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    Clinical Trial Results:
    Effects of oxycodon and venlafaxine on human pain processing. A randomized, double-blinded, placebo-controlled, cross-over study

    Summary
    EudraCT number
    		 2013-000170-30
    Trial protocol
    		 DK  
    Global end of trial date
    12 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MULTIPAIN-2-3-2013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital
    Sponsor organisation address
    Hobrovej 18-22, Aalborg, Denmark,
    Public contact
    Department of Gastroenterology, Mech-Sense, Aalborg University Hospital, +45 97663562, amd@rn.dk
    Scientific contact
    Department of Gastroenterology, Mech-Sense, Aalborg University Hospital, +45 97663562, amd@rn.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
    27 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to establish a model that is capable of evaluating the effects of analgesics on the pain matrix on both peripheral, spinal, supraspinal, and modulatory level.
    Protection of trial subjects
    Subjects were informed verbally and in written about the study before participating and were free to terminate and withdraw from the experiment at any time. Subjects with a history of substance abuse or psychiatric illness were not included in the study. Adverse effects were monitored during the stay at the hospital and after each treatment arm.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2013
    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
    Denmark: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Inclusion for the study required medical examinations to be normal, blood pressure below 140/90, no use of medication and Caucasian origin.

    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
    		 Investigator, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo
    Arm description
    		 Placebo arm
    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
    All drugs followed the same administration: on day 1 and day 5 once, and on day 2-4 b.i.d. in total 8 doses. The tablets were produced by the pharmacy at Aarhus University Hospital.

    Arm title
    		 Oxycodone
    Arm description
    		 Oxycodone arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oxycodone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg extended release. All drugs followed the same administration: on day 1 and day 5 once, and on day 2-4 b.i.d. in total 8 doses. The tablets were produced by the pharmacy at Aarhus University Hospital.

    Arm title
    		 Venlafaxine
    Arm description
    		 Venlafaxine arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Venlafaxine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Venlafaxine dosages were 37.5mg extended release. All drugs followed the same administration: on day 1 and day 5 once, and on day 2-4 b.i.d. in total 8 doses. The tablets were produced by the pharmacy at Aarhus University Hospital.

    Number of subjects in period 1
    		Placebo Oxycodone Venlafaxine
    Started
    20
    20
    20
    Completed
    20
    20
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 20 subjects participated in all treatment arms

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 20 20
    Age categorical
    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)
    		 20 20
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.6 ( 2.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo arm

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone arm

    Reporting group title
    Venlafaxine
    Reporting group description
    		 Venlafaxine arm

    Primary: Quantitative sensory testing

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    End point title
    		 Quantitative sensory testing
    End point description
    The overall sensory responses were investigated using ice water (the cold pressor test) and electrical stimulations (together with reflex determinations). The mean scores on the visual analogue scale (VAS) for the cold pressor test is presented as end point values for each treatment arm. More details are published by Lelic et al. (Neuropharmacology. 2017. DOI:10.1016/j.neuropharm.2017.06.022) and Lelic et al. (Eur J Neurosci. 2016. DOI: 10.1111/ejn.13443).
    End point type
    Primary
    End point timeframe
    At baseline and after 5 days of treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    20
    20
    20
    Units: VAS (no unit)
        number (not applicable)
    7.3
    6.8
    7.0
    Statistical analysis title
    		 Reflex pain (VAS)
    Statistical analysis description
    Reflex: mixed model with treatment and reflex intensity, mixed model with reflex sensory threshold, reflex threshold and treatment
    Comparison groups
    Placebo v Oxycodone
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.552
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Reflex pain (VAS)
    Statistical analysis description
    Reflex: mixed model with treatment and reflex intensity, mixed model with reflex sensory threshold, reflex threshold and treatment
    Comparison groups
    Placebo v Venlafaxine
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.288
    Method
    		 Mixed models analysis
    Confidence interval
    Statistical analysis title
    		 Ice pain (VAS)
    Statistical analysis description
    Ice pain: mixed model with treatment and time
    Comparison groups
    Placebo v Oxycodone
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.036
    Method
    		 Mixed models analysis
    Confidence interval

    Primary: Electroencephalography

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    End point title
    		 Electroencephalography
    End point description
    Electroencephalography (EEG) was recorded during tonic pain stimulation. Spectral analysis and sLORETA source localization were performed in five frequency bands: delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-18 Hz) and beta2 (18-32 Hz). The number of frequency bands that were significantly changed after treatment are presented in end point values. Details about the analyses and results are published by Lelic et al. (Neuropharmacology. 2017. doi: 10.1016/j.neuropharm.2017.06.022).
    End point type
    Primary
    End point timeframe
    From baseline and a 5-days treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    20
    20
    20
    Units: number of frequency bands, no unit
    0
    2
    1
    Statistical analysis title
    		 EEG during tonic pain, placebo
    Comparison groups
    Placebo v Oxycodone v Venlafaxine
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - Data from baseline and after five days of treatment were compared for the placebo arm and no changes were observed.
    Statistical analysis title
    		 EEG during tonic pain, oxycodone
    Comparison groups
    Oxycodone v Venlafaxine v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.05 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - Data from baseline and after five days of treatment were compared for the oxycodone arm.
    [3] - Oxycodone decreased the spectral indices and brain source activity in delta and theta frequency bands.
    Statistical analysis title
    		 EEG during tonic pain, venlafaxine
    Comparison groups
    Venlafaxine v Oxycodone v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.05 [5]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - Data from baseline and after five days of treatment were compared for the venlafaxine arm.
    [5] - Venlafaxine decreased spectral indices in one frequency band (alpha) of the EEG during tonic pain.

