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    Clinical Trial Results:
    CLINICAL TRIAL WITH PROPHYLACTIC TENOFOVIR FOR HAEMATOLOGICAL CANCER PATIENTS SHOWING A HBc-Ab POSITIVE AND HBs-Ag PATTERN AND TO BE TREATED WITH RITUXIMAB (PREBLIN STUDY)

    Summary
    EudraCT number
    		 2011-000905-30
    Trial protocol
    		 ES  
    Global end of trial date
    23 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Dec 2021
    First version publication date
    04 Dec 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    REM-TEN-2011-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    PORIB, Pharmacoeconomics & Outcomes Research Iberia, 34 917159147, MA_casado@porib.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
    23 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare in HBcAb- positive and HBsAg-negative haematological cancer patients, the prophylactic use of TDF versus observation assessed as the percentage of patients who experienced HBV reactivation (seroreversion or reappearance of the HBsAg) in plasma and/or an increase of HBV DNA levels ≥ 1 log10 IU/mL compared with the baseline value during the 18 months after the starting of treatment with rituximab
    Protection of trial subjects
    Patients were excluded during the study for any of the following reasons: Pregnancy during the treatment. Serious adverse reaction requiring the definitive discontinuation of the study treatment. Discontinuation of the treatment with the study drug for more than 2 weeks. At the patient's request. Patients with adverse events were monitored through clinical assessments and pertinent laboratory analyses, as indicated by the supervising physician. All adverse events were monitored until they were satisfactorily resolved or have stabilized
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Aug 2011
    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: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    10
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients with hematological malignancy receiving RTX either as monotherapy or in combination with chemotherapy were eligible. Inclusion criteria were age 18 years, prior serologic evidence of HBV exposure (anti-HBc positive), HBsAg-negative status, undetectable HBV viral load (<lower limit of quantification), signed informed consent.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RTX+TDF
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg each perfusion. 5-1 cycles, according to protocol

    Investigational medicinal product name
    Tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg once daily, orally

    Arm title
    		 RTX alone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    MabThera
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100 mg each perfusion. 5-1 cycles, according to protocol

    Number of subjects in period 1
    		RTX+TDF RTX alone
    Started
    33
    28
    Completed
    33
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RTX+TDF
    Reporting group description
    		 -

    Reporting group title
    RTX alone
    Reporting group description
    		 -

    Reporting group values
    		 RTX+TDF RTX alone Total
    Number of subjects
    		 33 28 61
    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)
    		 69.9 ± 13.3 71.0 ± 9.0 -
    Gender categorical
    Units: Subjects
        Female
    		 15 10 25
        Male
    		 18 18 36

    End points

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    End points reporting groups
    Reporting group title
    RTX+TDF
    Reporting group description
    		 -

    Reporting group title
    RTX alone
    Reporting group description
    		 -

    Primary: Undetectable HBV DNA levels

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    End point title
    		 Undetectable HBV DNA levels
    End point description
    The primary endpoint was the percentage of RTX-treated patients in the 2 groups with undetectable HBV-DNA levels (Group I and Group II) showing HBV reactivation within the 18 months of follow-up. Reactivation was defined by HBsAg and/or HBV DNA detection, or a confirmed 1 log10 IU/mL increase in HBV DNA levels from baseline
    End point type
    Primary
    End point timeframe
    18 months of follow-up
    End point values
    		 RTX+TDF RTX alone
    Number of subjects analysed
    31
    28
    Units: percent
        number (not applicable)
    0
    3
    Statistical analysis title
    		 HBV levels
    Comparison groups
    RTX alone v RTX+TDF
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.091
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months of follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    RTX + TDF
    Reporting group description
    		 -

    Reporting group title
    RTX alone
    Reporting group description
    		 -

    Serious adverse events
    		 RTX + TDF RTX alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 31 (25.81%)
    7 / 28 (25.00%)
         number of deaths (all causes)
    4
    5
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Asthenia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematologic toxicity
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 28 (10.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mucositis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
         subjects affected / exposed
    4 / 31 (12.90%)
    4 / 28 (14.29%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 28 (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
    		 RTX + TDF RTX alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 31 (58.06%)
    10 / 28 (35.71%)
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Neutropenia
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 28 (10.71%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Vomiting
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Asthenia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Infection
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Paraesthesia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1

    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.
    The difference in the HBV reactivation rate between patients receiving TDF and those under close monitoring was not statistically significant. The calculated sample size was not reached.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28898281
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