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    Clinical Trial Results:
    RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTRE CLINICAL TRIAL TO EVALUATE THE EFFICACY OF PALLIATIVE TREATMENT WITH METHYLPHENIDATE IN ASTHENIA (IN PATIENTS WITH ADVANCED CANCER).

    Summary
    EudraCT number
    		 2008-002171-27
    Trial protocol
    		 ES  
    Global end of trial date
    07 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Sep 2021
    First version publication date
    19 Sep 2021
    Other versions
    Summary report(s)
    		 FINAL REPORT (SPANISH)

    Trial information

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    Trial identification
    Sponsor protocol code
    METILÁS09/2008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01773837
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Clínica Universidad de Navarra
    Sponsor organisation address
    Avda. Pío XII, 36, Pamplona, Spain, 31008
    Public contact
    UCICEC, Clínica Universidad de Navarra, 34 948 255400 2723, ucicec@unav.es
    Scientific contact
    UCICEC, Clínica Universidad de Navarra, 34 948 255400 2723, ucicec@unav.es
    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
    01 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of methylphenidate in the treatment of asthenia in a population of patients with advanced cancer: treatment will be considered effective if in the methylphenidate group the improvement in mean asthenia intensity between baseline and day 6 is significantly greater than the improvement found in the placebo group. The response (symptomatic improvement in asthenia) will be measured with a EVN of weakness included in the Edmonton System Assesment Scale (ESAS) (0: no weakness at all, 10: greatest weakness imaginable).
    Protection of trial subjects
    This clinical trial has been carried out under conditions of respect for the fundamental rights of the individual and the ethical postulates that affect biomedical research involving human beings, following for these purposes those contained in the Declaration of Helsinki and subsequent updates. This study was conducted in accordance with the Standards of Good Clinical Practice and the standard operating procedures which outline the conduct to be followed in each of the aspects related to the organisation, conduct, data collection, documentation and verification of clinical trials. Freely given informed consent has been obtained and documented from each trial subject prior to inclusion. The confidentiality of the data and documents contained in the study file is assured.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Ethical reason
    Long term follow-up duration
    		 20 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    43
    From 65 to 84 years
    54
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment is carried out at the study centres, based on the clinical experience of the investigators and retrospective data. Recruitment is competitive, meaning that each centre will be able to recruit as many patients as it is able during the recruitment period of the study.

    Pre-assignment
    Screening details
    		 Patients over 18 years diagnosed with advanced cancer, including metastatic, locally advanced or relapsed cancer, with no option of radical intent treatment. Haemoglobin levels are ≥9 and on the EVN scale for "weakness" the patient should score ≥5.

    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
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental group
    Arm description
    		 A total of 55 patients are randomly assigned to this group who are administered methylphenidate (Rubifen) in an initial dose of 10 mg at breakfast and 5 mg at lunch. The dose can be adjusted during the trial but always within the range of 10-25mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    METHYLPHENIDATE HYDROCHLORIDE
    Investigational medicinal product code
    N06BA04
    Other name
    Rubifen
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The initial dose is 10 mg at breakfast and 5 mg at lunch during the 6 days of the study. . The dose can be adjusted during the trial but always within the range of 10-25mg/day. It is supplied in blister packs of 5 mg tablets, in the form of round, white, flat tablets for oral administration.

    Arm title
    		 Control group
    Arm description
    		 A total of 45 patients are randomly assigned to this group. For the placebo group, the manufacture of tablets without active ingredient, with the same external appearance as those containing methylphenidate, is carried out.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For the placebo group, the manufacture of tablets without active ingredient, with the same external appearance as those containing methylphenidate, is carried out.

    Number of subjects in period 1
    		Experimental group Control group
    Started
    55
    45
    Completed
    43
    34
    Not completed
    12
    11
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    5
    3
         others
    3
    3
         Lost to follow-up
    1
    -
         patient deterioration
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 A total of 55 patients are randomly assigned to this group who are administered methylphenidate (Rubifen) in an initial dose of 10 mg at breakfast and 5 mg at lunch. The dose can be adjusted during the trial but always within the range of 10-25mg/day.

    Reporting group title
    Control group
    Reporting group description
    		 A total of 45 patients are randomly assigned to this group. For the placebo group, the manufacture of tablets without active ingredient, with the same external appearance as those containing methylphenidate, is carried out.

    Reporting group values
    		 Experimental group Control group Total
    Number of subjects
    		 55 45 100
    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
        median (full range (min-max))
    		 66 (38 to 87) 68 (39 to 88) -
    Gender categorical
    Units: Subjects
        Female
    		 26 21 47
        Male
    		 29 24 53

    End points

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    End points reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 A total of 55 patients are randomly assigned to this group who are administered methylphenidate (Rubifen) in an initial dose of 10 mg at breakfast and 5 mg at lunch. The dose can be adjusted during the trial but always within the range of 10-25mg/day.

    Reporting group title
    Control group
    Reporting group description
    		 A total of 45 patients are randomly assigned to this group. For the placebo group, the manufacture of tablets without active ingredient, with the same external appearance as those containing methylphenidate, is carried out.

