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    Clinical Trial Results:
    Cyclophosphamide in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An open label phase-II study with 6 infusions of cyclophosphamide 4 weeks apart.

    Summary
    EudraCT number
    		 2014-004029-41
    Trial protocol
    		 NO  
    Global end of trial date
    25 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Aug 2021
    First version publication date
    29 Aug 2021
    Other versions
    Summary report(s)
    		 Frontiers in Medicine_290420

    Trial information

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    Trial identification
    Sponsor protocol code
    KTS-7-2015
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02444091
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Haukeland University Hospital
    Sponsor organisation address
    Jonas Lies vei 65, Bergen, Norway, 5021
    Public contact
    Øystein Fluge, Haukeland University Hospital, +47 5597358700, oystein.fluge@gmail.com
    Scientific contact
    Øystein Fluge, Haukeland University Hospital, +47 5597358700, oystein.fluge@gmail.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
    20 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to evaluate the efficacy, toxicity and feasibility of six infusions cyclophosphamide given four weeks apart, for patients with chronic fatigue syndrome (ME/CFS). The objective of part B of the trial is to evaluate feasibility of six infusions cyclophosphamide given six weeks apart with simplified follow-up for up to five patients with severe to very severe ME/CFS.
    Protection of trial subjects
    Physical stress tests before and after intervention were only performed for patients deemed physically capable of completing such tests with regards to disease severity and post-exertional malaise. Treatment was administered in a single room at a designated clinical trial unit to minimise sensory input. Premedication was administered to prevent nausea. In order to limit number of hospital visits, the trial unit organised house calls for blood sampling upon request. For part B (two participants with very severe ME/CFS) the protocol was adjusted to make the trial less taxing on patients, including longer intervals between treatments and simplified patient reporting.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Scientific research
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment lasted from March 2015 to December 2015. All participants were included at Haukeland University Hospital in Western Norway. Seven of the participants received parts of their treatment and follow-up at Oslo University Hospital.

    Pre-assignment
    Screening details
    		 Inclusion criteria were: a diagnosis of ME/CFS according to the Canadian criteria; age 18–66 years; disease duration more than 2 years; and disease severity mild-to-moderate, moderate, moderate-to-severe, or severe. Exclusion criteria and screening process are detailed in the trial protocol.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an unblinded trial.

    Arms
    Arm title
    		 Cyclophosphamide treatment
    Arm description
    		 Six 30-minute intravenous infusions of cyclophosphamide were administered at 4-week intervals with 600 mg/m2 at the first and 700 mg/m2 at further cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Six 30-minute intravenous infusions of cyclophosphamide were administered at 4-week intervals with 600 mg/m2 at the first and 700 mg/m2 at further cycles.

    Number of subjects in period 1
    		Cyclophosphamide treatment
    Started
    40
    Completed
    38
    Not completed
    2
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 -

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 40 40
    Age categorical
    Age on date of consent.
    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)
    		 40 40
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Age on date of consent
    Units: years
        arithmetic mean (full range (min-max))
    		 41.7 (21.5 to 61.1) -
    Gender categorical
    Units: Subjects
        Female
    		 31 31
        Male
    		 9 9
    ME/CFS disease duration
    Number of years from symptom debut to inclusion in study
    Units: Subjects
        2-5 years
    		 7 7
        5-10 years
    		 13 13
        10-15 years
    		 9 9
        >15 years
    		 11 11
    ME/CFS disease severity
    Units: Subjects
        Mild/moderate
    		 14 14
        Moderate
    		 13 13
        Moderate/severe
    		 7 7
        Severe
    		 6 6
    Infection prior to ME/CFS
    Units: Subjects
        Yes
    		 26 26
        No
    		 14 14
    HLA typing
    Units: Subjects
        HLA-DQB1*03:03 and/or HLA-C*07:04 positive
    		 12 12
        Negative for both HLA-DQB*03:03 and HLA-C*07:04
    		 28 28
    SF-36 Physical Function
    Short Form 36 Physical Function subscale, raw scores (range 0-100)
    Units: Points
        arithmetic mean (full range (min-max))
    		 33 (0 to 65) -
    SF-36 Physical Component summary score
    Short Form 36 Physical Component summary score, norm-based with population mean 50.
    Units: Points
        arithmetic mean (full range (min-max))
    		 23.3 (13.5 to 41.6) -
    Steps per 24h
    Steps, mean per 24 hours. Continuous measurement by Sensewear activity armband for 5 to 7 consecutive days
    Units: Steps
        arithmetic mean (full range (min-max))
    		 3199 (568 to 9637) -
    Total function level
    Baseline self-reported function level, scale 0 to 100%
    Units: Per cent
        arithmetic mean (full range (min-max))
    		 16.9 (5 to 40) -
    Subject analysis sets

