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    Clinical Trial Results:
    Phase II Trial of low-dose Sandimmun Optoral ® (Cyclosporine A) for the treatment of primary Sjögren's syndrome (pSS)

    Summary
    EudraCT number
    2009-013976-38
    Trial protocol
    DE  
    Global end of trial date
    11 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    28 May 2022
    First version publication date
    28 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COLO400BDE02T
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01693393
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Charité - University Hospital of Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Dr. Jan Zernicke, Medizinische Klinik m.S. Rheumatologie und Klinische Immunologie - Forschung, +49 030450 513025, jan.zernicke@charite.de
    Scientific contact
    Dr. Jan Zernicke, Medizinische Klinik m.S. Rheumatologie und Klinische Immunologie - Forschung, +49 030450 513025, jan.zernicke@charite.de
    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
    11 Feb 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of efficacy of low-dose Cyclosporine A in patients with primary Sjögren’s Syndrome and joint involvement after 16 week treatment period.
    Protection of trial subjects
    The study was reviewed and approved by the Independent Ethics Committee of Berlin (Landesamt für Gesundheit und Soziales (LaGeSo)) and conducted according to the ethical principles of the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 Dec 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    patients were recruited during a period of symptoms, the observed improvement could also be influenced by the variation of intensity of symptoms

    Pre-assignment
    Screening details
    Key inclusion criteria: a minimum of three tender joints and/or three swollen joints at screening and baseline, normal hematological, renal and liver lab results, stable treatment of Sjögren’s syndrome meaning stable doses of nonsteroidal anti-inflammatory drug and glucocorticoid. 36 Patients screened 6 screening failures 30 Patients randomized

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Cyclosporine A
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Sandimmun Optoral
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment consisted of the intake of low-dose CyA (approximately 2 mg kg−1 body weight day−1 divided in two intakes) over a period of 16 weeks

    Number of subjects in period 1
    Cyclosporine A
    Started
    30
    Completed
    22
    Not completed
    8
         Adverse event, non-fatal
    6
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cyclosporine A
    Reporting group description
    -

    Reporting group values
    Cyclosporine A Total
    Number of subjects
    30 30
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    54.9 (29 to 70) -
    Gender categorical
    Units: Subjects
        Female
    29 29
        Male
    1 1
    Disease duration
    Units: Years
        arithmetic mean (standard deviation)
    6.1 ± 5.7 -
    GC dose
    Current background medication
    Units: milligram(s)
        arithmetic mean (standard deviation)
    5.9 ± 3.8 -

    End points

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    End points reporting groups
    Reporting group title
    Cyclosporine A
    Reporting group description
    -

    Subject analysis set title
    Baseline
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All statistical analyses were performed in the intention to treat (ITT) collective. Twenty-eight (including six patients who dropped out during the study) had an EOT visit. For the two patients who were lost to follow-up (LTFU) after the baseline visit, the last observation carried forward (LOCF) method was used to impute the missing data.

    Primary: Change of the joints (tender/swollen)

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    End point title
    Change of the joints (tender/swollen)
    End point description
    Comparison between Baselin (BL) and end of treatment (EOT); TJC tender joint count, SJC swollen joint count,
    End point type
    Primary
    End point timeframe
    16 Weeks
    End point values
    Cyclosporine A Baseline
    Number of subjects analysed
    30
    30
    Units: Score
    arithmetic mean (standard deviation)
        TJC /28
    6.8 ± 6.9
    10.7 ± 7.3
        TJC /68
    10.4 ± 11.9
    16.2 ± 13.2
        SJC /28
    1.0 ± 2.3
    2.7 ± 2.6
        SJC /66
    1.3 ± 3.2
    3.2 ± 3.3
    Attachments
    Joint count
    Statistical analysis title
    improvement of number of swollen and tender joint
    Statistical analysis description
    All statistical analyses were performed in the intention to treat (ITT) collective. Twenty-eight (including six patients who dropped out during the study) had an EOT visit. For the two patients who were lost to follow-up (LTFU) after the baseline visit, the last observation carried forward (LOCF) method was used to impute the missing data. Figure 1 summarizes the flow of patients.
    Comparison groups
    Cyclosporine A v Baseline
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    ≤ 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Changes of the safety profile in patients