    Primary: Level of asthenia. ESAS scale

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    End point title
    		 Level of asthenia. ESAS scale
    End point description
    The main objective is to assess the level of asthenia using the Edmonton Symptom Assessment Questionnaire (ESAS). Overall, differences in effectiveness variables between methylphenidate and placebo were not statistically significant in the study population. The improvement in mean asthenia intensity between baseline and day 6 is similar in the Placebo and Methylphenidate groups. The intensity of asthenia (as assessed by ESAS) improved significantly in both groups of patients, both in the placebo-treated group and in the group receiving methylphenidate. The difference (mean) between baseline asthenia and asthenia on day 6 of treatment is statistically significant for both groups, placebo and methylphenidate (p<0,001).
    End point type
    Primary
    End point timeframe
    The level of asthenia is asseessed on day 6.
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    43
    34
    Units: NA
    arithmetic mean (standard deviation)
        Average improvement in asthenia (ESAS) on day 6
    -2.3 ( 2.6 )
    -1.9 ( 2.5 )
    Statistical analysis title
    		 Mean change
    Statistical analysis description
    The degree of improvement is assessed by the differences in baseline minus endpoint scores on the ESAS scale.
    Comparison groups
    Experimental group v Control group
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Level of asthenia. FACT-F subscale

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    End point title
    		 Level of asthenia. FACT-F subscale
    End point description
    As a secondary objective, the level of asthenia is assessed with the FACT-F subscale. The results of the FACT-F scale show a significant improvement of all patients at day 6, the difference between the groups receiving placebo or methylphenidate was not statistically significant (Placebo p=0,0002; Metilphenidate p=0,0004).
    End point type
    Secondary
    End point timeframe
    The level of asthenia is asseessed on day 6.
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    43
    30
    Units: NA
    median (confidence interval 95%)
        improvement in asthenia (FACT-F) on day 6.
    4.9 (1.6 to 8.2)
    6.4 (3.3 to 9.4)
    No statistical analyses for this end point

    Secondary: Cognitive function

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    End point title
    		 Cognitive function
    End point description
    Changes in cognitive level were studied with the Gagnon Test. No effects of methylphenidate on cognitive function were detected. There were no significant changes in the Gagnon Test between day 0 and day 6 in either the methylphenidate or placebo groups.
    End point type
    Secondary
    End point timeframe
    The Gagnon Test is assessed between day 0 and day 6.
    End point values
    		 Experimental group Control group
    Number of subjects analysed
    43
    34
    Units: NA
    arithmetic mean (standard deviation)
        Delayed repetition of a list of words
    -0.1 ( 1.0 )
    -0.4 ( 0.6 )
        Delayed repetition 1 of a list of words
    0.2 ( 1.8 )
    0.4 ( 2.0 )
        Delayed repetition 2 of a list of words
    0.3 ( 1.8 )
    0.4 ( 1.7 )
        Repetition of progressive series of digits forward
    4.1 ( 17.1 )
    1.9 ( 14.5 )
        Repetition of progressive series of digits backwar
    1.3 ( 9.4 )
    -0.2 ( 6.7 )
        Accuracy when copying figures
    0.0 ( 2.2 )
    -0.1 ( 1.7 )
        Writing a given sentence
    0.3 ( 0.7 )
    -0.3 ( 1.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The investigator shall notify the principal investigator of the occurrence of an SAA within 24 hours of becoming aware of it, even if it is not related to study medication. The principal investigator shall notify the sponsor immediately.
    Adverse event reporting additional description
    Adverse effects include the sensation of nausea, which is described 10 times among patients who received methylphenidate and never in the placebo group. Nausea intensity, at the beginning and at the end of the trial, shows no significant difference between the two groups.Other drug-related side effects are nervousnes sleep disturbances and headache
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ND
    Dictionary version
    ND
    Reporting groups
    Reporting group title
    Experimental group
    Reporting group description
    		 Patients in this group are administered with methylphenidate. 49% of patients had an adverse effect. 10% of these adverse events were serious.

    Reporting group title
    control group
    Reporting group description
    		 Patients in this group are given placebo. 38% of patients had an adverse effect. 4% of the adverse events were serious.

    Serious adverse events
    		 Experimental group control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 55 (7.27%)
    2 / 45 (4.44%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute right hemiplegia
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dysarthria
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Brain haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Exitus
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Oppressive central thoracic pain
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoptysis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (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: 1%
    Non-serious adverse events
    		 Experimental group control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 55 (49.09%)
    17 / 45 (37.78%)
    Vascular disorders
    Brain haemorrhage
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 45 (2.22%)
         occurrences all number
    1
    0
    Oedema
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Nervous system disorders
    Cefalea
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Deterioration of general condition
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 45 (2.22%)
         occurrences all number
    3
    1
    Pain
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    Discomfort
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    Social circumstances
    Sleep disturbances
         subjects affected / exposed
    3 / 55 (5.45%)
    2 / 45 (4.44%)
         occurrences all number
    7
    4
    Nervousness
         subjects affected / exposed
    3 / 55 (5.45%)
    1 / 45 (2.22%)
         occurrences all number
    6
    1
    Instability
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 55 (7.27%)
    0 / 45 (0.00%)
         occurrences all number
    10
    0
    diarrhea
         subjects affected / exposed
    1 / 55 (1.82%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 55 (1.82%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Redness
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Cellulitis
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anorexia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Infections and infestations
    Fever
         subjects affected / exposed
    2 / 55 (3.64%)
    3 / 45 (6.67%)
         occurrences all number
    3
    6
    Dental phlegmon
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Hyponatremia
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2010
    protocol generated version: v4. Notified to AEMPS and ethics committee.
    27 Sep 2011
    protocol generated version: v4. Notified to the ethics committee
    03 Apr 2012
    protocol generated version: v4. Notified to the ethics committee
    01 Aug 2012
    protocol generated version: v5. Notified to AEMPS and ethics committee.
    01 Jul 2015
    protocol generated version: v5. Notified to the ethics committee.

    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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