    Subject analysis set title
    Rituximab-naïve
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who had not received previous treatment with rituximab.

    Subject analysis set title
    Responders
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were classed as responders according to study response criteria.

    Subject analysis set title
    Non-responders
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were not classed as responders according to study response criteria.

    Subject analysis sets values
    		 Rituximab-naïve Responders Non-responders
    Number of subjects
    25
    22
    18
    Age categorical
    Age on date of consent.
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    25
    22
    18
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Age on date of consent
    Units: years
        arithmetic mean (full range (min-max))
    40.5 (21.5 to 60.3)
    41.4 (21.5 to 60.3)
    42.2 (23.4 to 61.1)
    Gender categorical
    Units: Subjects
        Female
    18
    18
    13
        Male
    7
    4
    5
    ME/CFS disease duration
    Number of years from symptom debut to inclusion in study
    Units: Subjects
        2-5 years
    7
    5
    2
        5-10 years
    7
    5
    8
        10-15 years
    4
    6
    3
        >15 years
    7
    6
    5
    ME/CFS disease severity
    Units: Subjects
        Mild/moderate
    10
    9
    5
        Moderate
    7
    9
    4
        Moderate/severe
    5
    4
    3
        Severe
    3
    0
    6
    Infection prior to ME/CFS
    Units: Subjects
        Yes
    17
    15
    11
        No
    8
    7
    7
    HLA typing
    Units: Subjects
        HLA-DQB1*03:03 and/or HLA-C*07:04 positive
    6
    10
    2
        Negative for both HLA-DQB*03:03 and HLA-C*07:04
    19
    12
    16
    SF-36 Physical Function
    Short Form 36 Physical Function subscale, raw scores (range 0-100)
    Units: Points
        arithmetic mean (full range (min-max))
    34 (0 to 65)
    35 (10 to 65)
    30.6 (0 to 65)
    SF-36 Physical Component summary score
    Short Form 36 Physical Component summary score, norm-based with population mean 50.
    Units: Points
        arithmetic mean (full range (min-max))
    24.5 (14.6 to 41.6)
    23.1 (13.5 to 41.6)
    23.5 (14.6 to 31.0)
    Steps per 24h
    Steps, mean per 24 hours. Continuous measurement by Sensewear activity armband for 5 to 7 consecutive days
    Units: Steps
        arithmetic mean (full range (min-max))
    3282 (568 to 9637)
    3622 (1083 to 8178)
    2681 (568 to 9637)
    Total function level
    Baseline self-reported function level, scale 0 to 100%
    Units: Per cent
        arithmetic mean (full range (min-max))
    17 (5 to 30)
    19.3 (10 to 40)
    14.1 (5 to 25)

    End points

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    End points reporting groups
    Reporting group title
    Cyclophosphamide treatment
    Reporting group description
    		 Six 30-minute intravenous infusions of cyclophosphamide were administered at 4-week intervals with 600 mg/m2 at the first and 700 mg/m2 at further cycles.

    Subject analysis set title
    Rituximab-naïve
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who had not received previous treatment with rituximab.

    Subject analysis set title
    Responders
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were classed as responders according to study response criteria.