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    End point title
    Changes of the safety profile in patients
    End point description
    DAS28 disease activity score using the 28 joint count, CRP C-reactive Protein, ESR erythrocyte sedimentation rate, ESSDAI EULAR Sjögren’s Syndrome Disease Activity Index, SF36 Short Form with 36 questions, MHD mental health domain, PHD physical health domain, HAQ-DI health assessment questionnaire disability index. For more detailed Secondary Endpoints see attachment
    End point type
    Secondary
    End point timeframe
    16 weeks
    End point values
    Cyclosporine A Baseline
    Number of subjects analysed
    30
    30
    Units: Score
    arithmetic mean (standard deviation)
        DAS28 CRP
    3.4 ± 1.4
    4.2 ± 0.9
        DAS28 ESR
    4.3 ± 1.4
    5.1 ± 1.0
        ESSDAI (0–123)
    3.9 ± 4.2
    5.5 ± 3.3
        ESSDAI articular (0–3)
    1.0 ± 0.96
    2.0 ± 0.53
        Physician’s disease activity (0–100)
    26.0 ± 19.1
    50.4 ± 13.4
        Patient’s disease activity (0–100)
    53.2 ± 27.0
    58.7 ± 21.0
        Pain (0–100)
    52.5 ± 27.9
    63.2 ± 20.9
        Fatigue (0–100)
    32.2 ± 20.5
    28.7 ± 18.3
        SF36 MHD
    42.2 ± 20.5
    39.3 ± 16.4
        SF36 PHD
    33.8 ± 20.2
    27.7 ± 15.1
        SF36 total
    38.1 ± 21.0
    33.9 ± 15.0
        HAQ-DI
    1.2 ± 0.7
    1.3 ± 0.6
    Attachments
    Changes from BL to EOT
    DAS28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks
    Adverse event reporting additional description
    No new or unexpected safety observations were made. Among the 30 patients, all had experienced at least one adverse event (AE). Gastrointestinal disorders were the most common AEs. All AEs were mild or moderate with exception of one serious AE (hypertension).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Cyclosporine A
    Reporting group description
    -

    Serious adverse events
    Cyclosporine A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cyclosporine A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    Vascular disorders
    Congenital cardiovascular disorders
         subjects affected / exposed
    11 / 30 (36.67%)
         occurrences all number
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    overall
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    nonspecific disorders that impact several body systems or sites
         subjects affected / exposed
    12 / 30 (40.00%)
         occurrences all number
    12
    Psychiatric disorders
    overall
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    overall
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Investigations
    clinical laboratory test and radiologic test concept
    Additional description: clinical laboratory test and radiologic test concept
         subjects affected / exposed
    13 / 30 (43.33%)
         occurrences all number
    16
    Respiratory, thoracic and mediastinal disorders
    Pleural infections and inflammations; Upper/ Lower respiratory tract disorders
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Nervous system disorders
    Spinal cord and nerve root disorders Cranial nerve disorders
         subjects affected / exposed
    16 / 30 (53.33%)
         occurrences all number
    23
    Eye disorders
    Ocular infections, irritations and inflammations and Ocular neoplasms
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Ocular infections, irritations and inflammations and Ocular neoplasms
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Gastrointestinal motility and defaecation conditions
         subjects affected / exposed
    21 / 30 (70.00%)
         occurrences all number
    41
    Renal and urinary disorders
    Bladder infections and inflammations/ Bladder reflux condition
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Angioedema and urticaria, Pigmentation disorders
         subjects affected / exposed
    10 / 30 (33.33%)
         occurrences all number
    18
    Musculoskeletal and connective tissue disorders
    Infectious arthritis Bone disorders Muscle disorders
         subjects affected / exposed
    20 / 30 (66.67%)
         occurrences all number
    29
    Metabolism and nutrition disorders
    Purine and pyrimidine metabolism disorders; Inborn errors of metabolism
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Infections and infestations
    Bacterial infectious disorders, fungal infectious disorders, Ectoparasitic disorders
         subjects affected / exposed
    9 / 30 (30.00%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27470087
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