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    Clinical Trial Results:
    ENSAYO CLÍNICO ALEATORIZADO Y CONTROLADO PARA EVALUAR LA EFICACIA DE LA AZATIOPRINA VS. MICOFENOLATO SÓDICO PARA EL TRATAMIENTO DE LA FASE DE INDUCCIÓN Y MANTENIMIENTO DE LA REMISIÓN DE LOS BROTES EXTRA RENALES DEL LUPUS ERITEMATOSO SISTÉMICO.

    Summary
    EudraCT number
    		 2008-008934-35
    Trial protocol
    		 ES  
    Global end of trial date
    31 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2021
    First version publication date
    27 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ORDI-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01112215
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VHIR
    Sponsor organisation address
    Passeig Vall Hebron 119-129, Barcelona, Spain, 08035
    Public contact
    Joaquin Lopez-Soriano, VHIR, joaquin.lopez.soriano@vhir.org
    Scientific contact
    Josefina Cortés, VHIR, fina.cortes@vhir.org
    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
    31 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) versus azathioprine (AZA) in patients with active systemic lupus erythematosus (SLE) disease.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice principles. The study protocol was reviewed and approved by every participant centre. Patients unable to tolerate the target dose or whose weight was below 50kg remained in the study if they tolerated a minimum daily dose of either 720mg of EC-MPS or 50mg of AZA during the first 6 months. Progressive immunosuppressant dose reduction was allowed after week 24 on a 3- to 6-monthly basis per clinical judgement. Changes in antimalarial and prednisone doses were not restricted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 May 2010
    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
    Spain: 240
    Worldwide total number of subjects
    240
    EEA total number of subjects
    240
    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)
    240
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited in 12 University hospitals in Spain: Vall d’Hebron; Sant Joan de Reus; Bellvitge; Arnau de Vilanova (Lleida); Corporació Sanitària Parc Taulí (Sabadell); Josep Trueta (Girona); Clinic (Barcelona); Sant Jaume Hospital (Calella); Figueres; Granollers; Mataró; Miguel Servet (Zaragoza).

    Pre-assignment
    Screening details
    		 Eligible patients were aged ≥18 years, had an SLE according to the revised ACR classification criteria and moderate-to-severe active disease defined as: a SLE Disease Activity Index 2000 (SLEDAI-2K) total score ≥6or at least 1 British Isles Lupus Assessment Group (BILAG) A or 2 BILAG B domain scores at screening.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The randomised list, stratified by centre and SLEDAI-2K score (6–9 vs ≥10), was created using computer-generated random number sequences in blocks of 10 by the Vall d’Hebrón Hospital investigational pharmacist, who was blind to patient enrolment. Sequentially numbered, concealed envelopes containing group assignment were provided to the investigators

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Azathioprine
    Arm description
    		 AZA (target dose: 2mg/kg, per thiopurine methyltransferase levels (TPMT)) in addition to background oral prednisone and antimalarial agents
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    AZA (target dose: 2mg/kg, per thiopurine methyltransferase levels (TPMT)) in addition to background oral prednisone and antimalarial agents, Progressive immunosuppressant dose reduction was allowed after week 24 on a 3- to 6-monthly basis per clinical judgement. Changes in antimalarial and prednisone doses were not restricted

    Arm title
    		 Mycophenolate
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Mycophenolate sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Enteric Coated mycophenolate sodium (EC-MPS), target dose: 1440mg/day . Changes in antimalarial and prednisone doses were not restricted

    Number of subjects in period 1
    		Azathioprine Mycophenolate
    Started
    120
    120
    Completed
    67
    87
    Not completed
    53
    33
         Adverse event, serious fatal
    1
    1
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    10
    6
         Lost to follow-up
    2
    2
         Lack of efficacy
    38
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Azathioprine
    Reporting group description
    		 AZA (target dose: 2mg/kg, per thiopurine methyltransferase levels (TPMT)) in addition to background oral prednisone and antimalarial agents

    Reporting group title
    Mycophenolate
    Reporting group description
    		 -

    Reporting group values
    		 Azathioprine Mycophenolate Total
    Number of subjects
    		 120 120 240
    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 (standard deviation)
    		 40.9 ± 12.9 42.1 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    		 111 108 219
        Male
    		 9 12 21

    End points

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    End points reporting groups
    Reporting group title
    Azathioprine
    Reporting group description
    		 AZA (target dose: 2mg/kg, per thiopurine methyltransferase levels (TPMT)) in addition to background oral prednisone and antimalarial agents