    Subject analysis set title
    Non-responders
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were not classed as responders according to study response criteria.

    Primary: Overall response rate

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    End point title
    		 Overall response rate [1]
    End point description
    Overall response: Fatigue score 4.5 or above for at least six consecutive weeks at any time during treatment or follow-up. Overall response rate: Proportion of patients fulfilling the response criteria.
    End point type
    Primary
    End point timeframe
    18 months from first treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This primary end point uses absolute numbers of patients with clinical response. There is no comparison within groups and so no statistical analysis is applied. Additional end points are based on changes from baseline to pre-specified time points during trial. They were assessed by a General Linear Model of repeated measures, which cannot be reported in this system. Details on endpoints and analyses can be found in the published article, attached herein.
    End point values
    		 Cyclophosphamide treatment Rituximab-naïve
    Number of subjects analysed
    40 [2]
    25 [3]
    Units: Subjects
        number (not applicable)
    22
    14
    Notes
    [2] - Intention to treat
    [3] - Intention to treat
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first treatment through 12 months follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Cyclophosphamide treatment
    Reporting group description
    		 Six 30-minute intravenous infusions of cyclophosphamide were administered at 4-week intervals with 600 mg/m2 at the first and 700 mg/m2 at further cycles.

    Serious adverse events
    		 Cyclophosphamide treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 40 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other (olfactory meningioma)
    Additional description: Admitted for elective procedure. Not related to treatment.
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Other (ME/CFS symptom exacerbation)
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Stomach pain
    Additional description: Admitted to hospital for check-up. No pathology found. Possibly related to treatment.
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
    Additional description: Possibly related to treatment
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal calculi
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Urinary tract infection
    Additional description: Possible relation to treatment.
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
    Additional description: Complication after planned surgery. Not related to treatment.
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory infection
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
    Additional description: Admitted for rehydration. Probably related to treatment.
         subjects affected / exposed
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cyclophosphamide treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 40 (97.50%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    12 / 40 (30.00%)
         occurrences all number
    21
    General disorders and administration site conditions
    Oedema
    Additional description: Grade 1 oedema of face or limbs
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    7
    Fatigue
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    6
    Gastrointestinal disorders
    Constipation
    Additional description: Grade 1-2. Probably related to treatment/premedication (anti-nausea medication).
         subjects affected / exposed
    22 / 40 (55.00%)
         occurrences all number
    34
    Diarrhoea
         subjects affected / exposed
    7 / 40 (17.50%)
         occurrences all number
    7
    Dry mouth
         subjects affected / exposed
    5 / 40 (12.50%)
         occurrences all number
    7
    Nausea
    Additional description: Grade 1-2 nausea lasting from two days to several weeks after individual treatments.
         subjects affected / exposed
    36 / 40 (90.00%)
         occurrences all number
    106
    Gastroenteritis
    Additional description: Unlikely relation to treatment
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Stomach pain
         subjects affected / exposed
    8 / 40 (20.00%)
         occurrences all number
    10
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    7 / 40 (17.50%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Grade 1 hair loss. Probably related to treatment
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Renal and urinary disorders
    Haematuria
    Additional description: Microscopic heamaturia grade 1-2
         subjects affected / exposed
    6 / 40 (15.00%)
         occurrences all number
    7
    Infections and infestations
    Common cold
    Additional description: Unlikely relation to treatment
         subjects affected / exposed
    7 / 40 (17.50%)
         occurrences all number
    10
    Sinusitis
    Additional description: Grade 2, unlikely relation to treatment
         subjects affected / exposed
    4 / 40 (10.00%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    8 / 40 (20.00%)
         occurrences all number
    11
    Urticaria
         subjects affected / exposed
    3 / 40 (7.50%)
         occurrences all number
    4

    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.
    Open trial, no placebo arm. Self-refferal. Self-reported primary outcome measures with possible recall bias. Lack of specific biomarkers could cause unintended heterogeneity in patient sample.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32411717
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