Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Estudio multicéntrico, aleatorizado, doble-ciego, controlado con placebo, sobre la eficacia de la asociación de simvastatina al tratamiento estándar en la prevención de la recidiva hemorrágica en pacientes con cirrosis hepática y hemorragia por varices.

    Summary
    EudraCT number
    		 2009-016500-24
    Trial protocol
    		 ES  
    Global end of trial date
    23 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2022
    First version publication date
    23 May 2022
    Other versions
    Summary report(s)
    		 BLEPS Results
    BLEPS Results

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BLEPS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01095185
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hopsital Clinic, University of Barcelona
    Sponsor organisation address
    C Villarroel 170, Barcelona, Spain, 08037
    Public contact
    Dr JC Garcia-Pagán, Hopsital Clinic, University of Barcelona, +34 661733611, jcgarcia@clinic.cat
    Scientific contact
    Dr Jaime Bosch, Hepatic Hemodynamic Laboratory, Liver Unit, Hopsital Clinic, +34 608110193, jbosch@clinic.cat
    Sponsor organisation name
    Hospital Clinic
    Sponsor organisation address
    Villarroel 136, Barcelona, Spain, 08037
    Public contact
    Dr JC Garcia-Pagán, Hopsital Clinic, University of Barcelona, +34 661733611, jcgarcia@clinic.cat
    Scientific contact
    Dr Jaime Bosch, Hepatic Hemodynamic Laboratory, Liver Unit, +34 608110193, jbosch@clinic.cat
    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
    21 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determinar si la asociación de simvastatina al tratamiento convencional para prevenir la recurrencia de la hemorragia por varices esofágicas (ß-bloqueantes no selectivos más ligadura endoscópica con bandas elásticas) mejora la supervivencia libre de recidiva hemorrágica en pacientes cirróticos.
    Protection of trial subjects
    Patients were closely monitored to detect potential adverse events related to the trial medication. Two cases of CPK elevation accompanied by muscle pain were identified and totally resolved uneventfully soon after withdrawal of the trial medication.
    Background therapy
    		 All patients received best standard of care medical therapy for their condition. This involved repeat sessions of endocopic band ligation of esophago-gastric varices and the administration of non-selective beta-blockers at near maximal tolerated doses (as determined by progressive titration and thereafter adjusted against clinical tolerance and follow-up visits). Patients were further subject to cross-sectional liver imaging and full biochemistry and hematological exams every 6 months.
    Evidence for comparator
    		 The rationale for the use of the study drug (Simvastatin) was provide by previous pre-clinical and clinical studies from our lab, demonstrating that simvastatin ammeliorates liver endothelial dysfunction, reduces portal pressure by decreasing liver vascular resistance through increased availability of nitric oxide at the liver microcirculation, improves liver function and decreases fibrogenesis. The evidence is summarized in the study protocol and in the trial report.
    Actual start date of recruitment
    07 Apr 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 158
    Worldwide total number of subjects
    158
    EEA total number of subjects
    158
    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)
    121
    From 65 to 84 years
    37
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment took place from 2010 to 2013

    Pre-assignment
    Screening details
    		 The study included patients with cirrhosis who recovered from a variceal bleeding. 287 pts were screened and 158 were randomized.

    Period 1
    Period 1 title
    baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    Blinding was guaranteed by providing the active and placebo medications under capsules of an identical aspect prepared at the hospital pharmacy and labelled with the patient code. The medication received is difficult to uncover since patients with cirrhosis have low cholesterol levels (a decrease in cholesterol is the most characteristic biochemical effect in patients with hyperlipidemia treated with simvastatin, but the decrease in cholesterol in subjects without hyperlipidemia is mild)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active treatment arm
    Arm description
    		 Active treatment arm refers patients receiving simvastatin as per randomization. Randomization to the two study arms was 1:1
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    D.3.9.2
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage was ff 20 mg per day in a single tablet to be taken per os. This was increased up to 40 mg per day if well tolerated and with no increase in CPK, AST and ALT after two-weeks of continued administration

    Arm title
    		 Placebo
    Arm description
    		 Patients randomized to placebo
    Arm type
    		 placebo group