    Reporting group title
    Mycophenolate
    Reporting group description
    		 -

    Primary: Clinical remission 3 motnhs

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    End point title
    		 Clinical remission 3 motnhs
    End point description
    The primary efficacy endpoints were the proportion of patients achieving at 3 and 24 months, at least 8 consecutive weeks of clinical remission (CR), defined as a clinical SLEDAI-2K=0,where serology was permitted (maximum SLEDAI=4) following the later Zen et al equivalent definition, in the absence of any BILAG A, B or C score.
    End point type
    Primary
    End point timeframe
    3 motnhs
    End point values
    		 Azathioprine Mycophenolate
    Number of subjects analysed
    120
    120
    Units: percent
        number (not applicable)
    19.2
    32.5
    Statistical analysis title
    		 SLEDAI 3months
    Comparison groups
    Azathioprine v Mycophenolate
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.034
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Clinical remission 24 months

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    End point title
    		 Clinical remission 24 months
    End point description
    The primary efficacy endpoints were the proportion of patients achieving at 3 and 24 months, at least 8 consecutive weeks of clinical remission (CR), defined as a clinical SLEDAI-2K=0,where serology was permitted (maximum SLEDAI=4) following the later Zen et al equivalent definition, in the absence of any BILAG A, B or C score.
    End point type
    Primary
    End point timeframe
    24 motnhs
    End point values
    		 Azathioprine Mycophenolate
    Number of subjects analysed
    118
    118
    Units: percent
        number (not applicable)
    48.3
    71.2
    Statistical analysis title
    		 SLEDAI 24 months
    Comparison groups
    Azathioprine v Mycophenolate
    Number of subjects included in analysis
    236
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: BILAG A/B flares

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    End point title
    		 BILAG A/B flares
    End point description
    Flares according to BILAG (British Isles Lupus Assessment Group) scores
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Azathioprine Mycophenolate
    Number of subjects analysed
    120
    120
    Units: percent
        number (not applicable)
    71.7
    50
    Statistical analysis title
    		 BILAG flares
    Comparison groups
    Mycophenolate v Azathioprine
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Corticosteroids use reduction

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    End point title
    		 Corticosteroids use reduction
    End point description
    Reduction of the prednisone dose (<7.5) by month 24 among those patients taking ≥7.5mg/day at inclusion
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Azathioprine Mycophenolate
    Number of subjects analysed
    120
    120
    Units: percent
        number (not applicable)
    83.5
    94.9
    Statistical analysis title
    		 Corticosteroids use
    Comparison groups
    Azathioprine v Mycophenolate
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.027
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 motnhs
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12
    Reporting groups
    Reporting group title
    AZA group
    Reporting group description
    		 -

    Reporting group title
    EC-MPS
    Reporting group description
    		 -

    Serious adverse events
    		 AZA group EC-MPS
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 120 (10.83%)
    11 / 120 (9.17%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thymoma
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 120 (0.83%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Subarachnoid haematoma
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
         subjects affected / exposed
    3 / 120 (2.50%)
    5 / 120 (4.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Renal and urinary disorders
    Pyelonephritis
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Soft tissue infection
         subjects affected / exposed
    2 / 120 (1.67%)
    0 / 120 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    		 AZA group EC-MPS
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 120 (57.50%)
    71 / 120 (59.17%)
    General disorders and administration site conditions
    No specified
         subjects affected / exposed
    19 / 120 (15.83%)
    28 / 120 (23.33%)
         occurrences all number
    19
    28
    Immune system disorders
    Pneumonia
         subjects affected / exposed
    1 / 120 (0.83%)
    3 / 120 (2.50%)
         occurrences all number
    1
    3
    Oral candidiasis
         subjects affected / exposed
    2 / 120 (1.67%)
    1 / 120 (0.83%)
         occurrences all number
    2
    1
    Leucopenia
         subjects affected / exposed
    5 / 120 (4.17%)
    0 / 120 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Upper gastrointestinal symptoms
         subjects affected / exposed
    16 / 120 (13.33%)
    9 / 120 (7.50%)
         occurrences all number
    16
    9
    Hepatobiliary disorders
    Liver toxicity
         subjects affected / exposed
    3 / 120 (2.50%)
    0 / 120 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 120 (10.00%)
    16 / 120 (13.33%)
         occurrences all number
    12
    16
    Urinary tract infection
         subjects affected / exposed
    4 / 120 (3.33%)
    4 / 120 (3.33%)
         occurrences all number
    4
    4
    Herpes sepsis
         subjects affected / exposed
    3 / 120 (2.50%)
    5 / 120 (4.17%)
         occurrences all number
    3
    5
    Soft tissue infection
         subjects affected / exposed
    2 / 120 (1.67%)
    2 / 120 (1.67%)
         occurrences all number
    2
    2
    Influenza
         subjects affected / exposed
    2 / 120 (1.67%)
    3 / 120 (2.50%)
         occurrences all number
    2
    3

    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.
    It was not a multiethnic study. Open-label and not double-blinded trial. Measures of active metabolites of AZA or EC-MPS) were not routinely performed. Corticosteroids were not adjusted during the study. Long-term potential outcomes not considered.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28450313
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