vials and placebo vials as well as the solutions to be administered were similar, in order to protect the blinding with regard to the patients and the investigators. Patients were randomised to S95011 or placebo in an overall 2:1 ratio by Interactive Web Response System (IWRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Experimental S95011
    Arm description
    Subjects randomized to receive S95011 concentrate for solution for infusion. S95011 is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.
    Arm type
    Experimental

    Investigational medicinal product name
    S95011
    Investigational medicinal product code
    S95011
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    S95011 - Dose: 750 mg (2 mL extractable volume vials containing 100 mg of S95011 (50 mg/mL) concentrate for solution for intravenous administration). The administration schedule is one IV infusion every 2 weeks (Q2W) for the first month (W000, W002, W004) and then every 3 weeks (Q3W) until W010 (W007, W010).

    Arm title
    Placebo
    Arm description
    Subjects randomized to receive matching placebo concentrate for solution for infusion. Placebo is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 mL extractable volume matching vials containing concentrate for solution for intravenous administration. The administration schedule is one IV infusion Q2W for the first month (W000, W002, W004) and then Q3W until W010 (W007, W010).

    Number of subjects in period 1
    Experimental S95011 Placebo
    Started
    31
    17
    Completed
    28
    15
    Not completed
    3
    2
         Adverse event, non-fatal
    2
    1
         Withdrawal nonmedical reason
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental S95011
    Reporting group description
    Subjects randomized to receive S95011 concentrate for solution for infusion. S95011 is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to receive matching placebo concentrate for solution for infusion. Placebo is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.

    Reporting group values
    Experimental S95011 Placebo Total
    Number of subjects
    31 17 48
    Age categorical
    Units: Subjects
        18 to 75 years
    31 17 48
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.7 ( 12.6 ) 53.6 ( 12.5 ) -
    Gender categorical
    Units: Subjects
        Female
    26 16 42
        Male
    5 1 6

    End points

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    End points reporting groups
    Reporting group title
    Experimental S95011
    Reporting group description
    Subjects randomized to receive S95011 concentrate for solution for infusion. S95011 is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to receive matching placebo concentrate for solution for infusion. Placebo is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.

    Primary: Change in ESSDAI Total Score from baseline to W013

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    End point title
    Change in ESSDAI Total Score from baseline to W013
    End point description
    Efficacy criterion Eular Sjögren Syndrome Disease Activity index (ESSDAI) is a physician-administered clinical index which has been validated to objectively assess systemic manifestations in Primary Sjögren’s Syndrome patients. Scores range from 0 - 123, with a lower score representing less disease activity. Among 48 patients in the Randomized Set (RS), at least one Intercurrent event (IE) occurred for 5 patients in the S95011 group and 4 in the placebo group. Change in ESSDAI Total Score is computed only on observed values before occurrence of Intercurrent Events, therefore some participant data is missing. Note: Due to the presence of missing data or intercurrent events before W013, the change from baseline to W013 was computed only on observed values, i.e.: 26 and 13 subjects respectively in S95011 and placebo groups.
    End point type
    Primary
    End point timeframe
    From baseline to W013
    End point values
    Experimental S95011 Placebo
    Number of subjects analysed
    31
    17
    Units: unit of score
    median (standard deviation)
        From baseline to W013 (26:13 subjects analyzed)
    -3.77 ( 4.55 )
    -5.54 ( 4.89 )
    Statistical analysis title
    Statistical Analysis: Change in ESSDAI Total Score
    Statistical analysis description
    General Linear Model This analysis was performed on all patients after imputation of missing data following several imputation strategies depending on the reason for missingness (already missing or set as missing post intercurrent event).
    Comparison groups
    Experimental S95011 v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.942
    Method
    General Linear Model
    Parameter type
    Mean difference (net)
    Point estimate
    2.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.61
         upper limit
    5.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.55

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study period from Selection visit to W028.
    Adverse event reporting additional description
    All patients who had taken at least one dose of IMP are included in the Safety Set.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Experimental S95011
    Reporting group description
    Subjects randomized to receive S95011 concentrate for solution for infusion. S95011 is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Subjects randomized to receive matching concentrate for solution for infusion. Placebo is administered by one IV infusion every 2 weeks for the first month and then every 3 weeks until W010.

    Serious adverse events
    Experimental S95011 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 17 (5.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Vascular stent stenosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Herpes zoster
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Experimental S95011 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 31 (77.42%)
    11 / 17 (64.71%)
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    2
    3
    Thermal burn
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    4 / 31 (12.90%)
    0 / 17 (0.00%)
         occurrences all number
    5
    0
    Neutropenia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Dry mouth
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Salivary gland pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Acne
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Skin ulcer
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Sjogren's syndrome
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 31 (16.13%)
    2 / 17 (11.76%)
         occurrences all number
    5
    2
    Parotitis
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Oral herpes
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Cystitis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Onychomycosis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Sialoadenitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2020
    Amendment No. 1: • Implementation of a DSMB who would review the safety data and give recommendations regarding the conduct of the study. Removal of the stopping rules for premature discontinuation and temporary halt, since DSMB recommendations were to be followed instead • Addition of ECG at W010 • Extension of the screening period to 4 weeks • Addition of instructions on premature discontinuation of the study in an investigator site (early site closure) • Modification of the exclusion criteria concerning prior administration of rituximab or other B cell depleting agents eg, VAY736 • Modification of exclusion criterion No. 31 (ongoing medication) • Addition of a paragraph about rescue treatment • Modification of the AEs list leading to premature discontinuation of the IMP • Specification that adjustments and/or interruptions of IMP were not allowed in the study • Modification of the reporting rules regarding the symptoms related to pSS
    24 Mar 2022
    Amendment No. 2: • Update to the exclusion criteria No. 30 to allow rituximab or other B cell depleting agents if the CD19 B cell count was within normal range at randomization (W000) and to specify that prior administration of JAK inhibitors was forbidden • Update of exclusion criterion No. 17 (in case of participation in another clinical study) • Update of exclusion criterion No. 31 adding medications known to cause dry mouth/eyes • Update of the oversight of a physician on safety data collected on e-CRF

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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