    Primary: Nociceptive withdrawel reflex

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    End point title
    		 Nociceptive withdrawel reflex
    End point description
    Nociceptive withdrawel reflex (NWR) was elicited under the sole of the foot. Both sensory threshold an reflex threshold was found. The following intensities were used for pain ratings: • 1.0 x reflex threshold • 1.3 x reflex threshold • 1.6 x reflex threshold 5 runs with 18 reflex stimulations in randomized intensity were applied for electromyography (EMG) recordings to assess the spinal (lumbar) response to pain and brain analysis with EEG evoked potentials was done to the same stimulations. The mean NWR thresholds after treatments are presented together with the statistical analysis of NWR area under the curve (AUCs). Details about the analyses and results are published by Lelic et al. (Eur J Neurosci. 2016. doi: 10.1111/ejn.13443.)
    End point type
    Primary
    End point timeframe
    From baseline and a 5-days treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    20
    20
    20
    Units: mA
        number (not applicable)
    14.5
    12.7
    14.2
    Statistical analysis title
    		 NWR AUC
    Statistical analysis description
    Details are published by Lelic et al. (Eur J Neurosci. 2016. doi: 10.1111/ejn.13443)
    Comparison groups
    Placebo v Oxycodone v Venlafaxine
    Number of subjects included in analysis
    60
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 < 0.05 [6]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [6] - Venlafaxine decreased the NWR AUC, and no differences were observed in the placebo or oxycodone arms

    Primary: Median nerve stimulation

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    End point title
    		 Median nerve stimulation
    End point description
    Median nerve stimulation was elicited on the right wrist, and both spinal (cervical) evoked potential (just above C7) to assess the upstream activity, and brain (EEG) evoked potentials were recorded. The sensory and twitch of the thumb thresholds were taken. Then two runs of 1000 stimulations (two per second) were done for spinal and evoked EEG recordings. Sensory thresholds to median nerve stimulation after treatments are provided and more details about analyses and results are published by Lelic et al. (Br J Clin Pharmacol. 2017. doi: 10.1111/bcp.13177).
    End point type
    Primary
    End point timeframe
    From baseline and a 5-days treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    20
    20
    20
    Units: mA
        number (confidence interval 95%)
    2.7 (2.4 to 3.0)
    2.5 (2.2 to 2.8)
    2.6 (2.4 to 2.8)
    Statistical analysis title
    		 Median nerve stimulation sensory data
    Statistical analysis description
    Two-way repeated measures analysis of variance with time point and treatment as the two factors were performed and no differences in sensory thresholds were identified.
    Comparison groups
    Placebo v Oxycodone v Venlafaxine
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: MR spectroscopy

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    End point title
    		 MR spectroscopy
    End point description
    MR spectroscopy was performed during rest at baseline and during treatments in the anterior cingulate cortex, insula and prefrontal cortex. Mean glutamate/creatine ratios from the anterior cingulate cortex are presented as end point values and statistics are provided including all three brain areas. More details about the analyses and results are published by Hansen et al. (J Neuroimaging. 2016. doi: 10.1111/jon.12345.)
    End point type
    Primary
    End point timeframe
    From baseline and after a 5-day treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    19
    19
    20
    Units: no units (ratio)
        number (not applicable)
    1.35
    1.29
    1.32
    Statistical analysis title
    		 Glutamate/creatine changes oxycodone vs placebo
    Statistical analysis description
    The change in glutamate/creatine following oxycodone was calculated as compared to the measurement before treatment and compared to placebo.
    Comparison groups
    Oxycodone v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 percentage
    Point estimate
    -8.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.2
         upper limit
    		 -1.7
    Variability estimate
    Standard deviation
    Dispersion value
    0.3
    Notes
    [7] - A mixed effect model with treatment type and area as fixed effects (full factorial) and subject as a random effect was used.
    Statistical analysis title
    		 Glutamate/creatine changes venlafaxine vs placebo
    Statistical analysis description
    The level of glutamate/creatine following venlafaxine was calculated as compared to the measurement before treatment and compared to placebo.
    Comparison groups
    Venlafaxine v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Post-hoc
    Analysis type
    		 other [8]
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 percentage
    Point estimate
    -6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.5
         upper limit
    		 0.2
    Variability estimate
    Standard deviation
    Dispersion value
    0.4
    Notes
    [8] - A mixed effect model with treatment type and area as fixed effects (full factorial) and subject as a random effect was used.