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule per day first two weeks of follow-up period, then increased to 2 capsules per day if tolerated

    Number of subjects in period 1
    		Active treatment arm Placebo
    Started
    75
    83
    Completed
    69
    78
    Not completed
    6
    5
         Consent withdrawn by subject
    4
    2
         Study drug not available
    1
    -
         terminated before end of baseline
    -
    2
         Protocol deviation
    1
    1
    Period 2
    Period 2 title
    follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    same as described in baseline period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active treatment arm
    Arm description
    		 Active treatment arm refers patients receiving simvastatin as per randomization. Randomization to the two study arms was 1:1
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Simvastatin
    Investigational medicinal product code
    D.3.9.2
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage was ff 20 mg per day in a single tablet to be taken per os. This was increased up to 40 mg per day if well tolerated and with no increase in CPK, AST and ALT after two-weeks of continued administration

    Arm title
    		 Placebo Arm
    Arm description
    		 patients randomized to placebo (n=78)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    D.3.9.2
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage was of 1 capsule per day to be taken per os. This was increased up to 2 capsules per day if well tolerated and with no increase in CPK, AST and ALT after two-weeks of continued administration

    Number of subjects in period 2
    		Active treatment arm Placebo Arm
    Started
    69
    78
    Completed
    69
    78

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    baseline
    Reporting group description
    		 -

    Reporting group values
    		 baseline Total
    Number of subjects
    		 158 158
    Age categorical
    Mean age was 57.5 years, with and standard deviation of 10.5 years. No patient was over 80 year old, and no patient was less than 35 year-old. 98 patients were male and 60 female.
    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
    All 158 included patients were adult. None was under 35 yea-old and none over 80 year-old
    Units: years
        arithmetic mean (standard deviation)
    		 57.5 ( 10.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 60 60
        Male
    		 98 98
    Subject analysis sets

    Subject analysis set title
    Simvastatin group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    pstients in the Simvastatin Group

    Subject analysis set title
    Placebo Group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    patients randomized to receive placebo, receiving placebo and completing the study

    Subject analysis sets values
    		 Simvastatin group Placebo Group
    Number of subjects
    69
    78
    Age categorical
    Mean age was 57.5 years, with and standard deviation of 10.5 years. No patient was over 80 year old, and no patient was less than 35 year-old. 98 patients were male and 60 female.
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    All 158 included patients were adult. None was under 35 yea-old and none over 80 year-old
    Units: years
        arithmetic mean (standard deviation)
    57.4 ( 10.6 )
    57.6 ( 11.3 )
    Gender categorical
    Units: Subjects
        Female
    24
    25
        Male
    45
    53

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Active treatment arm
    Reporting group description
    		 Active treatment arm refers patients receiving simvastatin as per randomization. Randomization to the two study arms was 1:1

    Reporting group title
    Placebo
    Reporting group description
    		 Patients randomized to placebo
    Reporting group title
    Active treatment arm
    Reporting group description
    		 Active treatment arm refers patients receiving simvastatin as per randomization. Randomization to the two study arms was 1:1

    Reporting group title
    Placebo Arm
    Reporting group description
    		 patients randomized to placebo (n=78)

    Subject analysis set title
    Simvastatin group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    pstients in the Simvastatin Group

    Subject analysis set title
    Placebo Group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    patients randomized to receive placebo, receiving placebo and completing the study

