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    Clinical Trial Results:
    The Qure study: Q-fever fatigue syndrome - response to treatment

    Summary
    EudraCT number
    		 2011-000643-25
    Trial protocol
    		 NL  
    Global end of trial date
    10 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jan 2021
    First version publication date
    13 Jan 2021
    Other versions
    Summary report(s)
    		 The Qure study: Q-fever fatigue syndrome - response to treatment
    Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial

    Trial information

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    Trial identification
    Sponsor protocol code
    205520003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01318356
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Nederlands Trial Register (NTR): NTR2797
    Sponsors
    Sponsor organisation name
    Radboud University Nijmegen Medical Centre
    Sponsor organisation address
    Geert Grooteplein 10, Nijmegen, Netherlands, 6500 HB
    Public contact
    Department of Internal Medicine, Radboud University Nijmegen Medical Centre, +31 243668256, Stephan.Keijmel@radboudumc.nl
    Scientific contact
    Department of Internal Medicine, Radboud University Nijmegen Medical Centre, +31 243668256, Stephan.Keijmel@radboudumc.nl
    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
    10 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of two treatment strategies for fatigue and disabilities in QFS: long term treatment with doxycycline or cognitive behavioral therapy (CBT). Both interventions will be compared to a placebo group. Primary outcome measure will be fatigue severity measured with the Checklist Individual Strength (CIS).
    Protection of trial subjects
    For safety considerations all participants in the medication condition will visit the Q fever outpatient clinic 4, 8, and 16 weeks after start of the treatment. Furthermore, liver enzymes will be checked, and drug utilization will be recorded. Therefore, patients are required to bring the study medication to all visits. In addition, blood samples drawn 8 weeks after start of treatment will be stored by the study pharmacist, who performed the double-blinded randomization. For patients allocated to CBT, AEs were monitored at 8 weeks after start of therapy and at EOT.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 May 2011
    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
    Netherlands: 156
    Worldwide total number of subjects
    156
    EEA total number of subjects
    156
    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)
    156
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible patients will be asked to participate in the Qure study after receiving verbal and written information about the study. If patients are willing to participate, written informed consent will be obtained.

    Pre-assignment
    Screening details
    		 Male/non-pregnant,-lactating females above 18, proven acute Q fever since 2007 and/or positive serology fitting a past infection with C. burnetii, being severly fatigued, being fatigued for >6m, being disabled because of fatigue +inclusion based on Dutch QFS algorithm +absence of fatigue before Q fever/increase of fatigue since Q fever infection

    Period 1
    Period 1 title
    Allocation to intervention (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Doxycycline
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxycycline Disp 100 PCH
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated with doxycycline 200 mg or placebo, orally administered once daily, for 24 weeks. Doxycycline was reencapsulated and placebo was prepared as capsules with identical appearance.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated with placebo, orally administered once daily, for 24 weeks. Placebo was prepared as capsules with identical appearance as doxycycline.

    Arm title
    		 Cognitive behavioural therapy (CBT)
    Arm description
    		 Patients allocated to CBT received approximately 24 weeks of individual CBT, based on the manual of CBT for CFS, by trained and supervised cognitive-behavioral therapists. Treatment frequency was determined on individual basis, with intended sessions once every 2 weeks.
    Arm type
    		 Experimental without product

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Started
    52
    52
    51
    Completed
    52
    52
    50
    Not completed
    0
    0
    1
         Consent withdrawn by subject
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject refused double-blind randomization after inclusion. Therefore, this subject enrolled in the trial but was not allocated medication.

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Cognitive behavioural therapy (CBT)
    Reporting group description
    		 Patients allocated to CBT received approximately 24 weeks of individual CBT, based on the manual of CBT for CFS, by trained and supervised cognitive-behavioral therapists. Treatment frequency was determined on individual basis, with intended sessions once every 2 weeks.

    Reporting group values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT) Total
    Number of subjects
    		 52 52 51 155
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 52 52 51 155
    Gender categorical
    Units: Subjects
        Female
    		 29 20 25 74
        Male
    		 23 32 26 81

    End points

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    End points reporting groups
    Reporting group title
    Doxycycline
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Cognitive behavioural therapy (CBT)
    Reporting group description
    		 Patients allocated to CBT received approximately 24 weeks of individual CBT, based on the manual of CBT for CFS, by trained and supervised cognitive-behavioral therapists. Treatment frequency was determined on individual basis, with intended sessions once every 2 weeks.

    Primary: Fatigue severity at EOT

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    End point title
    		 Fatigue severity at EOT
    End point description
    End point type
    Primary
    End point timeframe
    End of treatment (EOT) is 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: CIS subscale Fatigue Severity
        arithmetic mean (confidence interval 95%)
    40.8 (37.3 to 44.3)
    37.8 (34.2 to 41.2)
    31.6 (28.0 to 35.1)
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Questionnaires, SIP8 total score

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    End point title
    		 Questionnaires, SIP8 total score
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) is after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: SIP8 total score
        arithmetic mean (confidence interval 95%)
    1101.5 (933.5 to 1269.6)
    963.8 (795.8 to 1131.9)
    786.8 (615.3 to 958.3)
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Questionnaires, SCL90 total score

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    End point title
    		 Questionnaires, SCL90 total score
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) is after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: SCL90 total score
        arithmetic mean (confidence interval 95%)
    149.2 (141.6 to 156.7)
    142.6 (135.1 to 150.1)
    127.1 (119.4 to 134.7)
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Serology and PCR, IgM phase I

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    End point title
    		 Serology and PCR, IgM phase I
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: Positive subjects
    24
    28
    20
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Serology and PCR, IgM phase II

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    End point title
    		 Serology and PCR, IgM phase II
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) was after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: Positive subjects
    27
    32
    29
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Serology and PCR, IgG phase I

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    End point title
    		 Serology and PCR, IgG phase I
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) was after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: Positive subjects
    43
    39
    37
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Serology and PCR, IgG phase II

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    End point title
    		 Serology and PCR, IgG phase II
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) was after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: Positive subjects
    51
    50
    46
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Negative C. burnetii PCR

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    End point title
    		 Negative C. burnetii PCR
    End point description
    End point type
    Secondary
    End point timeframe
    End of treatment (EOT) was after 26 weeks.
    End point values
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Number of subjects analysed
    52
    52
    50
    Units: Negative subjects
    52
    52
    50
    Statistical analysis title
    		 Doxycycline vs. placebo
    Comparison groups
    Doxycycline v Placebo
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 CBT vs. placebo
    Comparison groups
    Placebo v Cognitive behavioural therapy (CBT)
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs in the medication condition were recorded during the study visits, and during the trial when reported by the patient. For patients allocated to CBT, AEs were monitored at 8 weeks after start and at EOT.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Doxycycline
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Cognitive behavioural therapy (CBT)
    Reporting group description
    		 -

    Serious adverse events
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Cardiological symptoms
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urosepsis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Doxycycline Placebo Cognitive behavioural therapy (CBT)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 52 (98.08%)
    45 / 52 (86.54%)
    42 / 50 (84.00%)
    Nervous system disorders
    Neurological
         subjects affected / exposed
    13 / 52 (25.00%)
    10 / 52 (19.23%)
    6 / 50 (12.00%)
         occurrences all number
    13
    11
    8
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    31 / 52 (59.62%)
    27 / 52 (51.92%)
    5 / 50 (10.00%)
         occurrences all number
    51
    33
    5
    Skin and subcutaneous tissue disorders
    Skin
         subjects affected / exposed
    20 / 52 (38.46%)
    10 / 52 (19.23%)
    5 / 50 (10.00%)
         occurrences all number
    29
    12
    5
    Musculoskeletal and connective tissue disorders
    Musculoskeletal
         subjects affected / exposed
    22 / 52 (42.31%)
    17 / 52 (32.69%)
    14 / 50 (28.00%)
         occurrences all number
    28
    22
    18
    Bone and teeth
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    4
    2
    1
    Infections and infestations
    Infection
         subjects affected / exposed
    22 / 52 (42.31%)
    26 / 52 (50.00%)
    29 / 50 (58.00%)
         occurrences all number
    33
    46
    54

    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.
    Study was not designed to compare doxycycline and CBT directly, due to limited number of available patients. Masking for CBT was not possible. It was not possible to include a control group without any form of treatment. Longterm effects unknown

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23536997
    http://www.ncbi.nlm.nih.gov/pubmed/28329131
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