    Secondary: Offset analgesia

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    End point title
    		 Offset analgesia
    End point description
    Offset analgesia (OA) was induced with a thermode on the arm. To determine the pain tolerance threshold, the temperature was slowly increased from 35ºC at 1.5ºC per second rate and the volunteers pressed a button when they reached their individual pain tolerance threshold. Offset analgesia magnitude (in percentage) was calculated as delta_VAS normalized with respect to peak value ((delta_VAS/peak)*100)) and presented.
    End point type
    Secondary
    End point timeframe
    From baseline and after 5-days treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    20
    20
    20
    Units: percent
        number (not applicable)
    60.3
    69.3
    61.2
    Statistical analysis title
    		 Offset analgesia magnitude
    Statistical analysis description
    Offset analgesia magnitude (in percentage) was calculated as delta_VAS normalized with respect to peakvalue ((delta_VAS/peak)*100)). The average baseline values were calculated as a mean of the three baseline measurements for each participant. A repeated measures regression with treatment as random effect was used. Detailed analysis description and results are published elsewhere (Olesen et al. Basic Clin Pharmacol Toxicol. 2018. doi: 10.1111/bcpt.13078).
    Comparison groups
    Placebo v Oxycodone v Venlafaxine
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Variability estimate
    Standard deviation

    Secondary: Resting state MRI

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    End point title
    		 Resting state MRI
    End point description
    Resting state magnetic resonance imaging was performed and functional connectivity analyses were explored between four predefined seeds (dorsal anterior cingulate cortex, rostral anterior cingulate cortex, posterior insula, and prefrontal cortex), and the whole brain. The number of seeds that revealed changed connectivity is presented. Details about the analyses and results are published by Hansen et al. (CNS Neurosci Ther. 2018. doi: 10.1111/cns.12827.)
    End point type
    Secondary
    End point timeframe
    From baseline and after a 5-day treatment
    End point values
    		 Placebo Oxycodone Venlafaxine
    Number of subjects analysed
    20
    18
    19
    Units: Number of seeds affected
    4
    4
    4
    Statistical analysis title
    		 Functional connectivity oxycodone vs placebo
    Statistical analysis description
    Treatment effects were investigated in four predefined seeds to the whole brain.
    Comparison groups
    Oxycodone v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [9]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [9] - The main results were that oxycodone decreased functional connectivity between limbic structures and to supra limbic areas.
    Statistical analysis title
    		 Functional connectivity venlafaxine vs placebo
    Statistical analysis description
    Treatment effects were investigated in four predefined seeds to the whole brain.
    Comparison groups
    Placebo v Venlafaxine
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [10]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [10] - The main results were that venlafaxine decreased functional connectivity between limbic structures and to supralimbic areas, and increased functional connectivity to structures in the midbrain and brain stem.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    November 2013 - December 2014
    Adverse event reporting additional description
    All the non-serious adverse events were known side-effects to the treatments. More details about side-effects are published in
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered once on day 1 and day 5, and twice a day on day 2-4, in total eight doses with 12 hours in between.

    Reporting group title
    Oxycodone
    Reporting group description
    		 Oxycodone (10 mg extended release) was administered orally as tablets once on day 1 and day 5 and twice on day 2-4 in total eight doses with 12 hours in between.

    Reporting group title
    Venlafaxine
    Reporting group description
    		 Venlafaxine (37.5 mg extended release) was administered orally once on day 1 and day 5, and twice a day on day 2-4, in total eight doses with 12 hours in between.

    Serious adverse events
    		 Placebo Oxycodone Venlafaxine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Oxycodone Venlafaxine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 20 (20.00%)
    17 / 20 (85.00%)
    18 / 20 (90.00%)
    Cardiac disorders
    Heart rate increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 20 (10.00%)
    4 / 20 (20.00%)
         occurrences all number
    2
    2
    4
    General disorders and administration site conditions
    Dizziness
         subjects affected / exposed
    0 / 20 (0.00%)
    4 / 20 (20.00%)
    6 / 20 (30.00%)
         occurrences all number
    0
    4
    6
    Sedation
         subjects affected / exposed
    2 / 20 (10.00%)
    8 / 20 (40.00%)
    5 / 20 (25.00%)
         occurrences all number
    2
    8
    5
    Discomfort
         subjects affected / exposed
    0 / 20 (0.00%)
    5 / 20 (25.00%)
    8 / 20 (40.00%)
         occurrences all number
    0
    5
    8
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    3 / 20 (15.00%)
    10 / 20 (50.00%)
         occurrences all number
    0
    3
    10
    Mouth dryness
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    8 / 20 (40.00%)
         occurrences all number
    0
    0
    8
    Constipation
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Low appetite
    alternative dictionary used: n/a 0
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Itching
         subjects affected / exposed
    0 / 20 (0.00%)
    6 / 20 (30.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    6
    0
    Sweating
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28648913
    http://www.ncbi.nlm.nih.gov/pubmed/29938898
    http://www.ncbi.nlm.nih.gov/pubmed/27748551
    http://www.ncbi.nlm.nih.gov/pubmed/27028269
    http://www.ncbi.nlm.nih.gov/pubmed/27808426
    http://www.ncbi.nlm.nih.gov/pubmed/29468854
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