    Primary: Composite of Rebleeding and Death

    		 Close Top of page
    End point title
    		 Composite of Rebleeding and Death
    End point description
    Number of patients with variceal rebleeding or dying during the follow-up
    End point type
    Primary
    End point timeframe
    3 years
    End point values
    		 Active treatment arm Placebo Arm
    Number of subjects analysed
    69
    78
    Units: number of events
    22
    30
    Statistical analysis title
    		 Main results combined end point
    Statistical analysis description
    There were no statistically significant differences between the number of patients with a primary combined end point in the Simvastatin group, 22 of 69 (32%) Vs the Placebo group, 30 of 78 (39%) (HR for simvastatin = 0.822; 95% CI: 0.473–1.427; stratified log-rank P = .423). Therefore, the addition of simvastatin to standard therapy was not statistically superior to placebo in preventing rebleeding or death after a variceal bleeding episode.
    Comparison groups
    Active treatment arm v Placebo Arm
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    30
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 41
    Variability estimate
    Standard deviation
    Dispersion value
    7
    Notes
    [1] - comparison between Simvastatin Group and Placebo group
    [2] - The HR for simvastatin was 0.822; 95% CI: 0.473–1.427; stratified log-rank P =0.423). Therefore, addition of simvastatin to standard therapy was not superior to placebo in preventing rebleeding or death after a variceal bleeding episode

    Secondary: Survival

    		 Close Top of page
    End point title
    		 Survival
    End point description
    Patients dying on follow-up from any cause. These were 6 in the active treatment arm (9%) and 17 in the placebo arm (22%) (HR: 0.387; 95% CI: 0.152 to 0.986; stratified log-rank p-value: 0.030). This indicates a 61% reduction in mortality.
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Active treatment arm
    Number of subjects analysed
    69
    Units: number of deaths during follow-up
    6
    No statistical analyses for this end point

    Secondary: Rebleeding

    		 Close Top of page
    End point title
    		 Rebleeding
    End point description
    Patients rebleeding from varices during the follow-up. These were 17 patients in the simvastatin group and 22 patients in the palcebo group. The rebleeding rate was not significantly decreased by the addition of simvastatin to the standard therapy (HR: 0.858; 95% CI: 0.455 to 1.620; stratified log-rank p-value: 0.583)
    End point type
    Secondary
    End point timeframe
    3 years
    End point values
    		 Active treatment arm Active treatment arm Placebo Arm Placebo
    Number of subjects analysed
    69
    69
    78
    78
    Units: Number of pts with variceal rebleeding
    17
    17
    22
    22
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Three years
    Adverse event reporting additional description
    117 of the 149 patients included in the safety population reported adverse events (60 patients on placebo vs. 57 on simvastatin; p=0.718). These were possibly or probably related to drug treatment occurred in 14 patients on placebo and in 16 patients on simvastatin. 2 patients on Simvastatin had CPK elevation & muscle pain, needing dose reduction
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Simvastatin
    Reporting group description
    		 patients receiving simvastatin

    Reporting group title
    Placebo group
    Reporting group description
    		 Patients receiving placebo

    Serious adverse events
    		 Simvastatin Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 78 (0.00%)
         number of deaths (all causes)
    6
    17
         number of deaths resulting from adverse events
    0
    0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
    Additional description: 2 patients under simvastatin, both in Child-Pugh class C and receiving 40 mg of simvatatin, developed muscle pain and CPK elevation that subsided upon dose reduction
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 6
    0 / 17
    Frequency threshold for reporting non-serious adverse events: 0.02%
    Non-serious adverse events
    		 Simvastatin Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 69 (17.39%)
    11 / 78 (14.10%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 69 (2.90%)
    3 / 78 (3.85%)
         occurrences all number
    2
    3
    Gynecomastia
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Iron-deficiency anemia
         subjects affected / exposed
    2 / 69 (2.90%)
    0 / 78 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 69 (0.00%)
    3 / 78 (3.85%)
         occurrences all number
    0
    3
    Gastrointestinal bleeding
         subjects affected / exposed
    1 / 69 (1.45%)
    2 / 78 (2.56%)
         occurrences all number
    1
    2
    Hepatobiliary disorders
    Ascites
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 78 (2.56%)
         occurrences all number
    2
    2
    Hepatic encephalopathy
         subjects affected / exposed
    3 / 69 (4.35%)
    1 / 78 (1.28%)
         occurrences all number
    3
    2

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Oct 2010
    Prolongation of trial duration (to 3 years) and of maximal interval between index bleeding and randomization (from 7 to 10 days)

    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.
    The study was sized for assessing chnages in rebleeding and mortality (combined end-point). The results shown a significant reduction in mortality, but the reduction in rebleeding was not statistically significant.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26774179
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Apr 26 19:16:41 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA