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    Clinical Trial Results:
    MethylphenIdate for fatigue in haematological cancer. A randomized, double-blind, placebo-controlled, CROssover trial - the MICRO trial

    Summary
    EudraCT number
    		 2017-001844-36
    Trial protocol
    		 DK  
    Global end of trial date
    16 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2026
    First version publication date
    14 Feb 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    Kløvervænget 10, Odense , Denmark, 5000
    Public contact
    Henrik Frederiksen, Odense University Hospital, +45 21849307, henrik.frederiksen@rsyd.dk
    Scientific contact
    Henrik Frederiksen, Odense University Hospital, +45 21849307, henrik.frederiksen@rsyd.dk
    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
    02 Dec 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study if methylphenidate is superior compared to placebo in relieving fatigue and thereby improving Primary end-point: Change in fatigue score from baseline to end of treatment in each treatment period Secondary end-points: • change ine hours awake • Change in time spend at work, being social, house work / gardening, being outside, participating in excercise • change in muscle strength and endurance • change in quality-of-life • change in number of blood transfusions
    Protection of trial subjects
    AEs and SAEs were continously monitored and managed. Visits were kept to the necessesay. Emergency unblinding of study drugs were available 24/7 and performed twice due to SAEs. Safety reports were submitted to Danish authorities who approved all. Safety was discussed among study board members at pre-specified time-points and did not result in any warnings.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2017
    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
    Denmark: 152
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    114
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from all Danish Hospitals treating hematological cancer from 2018 to 2024

    Pre-assignment
    Screening details
    		 No pre-screening results were recorded. Patients who expressed fatigue during their usual clinical follow-up were screened for eligibility. There were no systematic recording of (pre)screen failures. Main causes for non-inclusion were ongoing cancer treatment, concomitant anti-depressants, cardiovascular disease or glaucoma.

    Period 1
    Period 1 title
    RCT crossover design (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Study drug and placebo provided as identical looking tablets. Unblinding was performed after last patient last visit. Emergency unblinding was performed twice due to SAes

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 MTP period
    Arm description
    		 Period (first or second) where patients were receiving IMP
    Arm type
    		 Experimental

    Investigational medicinal product name
    Methylphenidate
    Investigational medicinal product code
    N06BA04
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    week 1: 5 mg twice daily week 2: 10 mg twice daily week 3-6: 20 mg twice daily

    Arm title
    		 Placebo
    Arm description
    		 Period (first or second) where participants received placebo
    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
    Week 1: half a tablet twice daily Week 2: one tablet twice daily From Week 3 2 tablets twice daily

    Number of subjects in period 1
    		MTP period Placebo
    Started
    152
    152
    Completed
    139
    143
    Not completed
    13
    9
         Consent withdrawn by subject
    7
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    5
    5
         Protocol deviation
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RCT crossover design
    Reporting group description
    		 -

    Reporting group values
    		 RCT crossover design Total
    Number of subjects
    		 152 152
    Age categorical
    Age span 21-83. n=114 age 18-64 n=38 age 65-84 n=0 age 85+
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 114 114
        From 65-84 years
    		 38 38
        85 years and over
    		 0 0
    Gender categorical
    Males: n= 85 Females: n=67
    Units: Subjects
        Female
    		 67 67
        Male
    		 85 85

    End points

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    End points reporting groups
    Reporting group title
    MTP period
    Reporting group description
    		 Period (first or second) where patients were receiving IMP

    Reporting group title
    Placebo
    Reporting group description
    		 Period (first or second) where participants received placebo

    Subject analysis set title
    Main analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All 130/152 who completed both treatment periods. As per CONSORT guidelines this is the relevant sample for analysis of primary outocme in a cross-over trail

    Primary: Fatigue score

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    End point title
    		 Fatigue score
    End point description
    Change in FACIT-F score between baseline and end of each treatment period (MTP period vs placebo period)
    End point type
    Primary
    End point timeframe
    Change in FACIT-F score between baseline and end of each treatment period (MTP period vs placebo period) - i.e. week 0 to end of week 6 and week 8 to end og week 13
    End point values
    		 MTP period Placebo
    Number of subjects analysed
    130 [1]
    130 [2]
    Units: FACIT-F score
        number (confidence interval 95%)
    8.9 (7.3 to 10.4)
    3.9 (2.3 to 5.4)
    Notes
    [1] - The 130 patients that completeted both periods
    [2] - The 130 patients that completed both periods
    Statistical analysis title
    		 mixed effects linear regression
    Statistical analysis description
    To evaluate whether statistical significant or minimal clinical important differences in FACIT-F scores are observed we formally tested differences in scores across treatment weeks and by treatment using mixed effects linear regression including a week x treatment interaction and a random Gaussian intercept for each patient.
    Comparison groups
    Placebo v MTP period
    Number of subjects included in analysis
    260
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 7.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study start to completion (last patient last study visit)
    Adverse event reporting additional description
    As recorded by investigators
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Both treatment periods
    Reporting group description
    		 Both periods. The n=130 number reflect subject who had an AE during MTP (n=73) or placebo (n=52). These numbers are not mutually exclusive

    Serious adverse events
    		 Both treatment periods
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 152 (3.95%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung cancer
    Additional description: One patient was diagnosed with lung cancer during trial and was excluded
         subjects affected / exposed
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
    Additional description: One patient was registered with nausea and dizziness as an SAE but the event was categorized as grade 1.
         subjects affected / exposed
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: One patient was registered with a SAE since a blood transfusion required hospital admission.
         subjects affected / exposed
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Allergic oedema
    Additional description: Angioedema after first IMP. Unblinded to be during MTP
         subjects affected / exposed
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Transaminases abnormal
    Additional description: Grade 4 transaminitis was unblinded to be during placebo treatment
         subjects affected / exposed
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fracture
    Additional description: Metatarsal fracture. Admitted for surgery
         subjects affected / exposed
    1 / 152 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Both treatment periods
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 152 (82.24%)
    Cardiac disorders
    Hypertension
    Additional description: Heart / circulation: Palpitations, hypertension, atrial fibrillation. across both treatment periods
         subjects affected / exposed
    25 / 152 (16.45%)
         occurrences all number
    25
    Nervous system disorders
    Headache
    Additional description: Headache, migraine, dizziness, tremor, sleeplessness, impaired concentration.
         subjects affected / exposed
    57 / 152 (37.50%)
         occurrences all number
    57
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 152 (7.24%)
         occurrences all number
    11
    Xerostomia
         subjects affected / exposed
    9 / 152 (5.92%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Sweating, dryness, oedema, flushing, itching, rash
         subjects affected / exposed
    18 / 152 (11.84%)
         occurrences all number
    18
    Psychiatric disorders
    Anxiety
    Additional description: Agitation, restlessness, anxiety
         subjects affected / exposed
    7 / 152 (4.61%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Pain
    Additional description: Muscle pain, joint pain, back pain, neck pain
         subjects affected / exposed
    17 / 152 (11.18%)
         occurrences all number
    17
    Infections and infestations
    Infection
    Additional description: Gastroenteritis, upper respiratory tract infection, lung infection, urinary tract infection, fever, herpes zoster, tooth infection, COVID-19.
         subjects affected / exposed
    19 / 152 (12.50%)
         occurrences all number
    19

    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
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    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.

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